Tail kinematics of the chub mackerel Scomber japonicus: testing the homocercal tail model of fish propulsion.
Scombrid fishes possess a homocercal caudal fin with reduced intrinsic musculature and dorso-ventrally symmetrical external and internal morphology. Because of this symmetrical morphology, it has often been assumed that scombrid caudal fins function as predicted by the homocercal tail model. According to that model, the caudal fin moves in a dorso-ventrally symmetrical manner and produces no vertical lift during steady swimming. To test this hypothesis, we examined the tail kinematics of chub mackerel, Scomber japonicus (24.8+/-1.3 cm total length, L). Markers were placed on the caudal fin to identify specific regions of the tail, and swimming chub mackerel were videotaped from lateral and posterior views, allowing a three-dimensional analysis of tail motion. Analysis of tail kinematics suggests that, at a range of swimming speeds (1.2-3.0 L s(-)(1)), the dorsal lobe of the tail undergoes a 15 % greater lateral excursion than does the ventral lobe. Lateral excursion of the dorsal tail-tip also increases significantly by 32 % over this range of speeds, indicating a substantial increase in tail-beat amplitude with speed. In addition, if the tail were functioning in a dorso-ventrally symmetrical manner, the tail should subtend an angle of 90 degrees relative to the frontal (or xz) plane throughout the tail beat. Three-dimensional kinematic analyses reveal that the caudal fin actually reaches a minimum xz angle of 79.8 degrees. In addition, there is no difference between the angle subtended by the caudal peduncle (which is anterior to the intrinsic tail musculature) and that subtended by the posterior lobes of the tail. Thus, asymmetrical movements of the tail are apparently generated by the axial musculature and transmitted posteriorly to the caudal fin. These results suggest that the caudal fin of the chub mackerel is not functioning symmetrically according to the homocercal model and could produce upward lift during steady swimming.


Beyond social support: Self-care confidence is key for adherence in patients with heart failure.
Adherence to treatment is crucial to improve outcomes in patients with heart failure. Good social support is associated with better adherence, but the mechanism for this association has not been well-explored. The aim of this secondary analysis was to examine whether self-care confidence mediates the relationship between social support and treatment adherence in heart failure patients hospitalized with acute exacerbation. A total of 157 inpatients with heart failure (63.5±13 years, 73% New York Heart Association class III/IV) were recruited from two hospitals located in urban areas in the USA. Participants completed the Self-Care of Heart Failure Index, the Multidimensional Perceived Social Support Scale, and the Medical Outcomes Study Specific Adherence Scale. A series of regression models were used to determine the mediation relationship. Controlling for marital status and hospital site, social support was associated with adherence ( p=0.03). When self-confidence was included in the model, the effect of social support became non-significant, indicating full mediation of the relationship between social support and adherence by self-care confidence. The indirect effect (0.04) of social support on adherence through self-confidence was significant (95% confidence interval: 0.01-0.09). Heart failure self-care confidence mediated the relationship between social support and treatment adherence. Thus interventions targeting patients' self-care confidence is essential to maximize patients' treatment adherence.


Use of a medical facility by Christian Scientists.
Our study, unique in its use of medical records as well as self-report data, was conducted to ascertain the extent to which Christian Scientists used a medical facility and whether or not such use was related to the experience of psychologic stress. Their use of medical facilities was found to be low, and it was positively related to stress.


GRP78 signaling hub a receptor for targeted tumor therapy.
Glucose-regulated protein 78 (GRP78) is a potential receptor for targeting therapy in cancer and chronic vascular disease due to its overexpression at the cell surface in tumor cells and in atherosclerotic lesions. Presence of the GRP78 autoantibody in cancer patient sera is generally associated with poor prognosis since it signals a prosurvival mechanism in response to cellular stress. Association of GRP78 with various binding partners involves coordination of multiple signaling pathways that result in either cell survival or cell death. Binding of activated alpha2-macroglobulin to cell-surface GRP78 activates Akt to suppress apoptotic pathways through multiple downstream effectors, and concomitantly upregulates NF-kappaBeta and induces the unfolded protein response (UPR) so that cell proliferation prevails. Interaction of GRP78 with cell-surface T-cadherin promotes endothelial cell survival. Association of oncogenic Cripto with GRP78 nullifies TGF-beta superfamily-dependent signaling through Smad2/3 to promote cell proliferation. In contrast, association of GRP78 with the plasminogen kringle 5 domain or extracellular Par-4 promotes apoptosis. Interaction of GRP78 with microplasminogen induces the UPR while association with tissue factor inhibits procoagulant activity. The diverse and multiple binding proteins of GRP78 and their equally diverse functional outcomes reflect the regulatory cellular functions that GRP78 orchestrates. Several GRP78 targeting peptides have been isolated from different tumors and they show remarkable tumor specificity. Conjugation of GRP78-targeting peptides to an apoptosis-inducing peptide suppresses tumor growth in tumor xenografts, thereby demonstrating that GRP78 is a viable target by which clinical cancer therapies can be successfully developed as well as its potential utility in treating vascular disease.


Murine models of cancer cytokine gene therapy using interleukin-12.
Cytokine gene therapy, in particular IL-12 gene therapy, is one of the more novel and promising approaches in cancer therapy based on significant preclinical data derived mainly from murine tumor models. IL-12 is a heterodimeric cytokine that requires the simultaneous expression of both the p35 and p40 chains from the same cell for production of biologically active IL-12. A variety of biological functions have been attributed to IL-12 including the induction of IFN-gamma production and the promotion of predominantly Th1-type immune responses to antigens. Our previous studies using systemic administration of recombinant murine IL-12 have demonstrated profound antitumor efficacy against all tumors tested with the concomitant long-lived specific antitumor immunity in some cases. To determine whether the local secretion of IL-12 achieved by gene transduction has significant antitumor effects, fibroblast cell lines or murine tumor cell lines were transduced with expression plasmids or the retroviral vector TFG-mIL-12-Neo and inoculated intradermally (i.d.). Our first study using IL-12-transfected NIH3T3 cells admixed with the murine melanoma, BL-6, showed that local IL-12 expression suppresses tumor growth and promotes the acquisition of specific antitumor immunity. Subsequent studies showed that IL-12 gene therapy is also effective in treating established day 3 tumors. CD4+ and CD8+ T cells, as well as NK cells, appear to play important roles in the observed antitumor effects resulting from IL-12 paracrine secretion. Administration of neutralizing antibody specific for IFN-gamma also abrogated some of the IL-12-associated antitumor effects. Finally, this IL-12 gene therapy strategy to elicit an antitumor immune response was more effective when used in combination with the transduction of tumor cells with B7.1. Based on these promising results, a clinical protocol for the treating patients with cancer using genetically engineered fibroblasts to express IL-12 has been initiated at our institution.


Effects of daily melatonin administration on circadian activity rhythms in the diurnal Indian palm squirrel (Funambulus pennanti).
Exogenous melatonin induces phase shifts in circadian rhythms according to a phase response curve in nocturnal rodents, several nonmammalian diurnal species, and humans. Daily administration of melatonin entrains rhythms within a narrow circadian window of sensitivity in these species. Entrainment to exogenous melatonin has not previously been demonstrated in a (nonhuman) diurnal mammal. The authors examined the effects of daily melatonin administration (via food) in the diurnal Indian palm squirrel, Funambulus pennanti. The effects of melatonin or vehicle were examined at two times of day: zeitgeber time 0 (ZT 0: light onset time) and ZT 12 (dark onset time). In addition to melatonin- and vehicle-treated squirrels, there was a third group of squirrels that received no treatment. Squirrels were held initially under 12:12 light-dark (LD) cycles, and melatonin (1 mg/kg) or vehicle was administered in food (a raisin) at either ZT 0 or ZT 12 for a total of 17 days. On the third day of treatment, constant lighting (LL) was imposed. Treatment continued at the same ZTs for a further 14 days. The number of days before free-running commenced under constant conditions was assessed for squirrels in each treatment group. Results showed that regardless of the ZT of administration, the number of days before free-running commenced was significantly greater in melatonin-treated squirrels than in vehicle-treated and untreated squirrels, and there was no difference between vehicle-treated and untreated squirrels. Although there was not a significant difference in the number of days before free-running commenced between the two times of administration, the results showed a trend for greater sensitivity to melatonin at ZT 12. This study has therefore demonstrated that the palm squirrel circadian system is entrainable to melatonin at both times of day tested, ZTs 0 and 12. This finding is in contrast to previous melatonin entrainment studies in other species, where entrainment generally occurred at only one phase, around circadian times 10 to 12. Interspecies differences in response to melatonin were discussed.


Infection following hip replacement: solution options.
The key to the optimal management of an acutely infected arthroplasty is an expeditious diagnosis with careful assessment of the mode of presentation and treatment variables to determine the appropriate management strategy. At our institution acute infection is managed early and aggressively with debridement and exchange of mobile parts and change of the implant if it is cementless. For established chronic infection, each case is considered individually, using single-stage exchange in selected circumstances (1 in 6 cases). Two-stage exchange with an articulating spacer is used in the remainder. Single-stage revision offers clinical and economic advantages over a two-stage revision in selected patients, and although ongoing evaluation is still in place, currently we have had no reinfections in our single-stage revision cohort.


Calcium dobesilate inhibits the alterations in tight junction proteins and leukocyte adhesion to retinal endothelial cells induced by diabetes.
Calcium dobesilate (CaD) has been used in the treatment of diabetic retinopathy in the last decades, but its mechanisms of action are not elucidated. CaD is able to correct the excessive vascular permeability in the retina of diabetic patients and in experimental diabetes. We investigated the molecular and cellular mechanisms underlying the protective effects of CaD against the increase in blood-retinal barrier (BRB) permeability induced by diabetes. Wistar rats were divided into three groups: controls, streptozotocin-induced diabetic rats, and diabetic rats treated with CaD. The BRB breakdown was evaluated using Evans blue. The content or distribution of tight junction proteins (occludin, claudin-5, and zonula occluden-1 [ZO-1]), intercellular adhesion molecule-1 (ICAM-1), and p38 mitogen-activated protein kinase (p38 MAPK) was evaluated by Western blotting and immunohistochemistry. Leukocyte adhesion was evaluated in retinal vessels and in vitro. Oxidative stress was evaluated by the detection of oxidized carbonyls and tyrosine nitration. NF-κB activation was measured by enzyme-linked immunosorbent assay. Diabetes increased the BRB permeability and retinal thickness. Diabetes also decreased occludin and claudin-5 levels and altered the distribution of ZO-1 and occludin in retinal vessels. These changes were inhibited by CaD treatment. CaD also inhibited the increase in leukocyte adhesion to retinal vessels or endothelial cells and in ICAM-1 levels, induced by diabetes or elevated glucose. Moreover, CaD decreased oxidative stress and p38 MAPK and NF-κB activation caused by diabetes. CaD prevents the BRB breakdown induced by diabetes, by restoring tight junction protein levels and organization and decreasing leukocyte adhesion to retinal vessels. The protective effects of CaD are likely to involve the inhibition of p38 MAPK and NF-κB activation, possibly through the inhibition of oxidative/nitrosative stress.


Efficacy of an Adenoviral Vectored Multivalent Centralized Influenza Vaccine.
Mice were immunized with Adenovirus expressing the H1-con, H2-con, H3-con and H5-con HA consensus genes in combination (multivalent) and compared to mice immunized with the traditional 2010-2011 FluZone and FluMist seasonal vaccines. Immunized mice were challenged with 10-100 MLD50 of H1N1, H3N1, H3N2 and H5N1 influenza viruses. The traditional vaccines induced robust levels of HA inhibition (HI) titers, but failed to protect against five different heterologous lethal influenza challenges. Conversely, the multivalent consensus vaccine (1 × 1010 virus particles (vp)/mouse) induced protective HI titers of ≥40 against 8 of 10 influenza viruses that represent a wide degree of divergence within the HA subtypes and protected 100% of mice from 8 of 9 lethal heterologous influenza virus challenges. The vaccine protection was dose dependent, in general, and a dose as low as 5 × 107 vp/mouse still provided 100% survival against 7 of 9 lethal heterologous influenza challenges. These data indicate that very low doses of Adenovirus-vectored consensus vaccines induce superior levels of immunity against a wide divergence of influenza subtypes as compared to traditional vaccines. These doses are scalable and translatable to humans and may provide the foundation for complete and long-lasting anti-influenza immunity.


Entrainment of the Circadian Rhythm in Egg Hatching of the Crab Dyspanopeus sayi by Chemical Cues from Ovigerous Females.
The subtidal crab Dyspanopeus sayi has a circadian rhythm in larval release with a free-running period of 24.1 h. Under constant conditions, eggs hatch primarily in the 4-h interval after the time of sunset. The study tested the new model for entrainment in subtidal crabs, which proposes that the female perceives the environmental cycles and entrains the endogenous rhythm in the embryos. Results verified the model for D. sayi. Hatching by embryos collected from the field when they had not yet developed eye pigments, and were kept in constant conditions attached to their mother, exhibited the circadian hatching rhythm. Attached embryos could also be entrained to a new photoperiod in the laboratory before they developed eye pigments. Further, mature embryos removed from the female hatched rhythmically, indicating that a circadian rhythm resides in the embryos. However, if mature embryos with eye pigments were removed from the female and exposed to a new light-dark cycle, they could not be entrained to the new cycle; rather, they hatched according to the timing of the original light-dark cycle. Nevertheless, detached, mature embryos would entrain to a new light-dark cycle if they were in chemical, but not physical, contact with the female. Thus, the female perceives the light-dark cycle, and uses chemical cues to entrain the circadian rhythm of hatching by the embryos.


A dinucleating ligand related to the beta-diketiminates.
A new ligand conceptually creates two sites reminiscent of beta-diketiminates, and upon deprotonation the salts exist in oligomeric forms with potassium ions linking multiple ligands.


Dynamical, bidirectional model for coherent beam combining in passive fiber laser arrays.
We generalize the recently proposed model for coherent beam combining in passive fiber laser arrays [Opt. Express 17, 19509 (2009)] to include the transient gain dynamics and the complication of counterpropagating waves, two important features characterizing actual experimental conditions. The extended model reveals that beam combining is not affected by the population relaxation process or the presence of backward propagating waves, which only serve to co-saturate the gain. The presence of nonresonant nonlinearity is found to reduce the coherent combining efficiency at high power levels. We show that the array lases at the frequencies with minimum overall losses when multiple loss mechanisms are present.


Psychiatric Munchausen's syndrome. Literature review with case reports.
The present study reviews the literature on Munchausen's syndrome. In a psychiatric hospital, out of a total of 775 admissions under the age of 65 in 1986, four patients were diagnosed as having Munchausen's syndrome (0.5%). The underlying pathology of these cases is discussed and suggestions for management and further research made.


Potential and limitations of the automatic detection of fiducial markers using an amorphous silicon flat-panel imager.
Amorphous silicon electronic portal imaging devices (a-Si EPIDs) allow fast acquisition of high resolution portal images (PI). A visualization of organ movement for adaptive image-guided radiotherapy (IGRT) can be reached by implantation and automatic detection of fiducial markers. A method of automatic detection has been developed for fiducial spherical tungsten markers on PIs, acquired with an a-Si flat-panel imager. The detection method consists of a 2D Mexican hat filter (MHF), whose parameters are tuned to the particular marker signal. The high selectivity of this filter allows a reliable and precise detection of tungsten markers down to a diameter of 1.5 mm. The presented method allows fast, automatic and unsupervised detection of markers. Inevitably, the detection is hampered by image background (bone structures, etc) and noise. A detection success rate higher than 95% was reached, analysing PIs of patients with markers fixed on their skin. Furthermore, this approach to automatic marker detection can also be generalized to elliptic MHFs for the detection of cylindrical markers. The accuracy and detection probability of this method may allow accurate and fast online localization of the considered organ.


Controversies in skin surgery: electrodessication and curettage versus excision for low-risk, small, well-differentiated squamous cell carcinomas.
Electrodesiccation and curettage (ED&C) of low-risk, cutaneous squamous cell carcinoma (SCC) generally consumes less time and resources than excision. Review of the literature reveals few recent studies examining cure rates for ED&C in the treatment of low risk cutaneous SCC. To evaluate via two retrospective studies the efficacy of ED&C in the treatment of low risk cutaneous SCC. A small controlled study in a Veterans Administration teaching hospital dermatology clinic compared cure rates of low risk SCC at one year by ED&C to those of surgical excision. A second study examined the cure rate of low risk lesions treated by curettage and electrodesiccation in a private practice. The first study found no significant difference in cure rates between ED&C (14 of 14 cases successfully treated) and excision (15 of 16 successfully treated and one recurrence) (P = 0.1711). The second study found the ED&C cure rate (106 of 106 successfully treated) to be significantly greater than an arbitrary cure rate of 95 percent (P = 0.0091). These findings support the efficacy of ED&C as a treatment modality for low-risk cutaneous SCC.


Fluid-Structure Interaction Models of Bicuspid Aortic Valves: The Effects of Nonfused Cusp Angles.
Bicuspid aortic valve (BAV) is the most common type of congenital heart disease, occurring in 0.5-2% of the population, where the valve has only two rather than the three normal cusps. Valvular pathologies, such as aortic regurgitation and aortic stenosis, are associated with BAVs, thereby increasing the need for a better understanding of BAV kinematics and geometrical characteristics. The aim of this study is to investigate the influence of the nonfused cusp (NFC) angle in BAV type-1 configuration on the valve's structural and hemodynamic performance. Toward that goal, a parametric fluid-structure interaction (FSI) modeling approach of BAVs is presented. Four FSI models were generated with varying NFC angles between 120 deg and 180 deg. The FSI simulations were based on fully coupled structural and fluid dynamic solvers and corresponded to physiologic values, including the anisotropic hyper-elastic behavior of the tissue. The simulated angles led to different mechanical behavior, such as eccentric jet flow direction with a wider opening shape that was found for the smaller NFC angles, while a narrower opening orifice followed by increased jet flow velocity was observed for the larger NFC angles. Smaller NFC angles led to higher concentrated flow shear stress (FSS) on the NFC during peak systole, while higher maximal principal stresses were found in the raphe region during diastole. The proposed biomechanical models could explain the early failure of BAVs with decreased NFC angles, and suggests that a larger NFC angle is preferable in suture annuloplasty BAV repair surgery.


A Method for the Automatic Exposure Control in Pediatric Abdominal CT: Application to the Standard Deviation Value and Tube Current Methods by Using Patient's Age and Body Size.
We aimed to apply the pediatric abdominal CT protocol of Donnelly et al. in the United States to the pediatric abdominal CT-AEC. Examining CT images of 100 children, we found that the sectional area of the hepatic portal region (y) was strongly correlated with the body weight (x) as follows: y=7.14x + 84.39 (correlation coefficient=0.9574). We scanned an elliptical cone phantom that simulates the human body using a pediatric abdominal CT scanning method of Donnelly et al. in, and measured SD values. We further scanned the same phantom under the settings for adult CT-AEC scan and obtained the relationship between the sectional areas (y) and the SD values. Using these results, we obtained the following preset noise factors for CT-AEC at each body weight range: 6.90 at 4.5-8.9 kg, 8.40 at 9.0-17.9 kg, 8.68 at 18.0-26.9 kg, 9.89 at 27.0-35.9 kg, 12.22 at 36.0-45.0 kg, 13.52 at 45.1-70.0 kg, 15.29 at more than 70 kg. From the relation between age, weight and the distance of liver and tuber ischiadicum of 500 children, we obtained the CTDIvol values and DLP values under the scanning protocol of Donnelly et al. Almost all of DRL from these values turned out to be smaller than the DRL data of IAEA and various countries. Thus, by setting the maximum current values of CT-AEC to be the Donnelly et al.'s age-wise current values, and using our weight-wise noise factors, we think we can perform pediatric abdominal CT-AEC scans that are consistent with the same radiation safety and the image quality as those proposed by Donnelly et al.


The ESRP1-GPR137 axis contributes to intestinal pathogenesis.
Aberrant alternative pre-mRNA splicing (AS) events have been associated with several disorders. However, it is unclear whether deregulated AS directly contributes to disease. Here, we reveal a critical role of the AS regulator epithelial splicing regulator protein 1 (ESRP1) for intestinal homeostasis and pathogenesis. In mice, reduced ESRP1 function leads to impaired intestinal barrier integrity, increased susceptibility to colitis and altered colorectal cancer (CRC) development. Mechanistically, these defects are produced in part by modified expression of ESRP1-specific Gpr137 isoforms differently activating the Wnt pathway. In humans, ESRP1 is downregulated in inflamed biopsies from inflammatory bowel disease patients. ESRP1 loss is an adverse prognostic factor in CRC. Furthermore, generation of ESRP1-dependent GPR137 isoforms is altered in CRC and expression of a specific GPR137 isoform predicts CRC patient survival. These findings indicate a central role of ESRP1-regulated AS for intestinal barrier integrity. Alterations in ESRP1 function or expression contribute to intestinal pathology.


[The results of the practical use of the destructive peritonitis' standartized treatment].
The results of inspection and treatment 117 patients with an acute destructive pancreatitis from 1998 to 2010 are presented. Distinguishing features of management approach of the patients, which was hospitalized in clinic from 2005 to 2010, were high frequency of octreotide use, de-escalated orientation of antibacterial therapy, without early laparotomy interventions and expansion of indications to program sanitation by development of widespread forms of infected pancreatic necrosis. Achievements of intensive therapy of last years and change of surgical tactics have allowed to reduce postoperative mortality by sterile necrosis from 21.1 to 11.8%, to reduce frequency of infected pancreatic necrosis from 68.3 to 40.4%. Development of the infected pancreatic necrosis accompanied by statistically significant growth of frequency of local purulent complications and the tendency to increase--extended.


Optimized extraction and characterization of antimicrobial phenolic compounds from mangosteen (Garcinia mangostana L.) cultivation and processing waste.
Applications for antimicrobials derived from the mangosteen (Garcinia mangostana L.) plant are presently restricted by high production costs. Extraction from cultivation or processing waste streams using a solvent-free approach could lessen to permit commercial applications in food processing and preservation. Phenolics were extracted from mangosteen bark, leaf and fruit pericarp in methanol and in water using response surface methodology to optimize recovery. Initial examination of antimicrobial effects revealed a lack of antimicrobial activity against fungi and weak activity against the Gram-negative bacteria Escherichia coli and Salmonella typhimurium. In contrast, extracts prepared from bark or fruit pericarp exhibited strong pH-dependent bacteriostatic and bactericidal effects against Listeria monocytogenes and Staphylococcus aureus. Activity was slightly weaker in aqueous extracts due to lower concentrations of tartaric acid esters and flavonols than in methanolic extracts. Measurement of propidium iodide uptake and ATP leakage indicated that the extracts induced damage to the membrane of Gram-positive bacteria. Extracts of mangosteen bark and fruit pericarp contain mixtures of phenolic compounds with activity against Gram-positive bacteria, notably Listeria monocytogenes. Extraction of phenolics from mangosteen waste could yield fractions for potential applications in the formulation of low-cost processing aids or sanitizers for the food industry.


Concordance among three self-reported measures of medication adherence and pharmacy refill records.
To evaluate the level of agreement among three previously validated self-reported medication adherence measures and pharmacy refill records (RRs). Cross-sectional study. Five primary care physician office sites in rural northeast Georgia. 139 adult patients with one or more of these chronic diseases: hypertension, diabetes mellitus, hypercholesterolemia, hypothyroidism, or a condition requiring hormone replacement therapy. Study participants completed the Brief Medication Questionnaire (BMQ), the Medication Adherence Survey (MAS), and the Medical Outcomes Study (MOS) instruments; pharmacy RRs for the medication or medications being used to treat the target disease were obtained from pharmacies used by the study participants. Adherence to medication therapy for target disease. Participants were nearly all white (98.6%), consistent with the Appalachian area in which the study was conducted, and mostly women (71.9%). While 91.4% of study participants reported taking their study medication most or all of the time, RRs showed mean adherence rates of 82.6%, 82.1%, 79.1%, 74.6%, and 69.8% for diabetes mellitus, hypertension, hypothyroidism, hypercholesterolemia, and hormone replacement therapy, respectively. Moderate correlations of .234, .261, and .213 were found between RRs and the MAS, MOS, and BMQ belief screen, respectively. Spearman correlations ranged from .091 between RRs and the BMQ regimen subscale to .313 between MOS and MAS. Pearson chi-square tests showed that only the BMQ belief subscale was significant in this study. Because of the weak to moderate concordance found among validated measures of adherence, the selection of a useful adherence measure in pharmacy practice is difficult. These findings underscore the difficulty in both assessing patients' medication-taking behavior and assessing and comparing the results of adherence research. The development of valid and reliable measures for easily assessing medication adherence behavior in community pharmacies is needed.


Pilot study comparing telephone to in-person delivery of cognitive-behavioural therapy for trauma-related insomnia for rural veterans.
Introduction It is estimated that 70% of patients with posttraumatic stress disorder (PTSD) have chronic insomnia. A recent meta-analysis examined cognitive-behavioural therapy for insomnia (CBT-I) in veterans with and without PTSD, and suggested that most studies had questionable methodology, but generally supported its effectiveness in this population. Further, while CBT-I via telehealth (i.e. using telecommunication and information technology to deliver health services) has shown effectiveness for primary insomnia, it has not been applied to PTSD-related insomnia. Methods Veterans with insomnia who were diagnosed with PTSD ( n = 12) or having significant subthreshold PTSD symptoms ( n = 6) on the Clinician Administered PTSD Scale were randomly assigned to receive CBT-I in-person ( n = 7) or by telephone ( n = 11), to pilot test the potential effectiveness, acceptability, and feasibility of administering CBT-I in rural veterans. A six-week CBT-I protocol was delivered, and the veteran's insomnia was assessed at post-treatment and follow-up. Results Given the small sample size, Cohen's d was used to detect group differences, finding large effect sizes favouring the in-person delivery, until three-months post-treatment when this difference diminished. Most veterans found the treatment acceptable, regardless of mode of delivery. Based on the results, a larger project is feasible. Feasibility for a larger project is favourable. Discussion In summary, our findings uphold and extend previous research. Specifically, current pilot data suggest that telephone-delivered CBT-I may be able to reduce trauma-related insomnia symptoms. Future trials are needed to assess the effectiveness of CBT-I delivered to rural veterans with posttraumatic insomnia.


Maturation of dendritic cell 2 phenotype by a helminth glycan uses a Toll-like receptor 4-dependent mechanism.
The biology of pathogen-associated molecular patterns (PAMPs) stimulating APCs to differentiate into a Th1-promoting phenotype has been well characterized. Conversely, not a single pathogen product that promotes a Th2 phenotype has been rigorously identified. Strong Th2 responses and dendritic cell 2 maturation are driven by helminth extracts, and carbohydrates have been shown to be responsible for much of this activity. In this study, we show that a helminth carbohydrate, lacto-N-fucopentaose III (LNFPIII) functions as an innate Th2 promoter via its action on murine dendritic cells, with the alpha1-3-linked fucose required for this activity. In contrast to Th1-type PAMPs, which activate extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinases, the Th2 PAMP LNFPIII preferentially activates extracellular signal-regulated kinase. Furthermore, the ability of LNFPIII to drive DC2 maturation is dependent on signaling via Toll-like receptor 4. These data support a new understanding of how APCs integrate signaling pathways to produce a Th1- or Th2-promoting phenotype.


Activated monocytes and platelet-monocyte aggregates in patients with sickle cell disease.
Tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) increase endothelial surface receptors that mediate the adherence of sickle erythrocytes to the endothelium. Increased circulating levels of these cytokines have been found in patients with sickle cell disease (SCD). Monocytes are a source of both of these inflammatory mediators; we therefore determined whether circulating monocytes were activated in SCD, as defined by intracellular expression of these cytokines. Blood was also assayed for the presence of platelet-monocyte aggregates (PMAs), as platelet adherence is one possible mechanism for monocyte activation. The median percentages of monocytes expressing intracellular TNF-alpha and IL-1beta in SCD patients were 6.8 (2.8-17.3) [median (range)] and 14.1 (1.3-44.8), respectively. In African-American controls the corresponding percentages were 0.3 (0.1-0.5) and 0.4 (0.1-3.0), and in Caucasians 0.2 (0.1-0.5) and 0.8 (0.8-1.9) (P < 0.001, Kruskal-Wallis). The mean percentage (+/- SD) of PMA was 14.0 +/- 8.3 for Caucasian controls, 25.7 +/- 7.3 for African-American controls, and 45.7 +/- 21.6 for patients with SCD (P < 0.001, RM ANOVA; P < 0.05, Newman-Keuls posthoc test). We conclude that there are increased circulating PMAs and monocyte activation in patients with SCD.


Egas Moniz: 90 Years (1927-2017) from Cerebral Angiography.
In June 2017 we celebrate the 90th anniversary of the pioneer discovery of cerebral angiography, the seminal imaging technique used for visualizing cerebral blood vessels and vascular alterations as well as other intracranial disorders. Egas Moniz (1874-1955) was the first to describe the use of this revolutionary technique which, until 1975 (when computed tomography, CT, scan was introduced in the clinical practice), was the sole diagnostic tool to provide an imaging of cerebral vessels and therefore alterations due to intracranial pathology. Moniz introduced in the clinical practice this fundamental and important diagnostic tool. The present contribution wishes to pay a tribute to the Portuguese neurosurgeon, who was also a distinguished neurologist and statesman. Despite his tremendous contribution in modern brain imaging, Egas Moniz was awarded the Nobel Prize in Physiology or Medicine in 1949 for prefrontal leucotomy, the neurosurgical intervention nowadays unacceptable, but should rather be remembered for his key contribution to modern brain imaging.


Alterations in the polynucleosomal structure of chromatin by poly ADP-ribosylation of nuclear proteins.
The chromatin-associated enzyme, poly (ADP-Rib) polymerase causes an NAD-dependent aggregation of modified oligonucleosomes as demonstrated by electrophoretic and sedimentation analysis. It has been speculated that poly ADP-ribosylation of histone H1 and its subsequent crosslinking may be crucial in this aggregation. The present work describes some approaches we have taken to investigate this hypothesis. We have characterized the synthesis of poly (ADP-Rib)-H1 dimer in isolated nucleosomes, and using a new immunological method have demonstrated the occurrence of this H1 adduct in living cells. The faithful reassociation of histone H1 with chromatin previously depleted of this histone, has been a major aim of our investigations in order to study the above phenomenon. Our approach has been to monitor this reconstitution by the accuracy of poly ADP-ribosylation of this histone. This criterion was assumed to be a highly sensitive indicator of H1-H1 alignment along oligonucleosome fibers, since a crosslinked dimer of H1 is one product of this reaction. Of special interest was the observation that the removal of H1 from nucleosomes abolished the NAD-promoted aggregation of poly ADP-ribosylated chromatin. This activity could be totally restored with the reconstitution of histone H1. The results suggest a major role for histone H1 and poly ADP-ribosylation in chromatin organization.


Pathogenic effects of human herpesvirus 6 in human lymphoid tissue ex vivo.
Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive agent that has been suggested to act as a cofactor in the progression of human immunodeficiency virus disease. However, the lack of suitable experimental models has hampered the elucidation of the mechanisms of HHV-6-mediated immune suppression. Here, we used ex vivo lymphoid tissue to investigate the cellular tropism and pathogenic mechanisms of HHV-6. Viral strains belonging to both HHV-6 subgroups (A and B) were able to productively infect human tonsil tissue fragments in the absence of exogenous stimulation. The majority of viral antigen-expressing cells were CD4(+) T lymphocytes expressing a nonnaive phenotype, while CD8(+) T cells were efficiently infected only with HHV-6A. Accordingly, HHV-6A infection resulted in the depletion of both CD4(+) and CD8(+) T cells, whereas in HHV-6B-infected tissue CD4(+) T cells were predominantly depleted. The expression of different cellular antigens was dramatically altered in HHV-6-infected tissues: whereas CD4 was upregulated, both CD46, which serves as a cellular receptor for HHV-6, and CD3 were downmodulated. However, CD3 downmodulation was restricted to infected cells, while the loss of CD46 expression was generalized. Moreover, HHV-6 infection markedly enhanced the production of the CC chemokine RANTES, whereas other cytokines and chemokines were only marginally affected. These results provide the first evidence, in a physiologically relevant study model, that HHV-6 can severely affect the physiology of secondary lymphoid organs through direct infection of T lymphocytes and modulation of key membrane receptors and chemokines.


Blockage of lysophosphatidic acid signaling improves spinal cord injury outcomes.
Evidence suggests a proinflammatory role of lysophosphatidic acid (LPA) in various pathologic abnormalities, including in the central nervous system. Herein, we describe LPA as an important mediator of inflammation after spinal cord injury (SCI) in zebrafish and mice. Furthermore, we describe a novel monoclonal blocking antibody raised against LPA that potently inhibits LPA's effect in vitro and in vivo. This antibody, B3, specifically binds LPA, prevents it from interacting with its complement of receptors, and blocks LPA's effects on the neuronal differentiation of human neural stem/progenitor cells, demonstrating its specificity toward LPA signaling. When administered systemically to mice subjected to SCI, B3 substantially reduced glial inflammation and neuronal death. B3-treated animals demonstrated significantly more neuronal survival upstream of the lesion site, with some functional improvement. This study describes the use of anti-LPA monoclonal antibody as a novel therapeutic approach for the treatment of SCI.


DISCO: Species Tree Inference using Multicopy Gene Family Tree Decomposition.
Species tree inference from gene family trees is a significant problem in computational biology. However, gene tree heterogeneity, which can be caused by several factors including gene duplication and loss, makes the estimation of species trees very challenging. While there have been several species tree estimation methods introduced in recent years to specifically address gene tree heterogeneity due to gene duplication and loss (such as DupTree, FastMulRFS, ASTRAL-Pro, and SpeciesRax), many incur high cost in terms of both running time and memory. We introduce a new approach, DISCO, that decomposes the multi-copy gene family trees into many single copy trees, which allows for methods previously designed for species tree inference in a single copy gene tree context to be used. We prove that using DISCO with ASTRAL (i.e., ASTRAL-DISCO) is statistically consistent under the GDL model, provided that ASTRAL-Pro correctly roots and tags each gene family tree. We evaluate DISCO paired with different methods for estimating species trees from single copy genes (e.g., ASTRAL, ASTRID, and IQ-TREE) under a wide range of model conditions, and establish that high accuracy can be obtained even when ASTRAL-Pro is not able to correctly roots and tags the gene family trees. We also compare results using MI, an alternative decomposition strategy from Yang Y. and Smith S.A. (2014), and find that DISCO provides better accuracy, most likely as a result of covering more of the gene family tree leafset in the output decomposition. [Concatenation analysis; gene duplication and loss; species tree inference; summary method.].


Off-Label Trazodone Prescription: Evidence, Benefits and Risks.
Although trazodone is approved and marketed in most countries worldwide for the sole treatment of Major Depressive Disorder, the use for this medication is very common for many other conditions, such as primary or secondary insomnia, Generalised Anxiety Disorder, Panic Disorder, Post-Traumatic Stress Disorder and Obsessive- Compulsive Disorder. Other, not officially approved, uses of trazodone include: the treatment of bulimia, benzodiazepine and/or alcohol dependence or abuse, fibromyalgia, degenerative diseases of the central nervous system such as dementia and other organic disorders, schizophrenia, chronic pain, and diabetic neuropathy. In addition, due to its 5HT2A receptor antagonistic action, trazodone may be used to prevent the occurrence of initial and long-term side effects of SSRI, such as anxiety, insomnia and sexual dysfunction. Despite the favorable clinical experience and the encouraging results from the studies that have tested the efficacy of trazodone for some of its off-label indications, it is paramount that large, randomized and controlled clinical trials be conducted in the near future to evaluate which of the many off-label indications are supported by a strong scientific evidence.


Telemedicine in vascular surgery: does it work?
Telemedicine (TM) using closed-circuit television systems allows specialists to evaluate patients at remote sites. Because an integral part of the vascular examination involves palpation of peripheral pulses the applicability of TM for the evaluation of vascular surgery patients is open to question. This study was carried out to test the hypothesis that TM is as effective as direct patient examination for the development of a care plan in vascular patients. Sixty-four vascular evaluations were done in 32 patients. The patients presented with a variety of vascular problems and were seen in regularly scheduled rural outreach vascular clinics. Two faculty vascular surgeons evaluated each patient; one was on site and the second, using TM, remained at the medical center. Each surgeon was blinded to the other's findings. The TM physician was aided by a nonphysician assistant, who obtained blood pressures, utilized a continuous-wave Doppler probe, positioned the patient, and operated the TM equipment. The results of each surgeon's evaluations were compared. Patient and physician satisfaction with the TM evaluation was appraised by questionnaires. Eight patients were seen for initial evaluations; 24 patients were seen for follow-up visits. Patients were seen with a variety of diagnoses, including aneurysm (seven), cerebrovascular disease (five), lower extremity occlusive disease (13), multiple vascular problems (three), and other disease (four). The average duration for the TM and on-site evaluations were 20.6+/-1.4 and 19.0+/-1.3 minutes, respectively (P = not significant). Physician concordance, as determined by treatment recommendations, was the same in 29 (91%) patients. Physician confidence in the ability to obtain an accurate history via TM was rated as excellent in 97 per cent; confidence in the TM physical examination was rated as excellent in 70 per cent. All patients rated the TM evaluation as the "same as" or "better than" the on-site examination, and all indicated a preference for being seen locally using TM as opposed to traveling to a regional medical center. We conclude that the TM evaluation of vascular patients is accurate and is as effective as on-site evaluations for a variety of vascular problems. Important adjuncts to enhance the success of a TM evaluation are physician experience with the technology and the presence of a knowledgeable on-site assistant. This technology can be easily adapted to other clinical situations.


Investigation of Simulated Adherence in Long-Term Buprenorphine/Naloxone Treatment Patients.
Buprenorphine is a medication that is used to treat opioid use disorder by reducing withdrawal symptoms and cravings for opioids. Patients with poor adherence are at higher risk of relapse and overdose. Providers often test adherence through urine testing but are not aware of simulated adherence, where patients may directly add buprenorphine to the urine samples. As of now, there exists no literature on the simulated adherence practices for patients who stayed in the treatment for more than three months. This study is a cross-sectional analysis of simulated adherence through urine toxicology results of 3950 patients undergoing buprenorphine/naloxone treatment. Simulated adherence was measured by the ratio of norbuprenorphine and buprenorphine <0.02 in the urine sample. Descriptive statistics as well as multivariate analysis was conducted to examine the relationship between patient information and outcomes. Out of 3950 patients, 411 (10.4%) had a history of one or more simulated adherence. On average, patients with multiple simulated adherences had 48.1% of their tests simulated, while on the contrary, patients with a single occurrence of simulated adherence had 17.6% of their tests simulated. Weekly testing and visit number of over 15 were associated with a higher likelihood of simulated adherence. The study demonstrates that simulated adherence is a recurring phenomenon among buprenorphine/naloxone treatment patients regardless of the duration in the treatment. Utilization of quantitative urine toxicology to identify simulated adherence will enable healthcare providers to formulate a more precise and effective treatment plan tailored to support individual patient needs.


Inhibition of cytoskeletal rearrangement by botulinum C2 toxin amplifies ligand-evoked lipid mediator generation in human neutrophils.
Botulinum C2 toxin, a binary toxin that ADP-ribosylates nonmuscle G-actin, was used as a selective tool to evaluate the role of actin-dependent cytoskeletal rearrangement in ligand-evoked lipid mediator generation. Human neutrophils (PMN) were preincubated with varying concentrations of the toxin for 30 min. Lipoxygenase products of arachidonic acid were measured by chromatographic techniques in the presence of exogenous arachidonic acid to probe PMN 5-lipoxygenase activity. Formation of platelet-activating factor (PAF) was assayed by the bioincorporation of [3H]acetate. Stimulation was performed with the soluble chemotactic ligands formyl-methionyl-leucyl-phenylalanine (FMLP) and PAF, as well as opsonized zymosan. PMN pretreatment with C2 toxin in the range between 200/400 and 800/1600 ng/ml C2I/II caused a dose-dependent suppression of the basal F-actin content and of stimulus-induced actin assembly. Phosphoinositide hydrolysis (measured as liberated inositol phosphates) and PAF generation in response to FMLP and exogenous PAF were markedly increased at these toxin doses. Minor C2 toxin concentrations (range, approximately 25/50 to 200/400 ng/ml C2I/II) were sufficient to amplify stimulus-induced formation of leukotriene B4 and its omega-oxidation products, nonenzymatic hydrolysis products of leukotriene A4, and 5-hydroxyeicosatetraenoic acid (5-HETE). With increasing toxin doses, leukotriene generation declined and 5-HETE became the predominant metabolite. In contrast to the soluble ligands, the zymosan-effected generation of PAF and leukotrienes was dose-dependently inhibited by C2 toxin concentrations of greater than 200/400 ng/ml, paralleled by a loss of motile and phagocytotic functions in these cells. We conclude that selective inhibition of actin assembly amplifies PAF and 5-lipoxygenase product formation in response to soluble chemoattractants with distinct dose dependences. The augmentation of PAF generation may be linked to amplified second messenger levels at higher doses of C2 toxin, whereas the sensitivity of the 5-lipoxygenase metabolism to low concentrations may indicate toxin effect on a small, functionally specified, actin pool. The present data support an important role of cytoskeletal rearrangement in temporal and/or spatial limitation of chemoattractant-evoked PMN activation.


Comparison of anterior and posterior trabecular bone microstructure of human mandible using cone-beam CT and micro CT.
The aim of this study was to compare the trabecular bone microstructures of anterior and posterior edentulous regions of human mandible using cone-beam computed tomography (CBCT) and micro computed tomography (µCT). Twenty volumes of interests consisting of six anterior and fourteen posterior edentulous regions were obtained from human mandibular cadavers. A CBCT system with a resolution of 80 µm (3D Accuitomo 170, J. Morita, Kyoto, Japan) and a µCT system with a resolution of 35 µm (SkyScan 1173, Kontich, Belgium) were used to scan the mandibles. Three structural parameters namely, trabecular number (Tb.N), trabecular thickness (Tb.Th), and trabecular separation (Tb.Sp) were analysed using CTAn software (v 1.11, SkyScan, Kontich, Belgium). For each system, the measurements obtained from anterior and posterior regions were tested using independent sample t-test. Subsequently, all measurements between systems were tested using paired t-test. In CBCT, all parameters of the anterior and posterior mandible showed no significant differences (p > 0.05). However, µCT showed a significant different of Tb.Th (p = 0.023) between anterior and posterior region. Regardless of regions, the measurements obtained using both imaging systems were significantly different (p ≤ 0.021) for Tb.Th and Tb.N. The current study demonstrated that only the variation of Tb.Th between anterior and posterior edentulous region of mandible can be detected using µCT. In addition, CBCT is less feasible than µCT in assessing trabecular bone microstructures at both regions.


[Do guidelines lead to better clinical practice?].
It appears from a review of the literature that at present a considerable number of psychiatric patients are being deprived of evidence-based treatment. However, Australian theoretical research has shown that if patients were to be treated entirely in accordance with evidence-based guidelines they would derive considerably more benefit from their treatment. This conclusion has been corroborated by various randomised controlled trials (RCT's) in which the effect of evidence-based treatment according to guidelines is compared with the effect of 'treatment as usual'. Studies carried out under less controlled circumstances than those prevailing in RCT's yield slightly less positive results. The literature stresses the difficulties of improving the quality of patient care. Studies on the implementations of guidelines show that carefully constructed, tailor-made interventions are needed to ensure that professionals adhere to guidelines. More research is required into effective ways of implementing guidelines in an adequate manner.


The disabled throwing shoulder: spectrum of pathology Part I: pathoanatomy and biomechanics.
PROLOGUE: Several years ago, when we began to question microinstability as the universal cause of the disabled throwing shoulder, we knew that we were questioning a sacrosanct tenet of American sports medicine. However, we were comfortable in our skepticism because we were relying on arthroscopic insights, clinical observations, and biomechanical data, thereby challenging unverified opinion with science. In so doing, we assembled a unified concept of the disabled throwing shoulder that encompassed biomechanics, pathoanatomy, kinetic chain considerations, surgical treatment, and rehabilitation. In developing this unified concept, we rejected much of the conventional wisdom of microinstability-based treatment in favor of more successful techniques (as judged by comparative outcomes) that were based on sound biomechanical concepts that had been scientifically verified. Although we have reported various components of this unified concept previously, we have been urged by many of our colleagues to publish this information together in a single reference for easy access by orthopaedic surgeons who treat overhead athletes. We are grateful to the editors of Arthroscopy for allowing us to present our view of the disabled throwing shoulder. Part I: Pathoanatomy and Biomechanics is presented in this issue. Part II: Evaluation and Treatment of SLAP Lesions in Throwers will be presented in the May-June issue. Part III: The "SICK" Scapula, Scapular Dyskinesis, the Kinetic Chain, and Rehabilitation will be presented in the July-August issue. We hope you find it thought-provoking and compelling.


Omnidirectional Monolithic Marker for Intraoperative MR-based Positional Sensing in Closed MRI.
We present a design of an inductively coupled radio frequency (ICRF) marker for magnetic resonance (MR)-based positional tracking, enabling the robust increase of tracking signal at all scanning orientations in quadrature-excited closed MR imaging (MRI). The marker employs three curved resonant circuits fully covering a cylindrical surface that encloses the signal source. Each resonant circuit is a planar spiral inductor with parallel plate capacitors fabricated monolithically on flexible printed circuit board (FPC) and bent to achieve the curved structure. Size of the constructed marker is Ø3 mm × 5 mm with quality factor > 22, and its tracking performance was validated with 1.5 T MRI scanner. As result, the marker remains as a high positive contrast spot under 360° rotations in 3 axes. The marker can be accurately localized with a maximum error of 0.56 mm under a displacement of 56 mm from the isocenter, along with an inherent standard deviation of 0.1 mm. Accrediting to the high image contrast, the presented marker enables automatic and real-time tracking in 3D without dependency on its orientation with respect to the MRI scanner receive coil. In combination with its small form-factor, the presented marker would facilitate robust and wireless MR-based tracking for intervention and clinical diagnosis. This method targets applications that can involve rotational changes in all axes (X-Y-Z).


Functionally Relevant Threshold of Quadriceps Muscle Strength in Patients with Chronic Obstructive Pulmonary Disease.
We aimed to identify the quadriceps muscle strength (QMS) thresholds below which exercise capacity is compromised in men with chronic obstructive pulmonary disease (COPD). We measured the quadriceps isometric maximum voluntary contraction (QMVC) and calculated the QMVC values normalized to weight (QMVC-BW), height squared (QMVC-H2), and body mass index (QMVC-BMI) in 113 patients with COPD. The functional exercise capacity was evaluated using the 6-minute walk distance (6MWD), and 6MWD <350 m was defined as functional exercise intolerance. Thresholds were determined for QMVC and its normalized values to achieve high specificity (>0.90) with maximal sensitivity. P-values <0.01 were considered statistically significant. Data from 99 male patients (age, 74 ± 6 years; percentages of predicted forced expiratory volume in 1-s, 56.9 ± 26.4%) were analyzed; 3 women and 11 participants with the missing data were excluded. Multivariate logistic regression models identified significant associations of QMVC and QMVC-H2 with 6MWD, after adjustment for age and dyspnea. C-statistics showed that the area under the curves of all QMVC parameters were comparable. The thresholds of QMVC and QMVC-H2 for predicting compromised exercise capacity were 26.2 kg and 9.6 kg/m2, respectively. QMS thresholds in men with COPD could help clinicians evaluate whether QMS is insufficient to achieve 6MWD ≥350 m and thereby identify patients who should be specifically targeted for muscle strengthening training during their pulmonary rehabilitation program.


An optimal order for ECG inverse problems with MDL.
A numerical simulation for body surface potential mapping was investigated using Boundary Element Method (B.E.M.). After forward simulation, we investigated the accuracy and stability of ECG inverse solution from the viewpoint of Minimum Description Length Principle (MDL). It became obvious that the solution containing up to 16th expansion components is optimal for ECG inverse problem.


Risk of Venous Thrombosis in Carriers of a Common Mutation in the Homocysteine Regulatory Enzyme Methylenetetrahydrofolate Reductase.
Background: Elevated levels of homocysteine are an independent risk factor for venous thrombosis. A common mutation in methylenetetrahydrofolate reductase (MTHFR), an enzyme required for efficient homocysteine metabolism, creates a thermolabile (tl-) enzyme with reduced activity that may predispose to hyperhomocysteinemia. Methods and Results: To assess whether this common mutation is a risk factor venous thromboembolism, a polymerase chain reaction-based genotyping assay was used to compare the prevalence of this mutation in a group with thrombosis versus several control groups. Of the 331 thrombosis subjects, 47% were heterozygous and 11% homozygous for tl-MTHFR. In comparison, heterozygotes constituted 42-47% and homozygous 15-16% of each of three control groups (totaling 593 subjects). There was no significant difference in the tl-MTHFR homozygote frequency or allele frequency between the thrombosis and control study groups. Although the prevalence of the factor V R506Q (Leiden) mutation causing activated protein C resistance was significantly higher in the thrombosis (19%) than in the control groups (4-9%), the concomitant presence of tl-MTHFR with factor V R506Q did not contribute to any excess thrombotic risk. Conclusions: Although the tl-MTHFR mutation may predispose to hyperhomocysteinemia, a known risk factor for venous thrombosis, this common genotype is not a direct genetic risk factor for venous thrombosis, either alone or in combination with the factor V R506Q mutation.


[Dynamics of the number of house dust mites and the accumulation of groups 1 and 2 allergens in simple periodic cultures].
Dynamics of the number and biomass of D. pteronyssinus and D. farinae and the concentration of major significant mite allergens of groups 1 and 2 were studied in simple periodic cultures. The experiments provided evidence for that there is a positive relationship between the concentration of mite allergens Der p I, Der p II, Der f I, Der f II and the number of mites D. pteronyssinus and D. farinae, as evidenced by both correlation coefficients and curves. The same relationship was seen while examining the number of mites and the exposure of mite allergens in house dust. The findings suggest that the concentration of major mite allergens of Groups 1 and 2 in addition to the number/biomass of mites are one of the most important criteria for the maturity of the culture. The cultures of D. pteronyssinus and D. farinae mature no later than on day 29 of the onset of cultivation, as shown by the maximum concentrations of Der p I, Der p II, Der f I, Der f II and mite biomass, achieved in this period.


Persistence of Multiple Paramyxoviruses in a Closed Captive Colony of Fruit Bats (Eidolon helvum).
Bats have been identified as the natural hosts of several emerging zoonotic viruses, including paramyxoviruses, such as Hendra and Nipah viruses, that can cause fatal disease in humans. Recently, African fruit bats with populations that roost in or near urban areas have been shown to harbour a great diversity of paramyxoviruses, posing potential spillover risks to public health. Understanding the circulation of these viruses in their reservoir populations is essential to predict and prevent future emerging diseases. Here, we identify a high incidence of multiple paramyxoviruses in urine samples collected from a closed captive colony of circa 115 straw-coloured fruit bats (Eidolon helvum). The sequences detected have high nucleotide identities with those derived from free ranging African fruit bats and form phylogenetic clusters with the Henipavirus genus, Pararubulavirus genus and other unclassified paramyxoviruses. As this colony had been closed for 5 years prior to this study, these results indicate that within-host paramyxoviral persistence underlies the role of bats as reservoirs of these viruses.


Renal function in hypercalcemia after renal transplantation.
A case of transient hypercalcemia in a 53-year-old female, who received a necro-kidney transplant, has been examined. The hypercalcemia was caused by vitamin D intoxication on three separate occasions. Each period of even moderate hypercalcemia produced a rapid fall in renal function. The effect was reversible. These findings are discussed in the light of earlier reports on stable renal function in post-transplant hypercalcemia.


[Analysis of disturbances in the three-layer model of associative memory: realization of path beating principle upon gradual changes in neuronal activity and transmission factors].
A model is considered in which the activity values, the weights of connections, and the transmission factors of neurons are positive, the connections are chosen by chance and are symmetric regarding the layer of associative neurons. Formulas were obtained for the mathematical expectation and the dispersion of activity values at the model outputs in the initial state and during the associative readout after recording the associations of input pairs and the association of the activity vector with the input-mark with two methods of recording. It was shown that (unlike quasiholographic models) in the beating model there arise hampering additions to the mathematical expectation, some of them being difficult to remove. Dispersive disturbances during vector recording considerably exceed the disturbances arising in quasiholographic models.


What do we know about the voluntary healthcare sector in Scotland?
To document sources of information available to the National Health Service in Scotland (NHSiS) which relate to the health voluntary sector. Interrogation of the databases of the Charities Register in Scotland (CRIS) and Health Education Board for Scotland (HEBS) for information on health voluntary organisations and a retrospective review of information held on health voluntary organisations recently funded by health boards. National Health Service in Scotland and the Scottish Council for Voluntary Organisations Nine hundred and fifty six health voluntary organisations in Scotland were registered with the CRIS database. Five hundred and forty five (57%) of these had annual incomes of less than 100,000 Pounds and two thirds of them (630) operated at a local level. Information on 3,106 health and support organisations was present on the HEBS database. In 1997-98 Scottish Health Boards grant funded 278 voluntary organisations. Eighty seven (31%) of these had information held on the CRIS database and another 87 (31%) with the HEBS database. Funding was much more likely to be given to organisations dealing with adult physical health and alcohol problems. Organisations dealing with specific diseases were less likely to be funded. Of the 87 funded organisations registered with CRIS, health boards typically contributed less than 10% of annual funding. Health planning decisions are made difficult by a deficiency of useful information on the existence, activities and financial positions of voluntary organisations. Construction of accurate and comprehensive national databases to inform these decisions would be expensive. However, the development of appropriate local databases by health boards and the voluntary sector would facilitate the development of a constructive partnership.


Edoxaban transport via P-glycoprotein is a key factor for the drug's disposition.
Edoxaban (the free base of DU-176b), an oral direct factor Xa inhibitor, is mainly excreted unchanged into urine and feces. Because active membrane transport processes such as active renal secretion, biliary excretion, and/or intestinal secretion, and the incomplete absorption of edoxaban after oral administration have been observed, the involvement of drug transporters in the disposition of edoxaban was investigated. Using a bidirectional transport assay in human colon adenocarcinoma Caco-2 cell monolayers, we observed the vectorial transport of [(14)C]edoxaban, which was completely inhibited by verapamil, a strong P-glycoprotein (P-gp) inhibitor. In an in vivo study, an increased distribution of edoxaban to the brain was observed in Mdr1a/1b knockout mice when compared with wild-type mice, indicating that edoxaban is a substrate for P-gp. However, there have been no observations of significant transport of edoxaban by renal or hepatic uptake transporters, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, or organic anion transporting polypeptide (OATP)1B1. Edoxaban exhibited no remarkable inhibition of OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, or P-gp up to 30 μM; therefore, the risk of clinical drug-drug interactions due to any edoxaban-related transporter inhibition seems to be negligible. Our results demonstrate that edoxaban is a substrate of P-gp but not of other major uptake transporters tested. Because metabolism is a minor contributor to the total clearance of edoxaban and strong P-gp inhibitors clearly impact edoxaban transport, the P-gp transport system is a key factor for edoxaban's disposition.


Pressure ulcers: e-learning to improve classification by nurses and nursing students.
To detect problems when classifying pressure ulcers and to examine whether an e-learning program is able to increase the classification skills of qualified nurses and nursing students. Both the distinction between pressure ulcer grades and the differentiation between moisture lesions is difficult. Misclassification and incorrect identification of the lesions results in inadequate preventive and therapeutic measures. Education and training are important for spreading evidence-based insights about this topic. Repeated measure design, consisting of one pretest and three posttests. The experimental intervention consisted of a one-hour session during which the participants independently went over an e-learning program. The control intervention consisted of a one-hour lecture. Both interventions had the same learning contents. A convenience sample of 212 qualified nurses and 214 final-year nursing students was randomly assigned to an experimental-and a control group. In the pretest, the classification skills were low. After the intervention, these skills improved significantly in both groups. The nursing students achieved better results when using the e-learning program. Among the qualified nurses, there was no difference between the learning methods. Although the classification skills decreased in the posttests, they did not drop under the level of the pretest. The actual classification system does not provide the necessary information about the severity of a pressure ulcer. The differential diagnosis between a moisture lesion was complicated. The classification skills of the qualified nurses and nursing students increased by both learning methods. Repetition remains, however, necessary. Both instruction methods are adequate to acquire the knowledge about the differences between moisture lesions and pressure ulcers. E-learning allows studying in one's own time and place, and could therefore be very suitable for repetition of the training. How to organise this training could be a subject for further research.


MIF-1 and its peptidomimetic analogs attenuate haloperidol-induced vacuous chewing movements and modulate apomorphine-induced rotational behavior in 6-hydroxydopamine-lesioned rats.
Two melanocyte-stimulating hormone release inhibiting factor-1 (MIF-1) also known as L-prolyl-L-leucyl-glycinamide (PLG) peptidomimetic analogs, 3(R)-[[[2(S)-pyrrolidinyl]carbonyl]-amino]-3-(butyl)-2-oxo-1-pyrrolidineacetamide trifluoroacetate (A) and 3(R)-[[[2(S)-pyrrolidinyl]carbonyl]amino]-3-(benzyl)-2-oxo-1-pyrrolidineacetamide trifluoroacetate (B), were evaluated for their ability to modulate dopaminergic activity by measuring apomorphine-induced rotations in 6-hydroxydopamine (6-OHDA)-lesioned rats, and haloperidol (HP)-induced vacuous chewing movements (VCMs) in rats; animal models of Parkinson's disease (PD) and human tardive dyskinesia (TD), respectively. In the 6-OHDA model, both analogs were found to potentiate the contralateral rotational behavior induced by apomorphine dose-dependently and with approximately the same potency. Furthermore, each analog was able to significantly attenuate HP-induced VCMs with almost equal efficacy. The potency and efficacy of these analogs were significantly greater than their parent compound, PLG. These results suggest that both analogs can modulate dopaminergic activity in vivo, likely by the same mechanisms recruited by PLG previously reported.


Use of Indocyanine Green for Sentinel Lymph Node Biopsy: Case Series and Methods Comparison.
Sentinel lymph node biopsy is indicated for patients with biopsy-proven thickness melanoma greater than 1.0 mm. Use of lymphoscintigraphy along with vital blue dyes is the gold standard for identifying sentinel lymph nodes intraoperatively. Indocyanine green (ICG) has recently been used as a method of identifying sentinel lymph nodes. We herein describe a case series of patients who have successfully undergone ICG-assisted sentinel lymph node biopsy for melanoma. We compare 2 imaging systems that are used for ICG-assisted sentinel lymph node biopsy. Fourteen patients underwent ICG-assisted sentinel lymph node biopsy for melanoma using the SPY Elite system (Novadaq, Mississigua, Canada) and the Hamamatsu PDE-Neo probe system (Mitaka USA, Park City, Utah). We analyzed costs for 2 systems that utilize ICG for sentinel lymph node biopsies. Intraoperative use of ICG for sentinel lymph node biopsies was successful in correctly identifying sentinel lymph nodes. There was no difference between the Hamamatsu PDE-Neo probe and SPY Elite systems in the ability to detect sentinel lymph nodes; however, the former was associated with a lower operating cost and ease of use compared with the latter. ICG-assisted sentinel lymph biopsy using the SPY Elite or the Hamamatsu PDE-Neo probe systems for melanoma are comparable in terms of sentinel node detection. The Neo probe system delivers pertinent clinical data with the advantages of lower cost and ease of operation.


Pulmonary removal of circulating endotoxin results in acute lung injury in sheep.
Endotoxemia has often been associated with the development of the adult respiratory distress syndrome. Our previous studies have shown that sheep, a popular animal model for adult respiratory distress syndrome, have abundant resident pulmonary intravascular macrophages that rapidly remove inorganic particles and live bacteria from the circulating blood. In this study, we examine the fate of circulating endotoxin in sheep and correlated the site of uptake with early morphologic evidence of tissue injury. Mature sheep and rats received intravenous 125I-labeled lipopolysaccharide (LPS). The dose was 0.8 microgram/kg in sheep and 17.0 micrograms/kg in rats. 125I-LPS clearance from the blood was assayed by gamma-counting of blood samples drawn over 1 hour and was correlated with circulating leukocyte numbers. The distribution of 125I-LPS was determined by gamma-counting of samples of major organs and tissues at time of necropsy. Lungs and liver were examined morphologically in both species. The half-life of circulating 125I-LPS was 2.38 minutes in sheep, and 12.39 minutes in rats. The endotoxin content of the lungs after injection was 77.58% of the total recovered dose in sheep, but only 2.02% in rats. Neutrophil margination occurred in the lungs of both species. In sheep, almost 25 minutes elapsed before peripheral neutrophil numbers decreased by 50%, much longer than the time required for LPS sequestration in the lungs. Rapid LPS uptake by the sheep lungs was associated with early (10-minute) ultrastructural changes including signs of pulmonary intravascular macrophage activation and microvascular congestion. By 60 minutes, many capillaries were occluded with neutrophils, platelets, and fibrin. There was interstitial edema, and endothelial cells showed evidence of severe injury. We conclude that in contrast to the rat, the sheep clears circulating endotoxin more rapidly and preferentially sequesters it in the lungs. Subsequent release of mediators by activated pulmonary intravascular macrophages may then lead to influx of other inflammatory cells and cascading injury.


Differentiating between demented and psychiatric patients with the Dutch version of the IQCODE.
This study presents psychometric data on the Dutch version of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE-N). We focused on differentiating between inpatients with dementia or a mood/psychotic disorder. A cutoff point of 3.9 on the IQCODE-N correctly predicted group membership in 87.8% and 78.8% respectively. Internal consistency and principal component analysis suggest that the IQCODE-N measures a unidimensional construct. Correlations with a Dementia Screening Test (r = 0.62), nurses' observations on memory disorders (r = 0.71) and a global assessment of severity of dementia (r = 0.72) support the validity of the informant ratings. Patients' age and level of education did not confound informant ratings. Only a small fraction of the informants could not complete the IQCODE-N, which makes it an easily applicable rating scale for cognitive decline.


Selection of T-DNA-tagged male and female gametophytic mutants by segregation distortion in Arabidopsis.
As a strategy for the identification of T-DNA-tagged gametophytic mutants, we have used T-DNA insertional mutagenesis based on screening for distorted segregation ratios by antibiotic selection. Screening of approximately 1000 transgenic Arabidopsis families led to the isolation of eight lines showing reproducible segregation ratios of approximately 1:1, suggesting that these lines are putative gametophytic mutants caused by T-DNA insertion at a single locus. Genetic analysis of T-DNA transmission through reciprocal backcrosses with wild type showed severe reductions in genetic transmission of the T-DNA through the male and/or female gametes. Direct evidence for mutant phenotypes in these lines was investigated by DAPI staining of mature pollen grains and by the analysis of seed set and embryo sac morphology in cleared ovules. One line, termed limpet pollen, showed a novel pollen phenotype in that the generative cell failed to migrate inward after pollen mitosis I, such that the generative or sperm cells remained against the pollen wall. Two other lines, andarta and tistrya, were defective in female transmission and showed an early arrest of embryo sac development with the viable megaspore not initiating the nuclear division cycles. These data demonstrate the efficacy of a segregation ratio distortion strategy for the identification of T-DNA-tagged gametophytic mutants in Arabidopsis.


Nuclear retinoic acid "orphan" receptors: progress towards an understanding of the new complexities in retinoid metabolism.
A new retinoic acid-related receptor has been identified. It is called the retinoid X receptor and is distinct from the retinoic acid receptors, alpha, beta and gamma. It represents an "orphan" receptor because its function and ligand are unknown. What is known is that it is structurally related to the steroid receptor genes. The ligand to which the retinoic acid X receptor binds has recently been determined to be either retinoic acid itself or another metabolically derived molecule. It is speculated that retinoic acid could serve as a precursor that is metabolized to a more active form as is the case for vitamin D and estrogen (24). The elucidation of an alternative pathway in retinoid metabolism will increase our understanding of the scope of retinoid action.


Effects of Yokukansan, a Japanese Kampo Medicine for Symptoms Associated Autism Spectrum Disorder.
A neuropsychiatric syndrome, Autism spectrum disorder (ASD) is qualified via impairments in qualitative communication, social interaction, and stereotyped or restricted, repetitive patterns of behavior, interests, or activities. While all ASDs are considered to have qualitative deficits in social relatedness to others, many people with ASDs have other symptoms, including irritability (which includes aggression, self-injurious behavior, and severe tantrums). In order to decrease these behaviors, it is often helpful to make use of behavioral therapy. In addition, due to the intensity and severity of irritability, adjunctive medications are sometimes needed. Although many of the adjunctive medications have been tested and demonstrated to be useful in treating ASD, no clear standardized treatment has emerged. While the adjunctive medications have shown efficacy, the associated side effects have proven to be a barrier to their accepted use. A traditional Japanese medicine, Yokukansan (YKS), is composed of seven kinds of dried herbs and is widely clinically prescribed for treating psychiatric disorders by acting mainly on the glutamatergic and serotonergic nervous systems. YKS may be safe and useful in treating dementia patients' behavioral and psychological symptoms according to indications from recent studies. We introduce in this review, the ameliorative effects of YKS on Asperger's disorder in open-label studies and on ASDs including pervasive developmental disorder not otherwise specified (PDD-NOS). This review will suggest that YKS is well tolerated and effective for the treatment for subjects with ASD who have severe hyperactivity/noncompliance and irritability/agitation. Additionally, the serotonergic, glutamatergic, anti-inflammatory and neurogenesis effects are explored which are thought to be involved in the mechanisms underlying the efficacy of YKS.


Differential COVID-19 case positivity in New York City neighborhoods: Socioeconomic factors and mobility.
New York City (NYC) has been one of the hotspots of the COVID-19 pandemic in the United States. By the end of April 2020, close to 165 000 cases and 13 000 deaths were reported in the city with considerable variability across the city's ZIP codes. In this study, we examine: (a) the extent to which the variability in ZIP code-level case positivity can be explained by aggregate markers of socioeconomic status (SES) and daily change in mobility; and (b) the extent to which daily change in mobility independently predicts case positivity. COVID-19 case positivity by ZIP code was modeled using multivariable linear regression with generalized estimating equations to account for within-ZIP clustering. Daily case positivity was obtained from NYC Department of Health and Mental Hygiene and measures of SES were based on data from the American Community Survey. Changes in human mobility were estimated using anonymized aggregated mobile phone location systems. Our analysis indicates that the socioeconomic markers considered together explained 56% of the variability in case positivity through April 1 and their explanatory power decreased to 18% by April 30. Changes in mobility during this time period are not likely to be acting as a mediator of the relationship between ZIP-level SES and case positivity. During the middle of April, increases in mobility were independently associated with decreased case positivity. Together, these findings present evidence that heterogeneity in COVID-19 case positivity during NYC's spring outbreak was largely driven by residents' SES.


Strategy-based reasoning training modulates cortical thickness and resting-state functional connectivity in adults with chronic traumatic brain injury.
Prior studies have demonstrated training-induced changes in the healthy adult brain. Yet, it remains unclear how the injured brain responds to cognitive training months-to-years after injury. Sixty individuals with chronic traumatic brain injury (TBI) were randomized into either strategy-based (N = 31) or knowledge-based (N = 29) training for 8 weeks. We measured cortical thickness and resting-state functional connectivity (rsFC) before training, immediately posttraining, and 3 months posttraining. Relative to the knowledge-based training group, the cortical thickness of the strategy-based training group showed diverse temporal patterns of changes over multiple brain regions (pvertex < .05, pcluster < .05): (1) increases followed by decreases, (2) monotonic increases, and (3) monotonic decreases. However, network-based statistics (NBS) analysis of rsFC among these regions revealed that the strategy-based training group induced only monotonic increases in connectivity, relative to the knowledge-based training group (|Z| > 1.96, pNBS < 0.05). Complementing the rsFC results, the strategy-based training group yielded monotonic improvement in scores for the trail-making test (p < .05). Analyses of brain-behavior relationships revealed that improvement in trail-making scores were associated with training-induced changes in cortical thickness (pvertex < .05, pcluster < .05) and rsFC (pvertex < .05, pcluster < .005) within the strategy-based training group. These findings suggest that training-induced brain plasticity continues through chronic phases of TBI and that brain connectivity and cortical thickness may serve as markers of plasticity.


Enhanced performance of p-type dye-sensitized solar cells based on ultrasmall Mg-doped CuCrO2 nanocrystals.
Herein, we present ultrasmall delafossite-type Mg-doped CuCrO2 nanocrystals prepared by using hydrothermal synthesis and their first application as photocathodes in efficient p-type dye-sensitized solar cells. The short-circuit current density (Jsc ) is notably increased by approximately 27% owing to the decreased crystallite size and the enhanced optical transmittance associated with Mg doping of the CuCrO2 nanocrystalline sample. An open-circuit voltage (Voc ) of 201 mV, Jsc of 1.51 mA cm(-2) , fill factor of 0.449, and overall photoconversion efficiency of 0.132% have been achieved with the CuCr0.9 Mg 0.1 O2 dye photocathode sensitized with the P1 dye under optimized conditions. This efficiency is nearly three times higher than that of the NiO-based reference device, which is attributed to the largely improved Voc and Jsc . The augmentation of Voc and Jsc can be attributed to the lower valance band position and the faster hole diffusion coefficient of CuCr0.9 Mg 0.1 O2 compared to those of the NiO reference, respectively, which leads to a higher hole collection efficiency.


Risks of Allergic Contact Dermatitis Elicited by Nickel, Chromium, and Organic Sensitizers: Quantitative Models Based on Clinical Patch Test Data.
Risks of allergic contact dermatitis (ACD) from consumer products intended for extended (nonpiercing) dermal contact are regulated by E.U. Directive EN 1811 that limits released Ni to a weekly equivalent dermal load of ≤0.5 μg/cm2 . Similar approaches for thousands of known organic sensitizers are hampered by inability to quantify respective ACD-elicitation risk levels. To help address this gap, normalized values of cumulative risk for eliciting a positive ("≥+") clinical patch test response reported in 12 studies for a total of n = 625 Ni-sensitized patients were modeled in relation to observed ACD-eliciting Ni loads, yielding an approximate lognormal (LN) distribution with a geometric mean and standard deviation of GMNi = 15 μg/cm2 and GSDNi = 8.0, respectively. Such data for five sensitizers (including formaldehyde and 2-hydroxyethyl methacrylate) were also ∼LN distributed, but with a common GSD value equal to GSDNi and with heterogeneous sensitizer-specific GM values each defining a respective ACD-eliciting potency GMNi /GM relative to Ni. Such potencies were also estimated for nine (meth)acrylates by applying this general LN ACD-elicitation risk model to respective sets of fewer data. ACD-elicitation risk patterns observed for Cr(VI) (n = 417) and Cr(III) (n = 78) were fit to mixed-LN models in which ∼30% and ∼40% of the most sensitive responders, respectively, were estimated to exhibit a LN response also governed by GSDNi . The observed common LN-response shape parameter GSDNi may reflect a common underlying ACD mechanism and suggests a common interim approach to quantitative ACD-elicitation risk assessment based on available clinical data.


Mesenchymal stem cells and acellular products attenuate murine induced colitis.
Mesenchymal stem cells (MSCs) are a well-established immunomodulatory agent which can also promote tissue repair and regeneration. Recent studies have demonstrated MSCs as a novel therapeutic for inflammatory bowel disease (IBD), a chronic idiopathic inflammatory disorder of the gastrointestinal tract. However, the precise role of MSCs in regulating immune responses is controversial, and its significance in the pathogenesis remains IBD undefined. In addition, MSCs' acellular product, extracellular vesicles (EVs), may also play an important role in the armamentarium of therapeutics, but how EVs compare to MSCs remains unknown due to the lack of side-by-side comparative investigation. We herein compared MSCs and MSC-derived EVs for the treatment of IBD using a DSS-induced colitis model. A DSS-induced colitis model was used. At day 4, mice received adipose-derived MSCs, MSC-derived EVs, or placebo. Weight loss, stool consistency, and hematochezia was charted. At day 8, murine colons were harvested, histologic analysis performed, and serum/tissue cytokine analysis conducted. MSCs and EVs demonstrated equivalent immunosuppressive function in DSS-treated mice through decreased colonic lymphocyte infiltration and attenuated disease severity after both MSC and EV treatment. Furthermore, both MSCs and EVs have an equivalent ability to inhibit inflammation in the DSS colitis model by inhibiting JAK, JNK 1/2, and STAT3 signaling. These results suggest that (i) both MSCs and EVs are effective therapeutic candidates for a DSS-induced mouse colitis model, (ii) MSCs and EVs have similar immunosuppressive and anti-inflammatory functions, and (iii) EVs may present a novel future therapeutic for the treatment of IBD.


[Monoarthritis of the knee as an isolated manifestation of paracoccidioidomycosis].
Osteoarthritis in paracoccidioidomycosis has been rarely reported. The present case describes a 36-"year"-old woman, with chronic monoarthritis in the knee lasting 4 years. The diagnosis was achieved only after synovial biopsy, by anatomopathological examination showing granulomatous reaction with a large number of the characteristic "pilot wheel"Paracoccidioides brasiliensis yeast cells. Specific therapy, initially with ketoconazole and followed by cotrimoxazole led to complete functional recovery of the compromised joint. No other affected site was detected by various propaedeutic methods, including computed axial tomography of the thorax and abdomen. The authors emphasize the rarity of the case and discuss its possible pathophysiology.


Respiratory physiotherapy in the pre and postoperative myocardial revascularization surgery.
The cardiovascular diseases are among the main death causes in the developed world. They have been increasing epidemically in the developing countries. In spite of several alternatives for the treatment of the coronary artery disease; the surgery of the myocardial revascularization is an option with proper indications of medium and long-term with good results. It provides the remission of the angina symptoms contributing to the increase of the expectation and improvement of the life quality. Most of patients undergoing myocardial revascularization surgery develop postoperative lung dysfunction with important reduction of the lung volumes, damages in the respiratory mechanism, decrease in the lung indulgence and increase of the respiratory work. The reduction of volumes and lung capacities can contribute to alterations in the gas exchanges, resulting in hypoxemia and decrease in the diffusion capacity. Taking this into account, the Physiotherapy has been requested more and more to perform in the pre as well as in the postoperative period of this surgery. This study aimed at updating the knowledge regarding the respiratory physiotherapy performance in the pre and postoperative period of the myocardial revascularization surgery enhancing the prevention of lung complications. The Physiotherapy uses several techniques in the preoperative period; such as: the incentive spirometry, exercises of deep breathing, cough, inspiratory muscle training, earlier ambulation and physiotherapeutic orientations. While in the postoperative period, the objective is the treatment after lung complications took place, performed by means of physiotherapeutic maneuvers and noninvasive respiratory devices, aiming at improving the respiratory mechanism, the lung reexpansion and the bronchial hygiene. Respiratory physiotherapy is an integral part in the care management of the patient with cardiopathy, either in the pre or in the postoperative period, since it contributes significantly to a better prognosis of these patients with the use of specific techniques.


Maternal-fetal surgery for treatment of myelomeningocele.
Maternal-fetal surgery for repair of fetal MMC is experimental treatment for which ethically justified clinical trials are not yet possible because equipoise is not established on medical or nonmedical grounds. We have focused here on only two of the important questions raised by this surgery. At least three others might have been considered. First is the question of access to the surgery. MMC is available only to those who can afford it. Given its poor results, that may be a good thing. However, if it were ever proved successful, it should be covered for the poor and affluent women who desire it. Second is the question of the autonomy of the women who seek the procedure. Although the women who undergo the surgery at Vanderbilt are counseled extensively by bioethicists, the autonomy of their decisions may be compromised by pressures from partners or others who think that any risk for the sake of a potential child is fully warranted. Third is the issue of potential discrimination against people with disabilities. Seeking or providing surgery that introduces the risk of fetal demise, a risk that could be avoided by postponing the surgery until after birth, suggests that life with disability is regarded as worse than death. Each of these questions deserves careful, critical analysis in its own right. Along with those addressed in this article, these issues are applicable to other ethical issues in perinatology, including those examined by other contributors to this issue.


Effect of selected antioxidants in beta-cyfluthrin-induced oxidative stress in human erythrocytes in vitro.
beta-Cyfluthrin is one of the most widely used type II pyrethroid in agriculture. The aim of this study was to examine (1) the possibility of beta-cyfluthrin to induce oxidative stress in human erythrocytes in vitro and its effect on catalase (CAT) and superoxide dismutase (SOD) activities as well as (2) the role of melatonin (MEL; 2mM), its precursor--N-acetylserotonin (NAS; 1mM), quercetin (Q; 80 microM) and rutin (R; 80 microM) in alleviating the cytotoxic effects of beta-cyfluthrin. Erythrocytes were divided into portions. The first portion was incubated for 4h at 37 degrees C with different concentrations (0, 43, 215, 1075 ppm) of beta-cyfluthrin. The other portions were preincubated with selected antioxidant, respectively for 30 min and followed by beta-cyfluthrin incubation for 4h. Malondialdehyde (MDA) concentrations, CAT and SOD activities, as well as haemolysis percentage (H) were measured in all treatment portions of erythrocytes. It could be concluded that the in vitro toxicity of beta-cyfluthrin may be associated with oxidative stress. Significant reduction in the activities of CAT was observed at all beta-cyfluthrin concentrations, while SOD activities were significantly decreased only in erythrocytes incubated with the highest beta-cyfluthrin concentration. SOD activity of the non-pretreated erythrocytes exposed to the lowest dose of beta-cyfluthrin was significantly greater when compared to comparably beta-cyfluthrin-exposed antioxidant pretreated cells. The highest concentration of beta-cyfluthrin has caused over 35% haemolysis, and the lowest concentration about 15%. MEL pretreatment had no effect on H and MDA induction by beta-cyfluthrin. NAS, Q and R reduced H and MDA level, but could not prevent induction of these parameters. Compared to other antioxidants NAS appeared to maintain better the CAT activity at control levels for all doses of beta-cyfluthrin. Pretreatment with Q was found to protect against the decrease in SOD activity induced by beta-cyfluthrin.


Preimplantation genetic diagnosis to prevent disorders in children.
Preimplantation genetic diagnosis (PGD) is an alternative reproductive option for couples at risk of having a child affected with a genetic disorder. Although prenatal diagnosis (PND) has been available for many years, it is not acceptable to many owing to issues relating to termination of pregnancy. PGD involves assisted-reproductive technology, even though most couples undertaking it are fertile. However, if the treatment is successful, the couple will not have to consider PND. PGD is only available at a small number of centres and for a limited number of genetic conditions. It is a complex and time-consuming procedure. The success rate is around 20%, consequently, there is a relatively low chance of success and this requires careful consideration by couples who generally can become spontaneously pregnant. However, PGD is now more widely understood and available to all at the point of referral. This article sets out to explain the PGD procedure, its implications, limitations, and regulation in the UK and to discuss associated dilemmas.


Anticancer effect of two diterpenoid compounds isolated from Annona glabra Linn.
To study the inhibitory effect of two diterpenoid compounds isolated from Annona glabra Linn (Cunabic acid and ent-kauran-19-al-17-oic acid) on the proliferation of Human Liver Cancer (HLC) cell line SMMC-7721 and its mechanism. Inhibition of cell proliferation was measured by MTT assay. The morphological changes of SMMC-7721 cells were observed under inverted phase-contrast microscope, fluorescent microscope, transmission electron microscope (TEM), and scanning electron microscope (SEM). Flow cytometer (FCM) was used to calculate the cell apoptotic rate, and immunohistochemical staining was used to observe the regulation of gene expression. The proliferation of SMMC-7721 cells was obviously inhibited after being treated with Cunabic acid at the concentration great than 5 micromol/L and ent-kauran-19-al-17-oic acid great than 10 micromol/L. The biggest inhibitory effect was 81.05% when treated with Cunabic acid at the concentration of 25 micromol/L. The effect had a linear relationship with concentration. The result indicated that drug-treated cells exhibit typical morphological changes of apoptosis, including condensed chromatin and a reduction in volume. Sub-G0/G1 peak was found by FCM analysis and the cell cycle was arrested at G0/G1 stage. The apoptotic rates of the cells treated by Cunabic acid and ent-kauran-19-al-17-oic acid were 43.31% and 24.95%, respectively. It was visualized by immunohistochemical staining that the drugs down-regulated the gene expression of bcl-2 gene and up-regulated that of bax gene. The two diterpenoid compounds isolated from Annona glabra Linn, Cunabic acid and ent-kauran-19-al-17-oic acid can obviously inhibit the proliferation of HLC cell line SMMC-7721. The mechanism is correlated with the induction of cell apoptosis by down-regulating the gene expression of bcl-2 gene and up-regulating that of bax gene.


Effects of hyperbaric oxygen therapy on an accelerated rate of mandibular distraction osteogenesis.
Distraction osteogenesis has become a standard therapy for lengthening of the human craniofacial skeleton. Because the technique is used predominately in a paediatric population, limiting the treatment protocol is beneficial. Twenty-four animals were divided into four groups with distraction rates of 1mm and 2mm/day with and without hyperbaric oxygen (HBO) therapy. Following a 5-day latency period, mandibular lengthening of 15mm was performed with a uniaxial distractor along the body of the mandible. Consolidation period was 4 weeks in all groups. HBO therapy was administered to one of the 1 and 2mm/day groups 1 day preoperatively, throughout the latency and distraction phases and 2 weeks into the consolidation period. Animals were euthanised after consolidation and the mandibles harvested for bone mineral densitometry evaluation. The mean bone mineral density (BMD) (g/cm(2)) was 0.208+/-0.04 in Group 1 (1mm/day distraction, no HBO therapy), 0.228+/-0.09 in Group 2 (1mm/day distraction, + HBO therapy), 0.180+/-0.1 in Group 3 (2mm/day distraction, no HBO therapy), and 0.269+/-0.05 in Group 4 (2mm/day distraction, + HBO therapy). Using the Student's t-test for equality of means and the one-way analysis of variance (ANOVA), we found that the mean BMD was significantly higher in the groups that were administered HBO (Groups 2 and 4) than not (P=< 0.05). For the groups that had distraction of 1mm/day and 2mm/day, those that underwent HBO therapy had significantly higher BMD than those without HBO therapy (P=< 0.05). We have found that HBO therapy may serve to augment the healing process in distraction osteogenesis, allowing for more rapid distraction in order to decrease the overall treatment time.