Emergence of Madariaga virus as a cause of acute febrile illness in children, Haiti, 2015-2016.
Madariaga virus (MADV), also known as South American eastern equine encephalitis virus, has been identified in animals and humans in South and Central America, but not previously in Hispaniola or the northern Caribbean. MADV was isolated from virus cultures of plasma from an 8-year-old child in a school cohort in the Gressier/Leogane region of Haiti, who was seen in April, 2015, with acute febrile illness (AFI). The virus was subsequently cultured from an additional seven AFI case patients from this same cohort in February, April, and May 2016. Symptoms most closely resembled those seen with confirmed dengue virus infection. Sequence data were available for four isolates: all were within the same clade, with phylogenetic and molecular clock data suggesting recent introduction of the virus into Haiti from Panama sometime in the period from October 2012-January 2015. Our data document the movement of MADV into Haiti, and raise questions about the potential for further spread in the Caribbean or North America.


Visual Selection: Usually Fast and Automatic; Seldom Slow and Volitional.
Recently it was argued that in addition to top-down and bottom-up processes, lingering biases of selection history play a major role in visual selection (Awh, Belopolsky & Theeuwes, 2012). Since its publication there has been a growing controversy about the terms top-down, bottom-up and selection-history in relation to visual selection. In the current paper we define these terms, discuss some controversies about these terms and explain what kind of effects should be considered to be the result of lingering biases of selection history, i.e., priming, reward/fear, and statistical learning. We discuss the properties of top-down selection (slow, effortful, and controlled) versus the properties of lingering biases of selection history (fast, effortless, and automatic). We adhere the position that the experience with selecting a particular feature or the location of a feature, may boost and sharpen its representation within the priority selection map above and beyond its physical salience. It is as if the experience may render a feature or location subjectively more salient. Our message of the current review is that true top-down control of visual selection occurs far less often than what is typically assumed. Most of the time, selection is based on experience and history. It is fast, automatic and occurs without much, if any, effort.


Improving the long-term care referral process: insights from patients and caregivers.
Large increases in the need for long-term care (LTC) services are expected as baby boomers age. Little has been published about patient and caregiver preferences for information about LTC. However, our qualitative research findings suggest that potential consumers may find it difficult to obtain accurate and timely information about LTC programs and services. In-person, semistructured interviews were conducted with 47 subjects, including patients (n = 25) within 90 days of their referral to a LTC placement (including NH, assisted living, home care, and community) and their caregivers (n = 22). Interview questions addressed the events that seemed to trigger their need for a LTC referral, the resources they used to become more informed about LTC options and the issues they confronted with the LTC referral process. Qualitative analyses identified a number of patient and informal caregiver-reported barriers to making decisions about LTC services, including insufficient information about LTC programs and community resources, unclear funding requirements and inadequate funding, and difficulty knowing how to plan for LTC or make LTC decisions. A potential solution may be an online LTC Guide designed to provide accurate information about the range of LTC services, with an emphasis on home and community-based services. This Guide was developed to address the gap in comprehensive LTC information identified in the findings of this study.


Genetic diversity and comparison of diagnostic tests for characterization of foot-and-mouth disease virus strains from Pakistan 2008-2012.
We report the laboratory analysis of 125 clinical samples from suspected cases of foot-and-mouth disease (FMD) in cattle and Asian buffalo collected in Pakistan between 2008 and 2012. Of these samples, 89 were found to contain viral RNA by rRT-PCR, of which 88 were also found to contain infectious FMD virus (FMDV) by virus isolation (VI), with strong correlation between these tests (κ = 0.96). Samples that were VI-positive were serotyped by antigen detection ELISA (Ag-ELISA) and VP1 sequence acquisition and analysis. Sequence data identified FMDV serotypes A (n = 13), O (n = 36) and Asia-1 (n = 41), including three samples from which both serotypes Asia-1 and O were detected. Serotype A viruses were classified within three different Iran-05 sublineages: HER-10, FAR-11 and ESF-10. All serotype Asia-1 were within Group VII (Sindh-08 lineage), in a genetic clade that differs from viruses isolated prior to 2010. All serotypes O were classified as PanAsia-2 within two different sublineages: ANT-10 and BAL-09. Using VP1 sequencing as the gold standard for serotype determination, the overall sensitivity of Ag-ELISA to correctly determine serotype was 74%, and serotype-specific sensitivity was 8% for serotype A, 88% for Asia-1 and 89% for O. Serotype-specific specificity was 100% for serotype A, 93% for Asia-1 and 94% for O. Interestingly, 12 of 13 serotype A viruses were not detected by Ag-ELISA. This study confirms earlier accounts of regional genetic diversity of FMDV in Pakistan and highlights the importance of continued validation of diagnostic tests for rapidly evolving pathogens such as FMDV.


Circulating microRNA-375 as biomarker of pancreatic beta cell death and protection of beta cell mass by cytoprotective compounds.
Previous studies demonstrated that circulating microRNA-375 (miR-375) is a suitable plasma biomarker for real-time detection of beta cell death. The present study evaluated the use of this biomarker to assess the beta cytoprotective effect of phenylpropenoic acid glucoside (PPAG), which was previously demonstrated to protect beta cells against various types of injury, and of exendin-4, which is an established antidiabetic drug. PPAG or exendin-4 were administered in mice treated with streptozotocin (STZ) to acutely induce beta cell death. Beta cell mass and apoptotic death were measured in pancreatic tissue sections. Circulating miR-375 was measured in blood plasma by RT-qPCR. The release of miR-375 was also measured in vitro by MIN-6 beta cells. Administration of STZ resulted in measurable circulating levels of miR-375, a decrease in beta cell mass and increase in frequency of apoptotic beta cells. In vitro, there was a good correlation between miR-375 release and the extent of beta cell death. Treatment of mice with PPAG or exendin-4 significantly attenuated STZ-induced loss of beta cell mass and beta cell apoptosis, and normalized the blood level of miR-375. These findings show the potential use of serological miR-375 measurements to evaluate the beta cytoprotective effect of (potential) antidiabetic drugs in vivo.


[Relationship between morcellation efficiency and enucleated tissue weight in holmium laser enucleation of the prostate (HoLEP) for patients with benign prostatic hyperplasia].
We examined the relationship between morcellation efficiency and enucleated tissue weight in holmium laser enucleation of the prostate (HoLEP) for patients with benign prostatic hyperplasia (BPH) retrospectively. From January to December 2010, 140 patients with BPH were treated by HoLEP combined with mechanical morcellation with up side down technique by a single surgeon. The mean age was 70.6 years, and the mean enucleated tissue weight was 46.8 g. The mean morcellation time was 9.9 min, and the mean rate of morcellation was 6.7 g/min. No complications were reported relating to morcellation such as bladder injury. Although morcellation time and enucleated tissue weigh were proportionally related (Estimate equation: Y = - 1.186 + 0.813 * X, R^2: 0.814), larger glands with more than 80 g of tissue enucleated did not match this distribution map. Five cases with more than 100 g of enucleated tissue weight required much longer operation time (range 66-90 min) and were disproportioned to tissue weight. Morcellation efficiency tended to decrease when enucleated tissue weight exceeds 80 g and less than average in almost all cases. Morcellation efficiency significantly worsen when enucleated tissue weight exceeds more than 100 g. Morcellation efficency may decrease in larger gland exceeds 80 g.


Regulation of cardiac sympathetic afferent reflex by GABA(A) and GABA(B) receptors in paraventricular nucleus in rats.
The aim of the present study was to determine the role of GABA(A) and GABA(B) receptors in paraventricular nucleus (PVN) in regulating cardiac sympathetic afferent reflex (CSAR). Under urethane (800 mg/kg) and alpha-chloralose (40 mg/kg) anesthesia, renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) were recorded in sinoaortic-denervated and cervical-vagotomized rats. CSAR was evaluated based in the response of RSNA to epicardial application of capsaicin (0.3 nmol) or bradykinin (1 nmol). Bilateral PVN microinjection of the GABA(A) receptor agonist isoguvacine (10 nmol) attenuated CSAR, while the GABA(B) receptor agonist baclofen (1 nmol) abolished CSAR. Both isoguvacine and baclofen greatly decreased baseline RSNA and MAP. The GABA(A) receptor antagonist gabazine (0.1 nmol) had no significant effect on CSAR, but the GABA(B) receptor antagonist CGP-35348 (10 nmol) enhanced CSAR. Gabazine caused greater increases in baseline RSNA and MAP than CGP-35348. Vigabatrin (10 nmol), a selective GABA-transaminase inhibitor which increases endogenous GABA level, abolished CSAR, and decreased baseline RSNA, MAP and HR. The effects of vigabatrin were antagonized by combined gabazine (0.1 nmol) and CGP-35348 (10 nmol). The results indicate that activation of either GABA(A) or GABA(B) receptors in the PVN inhibits CSAR, while blockage of GABA(B) receptors in the PVN enhances CSAR. Endogenous GABA in the PVN could have an important role in regulating CSAR.


Oropharyngeal colostrum immunotherapy and risk reduction of mortality in very low birth weight premature newborns: a clinical trial.
To evaluate the effect of oropharyngeal colostrum immunotherapy (OCI) on the mortality of preterm newborns (PTNB) with very low birth weight (VLBW). Non-randomized clinical trial, carried out with 138 mother-child pairs attended at a public maternity hospital. The treatment group used raw colostrum, dripping 4 drops (0.2 ml) into the oropharyngeal mucosa, totaling 8 administrations in 24 h, up to the 7th complete day of life (OCI). The control group was composed of newborns admitted to the same maternity hospital before the implementation of the OCI. Analyzes were performed: descriptive, bivariate, multiple logistic regression, and survival analysis, with a significance level of 5% and 95% CI. The treatment group had an RR of death of 0.26 (95% CI = 0.07-0.67; p = 0.00), adjusted for maternal age, marital status, gestational hypertension, type of delivery, number of prenatal visits, and birth weight. Number Needed to Treat (NNT) demonstrated that for every 5 individuals treated with OCI, one death was prevented NNT = 4.9 (95% CI = 1.84-5.20); however, for PTNB with VLBW who remained hospitalized for 50, 100 and 150 days, the NNT reduces to 4, 4 and 3, respectively. The OCI proved to be a beneficial intervention, since it reduced the risk of mortality in PTNB with VLBW when compared to the control group.


Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer.
Recent data showed improvement in progression-free survival (PFS) when adding everolimus to exemestane in patients with advanced breast cancer experiencing recurrence/progression after nonsteroidal aromatase inhibitor (AI) therapy. Here, we report clinical outcomes of combining the mammalian target of rapamycin (mTOR) inhibitor temsirolimus with letrozole in AI-naive patients. This phase III randomized placebo-controlled study tested efficacy/safety of first-line oral letrozole 2.5 mg daily/temsirolimus 30 mg daily (5 days every 2 weeks) versus letrozole/placebo in 1,112 patients with AI-naive, hormone receptor-positive advanced disease. An independent data monitoring committee recommended study termination for futility at the second preplanned interim analysis (382 PFS events). Patients were balanced (median age, 63 years; 10% stage III, 40% had received adjuvant endocrine therapy). Those on letrozole/temsirolimus experienced more grade 3 to 4 events (37% v 24%). There was no overall improvement in primary end point PFS (median, 9 months; hazard ratio [HR], 0.90; 95% CI, 0.76 to 1.07; P = .25) nor in the 40% patient subset with prior adjuvant endocrine therapy. An exploratory analysis showed improved PFS favoring letrozole/temsirolimus in patients ≤ age 65 years (9.0 v 5.6 months; HR, 0.75; 95% CI, 0.60 to 0.93; P = .009), which was separately examined by an exploratory analysis of 5-month PFS using subpopulation treatment effect pattern plot methodology (P = .003). Adding temsirolimus to letrozole did not improve PFS as first-line therapy in patients with AI-naive advanced breast cancer. Exploratory analyses of benefit in younger postmenopausal patients require external confirmation.


Alterations of thymus cortical epithelium and interdigitating dendritic cells but no increase of thymocyte cell death in the early course of simian immunodeficiency virus infection.
The role of the thymus in the pathogenesis of simian acquired immunodeficiency syndrome was investigated in 18 juvenile rhesus monkeys (Macaca mulatta). The thymus was infected from the first week post-SIVmac inoculation, but the amount of virus-positive cells was very low (< 1 in 10(4) T cells) as demonstrated by polymerase chain reaction and in situ hybridization. First morphological alteration was a narrowing of the cortex at 12 and 24 wpi. Morphometry revealed no increase of pyknotic T cells but a decrease of the proliferation rate and flow cytometry showed a reduction of the immature CD4+/CD8+ double-positive T cells. Ultrastructural analysis revealed vacuolization, shrinkage, and finally cytolysis of the cortical epithelial cells and the interdigitating dendritic cells. Immunofluorescence staining exhibited a widespread loss of cortical epithelial cells. This damage to the thymic microenvironment could explain the breakdown of the intrathymic T cell proliferation. It preceded fully developed simian acquired immunodeficiency syndrome and is therefore considered to play a major role in its pathogenesis.


Integration of family planning into HIV services: a synthesis of recent evidence.
Increasing access to contraception among women who enter the health system for HIV care is crucial to help them achieve their fertility intentions and reduce vertical transmission of HIV. Identifying intervention strategies that contribute to effective family planning/HIV service integration and synthesizing lessons for future integration programming and research is important to move the field forward. Using a standard review methodology, we searched for articles in the peer-reviewed literature published between January 2008 and August 2013 that addressed the integration of family planning interventions into HIV service settings. Eligible studies were assessed in terms of methodological rigor; documented outcomes; and reported process and cost data. Twelve studies met our inclusion criteria. Eight studies documented significant increases in contraceptive use by HIV service clients, and three reported significant increases in completed referrals from HIV services to family planning clinics. The outcomes of the seven studies implemented in public sector facilities were more modest than the five studies embedded in clinical trials. Process evaluation measures for some of the studies indicated weak implementation of the intervention as intended. The average rigor score was low, 3.4 out of 9. Our review reveals an expanding evidence base for integrated family planning/HIV service delivery innovations. However, the modest observed effect under typical settings and the evidence of weak intervention implementation emphasize the need for stronger programmatic efforts and implementation research to address the health system obstacles to integrating these two essential services.


[The prevention and treatment of the deep phlegmons of "diabetic foot"].
Based on clinical observations of pyo-necrotic lesions of the foot in patients with diabetic mellitus and on an analysis of their personal operations performed on these patients the authors support the tendency to local necrotomies. Two original operations are proposed: ablation of the great toe with a preliminary transection of the tendon of the long flexor and radical operation of the deep phlegmon of the foot with the dissection of plantar aponeurosis and short flexors of the toes. These methods allow the general amount of amputations and lethality to be decreased.


Bipotential actions of estrogen on progesterone biosynthesis by ovarian cells. II. Relation of estradiol's stimulatory actions to cholesterol and progestin metabolism in cultured swine granulosa cells.
Although both inhibitory and stimulatory actions of estradiol on swine granulosa cells have been described, the bases for these inconsistent effects are not clear. We have tested properties of ovarian follicles and in vitro culture conditions that result in consistently stimulatory effects of estradiol on progesterone biosynthesis. Stimulatory actions of estradiol (in contrast to inhibitory effects) were critically dependent upon the density of granulosa cells in culture and the size and maturational status of the parent Graafian follicles. Granulosa cells isolated from small, rather than medium or large sized, swine follicles exhibited the greatest peak response to estradiol, although half-maximally stimulatory concentrations (ED50) of estradiol were similar (mean, 81 ng/ml). Granulosa cells from atretic follicles also secreted increased quantities of progesterone in response to estradiol, but the ED50 for estrogen stimulation was significantly higher (ED50 = 322 ng/ml estradiol) than that of comparable healthy follicles (ED50 = 109 ng/ml). This estrogen-responsive system was used to test the mechanisms subserving estrogen's trophic actions on granulosa cells. Estradiol significantly enhanced the activity of 3 beta-hydroxysteroid dehydrogenase with consequently increased production of progesterone and 20 alpha-hydroxypregn-4-en-3-one. Estrogen also augmented functional cholesterol side-chain cleavage activity in a dose- and time-dependent fashion with a resultant increase in pregnenolone biosynthesis. Moreover, parallel observations documented concordant dose responses for the synthesis of all three major progestins by pig granulosa cells. The trophic actions of estrogen on the steroidogenic pathway were associated with enhanced hydrolysis of endogenous cholesteryl ester stores but were not significantly antagonized by inhibition of de novo cholesterol biosynthesis. We conclude that suitable follicle selection and appropriate in vitro culture conditions provide a consistently estrogen-responsive granulosa-cell system, in which estradiol modulates certain key aspects of progestin and cholesterol metabolism. These trophic actions of estrogen are likely to prepare granulosa cells for the increased rates of progesterone biosynthesis ultimately required by fully differentiated luteal cells.


Comparative clinical study of the effectiveness of three different bleaching methods.
The current study assessed the efficacy of three current bleaching methods. Seventy-five healthy subjects (45 female; 30 male) with anterior teeth, having a Vita Shade score of A2 or darker, participated in the study. The subjects were randomly assigned to one of three treatment groups: Group A: home-bleaching (illumine Home, 10% carbamide peroxide, trays, overnight, for two weeks), Group B: in-office bleaching (Illumine Office, 15% hydrogen peroxide, trays for 45 minutes, three times over three weeks), Group C: Whitestrips (strips, twice a day, 30 minutes each for two weeks). Following the screening visit, three weeks prior to the baseline examination, all subjects received a dental prophylaxis. The color of the teeth was determined using a colorimeter (ShadeEye NCC) and a custom-made stent at baseline (E0), immediately after completion of the bleaching (E3) and three months after treatment (E4). All subjects received oral hygiene instructions and a toothbrush and toothpaste for oral home care during the study period. The change of tooth color was determined for each treatment regimen between baseline and E3 and baseline and E4 and was statistically analyzed performing the Kruskal Wallis test and the Mann-Whitney-U test. The significance level was set atp < 0.01. The dropout rate was 0%. Mean (SD) deltaE* (overall color change) from baseline to immediately after treatment was 6.57 (2.13) for Group A, 5.77 (1.72) for Group B and 3.58 (1.57) for Group C. The mean (SD) tooth color change from baseline to three months after treatment deltaE* was: 4.98 (1.34) for Group A, 4.59 (1.42) for Group B and 2.99 (1.39) for Group C. Significant differences were found between home bleaching and Whitestrips, as well as between in-office bleaching and Whitestrips, but not between home-bleaching and in-office bleaching during the same time. Using an objective color measurement device, home bleaching and in-office bleaching were found to be superior to Whitestrips. Home bleaching and in-office bleaching were equally efficient for bleaching teeth and maintaining the results for up to three months.


Comparison of Two Detailed Models of Aedes aegypti Population Dynamics.
The success of control programs for mosquito borne diseases can be enhanced by crucial information provided by models of the mosquito populations. Models, however, can differ in their structure, complexity and biological assumptions, and these differences impact their predictions. Unfortunately, it is typically difficult to determine why two complex models make different predictions because we lack structured side-by-side comparisons of models using comparable parameterization. Here we present a detailed comparison of two complex, spatially-explicit, stochastic models of the population dynamics of Aedes aegypti, the main vector of dengue, yellow fever, chikungunya and Zika viruses. Both models describe the mosquito's biological and ecological characteristics, but differ in complexity and specific assumptions. We compare the predictions of these models in two selected climatic settings, a tropical and weakly seasonal climate in Iquitos, Peru, and a temperate and strongly seasonal climate in Buenos Aires, Argentina. Both models were calibrated to operate at identical average densities in unperturbed conditions in both settings, by adjusting parameters regulating densities in each model (number of larval development sites and amount of nutritional resources). We show that the models differ in their sensitivity to environmental conditions (temperature and rainfall), and trace differences to specific model assumptions. Temporal dynamics of the Ae. aegypti populations predicted by the two models differ more markedly under strongly seasonal Buenos Aires conditions. We use both models to simulate killing of larvae and/or adults with insecticides in selected areas. We show that predictions of population recovery by the models differ substantially, an effect likely related to model assumptions regarding larval development and (direct or delayed) density dependence. Our methodical comparison provides important guidance for model improvement by identifying key areas of Ae. aegypti ecology that substantially affect model predictions, and revealing the impact of model assumptions on population dynamics predictions in unperturbed and perturbed conditions.


Effect of heat stress on production parameters and immune responses of commercial laying hens.
The present study was conducted to determine the adverse effects of high temperature and humidity not only on live performance and egg quality but also on immune function in commercial laying hens. One hundred eighty 31-wk-old laying hens at peak production were used in this study. Hens were housed in cages (15 cages of 4 birds/cage) in each of 3 environmental chambers and received 1 of 3 treatments. The 3 treatments were control (average temperature and relative humidity), cyclic (daily cyclic temperature and humidity), and heat stress (constant heat and humidity) for 5 wk. Different production and immune parameters were measured. Body weight and feed consumption were significantly reduced in hens in the heat stress group. Egg production, egg weight, shell weight, shell thickness, and specific gravity were significantly inhibited among hens in the heat stress group. Likewise, total white blood cell (WBC) counts and antibody production were significantly inhibited in hens in the heat stress group. In addition, mortality was higher in the heat stress group compared to the cyclic and control groups. Even though T- and B-lymphocyte activities were not significantly affected by any of the treatments, lymphocytes from hens in the heat stress group had the least activity at 1 wk following treatment. These results indicate that heat stress not only adversely affects production performance but also inhibits immune function.


The role of zoledronic acid in the management of osteoporosis.
Bisphosphonates are the current standard of care for treatment of osteoporosis. However, oral bisphosphonates are associated with complicated dosing regimens because of poor absorption and have the potential for upper gastrointestinal (GI) tract irritation, resulting in poor adherence and persistence. Zoledronic acid (ZOL) 5 mg, a once-yearly intravenous bisphosphonate, is approved for treatment and prevention of postmenopausal osteoporosis, increasing bone mass in men with osteoporosis, and treatment and prevention of glucocorticoid-induced osteoporosis. Because it is administered as an infusion, ZOL ensures adherence and persistence over the entire 12-month dosing interval and bypasses the GI absorption/irritation problems associated with oral bisphosphonates. The objective of this study was to review the safety and efficacy of 5 mg ZOL and its potential for improving patient compliance. Published reports dating back to 2001 were reviewed, with emphasis on osteoporosis treatment. In the HORIZON-Pivotal Fracture Trial, annual infusions of 5 mg ZOL produced significant reductions in risk of morphometric vertebral fractures (70%) and hip fractures (41%) vs placebo over 3 years in postmenopausal women with osteoporosis. In the HORIZON-Recurrent Fracture Trial, an annual infusion of 5 mg ZOL after repair of a recent low-trauma hip fracture was associated with significant reductions in risk for new clinical fractures (35%) vs placebo. In men with osteoporosis, an annual treatment of ZOL over 2 years increased lumbar spine bone mineral density (BMD) by 6% compared with baseline. In patients starting or continuing treatment with chronic glucocorticoids, ZOL resulted in significantly greater increases in lumbar spine BMD over 1 year than an oral bisphosphonate. In postmenopausal women with osteopenia, a single infusion of ZOL over a 2-year period produced significantly greater gains in lumbar spine and hip BMD than placebo. ZOL is generally safe and well tolerated. Five milligrams of ZOL has the potential to improve compliance with osteoporosis therapy and, consequently, to reduce fracture risk in clinical practice.


Psychotherapeutic Techniques for Distressing Memories: A Comparative Study between EMDR, Brainspotting, and Body Scan Meditation.
We explored the effects of a single 40-min session of Eye Movement Desensitization and Reprocessing (EMDR), Brainspotting (BSP), and Body Scan Meditation (BSM) in the processing of distressing memories reported by a non-clinical sample of adult participants. A within-subject design was used. Participants (n = 40 Psychologists/MDs) reported four distressing memories, each of which treated with a single intervention. EMDR, BSP, and BSM were compared with each other, and with a Book Reading (BR) active control condition, using as dependent measures, SUD (Subjective Units of Disturbance) and Memory Telling Duration (MTD) on a 4-point timeline: Baseline, Pre-Intervention, Post-Intervention, Follow-up. SUD scores associated with EMDR, BSP, and BSM significantly decreased from Pre- to Post-Intervention (p < 0.001). At Post-Intervention and Follow-up, EMDR and BSP SUD scores were significantly lower than BSM and BR scores (p < 0.02). At both Post-Intervention and Follow-up, BSM SUD scores were lower than BR scores (p < 0.01). A reduction in MTD was observed from Pre- to Post-Intervention for EMDR and BSP conditions (p < 0.001). Overall, results showed beneficial effects of single sessions of EMDR, BSP, or BSM in the processing of healthy adults' distressing memories. Study limitations and suggestions for future research are discussed.


Coverage of Palmar Mini Plates with Flexor Pulleys in the Treatment of Dorsal Fracture-Subluxation of the Proximal Interphalangeal Joint.
Introduction: Dorsal fracture dislocations (DFD) of the proximal interphalangeal joint (PIPJ) are challenging fractures. A palmar surgical approach and plate fixation has a high complication rate, including flexor contractions, reduction of range of motion (ROM) and secondary need for plate removal. Methods: We use the flexor tendon pulleys to cover the mini plate with the assumption that it may reduce the adhesion between the mini plates and the tendons and reduce postoperative complications. We present the outcomes of using this technique in eight patients. Results: All patients had an excellent outcome at a mean follow-up of 17 months, and none required removal of the implants. Conclusions: This study presents a surgical technique that may potentially reduce the high complication rate found after ORIF for treatment of DFD of the PIPJ. Therefore, improving the clinical outcomes after this type of surgery. Level of Evidence: Level IV (Therapeutic).


Inorganic tin and organotin interactions with Candida maltosa.
As a consequence of the widespread industrial and agricultural applications of organotins, contamination of various ecosystems has occurred in recent decades. Understanding how these compounds interact with microorganisms is important in assessing the risks of organotin pollution. The organotins, tributyltin (TBT), trimethyltin (TMT) and inorganic tin, Sn(IV), were investigated for their physical interactions with non-metabolising cells and protoplasts of the yeast Candida maltosa, an organism that is often associated with contaminated environments. Uptake, toxicity and membrane-acting effects of these compounds, at concentrations approximating those found in polluted environments, were assessed. Sn(IV) and TBT uptake occurred by different mechanisms. Uptake of Sn(IV) was 2-fold greater in intact cells than protoplasts, underlining the importance of cell wall binding, whereas TBT uptake levels by both cell types were similar. TBT uptake resulted in cell death and extensive K+ leakage, while Sn(IV) uptake had no effect. TMT did not interact with cells. Of the three compounds, TBT alone altered membrane fluidity, as measured by the fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene incorporated into cells. Anisotropy of 1-(4-trimethylaminophenyl-6-phenyl-1,3,5-hexatriene) was not affected, implying that TBT is not confined to the surface of the cytoplasmic membrane, but acts within membrane lipids. These results indicate that the cell wall is the dominant site of Sn(IV) interactions with yeast, while lipophilic interactions play an important role in uptake and toxicity of TBT.


JAB1 expression is associated with inverse expression of p27(kip1) in hepatocellular carcinoma.
Recent studies have shown that overexpression of c-jun activation domain binding protein 1 (JAB1) and reduced expression of p27(kip1) are associated with advanced tumor stage and poor prognosis in several human cancers. Here, We investigated the functional role and correlation of JAB1 and p27(kip1) in hepatocellular carcinoma (HCC). Immunohistochemical study for JAB1, p27(kip1) was performed on 76 cases of HCC and adjacent nontumorous tissues. 6 Fresh specimens of HCC and the adjacent liver tissue were collected for Western blot analysis. The influence of As2O3 on HCC SMMC-7721 cells, was detected by flow cytometry and Hochest staining. The expression and subcellular localization of p27(kip1) and JAB1 were investigated by Western blot and immunofluorescence. The expression of JAB1 was higher but p27(kip1) was lower in HCC than that in adjacent liver tissue. As2O3 treatment inhibited the growth of SMMC-7721 cells. In As2O3-treated cells, p27(kip1) expression was increased while JAB1 was decreased. The location of p27(kip1) and JAB1 were transferred from cytoplasm to nucleus. In HCC, JAB1 was inversely correlated with p27(kip1). As2O3 attenuated the expression of JAB1, disturbed the location and expression of p27(kip1), which may participate in regulating the growth of human hepatoma cells.


mCherry on Top: A Positive Read-Out Cellular Platform for Screening DMD Exon Skipping Xenopeptide-PMO Conjugates.
Phosphorodiamidate morpholino oligomers (PMOs) are a special type of antisense oligonucleotides (ASOs) that can be used as therapeutic modulators of pre-mRNA splicing. Application of nucleic-acid-based therapeutics generally requires suitable delivery systems to enable efficient transport to intended tissues and intracellular targets. To identify potent formulations of PMOs, we established a new in vitro-in vivo screening platform based on mdx exon 23 skipping. Here, a new in vitro positive read-out system (mCherry-DMDEx23) is presented that is sensitive toward the PMO(Ex23) sequence mediating DMD exon 23 skipping and, in this model, functional mCherry expression. After establishment of the reporter system in HeLa cells, a set of amphiphilic, ionizable xenopeptides (XPs) was screened in order to identify potent carriers for PMO delivery. The identified best-performing PMO formulation with high splice-switching activity at nanomolar concentrations in vitro was then translated to in vivo trials, where exon 23 skipping in different organs of healthy BALB/c mice was confirmed. The predesigned in vitro-in vivo workflow enables evaluation of PMO(Ex23) carriers without change of the PMO sequence and formulation composition. Furthermore, the identified PMO-XP conjugate formulation was found to induce highly potent exon skipping in vitro and redistributed PMO activity in different organs in vivo.


Tolerability of the Oscar 2 ambulatory blood pressure monitor among research participants: a cross-sectional repeated measures study.
Ambulatory blood pressure monitoring (ABPM) is increasingly used to measure blood pressure (BP) in research studies. We examined ease of use, comfort, degree of disturbance, reported adverse effects, factors associated with poor tolerability, and association of poor tolerability with data acquisition of 24-hour ABPM using the Oscar 2 monitor in the research setting. Sixty adults participating in a research study of people with a history of borderline clinic BP reported on their experience with ABPM on two occasions one week apart. Poor tolerability was operationalized as an overall score at or above the 75th percentile using responses to questions adapted from a previously developed questionnaire. In addition to descriptive statistics (means for responses to Likert-scaled "0 to 10" questions and proportions for Yes/No questions), we examined reproducibility of poor tolerability as well as associations with poor tolerability and whether poor tolerability was associated with removal of the monitor or inadequate number of BP measurements. The mean ambulatory BP of participants by an initial ABPM session was 148/87 mm Hg. After wearing the monitor the first time, the degree to which the monitor was felt to be cumbersome ranged from a mean of 3.0 to 3.8, depending on whether at work, home, driving, or other times. The most bother was interference with normal sleeping pattern (mean 4.2). Wearers found the monitor straightforward to use (mean 7.5). Nearly 67% reported that the monitor woke them after falling asleep, and 8.6% removed it at some point during the night. Reported adverse effects included pain (32%), skin irritation (37%), and bruising (7%). Those categorized as having poor tolerability (kappa = 0.5 between sessions, p = 0.0003) were more likely to report being in fair/poor health (75% vs 22%, p = 0.01) and have elevated 24-hour BP average (systolic: 28% vs 17%, p = 0.56; diastolic: 30% vs 17%, p = 0.37). They were also more likely to remove the monitor and have inadequate numbers of measurements. The Oscar 2 ABPM device is straightforward to use but can interfere with sleep. Commonly reported adverse effects include pain, skin irritation, and bruising. Those who tolerate the monitor poorly are more likely to report being in fair or poor health and to remove it, particularly at night.


Effect of crowding by Ficolls on OmpA and OmpT refolding and membrane insertion.
Folding of outer membrane proteins (OMPs) has been studied extensively in vitro. However, most of these studies have been conducted in dilute buffer solution, which is different from the crowded environment in the cell periplasm, where the folding and membrane insertion of OMPs actually occur. Using OmpA and OmpT as model proteins and Ficoll 70 as the crowding agent, here we investigated the effect of the macromolecular crowding condition on OMP membrane insertion. We found that the presence of Ficoll 70 significantly slowed down the rate of membrane insertion of OmpA while had little effect on those of OmpT. To investigate if the soluble domain of OmpA slowed down membrane insertion in the presence of the crowding agent, we created a truncated OmpA construct that contains only the transmembrane domain (OmpA171). In the absence of crowding agent, OmpA171 refolded at a similar rate as OmpA, although with decreased efficiency. However, under the crowding condition, OmpA171 refolded significantly faster than OmpA. Our results suggest that the periplasmic domain slows down the rate, while improves the efficiency, of OmpA folding and membrane insertion under the crowding condition. Such an effect was not obvious when refolding was studied in buffer solution in the absence of crowding.


Larger regional and rural areas in Victoria, Australia, experience more alcohol-related injury presentations at emergency departments.
Alcohol consumption is higher in regional and rural areas compared to metropolitan locations, but it is unclear which areas suffer different levels of harm. The current study investigated the rates of alcohol-related injury presentations at emergency departments (EDs) in Victoria, Australia, across metropolitan, regional, rural, and remote areas, and within coastal locations. Using ED injury presentations data for Victorian hospitals from June 1999 to June 2011, the trends in alcohol-related injury rates over time were investigated. Compared to metropolitan locations, alcohol-related injuries were higher in larger regional and rural areas and similar in small rural towns. The rates of alcohol-related injuries are also significantly increasing over time for regional and rural locations. Lastly, for males, rates of alcohol-related injuries increased in coastal areas during November to February compared to the remaining months. Regional and coastal areas experience increased alcohol-related injury rates. The causes of this have yet to be investigated and future research is required to determine why and what interventions may be most effective at reducing these harms.


Efficacy of Reduced-Intensity Chemotherapy With Oxaliplatin and Capecitabine on Quality of Life and Cancer Control Among Older and Frail Patients With Advanced Gastroesophageal Cancer: The GO2 Phase 3 Randomized Clinical Trial.
Older and/or frail patients are underrepresented in landmark cancer trials. Tailored research is needed to address this evidence gap. The GO2 randomized clinical trial sought to optimize chemotherapy dosing in older and/or frail patients with advanced gastroesophageal cancer, and explored baseline geriatric assessment (GA) as a tool for treatment decision-making. This multicenter, noninferiority, open-label randomized trial took place at oncology clinics in the United Kingdom with nurse-led geriatric health assessment. Patients were recruited for whom full-dose combination chemotherapy was considered unsuitable because of advanced age and/or frailty. There were 2 randomizations that were performed: CHEMO-INTENSITY compared oxaliplatin/capecitabine at Level A (oxaliplatin 130 mg/m2 on day 1, capecitabine 625 mg/m2 twice daily on days 1-21, on a 21-day cycle), Level B (doses 0.8 times A), or Level C (doses 0.6 times A). Alternatively, if the patient and clinician agreed the indication for chemotherapy was uncertain, the patient could instead enter CHEMO-BSC, comparing Level C vs best supportive care. First, broad noninferiority of the lower doses vs reference (Level A) was assessed using a permissive boundary of 34 days reduction in progression-free survival (PFS) (hazard ratio, HR = 1.34), selected as acceptable by a forum of patients and clinicians. Then, the patient experience was compared using Overall Treatment Utility (OTU), which combines efficacy, toxic effects, quality of life, and patient value/acceptability. For CHEMO-BSC, the main outcome measure was overall survival. A total of 514 patients entered CHEMO-INTENSITY, of whom 385 (75%) were men and 299 (58%) were severely frail, with median age 76 years. Noninferior PFS was confirmed for Levels B vs A (HR = 1.09 [95% CI, 0.89-1.32]) and C vs A (HR = 1.10 [95% CI, 0.90-1.33]). Level C produced less toxic effects and better OTU than A or B. No subgroup benefited from higher doses: Level C produced better OTU even in younger or less frail patients. A total of 45 patients entered the CHEMO-BSC randomization: overall survival was nonsignificantly longer with chemotherapy: median 6.1 vs 3.0 months (HR = 0.69 [95% CI, 0.32-1.48], P = .34). In multivariate analysis in 522 patients with all variables available, baseline frailty, quality of life, and neutrophil to lymphocyte ratio were independently associated with OTU, and can be combined in a model to estimate the probability of different outcomes. This phase 3 randomized clinical trial found that reduced-intensity chemotherapy provided a better patient experience without significantly compromising cancer control and should be considered for older and/or frail patients. Baseline geriatric assessment can help predict the utility of chemotherapy but did not identify a group benefiting from higher-dose treatment. isrctn.org Identifier: ISRCTN44687907.


Clinical and functional outcome of modified Quad surgery in adult obstetric brachial plexus injury patients: Case reports.
Untreated adult obstetric brachial plexus injury (OBPI) patients, in general, use compensatory strategies to achieve their lost upper extremity functions; they cause some adverse effects. Our present study is a case series of 3 female adult OBPI patients, aged 46, 23 and 21 years old. They all had a modified Quad surgical procedure. All patients were assessed preoperatively and postoperatively by evaluating video recordings of standardized upper extremity movements using the modified Mallet scale. The average postoperative follow-up was 4.3 months (1 to 9 months). Total Mallet score significantly improved from 15 and 18 to 21 in two patients. Supination angle measured from active movement of these 3 patients improved from 40°, 0° and -60° to 80°, 40° and -40°, respectively. The modified Quad surgical procedure significantly improves active abduction and other shoulder functions not only in young pediatric and adolescent patients, as we have previously reported, but also in adult patients with muscle imbalance secondary to brachial plexus injury sustained at birth.


[Renal injury in children].
For over a 20 year period 183 children with renal injuries have been under observation (102 boys and 81 girls). As a rule, the diagnosis of such injuries was established due to roentgenological and radioisotopic studies. 131 children were treated conservatively, 52--surgically. The study of late results in renal injuries has shown that the highest incidence of complications was revealed in a group of patients in whom no revision of the kidney and pararenal space was performed. The presence of postoperative and posttraumatic complications in some patients enabled to revise the surgical policy in such injuries in favour of widening indications to surgical therapy.


[Laparoscopic ovarian biopsy and infertility].
In the most developed countries, laparoscopic diagnostics and surgical procedures in the chosen cases still play a very important role and represent the acceptable alternative to the extrauterine fertilization. On the basis of histopathological verification of ovary biopsy cuts taken during the laparoscopy, the optimum conditions are fulfilled for determination of the ovary potentiality enabling the selection of patients for the further proper treatment. 113 patients that, due to the marriage infertility, were examined and treated at the Department of Sterility and infertility of the Obstetrics and Gynecology Clinic, Clinical Center of Nis, with the average age of 31.39 +/- 6.10 and with the average marriage infertility period lasting from 4.11 +/- 2.99 had undergone the surgical laparoscopy. The most frequently used interventions that were performed, disregarding the adnexial findings, were salipongovariolyses in 73 cases (64.60%), then fimbrioplastic in 60 cases (53.10%). Ovary biopsy and histopathological analysis of the cuts taken were performed in 110 patients (89.39%). We got 105 histopathological findings. The most common histopathological findings showed the existence of the primordial folicules in 39.60% of women, with the prevalence in younger ones. (In patients younger than 20--66.67%, while in patients over 40--25%). We found out that the prevailing number of women had the histological findings that spoke on behalf of the potential ovaries in case the infertility lasted shorter. The ovary tissue cuts taken by biopsy that were histopathologically analyzed, showed the significantly higher pregnancy and delivery rate in findings with the primordial folicules present (67.5% of the pregnancy rate 57.5% of the intrauterine pregnancy rate and 47.5% of the delivery rate).


The prion protein gene is dispensable for the development of spongiform myeloencephalopathy induced by the neurovirulent Cas-Br-E murine leukemia virus.
The Cas-Br-E murine leukemia virus (MuLV) induces paralysis in susceptible mice that is accompanied by a severe spongiform myeloencephalopathy. These neurodegenerative lesions are very similar to those observed in prion diseases. To determine whether the prion protein gene (Prn-p) product was a downstream effector of this neurovirulent MuLV, we inoculated Prn-p(-/-) knockout homozygote and control heterozygote or wild-type mice with this retrovirus. All groups developed typical paralysis and spongiform encephalopathy, and no differences in clinical or histological phenotypes were observed between these groups. These results indicate that the Cas-Br-E MuLV does not require the prion protein to induce lesions. Thus, MuLV and prion proteins may induce a very similar disease through distinct pathways, or the viral Env protein, which harbors the primary determinant of pathogenicity, may act in a common pathway but downstream of the prion protein.


Homeostatic Regulation of Glucocorticoid Receptor Activity by Hypoxia-Inducible Factor 1: From Physiology to Clinic.
Glucocorticoids (GCs) represent a well-known class of lipophilic steroid hormones biosynthesised, with a circadian rhythm, by the adrenal glands in humans and by the inter-renal tissue in teleost fish (e.g., zebrafish). GCs play a key role in the regulation of numerous physiological processes, including inflammation, glucose, lipid, protein metabolism and stress response. This is achieved through binding to their cognate receptor, GR, which functions as a ligand-activated transcription factor. Due to their potent anti-inflammatory and immune-suppressive action, synthetic GCs are broadly used for treating pathological disorders that are very often linked to hypoxia (e.g., rheumatoid arthritis, inflammatory, allergic, infectious, and autoimmune diseases, among others) as well as to prevent graft rejections and against immune system malignancies. However, due to the presence of adverse effects and GC resistance their therapeutic benefits are limited in patients chronically treated with steroids. For this reason, understanding how to fine-tune GR activity is crucial in the search for novel therapeutic strategies aimed at reducing GC-related side effects and effectively restoring homeostasis. Recent research has uncovered novel mechanisms that inhibit GR function, thereby causing glucocorticoid resistance, and has produced some surprising new findings. In this review we analyse these mechanisms and focus on the crosstalk between GR and HIF signalling. Indeed, its comprehension may provide new routes to develop novel therapeutic targets for effectively treating immune and inflammatory response and to simultaneously facilitate the development of innovative GCs with a better benefits-risk ratio.


The role of complement in Streptococcus pneumoniae-associated haemolytic uraemic syndrome.
Atypical forms of haemolytic uraemic syndrome (aHUS) include HUS caused by defects in the regulation of alternative complement pathway and HUS linked to neuraminidase-producing pathogens, such as Streptococcus pneumoniae. Increasing data support a pathogenic role of neuraminidase in the development of S. pneumoniae-associated haemolytic uraemic syndrome (SP-HUS), but the role of complement has never been clarified in detail. Therefore, we aimed to investigate whether the pathologic complement profile and genetic risk factors of aHUS are present in patients with SP-HUS. Enrolling five patients with SP-HUS classical and alternative pathway activity, besides C3, C4, factors H, B, I and anti-factor H autoantibody levels were determined. The coding regions of CFH, CFI, CD46 (MCP), THBD, C3 and CFB genes were sequenced and the copy number of CFI, CD46, CFH and related genes were also analyzed. We found that in the acute phase samples of SP-HUS patients, complement components C4, C3 and activity of the classical and alternative pathways were decreased, indicating severe activation and complement consumption, but most of these alterations normalized later in remission. Three of the patients carried mutations and risk haplotypes in complement-mediated aHUS associated genes. The identified mutations include a previously published CFI variant (P50A) and two novel ones in CFH (R1149X) and THBD (T44I) genes. Our results suggest that severe complement dysregulation and consumption accompany the progress of invasive pneumococcal disease (IPD)-associated SP-HUS and genetic variations of complement genes may contribute to the development of this complication in a proportion of the affected patients.


Exploring the applicability of the CAM18sl brightness prediction.
Recently, a color appearance model, CAM18sl, has been published. The model can predict the color perception (hue, colorfulness, brightness) of self-luminous stimuli seen against neutral backgrounds varying in luminance. In this paper, the applicability of CAM18sl to situations different from the one for which it was originally developed is explored. The brightness perception predicted by this model (expressed in "bright") is compared with the outcome of the CIE Unified Glare Rating (UGR) for luminaires, the limiting luminance values for Variable Message Signs as indicated in the European standard for outdoor situations, the visual gloss (VG) formula to characterize the gloss of objects, the CIE grey-scale calculation for self-luminous devices, and the predicted brightness value of illuminated objects according to CIECAM02. Although the application domains mentioned above are very distinct, it appears that the predicted brightness perception of the CAM18sl model correlates well with the outcome of the particular and dedicated metrics. It seems that, for brightness perception, CAM18sl can be considered as a general model applicable for a wide range of applications. This could lead to a reduction of a number of application-specific metrics.


Functional heartburn: definition and management strategies.
Functional heartburn (FH) is a functional gastro-intestinal disorder characterized by symptoms of heartburn not related to gastro-esophageal reflux. The absence of evidence of reflux-related symptoms relies on absence of esophagitis at endoscopy (including biopsies to exclude eosinophilic esophagitis), a normal esophageal acid exposure during esophageal pH-monitoring together with a negative symptom-reflux association analysis and an unsatisfactory response to proton pump inhibitor therapy. Addition of impedance measurement to pH-monitoring is likely to increase the number of patients with recognized reflux-related symptoms. The pathophysiology of functional heartburn remains largely unknown but involves disturbed esophageal perception and psychological factors such as depression, anxiety and somatization. The treatment of FH remains largely empirical and an individual approach is therefore recommended. The clinician should provide reassurance and refrain from performing too many invasive tests or therapeutic procedures. The use of pain modulators is recommended by most experts despite the lack of appropriate clinical trials to support it.


The effect object paradigm--a means to support medication safety with clinical decision support.
In many countries, officially approved drug information known as summary of product characteristics (SPC) is mostly available in text form, which cannot be used for Clinical Decision Support Systems (CDSS). It may be essential however to substantiate CDSS advice with such legally binding text snippets. In an attempt to link various drug data sources including SPC towards a CDSS to support medication safety in psychiatric patients we arrived at the notion of an effect object. A requirements analysis revealed data items and data structure which are needed from the patient and from the drug information source for the CDSS functionality. Published drug data modelling approaches were analyzed and found unsuitable. A conceptional database modeling approach using top down and bottom up modeling was performed. The schema based data model implemented within the django framework centered on SPC "effect objects" which comprise all SPC data required for the respective CDSS function such as search for contraindications in the proposed medication. Today six effect objects have been defined for contraindications and warnings, missing indications, adverse effects, drug-drug interactions, dosing and pharmacokinetics. The transformation of SPC data to a database-driven "effect objects" structure permits decoupling between the CDSS functions and different underlying data sources and supports the design of reusable, stable and verified CDSS functions.


Role of renal transporters and novel regulatory interactions in the TAL that control blood pressure.
Hypertension (HTN), a major public health issue is currently the leading factor in the global burden of disease, where associated complications account for 9.4 million deaths worldwide every year. Excessive dietary salt intake is among the environmental factors that contribute to HTN, known as salt sensitivity. The heterogeneity of salt sensitivity and the multiple mechanisms that link high salt intake to increases in blood pressure are of upmost importance for therapeutic application. A continual increase in the kidney's reabsorption of sodium (Na+) relies on sequential actions at various segments along the nephron. When the distal segments of the nephron fail to regulate Na+, the effects on Na+ homeostasis are unfavorable. We propose that the specific nephron region where increased active uptake occurs as a result of variations in Na+ reabsorption is at the thick ascending limb of the loop of Henle (TAL). The purpose of this review is to urge the consideration of the TAL as contributing to the pathophysiology of salt-sensitive HTN. Further research in this area will enable development of a therapeutic application for targeted treatment.


Colloidal CuFeS2 Nanocrystals: Intermediate Fe d-Band Leads to High Photothermal Conversion Efficiency.
We describe the colloidal hot-injection synthesis of phase-pure nanocrystals (NCs) of a highly abundant mineral, chalcopyrite (CuFeS2). Absorption bands centered at around 480 and 950 nm, spanning almost the entire visible and near-infrared regions, encompass their optical extinction characteristics. These peaks are ascribable to electronic transitions from the valence band (VB) to the empty intermediate band (IB), located in the fundamental gap and mainly composed of Fe 3d orbitals. Laser-irradiation (at 808 nm) of an aqueous suspension of CuFeS2 NCs exhibited significant heating, with a photothermal conversion efficiency of 49%. Such efficient heating is ascribable to the carrier relaxation within the broad IB band (owing to the indirect VB-IB gap), as corroborated by transient absorption measurements. The intense absorption and high photothermal transduction efficiency (PTE) of these NCs in the so-called biological window (650-900 nm) make them suitable for photothermal therapy as demonstrated by tumor cell annihilation upon laser irradiation. The otherwise harmless nature of these NCs in dark conditions was confirmed by in vitro toxicity tests on two different cell lines. The presence of the deep Fe levels constituting the IB is the origin of such enhanced PTE, which can be used to design other high performing NC photothermal agents.


Intralymphatic histiocytosis following placement of a metal implant.
Intralymphatic histiocytosis (IH) is a rare condition first reported in 1994 by O'Grady et al. Less than 40 cases have been reported, with the majority occurring in patients with rheumatoid arthritis. We present a case of a 72-year-old man who developed an asymptomatic rash on his left upper arm 3 years after placement of a metal implant to stabilize a fractured humerus. Examinations revealed a poorly demarcated erythematous to brown indurated plaque with a pebbly surface overlying the inferior portion of the surgical scar. Biopsy revealed a mixed dermal infiltrate with a complex glomeruloid intravascular accumulation of histiocytes and neutrophils. Histiocytes were identified with immunostaining for CD68. Immunostains for CD31 and D2-40 confirmed the intravascular location of the histiocytes. This reactive process is closely related to reactive angioendotheliomatosis, but is best classified as IH. This is the only case of IH reported in association with a metal implant of the upper arm and the fourth case reported in association with a metal implant. Although the pathogenesis of IH is unknown, a role for lymphatic stasis secondary to chronic inflammation or surgery has been suggested. This is a benign process with a chronic course, and there are no known efficacious treatments.


Sulforaphane causes epigenetic repression of hTERT expression in human breast cancer cell lines.
Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, is a common dietary component that has histone deacetylase inhibition activity and exciting potential in cancer prevention. The mechanisms by which SFN imparts its chemopreventive properties are of considerable interest and little is known of its preventive potential for breast cancer. We found that SFN significantly inhibits the viability and proliferation of breast cancer cells in vitro while it has negligible effects on normal breast cells. Inhibition of telomerase has received considerable attention because of its high expression in cancer cells and extremely low level of expression in normal cells. SFN treatment dose- and time-dependently inhibited human telomerase reverse transcriptase (hTERT), the catalytic regulatory subunit of telomerase, in both MCF-7 and MDA-MB-231 human breast cancer cells. DNA methyltransferases (DNMTs), especially DNMT1 and DNMT3a, were also decreased in SFN-treated breast cancer cells suggesting that SFN may repress hTERT by impacting epigenetic pathways. Down-regulation of DNMTs in response to SFN induced site-specific CpG demethylation occurring primarily in the first exon of the hTERT gene thereby facilitating CTCF binding associated with hTERT repression. Chromatin immunoprecipitation (ChIP) analysis of the hTERT promoter revealed that SFN increased the level of active chromatin markers acetyl-H3, acetyl-H3K9 and acetyl-H4, whereas the trimethyl-H3K9 and trimethyl-H3K27 inactive chromatin markers were decreased in a dose-dependent manner. SFN-induced hyperacetylation facilitated the binding of many hTERT repressor proteins such as MAD1 and CTCF to the hTERT regulatory region. Depletion of CTCF using siRNA reduced the SFN-induced down-regulation of hTERT mRNA transcription in these breast cancer cells. In addition, down-regulation of hTERT expression facilitated the induction of cellular apoptosis in human breast cancer cells. Collectively, our results provide novel insights into SFN-mediated epigenetic down-regulation of telomerase in breast cancer prevention and may open new avenues for approaches to SFN-mediated cancer prevention.


[Autogenous transplantation of pedicle iliac crest epiphysis to epiphyseal defect of joint. An experimental study in puppy].
In 24 immature dogs, autogenous iliac-crest apophyseal graft was transplanted into the defect created in epiphysis of the femoral head. The dogs were divided into 2 group. In the group I, the graft was pedicled with circumflex iliac vessels. In the group II, the same technique was used without pedicle. All the animals were followed up for 1-6 months. The specimens were studied by macroscopic, histological, histochemical and electron-microscopical examinations. The examinations revealed that the pedicle grafts survived with good remodelling in joint defects. The ossification of the iliac-crest physis seemed to be normal. The superficial part of the graft did not undergo ossification, and the histologic structure of the graft was similar to the articular cartilage of the femoral head. It is possible to reconstruct a joint surface and to repair the epiphyseal defect of joint.


In vitro growth and development of isolated secondary follicles from vitrified caprine ovarian cortex.
The aim of this study was to evaluate the viability, antrum formation and in vitro development of isolated secondary follicles from vitrified caprine ovarian cortex in a medium previously established for fresh isolated secondary follicles, in the absence (α-minimum essential medium (α-MEM+) alone) or presence of FSH and vascular endothelial growth factor (VEGF; α-MEM++FSH+VEGF). Ovarian fragments were distributed among five treatments (T1 to T5): fresh follicles were fixed immediately (T1), follicles from fresh tissue were cultured in vitro in α-MEM+ (T2) or α-MEM++FSH+VEGF (T3) and follicles from vitrified tissue were cultured in vitro in α-MEM+ (T4) or α-MEM++FSH+VEGF (T5). After 6 days of culture, treated follicles (T2, T3, T4 and T5) were evaluated for morphology, viability and follicular development (growth, antrum formation and proliferation of granulosa cells by Ki67 and argyrophilic nucleolar organiser region (AgNOR) staining). The levels of reactive oxygen species (ROS) in the culture media were also assessed. Overall, morphology of vitrified follicles was altered (P<0.05) compared with the fresh follicles. Follicular viability, antrum formation and ROS were similar between treatments (P>0.05). The average overall and daily follicular growth was highest (P<0.05) in T3. Granulosa cells in all treatments (T1, T2, T3, T4 and T5) stained positive for Ki67. However, fresh follicles from T3 had significantly higher AgNOR staining (P<0.05) compared with follicles of T1, T2, T4 and T5. In conclusion, secondary follicles can be isolated from vitrified and warmed ovarian cortex and survive and form an antrum when growing in an in vitro culture for 6 days.


Developmental toxicity assessment of medicinal mushroom Antrodia cinnamomea T.T. Chang et W.N. Chou (higher Basidiomycetes) submerged culture mycelium in rats.
Antrodia cinnamomea is a Taiwanese medicinal mushroom with high antioxidant and polysaccharide content. The objective of this study is to investigate developmental toxicity of A. cinnamomea in pregnant Sprague-Dawley rats. Animals were daily gavaged with A. cinnamomea mycelium at dosage levels of 0 (reverse osmosis water), 50, 150, and 500 mg/kg from gestation day (GD) 6 to 15. All dams were sacrificed on GD 20 and were subjected to cesarean section. Fetuses were examined for external, visceral, and skeletal abnormalities. All copulated females survived until the end of the study. No significant differences were recorded in body weight change, food consumption, and maternal gestational parameters. Only two fetal malformations were noted in 970 fetuses from the treatment groups. Some variations, such as enlarged fontanel, split sternebrae, absent sacral, absent caudal vertebral centra, absent thoracic centra, absent 13th-14th ribs, and fused ribs, were found during the skeletal examination, but no treatment-induced abnormalities occurred. No dose dependency was observed in any of the developmental variations. Overall observation of foetal malformations from rats given A. cinnamomea mycelium during pregnancy demonstrates that this material is not teratogenic at doses up to 500 mg/kg. It is concluded that A. cinnamomea BCRC 35398 mycelium has no teratogenic effects in female rats and is safe to be used as a functional food ingredient.


Investigation on acute effects of enzyme replacement therapy and influence of clinical severity on physiological variables related to exercise tolerance in patients with late onset Pompe disease.
Exercise intolerance is one of the clinical hallmarks of late-onset Pompe disease (LOPD). We studied the acute effects of ERT on the physiological variables associated with exercise tolerance in patients chronically ERT treated. Moreover, we assessed the influence of clinical severity on the investigated variables. The day before (B) and the day after (A) ERT injection, 11 LOPD patients performed on a cycle-ergometer an exercise tolerance test to voluntary exhaustion; VO2, HR, RPE, and GAA activity were determined in B and A. The disease severity was characterized by Walton scale, 6MWT, and pulmonary function tests. No significant differences in the variables related to exercise tolerance were found in A vs B, despite a significant increase in GAA activity in peripheral lymphocytes. No differences in VO2 peak were observed between patients with only skeletal muscle impairment and patients with both skeletal and respiratory muscle impairment. Distance walked at 6MWT was significantly higher than VO2 peak expressed as percentage of normal values. In conclusion, in LOPD patients the exercise tolerance test is not acutely affected by ERT administration; the peripheral muscle component seems more prominent in determining the VO2 peak decrease than the respiratory component; VO2 peak might be more sensitive than 6MWT in estimating exercise tolerance in LOPD.


A multi-site Canadian perspective: examining the functional outcome from first-episode psychosis.
To examine factors contributing to variance in functional outcome in first-episode psychosis (FEP) following 1 year of treatment. Naturalistic 1-year follow-up of a FEP cohort (n = 200), from programs in four university centers in Ontario, Canada. Functional recovery was defined by 'Social and Occupational Functioning Assessment Scale' (SOFAS) score>60. Regression analysis examined the contribution of independent variables to variance in functional outcome. Twelve-month outcome measures were available for 76.5% of the original cohort. Of these, 70% reported being in school/work and in satisfactory relationships. The functional recovery rate was 51%, compared to 74% attaining symptomatic remission. The greatest contributors to variance in outcome were ongoing symptoms at 6 months and substance abuse comorbidity. After 1 year of treatment, FEP patients show high rates of symptomatic remission and relatively lower rates of functional recovery. Symptoms and substance abuse contribute to variance in outcome.


Potential Noncutaneous Sites of Chelonid Herpesvirus 5 Persistence and Shedding in Green Sea Turtles Chelonia mydas.
Chelonid herpesvirus 5 (ChHV5), the likely etiologic agent of sea turtle fibropapillomatosis (FP), is predicted to be unevenly distributed within an infected turtle, in which productive virus replication and virion shedding occurs in cutaneous tumor keratinocytes. In this study, we measured and compared ChHV5 DNA quantities in tumors, skin, urine, major organs, and nervous tissue samples from green turtles Chelonia mydas. These samples were taken from the carcasses of 10 juvenile green turtles with and without clinical signs of FP that stranded in Florida during 2014. Quantitative PCR for ChHV5 UL30 was used to identify ChHV5 DNA in tumors, skin, heart, kidney, nerves, and urine sampled from five out of five FP-positive and three out of five FP-free turtles. The most frequently co-occurring sites were cutaneous tumor and kidney (n = 4). Novel data presented here include the identification of ChHV5 DNA in kidney, heart, and nerve samples from three FP-free turtles. These data support candidate nontumored anatomic sites of ChHV5 DNA localization and mobilization during two different disease states that may be involved in the ChHV5 infection cycle. Received September 8, 2016; accepted April 17, 2017.


Identifying latent trajectories of personality disorder symptom change: growth mixture modeling in the longitudinal study of personality disorders.
Although previous reports have documented mean-level declines in personality disorder (PD) symptoms over time, little is known about whether personality pathology sometimes emerges among nonsymptomatic adults, or whether rates of change differ qualitatively among symptomatic persons. Our study sought to characterize heterogeneity in the longitudinal course of PD symptoms with the goal of testing for and describing latent trajectories. Participants were 250 young adults selected into two groups using a PD screening measure: those who met diagnostic criteria for a DSM-III-R PD (PPD, n = 129), and those with few PD symptoms (NoPD, n = 121). PD symptoms were assessed three times over a 4-year study using semistructured interviews. Total PD symptom counts and symptoms of each DSM-III-R PD were analyzed using growth mixture modeling. In the NoPD group, latent trajectories were characterized by stable, minor symptoms; the rapid or gradual remission of subclinical symptoms; or the emergence of symptoms of avoidant, obsessive-compulsive, or paranoid PD. In the PPD group, three latent trajectories were evident: rapid symptom remission, slow symptom decline, or a relative absence of symptoms. Rapid remission of PD symptoms was associated with fewer comorbid disorders, lower Negative Emotionality, and greater Positive Emotionality and Constraint, whereas emergent personality dysfunction was associated with comorbid PD symptoms and lower Positive Emotionality. In most cases, symptom change for one PD was associated with concomitant changes in other PDs, depressive symptoms, and anxiety. These results indicate that the longitudinal course of PD symptoms is heterogeneous, with distinct trajectories evident for both symptomatic and nonsymptomatic individuals. The prognosis of PD symptoms may be informed by an assessment of personality and comorbid psychopathology.


Methylation of the ABL1 promoter in chronic myelogenous leukemia: lack of prognostic significance.
The BCR-ABL chromosomal translocation is a central event in the pathogenesis of chronic myelogenous leukemia (CML). One of the ABL1 promoters (Pa) and the coding region of the gene are usually translocated intact to the BCR locus, but the translocated promoter appears to be silent in most cases. Recently, hypermethylation of Pa was demonstrated in CML and was proposed to mark advanced stages of the disease. To study this issue, we measured Pa methylation in CML using Southern blot analysis. Of 110 evaluable samples, 23 (21%) had no methylation, 17 (15%) had minimal (<15%) methylation, 12 (11%) had moderate methylation (15% to 25%), and 58 (53%) had high levels of methylation (>25%) at the ABL1 locus. High methylation was more frequent in advanced cases of CML. Among the 76 evaluable patients in early chronic phase (ECP), a major cytogenetic response with interferon-based therapy was observed in 14 of 34 patients with high methylation compared with 19 of 42 among the others (41% v 45%; P value not significant). At a median follow-up of 7 years, there was no significant difference in survival by ABL1 methylation category. Among patients who achieved a major cytogenetic response, low levels of methylation were associated with a trend towards improved survival, but this trend did not reach statistical significance. Thus, Pa methylation in CML is associated with disease progression but does not appear to predict for survival or response to interferon-based therapy.


Effect of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer.
Eicosapentaenoic acid (EPA) has been shown to modulate aspects of the inflammatory response that may contribute to weight loss in cancer. This study aimed to evaluate the acceptability and effects of oral supplementation with high-purity EPA in weight-losing patients with advanced pancreatic cancer. Twenty-six patients were entered into the study. EPA (95% pure) was administered as free acid starting at 1 g/day; the dose was increased to 6 g/day over four weeks, and then a maintenance dose of 6 g/day was administered. Patients were assessed before EPA and at 4, 8, and 12 weeks while receiving EPA, for weight, body composition, hematologic and clinical chemistry variables, acute-phase protein response, and performance status. Overall survival was noted. Supplementation was well tolerated, with only five patients experiencing side effects possibly attributable to the EPA. Before starting EPA, all patients had been losing weight at a median rate of 2 kg/mo. In general, after EPA supplementation, weight was stable. After four weeks of EPA supplementation, patients had a median weight gain of 0.5 kg (p = 0.0009 vs. rate of weight loss at baseline), and this stabilization of weight persisted over the 12-week study period. Total body water as a percentage of body weight remained stable, as did the proportion of patients with an acute-phase protein response, patients' nutritional intake, and performance status. Overall median survival from diagnosis in this study was 203 days. This study suggests that EPA is well tolerated, may stabilize weight in cachectic pancreatic cancer patients, and should be tested as an anticachectic agent in controlled trials.


Interleukin 18 induces angiogenesis in vitro and in vivo via Src and Jnk kinases.
Interleukin 18 (IL-18) is a novel mediator of angiogenesis in rheumatoid arthritis (RA). To examine the role of IL-18 in RA angiogenesis and the signalling mechanisms involved. Human dermal microvascular endothelial cell (HMVEC) chemotaxis, capillary morphogenesis assays and Matrigel plug angiogenesis assays were performed in vivo using IL-18 with or without signalling inhibitors. A novel model of angiogenesis was devised using dye-tagged HMVECs to study their homing into RA and normal (NL) synovial tissues (STs) engrafted in severe combined immunodeficient (SCID) mice. IL-18-mediated angiogenesis depended on Src and Jnk, as the inhibitors of Src and Jnk blocked IL-18-induced HMVEC chemotaxis, tube formation and angiogenesis in Matrigel plugs. However, inhibitors of Janus kinase 2, p38, MEK, phosphatidylinositol-3-kinase and neutralising antibodies to vascular endothelial growth factor or stromal derived factor-1α did not alter IL-18-induced HMVEC migration. These results were confirmed with Jnk or Src sense or antisense oligodeoxynucleotides. Moreover, IL-18 induced phosphorylation of Src and Jnk in HMVECs. As proof of principle, IL-18 null mice had a significantly decreased angiogenesis compared with wild-type mice in Matrigel plug angiogenesis assays in vivo. IL-18 markedly enhanced mature HMVEC homing to human RA ST compared with NL ST in SCID mice, confirming the role of IL-18-induced angiogenesis in RA ST in vivo. Targeting IL-18 or its signalling intermediates may prove to be a potentially novel therapeutic strategy for angiogenesis-dependent diseases, such as RA.


How much do elders with chronic conditions know about their medications?
Patients with chronic diseases often undertake multiple medication regimes to manage their condition, prevent complications and to maintain their quality of life. A patient's medication knowledge has been defined as the awareness of drug name, purpose, administration schedule, adverse effects or side-effects and special administration instructions. Poor medication knowledge can have a negative impact on medication adherence and patient safety and, in increasing the use of medical resources. The objective of the study is to assess the medication knowledge of elderly patients with chronic disease conditions and the factors affecting this knowledge. A cross-sectional survey was conducted in patients aged ≥ 60 with chronic disease conditions or their caregivers were recruited from two general outpatient clinics and two medical outpatient clinics in the public sector. Participants were approached by trained interviewers to complete a semi-structured questionnaire to assess their understanding of the instructions and information relating to their regular medications, which included medication name, regimen, purpose and common side-effects and precautions. A total of 412 patients were recruited with the mean age of 72.86 ± 7.70. Of those, 221 (54.2%) were male and 226 (55.4%) were of primary school educational level or below. The mean number of medications taken per patient was 3.75 ± 1.93. Overall, 52.7% of patients felt that healthcare staff or clinic pharmacists had very clearly explained the administration instruction of the prescribed medications whilst 47.9% had very clear explanations of drug purpose but only 11.4% felt they had very clear explanations of side-effects. 396 patients (96.1%) failed to recall any side effects or precautions of each of their prescribed medications, although 232 patients (58.4%) would consult a doctor if they encountered problems with their medications. Logistic regression analysis showed that for every additional medication prescribed, the likeliness of patients to recall side-effects of all the medications prescribed was significantly lowered by 35% (OR = 0.65; 95% CI = 0.44-0.94; P = 0.023). In addition, those who finished secondary school or higher education were likely to possess more knowledge of side-effects (OR = 9.88; 95% CI = 2.11-46.25; P = 0.004). Patients who take medications for their chronic diseases generally lack knowledge on side-effects of their medications which could potentially affect medication compliance and medication safety.


Survey of the antimicrobial activity of commercially available Australian tea tree (Melaleuca alternifolia) essential oil products in vitro.
The aim of this study was to investigate the antimicrobial activity of a range of commercially available tea tree oil (TTO) products and to evaluate whether formulation plays a significant part in their antiseptic activity. The antimicrobial activity of the purchased products and control TTO solutions was assessed against Escherichia coli, Staphylococcus aureus, Salmonella typhimurium, Pseudomonas aeruginosa, and Candida albicans using well diffusion, broth microdilution, and broth macrodilution assays. Zone sizes obtained by the agar well diffusion assay ranged from 0 to 49.8 mm, with the more viscous and lipophilic products producing the smallest zones. Micro- and macrodilution methods showed that eight products had minimum inhibitory concentrations that were lower than the nonformulated TTO control. The remaining three products showed activity equivalent to the TTO control. In general, the commercially available antiseptic TTO products showed antimicrobial activity that was equivalent to, or greater than the nonformulated TTO control. This suggests that the TTO within these products has retained its antimicrobial activity. Furthermore, the enhanced activity of the products may be attributed to other antimicrobial excipients within the products such as preservatives, or to synergistic antimicrobial interactions between the TTO and other product excipients. The observation that the commercially available antiseptic TTO products tested in this study retained adequate antimicrobial activity emphasizes the importance of considering how product bases and excipients may interact with the active compound during formulation to ensure efficacy of the final product. Finally, the current data suggest that these TTO products may also be active in vivo. However, this can only be determined through further studies and in clinical trials.


Ultradian corticosterone secretion is maintained in the absence of circadian cues.
Plasma levels of corticosterone exhibit both circadian and ultradian rhythms. The circadian component of these rhythms is regulated by the suprachiasmatic nucleus (SCN). Our studies investigate the importance of the SCN in regulating ultradian rhythmicity. Two approaches were used to dissociate the hypothalamic-pituitary-adrenal (HPA) axis from normal circadian input in rats: (i) exposure to a constant light (LL) environment and (ii) electrolytic lesioning of the SCN. Blood was sampled using an automated sampling system. As expected, both treatments resulted in a loss of the circadian pattern of corticosterone secretion. Ultradian pulsatile secretion of corticosterone however, was maintained across the 24 h in all animals. Furthermore, the loss of SCN input revealed an underlying relationship between locomotor and HPA activity. In control (LD) rats there was no clear correlation between ultradian locomotor activity and hormone secretion, whereas, in LL rats, episodes of ultradian activity were consistently followed by periods of increased pulsatile hormone secretion. These data clearly demonstrate that the ultradian rhythm of corticosterone secretion is generated through a mechanism independent of the SCN input, supporting recent evidence for a sub-hypothalamic pulse generator.


[Migration in different sorts of work, unemployment and retirement of 81 epileptic patients. 3 years of ambulatory follow-up].
This study aims to assess epileptic patients migration in different sorts of paid/non paid and formal/informal work, unemployment and retirement. Eighty one epileptic patients were evolutively analyzed (cohort) at the Epilepsy Department of Hospital de Base, Medical School, São José do Rio Preto, Brazil. The epileptic percentages in different sorts of work, in March 1996 was compared with the one after three-year follow-up period in March 1999. There were no statistical significant changes among the same sorts of work in this period. However, there were intense migrations in relation to different sorts of work. Paid work showed migration to unemployment and retirement. This research shows the significant migration of epileptic patient either to some kind of a less qualified work or to some social security dependence as well as to early retirement.


Cryptosporidium parvum Infection Following Contact with Livestock.
Scours, or calf diarrhea, is an infectious gastrointestinal disease commonly found in the calves of dairy farms. It primarily presents with diarrhea that can be life threatening to the animal and is also contagious and threatening to the other livestock. Cryptosporidium is one of the major causes of scours and can be transmitted to humans via fecal-oral route, resulting in diarrheal illnesses. Cryptosporidiosis infection usually occurs as a waterborne outbreak with the potential to affect many people at once. We report a case of a 24-year-old female farmer who presented to the emergency department with diarrhea after taking care of ill cattle with similar symptoms. Fecal cultures were positive for Cryptosporidium parvum. Given the patient was immunocompetent, no further treatment was warranted. Confirmed cases should be reported, however, treatment is only recommended in children and immunocompromised adults. Clinicians should educate patients on the importance of proper hygiene and handling techniques in order to decrease transmission and recurrence of the protozoan infection.


Preconditioning in neuroprotection: From hypoxia to ischemia.
Sublethal hypoxic or ischemic events can improve the tolerance of tissues, organs, and even organisms from subsequent lethal injury caused by hypoxia or ischemia. This phenomenon has been termed hypoxic or ischemic preconditioning (HPC or IPC) and is well established in the heart and the brain. This review aims to discuss HPC and IPC with respect to their historical development and advancements in our understanding of the neurochemical basis for their neuroprotective role. Through decades of collaborative research and studies of HPC and IPC in other organ systems, our understanding of HPC and IPC-induced neuroprotection has expanded to include: early- (phosphorylation targets, transporter regulation, interfering RNA) and late- (regulation of genes like EPO, VEGF, and iNOS) phase changes, regulators of programmed cell death, members of metabolic pathways, receptor modulators, and many other novel targets. The rapid acceleration in our understanding of HPC and IPC will help facilitate transition into the clinical setting.


Resolution of chronic bacterial-induced prostatic inflammation reverses established fibrosis.
Prostatic inflammation has been suggested to contribute to the etiology of lower urinary tract symptoms by inducing fibrosis. We previously used a well-characterized mouse model of bacterial-induced prostate inflammation to demonstrate that chronic prostatic inflammation induces collagen deposition. Here, we examined stability of the newly synthesized collagen in bacterial-induced prostatic inflammation and the reversibility of fibrosis after resolution of infection and inflammation. Uropathogenic Escherichia coli 1677 was instilled transurethrally into adult C3H/HeOuJ male mice to induce chronic prostatic inflammation. Collagen was labeled by (3) H-proline administration for 28 days post-inoculation and (3) H-hydroxyproline incorporation measured to determine stability of the newly synthesized collagen. Inflammation score was graded using a previously established system and total collagen content was measured by picrosirius red staining quantitation and hydroxyproline content. Resolution of inflammation and reversal of collagen deposition was assessed after treatment with antibiotic enrofloxacin for 2 weeks on day 28 post-inoculation followed by an 8-week recovery period. Decay analysis of incorporated (3) H-hydroxyproline revealed the half-life of newly synthesized collagen to be significantly shorter in infected/inflamed prostates than in controls. Treatment with antibiotic enrofloxacin completely eradicated bacterial infection and allowed resolution of inflammation. This was followed by marked attenuation of collagen content and correlation analysis verified a positive association between the resolution of inflammation and the reversal of collagen deposition. These data demonstrate, for the first time, that inflammation-induced prostatic fibrosis is a reversible process.


Ab initio calculations for industrial materials engineering: successes and challenges.
Computational materials science based on ab initio calculations has become an important partner to experiment. This is demonstrated here for the effect of impurities and alloying elements on the strength of a Zr twist grain boundary, the dissociative adsorption and diffusion of iodine on a zirconium surface, the diffusion of oxygen atoms in a Ni twist grain boundary and in bulk Ni, and the dependence of the work function of a TiN-HfO(2) junction on the replacement of N by O atoms. In all of these cases, computations provide atomic-scale understanding as well as quantitative materials property data of value to industrial research and development. There are two key challenges in applying ab initio calculations, namely a higher accuracy in the electronic energy and the efficient exploration of large parts of the configurational space. While progress in these areas is fueled by advances in computer hardware, innovative theoretical concepts combined with systematic large-scale computations will be needed to realize the full potential of ab initio calculations for industrial applications.


The role of mechanical and neural restraints to joint range of motion during passive stretch.
Musculoskeletal flexibility is typically characterized by maximum range of motion (ROM) in a joint or series of joints. Resistance to passive stretch in the mid-range of motion is a function of the passive mechanical restraints to motion. However, an active contractile response may contribute resistance at terminal ROM. The purpose of this study was to examine whether maximum straight leg raise (SLR) ROM was limited by passive mechanical forces or stretch-induced contractile responses to stretch. An instrumented SLR stretch was applied to the right leg of 16 subjects ending at the point of discomfort. Torque was measured with a load cell attached to the ankle. An electrogoniometer was placed on the hip, and the knee was braced in extension. Surface electrodes were placed over the rectus and biceps femoris muscles. Following the instrumented SLR test, maximum ROM was measured goniometrically by a physical therapist using the standard SLR test (PT SLR ROM). Torque/ROM curves were plotted for each subject. PT SLR ROM was positively related to total energy absorbed (area under the curve) (r = 0.49, P = 0.044), negatively related to the increase in torque from 20 to 50 degrees (r = -0.81, P < 0.0001) and negatively related to energy absorbed from 20 to 50 degrees (r = -0.73, P < 0.001). Minimal stretch-induced hamstring activity was elicited (3 +/- 1% MVC), and the EMG activity was unrelated to PT SLR ROM (r = -0.06, P = 0.8). A combination of the increase in torque from 20 to 50 degrees and total energy absorbed improved the relationship to PT SLR ROM (r = 0.89, P = 0.001). Seventy-nine percent of the variability in maximum SLR ROM could be explained by the passive mechanical response to stretch. These data lend support to the concept that musculoskeletal flexibility can be explained in mechanical terms rather than by neural theories.


Practical reconstruction protocol for quantitative (90)Y bremsstrahlung SPECT/CT.
To develop a practical background compensation (BC) technique to improve quantitative (90)Y-bremsstrahlung single-photon emission computed tomography (SPECT)/computed tomography (CT) using a commercially available imaging system. All images were acquired using medium-energy collimation in six energy windows (EWs), ranging from 70 to 410 keV. The EWs were determined based on the signal-to-background ratio in planar images of an acrylic phantom of different thicknesses (2-16 cm) positioned below a (90)Y source and set at different distances (15-35 cm) from a gamma camera. The authors adapted the widely used EW-based scatter-correction technique by modeling the BC as scaled images. The BC EW was determined empirically in SPECT/CT studies using an IEC phantom based on the sphere activity recovery and residual activity in the cold lung insert. The scaling factor was calculated from 20 clinical planar (90)Y images. Reconstruction parameters were optimized in the same SPECT images for improved image quantification and contrast. A count-to-activity calibration factor was calculated from 30 clinical (90)Y images. The authors found that the most appropriate imaging EW range was 90-125 keV. BC was modeled as 0.53× images in the EW of 310-410 keV. The background-compensated clinical images had higher image contrast than uncompensated images. The maximum deviation of their SPECT calibration in clinical studies was lowest (<10%) for SPECT with attenuation correction (AC) and SPECT with AC + BC. Using the proposed SPECT-with-AC + BC reconstruction protocol, the authors found that the recovery coefficient of a 37-mm sphere (in a 10-mm volume of interest) increased from 39% to 90% and that the residual activity in the lung insert decreased from 44% to 14% over that of SPECT images with AC alone. The proposed EW-based BC model was developed for (90)Y bremsstrahlung imaging. SPECT with AC + BC gave improved lesion detectability and activity quantification compared to SPECT with AC only. The proposed methodology can readily be used to tailor (90)Y SPECT/CT acquisition and reconstruction protocols with different SPECT/CT systems for quantification and improved image quality in clinical settings.


Can CT scan protocols used for radiotherapy treatment planning be adjusted to optimize image quality and patient dose? A systematic review.
This article reviews publications related to the use of CT scans for radiotherapy treatment planning, specifically the impact of scan protocol changes on CT number and treatment planning dosimetry and on CT image quality. A search on PubMed and EMBASE and a subsequent review of references yielded 53 relevant articles. CT scan parameters significantly affect image quality. Some will also affect Hounsfield unit (HU) values, though this is not comprehensively reported on. Changes in tube kilovoltage and, on some scanners, field of view and reconstruction algorithms have been found to produce notable HU changes. The degree of HU change which can be tolerated without changing planning dose by >1% depends on the body region and size, planning algorithms, treatment beam energy and type of plan. A change in soft-tissue HU value has a greater impact than changes in HU for bone and air. The use of anthropomorphic phantoms is recommended when assessing HU changes. There is limited published work on CT scan protocol optimization in radiotherapy. Publications suggest that HU tolerances of ±20 HU for soft tissue and of ±50 HU for the lung and bone would restrict dose changes in the treatment plan to <1%. Literature related to the use of CT images in radiotherapy planning has been reviewed to establish the acceptable level of HU change and the impact on image quality of scan protocol adjustment. Conclusions have been presented and further work identified.


An emphatic study on the luciferin-luciferase bioluminescence system of Benthosema pterotum.
Approximately 80% of luminous organisms live in the oceans, and considerable diversity of life dependence on bioluminescence has been observed in marine organisms. Among vertebrates, luminous fish species are the only group of vertebrates that have the ability to emit bioluminescent light. Meanwhile, the lantern fish family (Myctophidae), with 33 genera all of which have the ability to emit light, is considered the most prominent family among the luminous fish of the deep oceans and seas. Lantern fish Benthosema pterotum has bioluminescence properties due to the presence of photophores scattered in its ventral-lateral region. However, no research has been performed on its bioluminescence system and light emission mechanism. The present research aimed to assess the type of bioluminescence, pigment, photoprotein, or luciferin-luciferase system in B. pterotum. In order to determine the type of light-emitting system in B. pterotum species, several specific experiments were designed and performed. It was shown that the light emission system in B. pterotum species is categorized into the luciferin-luciferase type. Conducting this research was not only innovative, but it also could be the beginning of further research in the field of marine biochemistry and production of the recombinant active forms of enzymes for industrial, commercial, medical, and pharmaceutical purposes.