Sotalol as adjunctive therapy to implantable cardioverter-defibrillators in heart failure patients.
The number of heart failure patients with implantable cardioverter-defibrillators is rising. Common issues encountered in this population are high defibrillation thresholds and inappropriate shocks. In order to resolve these problems, the addition of a class III antiarrhythmic such as sotalol is often considered. Given the emerging issue of polypharmacy and medication compliance in the heart failure population, the question of the efficacy of sotalol in reducing inappropriate shocks, defibrillation thresholds, and its ability to replace conventional beta-blockers is often raised. Current literature review suggests that sotalol is a useful adjunct to the contemporary heart failure regimen. It has the ability to reduce inappropriate shocks and defibrillation thresholds, but appears not to fully reproduce the pleiotropic beneficial effects of the beta-blockers more commonly employed for their mortality/remodeling benefits in heart failure patients.


Quantitative proton spectroscopy and histology of a canine brain tumor model.
Quantitative, single voxel proton nuclear magnetic resonance (NMR) spectroscopy and histological analysis was performed in eight dogs implanted with the transplantable canine glioma model of Wodinsky (Proc. Am. Assoc. Cancer Res. 10, 99 (1969)). Signals from choline, creatine, N-Acetyl Aspartate (NAA) and lactate were converted to molar concentration units and correlated with the quantitative analysis of histologically determined tissue types within the localized volume selected for NMR spectroscopy. In general, compared with normal brain, the lesions were associated with reductions in all metabolite concentrations, with the exception of lactate, which was increased. NAA and creatine decreases were most significantly correlated with the total lesion volume (P < 0.01), suggesting that these compounds are present in normal brain only. Changes in choline levels did not correlate strongly with any particular tissue type. Lactate was found to increase with increasing total lesion volume (P < 0.01), but not with increasing percent tumor, suggesting that it accumulates in abnormal tissue other than the tumor. The spectra reported were similar to those observed in human glioblastomas, with the exception that elevations of choline were not observed. The transplantable canine gliosarcoma system appears to be a suitable tumor model for evaluation by clinical radiological techniques such as magnetic resonance imaging (MRI) and proton NMR spectroscopy.


"Magia sexualis": sex, secrecy, and liberation in modern western esotericism.
Although the forces of Eros and Magic have long been linked in western esoteric traditions, it is really not until the nineteenth century that we see the emergence of a large and sophisticated body of literature on the art of sexual magic. This article examines the rise of sexual magic in the late nineteenth and early twentieth centuries, placing it in the context of the larger discourse surrounding sexuality in American and British society of the Victorian era. Specifically, I focus on the teachings of the American spiritualist Paschal Beverly Randolph; the infamous "Great Beast 666," Aleister Crowley; and the founder of the first Tantrik Order in America, Pierre Bernard. Following the lead of Michel Foucault, I argue that this new literature on sexual magic was part of the larger interest in sex that pervaded Victorian culture. Far from being a period of repression and prudery, the Victorian era witnessed an unprecedented explosion of discourse on sex, particularly in its "deviant" and nonproductive forms. The rise of sexual magic at once reflects and yet also subverts many of the sexual values of mainstream Victorian culture. At the same time, however, I argue that Randolph, Crowley, and Bernard were all in their own ways somewhat ahead of their times and foreshadowed much of the obsession with sex and its liberation in contemporary America at the turn of the millennium.


Translating the biology of aging into novel therapeutics for Alzheimer disease.
Aging is the leading risk factor for most chronic illnesses of old age, including Alzheimer disease (AD), a progressive neurodegenerative disease with currently no therapies that prevent, slow, or halt disease progression. Like other chronic diseases of old age, the progressive pathology of AD begins decades before the onset of symptoms. Many decades of research in biological gerontology have revealed common processes that are relevant to understanding why the aging brain is vulnerable to AD. In this review, we frame the development of novel therapeutics for AD in the context of biological gerontology. The many therapies currently in development based on biological gerontology principles provide promise for the development of a new generation of therapeutics to prevent and treat AD.


On the design of a bioacoustic sensor for the early detection of the red palm weevil.
During the last two decades Red Palm Weevil (RPW, Rynchophorus Ferrugineus) has become one of the most dangerous threats to palm trees in many parts of the World. Its early detection is difficult, since palm trees do not show visual evidence of infection until it is too late for them to recover. For this reason the development of efficient early detection mechanisms is a critical element of RPW pest management systems. One of the early detection mechanisms proposed in the literature is based on acoustic monitoring, as the activity of RPW larvae inside the palm trunk is audible for human operators under acceptable environmental noise levels (rural areas, night periods, etc.). In this work we propose the design of an autonomous bioacoustic sensor that can be installed in every palm tree under study and is able to analyze the captured audio signal during large periods of time. The results of the audio analysis would be reported wirelessly to a control station, to be subsequently processed and conveniently stored. That control station is to be accessible via the Internet. It is programmed to send warning messages when predefined alarm thresholds are reached, thereby allowing supervisors to check on-line the status and evolution of the palm tree orchards. We have developed a bioacoustic sensor prototype and performed an extensive set of experiments to measure its detection capability, achieving average detection rates over 90%.


Ventromedial hypothalamic neurons control a defensive emotion state.
Defensive behaviors reflect underlying emotion states, such as fear. The hypothalamus plays a role in such behaviors, but prevailing textbook views depict it as an effector of upstream emotion centers, such as the amygdala, rather than as an emotion center itself. We used optogenetic manipulations to probe the function of a specific hypothalamic cell type that mediates innate defensive responses. These neurons are sufficient to drive multiple defensive actions, and required for defensive behaviors in diverse contexts. The behavioral consequences of activating these neurons, moreover, exhibit properties characteristic of emotion states in general, including scalability, (negative) valence, generalization and persistence. Importantly, these neurons can also condition learned defensive behavior, further refuting long-standing claims that the hypothalamus is unable to support emotional learning and therefore is not an emotion center. These data indicate that the hypothalamus plays an integral role to instantiate emotion states, and is not simply a passive effector of upstream emotion centers.


Modeling the recurrent failure to thrive in less than two-year children: recurrent events survival analysis.
This study aimes to evaluate the failure to thrive (FTT) recurrent event over time. This longitudinal study was conducted during February 2007 to July 2009. The primary outcome was growth failure. The analysis was done using 1283 children who had experienced FTT several times, based on recurrent events analysis. Fifty-nine percent of the children had experienced the FTT at least one time and 5.3% of them had experienced it up to four times. The Prentice-Williams-Peterson (PWP) model revealed significant relationship between diarrhea (HR=1.26), respiratory infections (HR=1.25), urinary tract infections (HR=1.51), discontinuation of breast-feeding (HR=1.96), teething (HR=1.18), initiation age of complementary feeding (HR=1.11) and hazard rate of the first FTT event. Recurrence nature of the FTT is a main problem, which taking it into account increases the accuracy in analysis of FTT event process and can lead to identify different risk factors for each FTT recurrences.


Purification of horse muscle acylphosphatase antibodies by affinity chromatography.
Horse muscle acylphosphatase antibodies were obtained by immunizing rabbits with the highly purified antigen cross-linked with glutaraldehyde. Specific antibodies were purified from the immunoglobulin fraction by affinity chromatography using a matrix coupled with the pure antigen as immunoadsorbent. The purified antibodies were partially characterized by immunodiffusion and immunoprecipitin techniques. These antibodies could be used to study aspects of the muscle acylphosphatase structure, localization and other biological properties.


Shaping the development and use of Artificial Intelligence: how human factors and ergonomics expertise can become more pertinent.
New developments in Artificial Intelligence (AI) are extensively discussed in public media and scholarly publications. While in many academic disciplines debates on the challenges and opportunities of Artificial Intelligence (AI) and how to best address them have been launched, the human factors and ergonomics (HFE) community has been strangely quiet. I discuss three main areas in which HFE could and should significantly contribute to the socially and economically viable development and use of AI: decisions on automation versus augmentation of human work; alignment of control and accountability for AI outcomes; counteracting power imbalances among AI stakeholders. I then outline actions that the HFE community could undertake to improve their involvement in AI development and use, foremost translating ethical into design principles, strengthening the macro-turn in HFE, broadening the HFE design mindset, and taking advantage of new interdisciplinary research opportunities.Practitioner summary: HFE expertise could and should significantly contribute to the socially and economically viable development and use of AI. Translating ethical into design principles, opening up to broader multi-stakeholder perspectives, and engaging in interdisciplinary collaboration within a design science framework are discussed as measures to achieve that.


Novel contrast-enhanced ultrasound imaging in prostate cancer.
The purposes of this paper were to present the current status of contrast-enhanced transrectal ultrasound imaging and to discuss the latest achievements and techniques now under preclinical testing. Although grayscale transrectal ultrasound is the standard method for prostate imaging, it lacks accuracy in the detection and localization of prostate cancer. With the introduction of contrast-enhanced ultrasound (CEUS), perfusion imaging of the microvascularization became available. By this, cancer-induced neovascularisation can be visualized with the potential to improve ultrasound imaging for prostate cancer detection and localization significantly. For example, several studies have shown that CEUS-guided biopsies have the same or higher PCa detection rate compared with systematic biopsies with less biopsies needed. This paper describes the current status of CEUS and discusses novel quantification techniques that can improve the accuracy even further. Furthermore, quantification might decrease the user-dependency, opening the door to use in the routine clinical environment. A new generation of targeted microbubbles is now under pre-clinical testing and showed avidly binding to VEGFR-2, a receptor up-regulated in prostate cancer due to angiogenesis. The first publications regarding a targeted microbubble ready for human use will be discussed. Ultrasound-assisted drug delivery gives rise to a whole new set of therapeutic options, also for prostate cancer. A major breakthrough in the future can be expected from the clinical use of targeted microbubbles for drug delivery for prostate cancer diagnosis as well as treatment.


Structural determination of novel sulfated octasaccharides isolated from chondroitin sulfate of shark cartilage and their application for characterizing monoclonal antibody epitopes.
Twelve octasaccharide fractions were obtained from chondroitin sulfate C derived from shark cartilage after hyaluronidase digestion. Their sugar and sulfate composition was assigned by matrix-assisted laser desorption ionization time of flight mass spectrometry. The sequences were determined at low picomole amounts by a combination of enzymatic digestions with high-performance liquid chromatography, and were composed of disaccharide building units including O [GlcUAbeta1-3GalNAc], C [GlcUAbeta1-3GalNAc(6S)], A [GlcUAbeta1-3GalNAc(4S)], and/or D [GlcUA(2S)beta1-3GalNAc(6S)], where 2S, 4S, and 6S represent 2-O-, 4-O-, and 6-O-sulfate, respectively. As many as 24 different sequences including minor ones were revealed, exhibiting a high degree of structural diversity reflecting the enormous heterogeneity of the parent polysaccharides. Nineteen of them were novel, with the other four reported previously as unsaturated counterparts obtained after digestion with chondroitinase. Microarrays of these structurally defined octasaccharide fractions were prepared using low picomole amounts of their lipid-derivatives to investigate the binding specificity of four commercial anti-chondroitin sulfate antibodies CS-56, MO-225, 2H6, and LY111. The results revealed that multiple unique sequences were recognized by each antibody, which implies that the common conformation shared by the multiple primary sequences in the intact chondroitin sulfate chains is important as an epitope for each monoclonal antibody. Comparison of the specificity of the tested antibodies indicates that CS-56 and MO-225 specifically recognize octasaccharides containing an A-D tetrasaccharide sequence, whereas 2H6 and LY111 require a hexasaccharide as a minimum size for their binding, and prefer sequences with A- and C-units such as C-C-A-C (2H6) or C-C-A-O, C-C-A-A, and C-C-A-C (LY111) for strong binding but require no D-unit.


Segmenting Diabetic Retinopathy Lesions in Multispectral Images Using Low-Dimensional Spatial-Spectral Matrix Representation.
Multispectral imaging (MSI) provides a sequence of en-face fundus spectral slices and allows for the examination of structures and signatures throughout the thickness of retina to characterize diabetic retinopathy (DR) lesions comprehensively. Manual interpretation of MSI images is commonly conducted by qualitatively analyzing both the spatial and spectral properties of multiple spectral slices. Meanwhile, there exist few computer-based algorithms that can effectively exploit the spatial and spectral information of MSI images for the diagnosis of DR. We propose a new approach that can quantify the spatial-spectral features of MSI retinal images for automatic DR lesion segmentation. It combines a generalized low-rank approximation of matrices with a supervised regularization term to generate low-dimensional spatial-spectral representations using the feature vectors in all spectral slices. Experimental results showed that the proposed approach is very effective for the segmentation of DR lesions in MSI images, which suggests it as an interesting tool for assisting ophthalmologists in diagnosing, analyzing, and managing DR lesions in MSI.


Midodrine for orthostatic hypotension: a systematic review and meta-analysis of clinical trials.
To perform a systematic review and meta-analysis of clinical trials evaluating the efficacy and safety of midodrine in orthostatic hypotension (OH). We searched major databases and related conference proceedings through June 30, 2012. Two reviewers independently selected studies and extracted data. Random-effects meta-analysis was used to pool the outcome measures across studies. Seven trials were included in the efficacy analysis (enrolling 325 patients, mean age 53 years) and two additional trials were included in the safety analysis. Compared to placebo, the mean change in systolic blood pressure was 4.9 mmHg (p = 0.65) and the mean change in mean arterial pressure from supine to standing was -1.7 mmHg (p = 0.45). The change in standing systolic blood pressure before and after giving midodrine was 21.5 mmHg (p < 0.001). A significant improvement was seen in patients' and investigators' global assessment symptoms scale (a mean difference of 0.70 [95 % CI 0.30-1.09; p < 0.001] and 0.80 [95 % CI 0.76-0.85; p < 0.001], respectively). There was a significant increase in risk of piloerection, scalp pruritis, urinary hesitancy/retention, supine hypertension and scalp paresthesia after giving midodrine. The quality of evidence was limited by imprecision, heterogeneity and increased risk of bias. There is insufficient and low quality evidence to support the use of midodrine for OH.


A novel method for radiotherapy patient identification using surface imaging.
Performing a procedure on the wrong patient or site is one of the greatest errors that can occur in medicine. The addition of automation has been shown to reduce errors in many processes. In this work we explore the use of an automated patient identification process using optical surface imaging for radiotherapy treatments. Surface imaging uses visible light to align the patient to a reference surface in the treatment room. It is possible to evaluate the similarity between a daily set-up surface image and the reference image using distance to agreement between the points on the two surfaces. The higher the percentage overlapping points within a defined distance, the more similar the surfaces. This similarity metric was used to intercompare 16 left-sided breast patients. The reference surface for each patient was compared to 10 daily treatment surfaces for the same patient, and 10 surfaces from each of the other 15 patients (for a total of 160 comparisons per patient), looking at the percent of points overlapping. For each patient, the minimum same-patient similarity score was higher than the maximum different-patient score. For the group as a whole a threshold was able to classify correct and incorrect patients with high levels of accuracy. A 10-fold cross-validation using linear discriminant analysis gave cross-validation loss of 0.0074. An automated process using surface imaging is a feasible option to provide nonharmful daily patient identification verification using currently available technology.


An integrative approach to enhancing small-scale poultry slaughterhouses by addressing regulations and food safety in northern -Thailand.
In Asian countries, small-scale rural poultry meat production can face challenges due to food safety policies that limit economic growth and hinder improvement of sanitation and disease prevention. In this study, an integrative, participatory research approach was used to elucidate the sanitation and disease prevention practices in small-scale poultry slaughterhouses in rural northern Thailand. Initial steps included the identification of key stakeholders associated with the meat production chain, development of a research framework, and design of a methodology based on stakeholder consultations. The framework and methodology combine issues in five major areas: (1) public health, (2) socioeconomics, (3) policy, (4) veterinary medicine, and (5) communities and the environment. Methods used include questionnaires, direct observation, focus groups, and in-depth interviews. In addition, a microbiological risk assessment approach was employed to detect Salmonella contamination in meat processing facilities. The microbial risk assessment was combined with stakeholder perceptions to provide an overview of the existing situation, as well as to identify opportunities for upgrading slaughterhouses in order to more effectively address matters of food safety, processing, and government licensing. The conceptual framework developed elucidated the complex factors limiting small-scale slaughterhouse improvement including a lack of appropriate enabling policies and an apparent absence of feasible interventions for improvement. Unhygienic slaughterhouse management was reflected in the incidence of Salmonella contamination in both the meat and the surrounding environment. There is potential for the use of an integrative approach to address critical problems at the interface of rural development and public health. The findings of this study could serve as a model for transdisciplinary studies and interventions related to other similar complex challenges.


Mobile coronary care provided by ambulance personnel.
Mobile coronary care has been provided in Brighton by ambulance personnel without immediate help from physicians or nurses. No additional vehicles or staff were required. The capital cost of the experiment was therefore small and additional running costs were negligible. The results have been monitored by retrospective analysis of electrocardiograms recorded in the ambulance and stored on magnetic tape. In the first 12 months of operation to July 1972, 1,082 patients with suspected cardiac emergencies were carried in two vehicles. Subsequent analysis showed that 76% of these patients had acute symptoms from ischaemic heart disease or had circulatory arrest. Eighty-six per cent. of arrhythmias were diagnosed correctly by the ambulance attendants. Though only eight cases of primary ventricular fibrillation occurred during or shortly before transit all were successfully reversed, and five of these patients subsequently left hospital alive. Other benefits of the scheme have included an appreciable reduction in the median delay between onset of presenting symptoms in patients with acute myocardial ischaemia and their admission to hospital.


Bi-directional modulation of food habit expression by the endocannabinoid system.
The compulsive, habitual behaviors that have been observed in individuals diagnosed with substance use disorders may be due to disruptions in the neural circuits that mediate goal-directed actions. The endocannabinoid system has been shown to play a critical role in habit learning, but the role of this neuromodulatory system in habit expression is unclear. Here, we investigated the role of the endocannabinoid system in established habitual actions using contingency degradation in male C57BL/6 mice. We found that administration of the endocannabinoid transport inhibitor AM404 reduced habitual responding for food and that antagonism of cannabinoid receptor type 1 (CB1), but not transient receptor potential cation subfamily V (TRPV1), receptors produced a similar reduction in habitual responding. Moreover, pharmacological stimulation of CB1 receptors increased habitual responding for food. Co-administration of an enzyme inhibitor that selectively increases the endocannabinoid 2-arachidonoyl glycerol (2-AG) with AM404 partially restored habitual responding for food. Together, these findings demonstrate an important role for the endocannabinoid system in the expression of habits and provide novel insights into potential pharmacological strategies for reducing habitual behaviors in mental disorders.


Enzalutamide, an androgen receptor signaling inhibitor, induces tumor regression in a mouse model of castration-resistant prostate cancer.
Enzalutamide (formerly MDV3100 and available commercially as Xtandi), a novel androgen receptor (AR) signaling inhibitor, blocks the growth of castration-resistant prostate cancer (CRPC) in cellular model systems and was shown in a clinical study to increase survival in patients with metastatic CRPC. Enzalutamide inhibits multiple steps of AR signaling: binding of androgens to AR, AR nuclear translocation, and association of AR with DNA. Here, we investigate the effects of enzalutamide on AR signaling, AR-dependent gene expression and cell apoptosis. The expression of AR target gene prostate-specific antigen (PSA) was measured in LnCaP and C4-2 cells. AR nuclear translocation was assessed in HEK-293 cells stably transfected with AR-yellow fluorescent protein. The in vivo effects of enzalutamide were determined in a mouse xenograft model of CRPC. Differential gene expression in LNCaP cells was measured using Affymetrix human genome microarray technology. We found that unlike bicalutamide, enzalutamide lacked AR agonistic activity at effective doses and did not induce PSA expression or AR nuclear translocation. Additionally, it is more effective than bicalutamide at inhibiting agonist-induced AR nuclear translocation. Enzalutamide induced the regression of tumor volume in a CRPC xenograft model and apoptosis in AR-over-expressing prostate cancer cells. Finally, gene expression profiling in LNCaP cells indicated that enzalutamide opposes agonist-induced changes in genes involved in processes such as cell adhesion, angiogenesis, and apoptosis. These results indicate that enzalutamide efficiently inhibits AR signaling, and we suggest that its lack of AR agonist activity may be important for these effects.


BRCA2 phosphorylated by PLK1 moves to the midbody to regulate cytokinesis mediated by nonmuscle myosin IIC.
Cytokinesis is the critical final step in cell division. BRCA2 disruption during cytokinesis is associated with chromosome instability, but mechanistic information is lacking that could be used to prevent cancer cell division. In this study, we report that BRCA2 phosphorylation by the mitotic polo-like kinase (PLK1) governs the localization of BRCA2 to the Flemming body at the central midbody, permitting an interaction with nonmuscle myosin IIC (NM-IIC). Formation of an NM-IIC ring-like structure at the Flemming body shows that the IIC-ring relies on its ATPase activity stimulated by interaction with BRCA2 and associated proteins. Notably, inhibiting this binding inactivated the ATPase activity, causing disassembly of the IIC-ring, defective formation of the midbody, and interruption of cytokinesis. An analysis of cancer-associated mutations in BRCA2 at the PLK1-binding site suggests that they may contribute to cytokinetic defects by altering BRCA2 localization. Our findings suggest that BRCA2-dependent IIC-ring formation is a critical step in proper formation of the midbody, offering an explanation for how chromosome instability may arise in breast cancer.


Summary and recommendations.
Iron deficiency affects the well being of > 1 billion people worldwide, with a range of adverse health and social consequences, yet efforts to address the problem have had only limited success. To better assess this issue and define more effective strategies, an international conference was convened in Atlanta, GA, in May 2001. Key policy issues discussed included setting a global goal for prevention and control of iron deficiency, building partnerships, and identifying ways to mobilize financial and human resources. The strengths and limitations of specific intervention strategies were discussed including iron fortification of staple foods and condiments, supplementation, dietary diversification, application of biotechnology to increase micronutrient content of staple foods, and public health measures such as infection control and provision of health care services. The importance of utilizing multiple and integrated strategies was emphasized. Representatives from several countries reported successful intervention programs as well as promising results in implementing new strategies. The critical role of effective communications was also emphasized, both to increase awareness of the impact of iron deficiency and to advocate for policy changes and resources to address the problem. The conference concluded with specific recommendations for action.


Cesarean delivery and metabolic risk factors in young adults: a Brazilian birth cohort study.
Cesarean delivery (CD) perturbs the assembly of the neonatal gut microbiome and has been associated with child and adult obesity. However, it is still unknown whether CD is associated with metabolic risk factors in young adults. We investigated the association of CD and metabolic risk factors in young adults in a cohort study who were 23-25 y of age at follow-up. We used data from a cohort study in Ribeirão Preto, Brazil. Baseline data on 6827 singleton pregnancies were collected in 1978-1979, and a sample of 2063 subjects were followed up 23-25 y later (2002-2004). Information on the type of delivery, birth weight, maternal age, parity, maternal schooling, and maternal smoking was obtained after birth. Anthropometric data, biochemical measurements, and information on participant schooling and smoking history were collected at 23-25 y of age. A linear regression was performed to assess the association between CD and biochemical measurements in early adulthood, controlling for a minimum set of confounders that were identified in a directed acyclic graph. The mean ± SD age of the subjects was 23.9 ± 0.71 y, and 51.8% of the sample were women. The CD rate was 32.0% and was more common in older (P < 0.001) and more educated mothers (P < 0.001). Compared with vaginal delivery, CD was associated with higher body mass index (BMI) after multivariable adjustment (P < 0.001) but not with glucose, homeostasis model assessment of insulin resistance, the quantitative insulin-sensitivity check index, total cholesterol, LDL cholesterol, HDL cholesterol, or triglycerides (all P > 0.05). In our sample of Brazilian adults, CD was associated with higher BMI but not with other metabolic risk factors.


Evaluation design of the Social Engagement Framework for Addressing the Chronic-disease-challenge (SEFAC): a mindfulness-based intervention to promote the self-management of chronic conditions and a healthy lifestyle.
The Social Engagement Framework for Addressing the Chronic-disease-challenge (SEFAC) project intends to empower citizens at risk of or with type 2 diabetes (T2DM) and/or cardiovascular disease (CVD) to self-manage their chronic conditions through the SEFAC intervention. The intervention combines the concepts of mindfulness, social engagement and information and communication technology support, in order to reduce the burden of citizens with chronic conditions and to increase the sustainability of the health system in four European countries. A prospective cohort study with a 6-month pre-post design will be conducted in four European countries: Croatia, Italy, the Netherlands and the United Kingdom. A total of 360 community-dwelling citizens ≥50 years of age will be recruited; 200 citizens at risk of T2DM and/or CVD in the next 10 years (50 participants in each country) and 160 citizens with T2DM and/or CVD (40 participants in each country). Effects of the intervention in terms of self-management, healthy lifestyle behavior, social support, stress, depression, sleep and fatigue, adherence to medications and health-related quality of life will be assessed. In addition, a preliminary cost-effectiveness analysis will be performed from a societal and healthcare perspective. The SEFAC project will further elucidate whether the SEFAC intervention is feasible and (cost-) effective among citizens at risk of and suffering from T2DM and/or CVD in different settings. ISRCTN registry number is ISRCTN11248135 . Date of registration is 30/08/2018 (retrospectively registered).


[Impact of abdominoplasty on quality of life in patients, suffering anterior abdominal wall deformity and obesity].
The modern tendencies of surgery development include not only the operative procedures improvement but guaranteeing also a maximally high level achievement in the patients quality of life in the early, as well as during remote, postoperative period. The quality of life analysis was done in 132 patients, operated on for the anterior abdominal wall defects, obesity and other surgical diseases, using special questionnaire SF-36. The patients have aged 23-65 years old, in all of them the excessive body mass or obesity of abdominal type was noted.


Products from the reaction of meso-tetrakis(4-halophenyl)porphinato-manganese(II) and hexacyanobutadiene (HCBD): formation of pi-
The reaction of hexacyanobutadiene (HCBD) and meso-tetrakis(4-chlorophenyl)porphinatomanganese(II) pyridine [MnIITClPPpy] (1Cl) leads to two phases of [MnIIITClPPpy][HCBD].PhMe (alpha-2Clpy, beta-2Clpy). Similarly, the reaction of HCBD and tetrakis(4-bromophenyl)porphinatomanganese(II) pyridine [MnIITBrPPpy] (1Br) leads to two products [MnIIITBrPPpy] [HCBD] * PhMe (2 Brpy) and [MnIIITBrPP][HCBD]*2 PhMe (3Br). The structure of dark-green alpha-2Clpy consists of one porphyrin unit with MnIII in a square pyramidal coordination environment axially bound to one pyridine. The cation forms [MnIIITCIPPpy](2)2+ as cofacial dimerized porphyrins. Each [HCBD]*- is nonplanar with a torsion angle of 170.8(4) degrees about the center C-C bound, and forms [HCBD](2)2- dimers in the solid state with sub-van der Waals contacts of 3.325 and 3.340 angstroms. The magnetic data above 10 K obey the Curie-Weiss expression with a theta of -2.5 K, and mueff (300 K) = 4.91 muB as expected for S=2MnIII and S = 0 [HCBD](2)2-. The magnetic data for alpha-2Clpy can be fit with an zero-field-splitting D of -1.45 K. beta-2 Clpy consists of one porphyrin unit with MnIII in a distorted octahedral coordination environment axially bound to py and to a monodentate [HCBD]*- bound via an exo-nitrile. [HCBD]*- is nonplanar with a torsion angle of 169.7(5) degrees about the center C-C bound. The ueff (350 K) is 5.09 muB; however, the magnetic data do not obey the Curie-Weiss expression above 70 K. The low temperature data may be fit with a theta of -5.4 K. The data was modeled to an isolated S = 2 and S = 1/2 dinuclear spin system with J/kappaB = - 90 K. Decomposition of [HCBD]*- to [C4(CN)5O]- was evidenced by the determination of the structure of [MnIIITCIPP][C4(CN)5O] 2PhMe (3ClO). Crystals of 3 Cl-O were prepared by reaction of HCBD and 1Cl in the presence of a drop of water. The molecular structure consists of [HCBD]*-trans-mu-N-2,3-bound to [MnIIITBrPP]+ forming a 1-D coordination polymer of alternating [MnIIITBrPP]+ and [HCBD]*-. The intrachain Mn***Mn distance was 10.675(3) angstroms, with important interchain Mn***Mn distances of 10.832, 11.016, and 14.696 A. The magnetic data were fit to a Curie-Weiss law (10 < T< 290 K) with a theta of -3.5 K, and D = 0.3 K with mueff = 4.97 muB at 300 K.


GRIN2B gain of function mutations are sensitive to radiprodil, a negative allosteric modulator of GluN2B-containing NMDA receptors.
De novo gain of function mutations in GRIN2B encoding the GluN2B subunit of the N-methyl-d-aspartate (NMDA) receptor have been linked with epileptic encephalopathies, including infantile spasms. We investigated the effects of radiprodil, a selective GluN2B negative allosteric modulator and other non-selective NMDA receptor inhibitors on glutamate currents mediated by NMDA receptors containing mutated GluN2B subunits. The experiments were performed in Xenopus oocytes co-injected with the following human mRNAs: GRIN1/GRIN2B, GRIN1/GRIN2B-R540H, GRIN1/GRIN2B-N615I and GRIN1/GRIN2B-V618G. Glutamate displayed slightly increased potency in the R540H variant, but not in N615I and V618G variants. However, the inhibition by Mg2+ was completely abolished in N615I and V618G variants. In fact, Mg2+ enhanced glutamate responses in those variants. The potency of radiprodil to block glutamate-evoked currents was not affected in any of the variants, while the effects by non-selective NMDA inhibitors were greatly reduced in some of the variants. Additionally, in the Mg2+ insensitive variants, radiprodil blocked glutamate-activated currents with the same potency as in the absence of Mg2+. The gain of function observed in the reported GRIN2B variants could be a key pathophysiological factor leading to neuronal hyper-excitability in epileptic encephalopathies. The GluN2B-selective inhibitor radiprodil fully retained its pharmacological profile under these conditions, while other non-selective NMDA receptor antagonists lost their potency. Consequently, our data suggest that radiprodil may be a valuable therapeutic option for treatment of pediatric epileptic encephalopathies associated with GRIN2B mutations.


Serum YKL-40 level is correlated with apnea hypopnea index in patients with obstructive sleep apnea sindrome.
Obstructive sleep apnea syndrome (OSAS) has been associated with elevated biochemical markers of inflammation. Although the exact mechanism is unknown, both sleep deprivation and hypoxemia are believed to be important causative factors. YKL-40, also known as chitinase-like protein, has been shown to be related to various inflammatory conditions including atherosclerosis, diabetes, cancer, and asthma. The present study aimed to evaluate the relationship between YKL-40 levels and the Apnea Hypopnea Index (AHI) in patients with obstructive sleep apnea syndrome. The study was conducted at the Sleep Unit of the Namik Kemal University Research Center. From January 2013 to December 2013, 120 patients diagnosed with OSAS by polysomnography and 40 subjects without OSAS were recruited. Patients in both groups were matched by age, sex, and body mass index (BMI). They were further divided into groups of mild, moderate and severe OSAS based on their AHI value. Serum YKL-40 concentrations were measured by the enzyme-linked immunosorbent assay (ELISA). OSAS patients showed significantly elevated YKL-40 levels compared to the control group; 102,05 (23.14) pg/ml in the control group vs. 144.81 (65.53) pg/ml in the OSAS group. A Spearman correlation analysis showed that serum YKL-40 levels were significantly and positively correlated with AHI (r = 0.434, p < 0.001) and oxygen desaturation index (r = 0.374, p < 0.001). The study demonstrated that high serum YKL-40 levels correlated with the severity of OSAS and might serve as a nonspecific biomarker for prediction and progression of the disease.


Performance of elite maize genotypes under selected sustainable intensification options in Kenya.
Combining different cropping and tillage systems with different genotypes across several cropping seasons can reveal opportunities for sustainable intensification (SI). The objective of this study was to assess the performance of six maize genotypes under intercropping with conservation tillage (no-till) - two promising options for SI. The experiment was carried out over three years (or six cropping seasons) at Kiboko Research Station, Kenya with sole cropping and mouldboard ploughing as baseline production systems. Results showed that maize genotypes and cropping systems had a significant effect on yield, but the effect of tillage was not significant. Moreover, there was no significant interactive effects of the tested factors on maize yield. The maize genotype CKH10085 had the highest yield of 7.7 t ha-1 under sole cropping yet it also recorded the largest yield penalty due to intercropping of 1.1 t ha-1. On the other hand, genotype CKH10717 maintained the same average yield of 7.1 t ha-1 in both conventional and conservation tillage systems. The commercial genotype genotype CKH10080 and CKH08051 were more stable than the other experimental genotypes under the variable growing and management conditions. These two genotypes are of intermediate maturity and drought tolerance, two critical attributes to improved maize production. Intercropping reduced maize yields due to increased competition, for example the overall yield of sole cropping was 7.1 t ha-1 compared with 6.4 t ha-1 under intercropping; representing an overall yield penalty of 0.7 t ha-1. The differences in performance of maize genotypes revealed opportunities to deploy genotypes to reduce risk or maximize yield, depending on the biophysical circumstances and the production objective of the farmer.


MRI-based radiomic signatures for pretreatment prognostication in cervical cancer.
Accurate pretherapeutic prognostication is important for tailoring treatment in cervical cancer (CC). To investigate whether pretreatment MRI-based radiomic signatures predict disease-specific survival (DSS) in CC. Retrospective. CC patients (n = 133) allocated into training(T) (nT = 89)/validation(V) (nV = 44) cohorts. T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) at 1.5T or 3.0T. Radiomic features from segmented tumors were extracted from T2WI and DWI (high b-value DWI and apparent diffusion coefficient (ADC) maps). Radiomic signatures for prediction of DSS from T2WI (T2rad ) and T2WI with DWI (T2 + DWIrad ) were constructed by least absolute shrinkage and selection operator (LASSO) Cox regression. Area under time-dependent receiver operating characteristics curves (AUC) were used to evaluate and compare the prognostic performance of the radiomic signatures, MRI-derived maximum tumor size ≤/> 4 cm (MAXsize ), and 2018 International Federation of Gynecology and Obstetrics (FIGO) stage (I-II/III-IV). Survival was analyzed using Cox model estimating hazard ratios (HR) and Kaplan-Meier method with log-rank tests. The radiomic signatures T2rad and T2 + DWIrad yielded AUCT /AUCV of 0.80/0.62 and 0.81/0.75, respectively, for predicting 5-year DSS. Both signatures yielded better or equal prognostic performance to that of MAXsize (AUCT /AUCV : 0.69/0.65) and FIGO (AUCT /AUCV : 0.77/0.64) and were significant predictors of DSS after adjusting for FIGO (HRT /HRV for T2rad : 4.0/2.5 and T2 + DWIrad : 4.8/2.1). Adding T2rad and T2 + DWIrad to FIGO significantly improved DSS prediction compared to FIGO alone in cohort(T) (AUCT 0.86 and 0.88 vs. 0.77), and FIGO with T2 + DWIrad tended to the same in cohort(V) (AUCV 0.75 vs. 0.64, p = 0.07). High radiomic score for T2 + DWIrad was significantly associated with reduced DSS in both cohorts. Radiomic signatures from T2WI and T2WI with DWI may provide added value for pretreatment risk assessment and for guiding tailored treatment strategies in CC.


Variation in cutaneous perfusion due to synthetic pyrethroid exposure.
Synthetic pyrethroids are neurotoxic insecticides with a low mammalian toxicity. Prior investigations have found these agents to be neither cutaneous irritants nor sensitisers. Clinically demonstrable inflammation, as judged by erythema, oedema, or vesiculation, has not been apparent. Nevertheless, paraesthesia does result from cutaneous exposure. In this investigation technical grade flucythrinate was applied to the forearms of human participants twice daily for five consecutive days. Laser Doppler velocimeter measurements were made before each topical application, with histamine phosphate being intradermally injected on termination of the study. Results of both laser Doppler velocimetry and histamine induced axon reflex vasodilatation were not statistically significant at an alpha = 0.05 level. This investigation suggests that the synthetic pyrethroids have little influence on neurogenic vasodilatation on topical exposure.


Phase and power modulations on the amplitude of TMS-induced motor evoked potentials.
The evaluation of transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs) promises valuable information about fundamental brain related mechanisms and may serve as a diagnostic tool for clinical monitoring of therapeutic progress or surgery procedures. However, reports about spontaneous fluctuations of MEP amplitudes causing high intra-individual variability have led to increased concerns about the reliability of this measure. One possible cause for high variability of MEPs could be neuronal oscillatory activity, which reflects fluctuations of membrane potentials that systematically increase and decrease the excitability of neuronal networks. Here, we investigate the dependence of MEP amplitude on oscillation power and phase by combining the application of single pulse TMS over the primary motor cortex with concurrent recordings of electromyography and electroencephalography. Our results show that MEP amplitude is correlated to alpha phase, alpha power as well as beta phase. These findings may help explain corticospinal excitability fluctuations by highlighting the modulatory effect of alpha and beta phase on MEPs. In the future, controlling for such a causal relationship may allow for the development of new protocols, improve this method as a (diagnostic) tool and increase the specificity and efficacy of general TMS applications.


Idiopathic polypoidal choroidal vasculopathy (IPCV).
Eleven patients, 40 to 71 years old, had a choroidal vasculopathy that led to hemorrhagic and exudative macular degeneration. The patients had peculiar polypoidal, subretinal, vascular lesions associated with serious and hemorrhagic detachments of the retinal pigment epithelium. This macular disorder, which we have named idiopathic polypoidal choroidal vasculopathy (IPCV), appears to represent a distinct entity that differs clinically and demographically from age-related macular degeneration (AMD) and other macular diseases associated with subretinal neovascularization. Recognition of this condition is important because it may have specific risk factors, natural course, and management considerations that differ from those of age-related macular degeneration.


Apparently conclusive meta-analyses may be inconclusive--Trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta-analyses.
Random error may cause misleading evidence in meta-analyses. The required number of participants in a meta-analysis (i.e. information size) should be at least as large as an adequately powered single trial. Trial sequential analysis (TSA) may reduce risk of random errors due to repetitive testing of accumulating data by evaluating meta-analyses not reaching the information size with monitoring boundaries. This is analogous to sequential monitoring boundaries in a single trial. We selected apparently conclusive (P </= 0.05) Cochrane neonatal meta-analyses. We applied heterogeneity-adjusted and unadjusted TSA on these meta-analyses by calculating the information size, the monitoring boundaries, and the cumulative Z-statistic after each trial. We identified the proportion of meta-analyses that did not reach the required information size and the proportion of these meta-analyses in which the Z-curve did not cross the monitoring boundaries. Of 54 apparently conclusive meta-analyses, 39 (72%) did not reach the heterogeneity-adjusted information size required to accept or reject an intervention effect of 25% relative risk reduction. Of these 39, 19 meta-analyses (49%) were considered inconclusive, because the cumulative Z-curve did not cross the monitoring boundaries. The median number of participants required to reach the required information size was 1591 (range, 339-6149). TSA without heterogeneity adjustment largely confirmed these results. Many apparently conclusive Cochrane neonatal meta-analyses may become inconclusive when the statistical analyses take into account the risk of random error due to repetitive testing.


Cutting seton without preliminary internal sphincterotomy in management of complex high fistula-in-ano.
The traditional treatment of a complex high fistula-in-ano by internal sphincterotomy and insertion of a cutting seton carries a risk of fecal incontinence. We have assessed the functional impact of treating patients with a complex fistula-in-ano by a cutting seton fistulotomy technique that preserves the internal sphincter. The operative steps consisted of initial eradication of sepsis, identification of the internal and external openings of the fistula tract, excision of the fistula tract with anal canal mucosa, and insertion of a cutting silk seton around both the internal and external sphincters. In this way open drainage of the intersphincteric space was avoided, and integrity of the internal sphincter was maintained. Functional outcome following treatment with this technique, with regard to fistula eradication and effect on fecal continence was assessed in 27 patients (15 males) who were treated during a six-year period. Twenty-three patients (85 percent) had a history of previous fistula surgery. The fistula was cured in 26 patients (96 percent) with no reports of altered continence at the time of discharge from outpatient review. Recurrence developed in one patient (4 percent) in whom hidradenitis suppurativa was subsequently diagnosed. All four patients with Crohn's disease had their fistulas eradicated; three (75 percent) have subsequently undergone proctectomy for severe perianal and rectal Crohn's involvement. Long-term follow-up revealed three patients (19 percent, all rectovaginal fistulas) who experienced a deterioration in continence after discharge. Although this procedure may not be appropriate for rectovaginal fistulas, the data suggest that cutting setons are effective in treating complex fistula-in-ano, including those that have failed to respond to other forms of surgery. Avoidance of preliminary internal sphincterotomy may prevent deterioration in continence.


Inadvertent exposure of pregnant women to ivermectin and albendazole during mass drug administration for lymphatic filariasis.
The current strategy for the interruption of transmission of lymphatic filariasis in areas where the disease is co-endemic with onchocerciasis is repeated annual mass treatment of endemic communities with ivermectin and albendazole. These drugs are not recommended for use in pregnancy. Pregnant women are excluded on the basis of their last menses. This exclusion criterion based on recall carries some inherent errors, leading sometimes to inadvertent exposure of foetuses to these drugs. This study set out to document the extent of inadvertent exposure of pregnant women to albendazole and ivermectin and assess the relative risk of congenital malformations because of inadvertent treatment with these drugs in early pregnancy. The study was conducted in the Ahanta West District of Ghana. Local pregnancy revelation norms were studied, followed by a household survey of women aged 15-45 years to assess drug administration coverage. All infants born within 42 weeks of the mass drug treatment were examined to document any congenital malformations. Mothers who had lost any such infants responded to a verbal autopsy to ascertain the probable cause of death. Health facilities and local Traditional Birth Attendants were also visited to review maternity records. Of 2985 women of childbearing age (15-49 years) who were interviewed, 343 were pregnant during the mass drug administration. The sensitivity of the last menstrual period in detecting pregnancy and thus being excluded from treatment was 0.854 (293 of 343). Some pregnant women 50 of 343 (14.6%) had thus been inadvertently treated. This represents 1.7% of women in fertile age group (15-49 years). Of the six children found with some congenital malformations in these communities, one had been exposed to the drugs in-utero. The relative risk for congenital malformation after exposure was 1.05 (P=1.0). Two of nine reported spontaneous abortions had been exposed to the drugs (P=0.62). We conclude that the local mode of excluding pregnancy in the current programme, while not perfect, is sufficiently effective and reliable for such a public health intervention; and importantly, that there is no evidence of a higher risk of congenital malformation or abortions in those who are inadvertently exposed.


Fibroblast Viability after Storage at 20 °C in Milk, Hank's Balanced Salt Solution and Coconut Water.
The objective of this study was to evaluate the effectiveness of various storage media at 20 °C in maintaining the viability of human periodontal ligament fibroblasts (HPLF) over time. HPLF were maintained at 20 °C in skim milk (SM), whole milk (WM), freshly prepared Hank's balanced salt solution (HBSS), Save-A-Tooth(r), natural coconut water (NCW), coconut water industrialized (ICW) and tap water (negative control) for 3, 6, 24, 48, 72, 96 and 120 h. Cells maintained in Minimal Essential Medium (MEM-37) at 37 °C served as a positive control. Cell viability was determined by MTT assay. Statistical analysis was performed by Kruskal-Wallis test and Scheffe test (α = 5%). From 24 h, NCW was significantly better in maintaining cell viability than all other tested storage media (p<0.05). SM and WM were significantly better than HBSS for up to 72 h. Save-A-Tooth(r) and ICW were the worst conservation storage media. In conclusion, the effectiveness of the tested storage media to maintain the viability of the periodontal ligament cells was as follows, in a descending order: NCW > MEM-37> SM and IM> HBSS> ICW > Save-A-Tooth(r)> tap water.


Out-of-equilibrium dynamics of photoexcited spin-state concentration waves.
The spin crossover compound [FeIIH2L2-Me][PF6]2 presents a two-step phase transition. In the intermediate phase, a spin state concentration wave (SSCW) appears resulting from a symmetry breaking (cell doubling) associated with a long-range order of alternating high and low spin molecular states. By combining time-resolved optical and X-ray diffraction measurements on a single crystal, we study how such a system responds to femtosecond laser excitation and we follow in real time the erasing and rewriting of the SSCW.


Modeling for scaling to humans: time to get serious.
The subject matter for this 26th Annual Hanford Life Sciences Symposium evolved from the deliberations of a Task Group on Modeling for Scaling to Humans, which was established in January 1986 through the efforts of the Office of Health and Environmental Research of the Department of Energy (OHER/DOE). Several laboratories that utilize animals in radiobiological research sponsored by the OHER/DOE were extensively reviewed in the spring of 1985, and, as a result, OHER recommended establishment of eight task groups designed for selected purposes. The current membership of the Task Group on Modeling for Scaling to Humans is shown in Table 1; Dr. James A. Mewhinney of the Lovelace Inhalation Toxicology Research Institute has been Chairman since these Task Groups were established. Ms. Judy Mahaffey of Battelle. Pacific Northwest Laboratories served as chairperson for this symposium, and the Task Group membership has served as the Program Committee. The OHER/DOE thanks all of them for their work as members of the Task Group as well as for their arranging such a potentially productive and informative meeting.


Depressive symptoms in elderly living in areas covered by Primary Health Care Units in urban area of Bagé, RS.
To identify the prevalence of depressive symptoms and associated factors in elderly. Cross-sectional study of population-based sample of 1,593 individuals aged 60 years or more in the urban area of Bagé, Rio Grande do Sul, Brazil, in 2008. Data were collected in household interviews. The prevalence of depressive symptoms was assessed using the Geriatric Depression Scale. The analysis was performed using Poisson regression with robust variance estimation. The prevalence of depressive symptoms was 18.0%, with the 95% confidence interval 16.1 - 19.9. The majority of the sample consisted of women (62.8%). The mean age was 70 years, with a 8.24 standard deviation (SD); 25.1% of seniors aged 60 to 64 years and 31.2% were 75 years or older. In the adjusted analysis, depressive symptoms were significantly associated (p value < 0.05) with the elderly female, yellow, brown or indigenous descendancy, lower economic status, retired, with history of heart problems, incapacity to basic and instrumental activities of daily living, worse self-rated health and dissatisfaction with life in general. Age, marital status, education, self-reported hypertension and diabetes were not associated with depressive symptoms after adjusting for confounders. The high prevalence of depressive symptoms in the population requires investment in preventive actions, noting the need for practices that promote active aging with the maintenance of functional activity, improving self-rated health and life satisfaction.


[Effect of simulated heavy metal leaching solution of electroplating sludge on the bioactivity of Acidithiobacillus ferrooxidans].
An Acidithiobacillus ferrooxidans strain WZ-1 was isolated from the tannery sludge in Wenzhou, Zhejiang Province in China. The cell of WZ-1 strain is Gram negative and rod-shaped, its 16S rDNA sequence is closely related to that of Acidithiobacillus ferrooxidans ATCC23270 with 99% similarity. These results reveal that WZ-1 is a strain of Acidithiobacillus ferrooxidans. The effects of Ni2+, Cr3+, Cu2+, Zn2+ and 5 kinds of simulated leaching solutions of electroplating sludge on the bioactivity of Fe2+ oxidation and apparent respiratory rate of WZ-1 were investigated. The results showed that Ni2+ and Cr3+ did not have any influence on the bioactivity of WZ-1 at concentrations of 5.0 g x L(-1) and 0.1 g x L(-1), respectively. WZ-1 showed tolerance to high levels of Ni2+, Zn2+ (about 30.0 g x L(-1)), but it had lower tolerance to Cr3+ and Cu2+ (0.1 g x L(-1) Cr3+ and 2.5 g x L(-1) Cu2+). Different kinds of simulated leaching solution of electroplating sludge had significant differences in terms of their effects on the bioactivity of WZ-1 with a sequence of Cu/Ni/Cr/Zn > Cu/Ni/Zn > Cu/Cr/Zn > Cu/Ni/Cr > Ni/Cr/Zn.


Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418.
Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in pathological conditions such as diabetes and Alzheimer's disease. We report the characterization of a GSK3 inhibitor, AR-A014418, which inhibits GSK3 (IC50 = 104 +/- 27 nM), in an ATP-competitive manner (Ki = 38 nM). AR-A014418 does not significantly inhibit cdk2 or cdk5 (IC50 > 100 microM) or 26 other kinases demonstrating high specificity for GSK3. We report the co-crystallization of AR-A014418 with the GSK3beta protein and provide a description of the interactions within the ATP pocket, as well as an understanding of the structural basis for the selectivity of AR-A014418. AR-A014418 inhibits tau phosphorylation at a GSK3-specific site (Ser-396) in cells stably expressing human four-repeat tau protein. AR-A014418 protects N2A neuroblastoma cells against cell death mediated by inhibition of the phosphatidylinositol 3-kinase/protein kinase B survival pathway. Furthermore, AR-A014418 inhibits neurodegeneration mediated by beta-amyloid peptide in hippocampal slices. AR-A014418 may thus have important applications as a tool to elucidate the role of GSK3 in cellular signaling and possibly in Alzheimer's disease. AR-A014418 is the first compound of a family of specific inhibitors of GSK3 that does not significantly inhibit closely related kinases such as cdk2 or cdk5.


NUCLEOTIDE ACCUMULATION INDUCED IN STAPHYLOCOCCUS AUREUS BY GLYCINE.
Strominger, Jack L. (Washington University School of Medicine, St. Louis, Mo.), and Claire H. Birge. Nucleotide accumulation induced in Staphylococcus aureus by glycine. J. Bacteriol. 89:1124-1127. 1965.-High concentrations of glycine induce accumulation of four uridine nucleotides in Staphylococcus aureus. Investigations of their structure suggest that these compounds are uridine diphosphate (UDP)-acetylmuramic acid, UDP-acetylmuramyl-gly-d-glu-l-lys, UDP-acetylmuramyl-l-ala-d-glu-l-lys and UDP-acetylmuramyl-gly-d-glu-l-lys-d-ala-d-ala. The mechanism by which glycine may induce uridine nucleotide accumulation and protoplast formation is discussed.


Ebola virus disease and the eye.
The world has witnessed the largest Ebola virus disease (EVD) epidemic in West Africa with an unprecedented number of infected individuals and survivors. Many systemic and ocular complications have been reported in survivors. Herein, we review the ophthalmic complications associated with Ebolavirus. EVD causes ocular disease during acute infection and during convalescence. Acute patients manifest with conjunctivitis, subconjunctival hemorrhages, and acute vision loss of unclear cause. The most common complication during recovery is uveitis with live virus implicated in the pathogenesis in one case. This epidemic has brought to surface the spectrum of medical complications in EVD survivors with ophthalmic disease being one of the most critical because of its impact on individual functional status and its long-term economic implications. Future studies and programs are needed to appropriately evaluate the spectrum of ophthalmic disease in this at-risk population.


Pulmonary function changes in rats with taurocholate-induced pancreatitis are attenuated by pretreatment with melatonin.
Melatonin is a free radical scavenger and broad-spectrum antioxidant with immunomodulatory effects. We studied the effects of melatonin on changes in lung function, oxidative/nitrosative stress, and inflammatory cell sequestration in an acute pancreatitis (AP)-associated lung inflammation model. Acute pancreatitis was induced by injection of 5% sodium taurocholate into the pancreatic duct of rats. Animals were randomized into control, AP, and a melatonin pretreatment (10 mg/kg)/AP group. Functional residual capacity (FRC), lung compliance (Cchord), expiratory flow rate at 50% (FEF50), airway resistance index (RI), and peak expiratory flow rate (PEF) were evaluated. White blood cell count (WBC) and hydrogen peroxide, lung lavage fluid WBC, methylguanidine, protein, lactic dehydrogenase (LDH), nitric oxide (NO), and leukotriene B4 (LTB4) levels were determined. Lung wet-to-dry weight ratio, peroxynitrite, and inducible nitric oxide synthase (NOS) mRNA and protein were measured. AP induction resulted in reductions in FRC, Cchord, FEF50, and PEF, and increase in RI and lung wet-to-dry weight ratio. Blood and lung lavage fluid WBC, lavage fluid LDH, protein, and blood hydrogen peroxide also increased. Levels of hydroxyl radicals, nitric oxide, and LTB4 in lung lavage fluid, inducible NOS mRNA, protein expression, and peroxynitrite in lung tissue also were significantly elevated. Pretreatment with melatonin attenuated obstructive and restrictive ventilatory insufficiency induced by AP. Blood and lavage WBC, lavage LDH and protein, lung edema, oxidative/nitrosative stress, and lipoxygenase pathway derivatives were also significantly attenuated by melatonin. We conclude that melatonin decreases AP-induced obstructive and restrictive lung function changes via its antioxidant and anti-inflammatory properties.


Reactivity of cloned, expressed human Fc gamma RIII isoforms with monoclonal antibodies which distinguish cell-type-specific and allelic forms of Fc gamma RIII.
We have isolated and expressed a cDNA encoding human NK cell Fc gamma RIII. The NK cell cDNA differs from the neutrophil Fc gamma RIII cDNA by a number of point mutations and encodes an additional 21 amino acids at its C-terminus. When transiently expressed neutrophil and NK cell Fc gamma RIII were digested with N-glycanase, deglycosylated neutrophil Fc gamma RIII had a more rapid electrophoretic mobility than NK cell Fc gamma RIII, as is observed for the human Fc gamma RIII isoforms on normal cells. The neutrophil and NK cell Fc gamma RIII isoforms apparently result from cell-type specific expression of different forms of Fc gamma RIII mRNA. A TaqI RFLP was also found for human Fc gamma RIII. Monoclonal antibodies which have been used to distinguish the neutrophil and NK cell Fc gamma RIII isoforms and the NA1 and NA2 alleles of human neutrophil Fc gamma RIII were employed to study the expression of two Fc gamma RIII cDNA clones derived from neutrophils and NK cells. Fc gamma RIII encoded by the neutrophil-derived cDNA reacts with the monoclonal antibody CLBgran11, while the NK-cell Fc gamma RIII cDNA expresses the Fc receptor which carries an antigenic determinant recognized by the antibody GRM1. Characterization of hybrid Fc gamma RIII constructed by interchange of restriction fragments between the neutrophil and NK cell cDNAs allowed localization of antigenic determinants recognized by the monoclonal antibodies.


Phylogeny and taxonomy of the genus Tubakia s. lat.
The genus Tubakia is revised on the basis of morphological and phylogenetic data. The phylogenetic affinity of Tubakia to the family Melanconiellaceae (Diaporthales) was recently postulated, but new analyses based on sequences retrieved from material of the type species of Tubakia, T. dryina, support a family of its own, viz. Tubakiaceae fam. nov. Our phylogenetic analyses revealed the heterogeneity of Tubakia s. lat. which is divided into several genera, viz., Tubakia s. str., Apiognomonioides gen. nov. (type species: Apiognomonioides supraseptata), Involutiscutellula gen. nov. (type species: Involutiscutellula rubra), Oblongisporothyrium gen. nov. (type species: Oblongisporothyrium castanopsidis), Paratubakia gen. nov. (type species: Paratubakia subglobosa), Racheliella gen. nov. (type species: Racheliella wingfieldiana sp. nov.), Saprothyrium gen. nov. (type species: Saprothyrium thailandense) and Sphaerosporithyrium gen. nov. (type species: Sphaerosporithyrium mexicanum sp. nov.). Greeneria saprophytica is phylogenetically closely allied to Racheliella wingfieldiana and is therefore reallocated to Racheliella. Particular emphasis is laid on a revision and phylogenetic analyses of Tubakia species described from Japan and North America. Almost all North American collections of this genus were previously referred to as T. dryina s. lat., which is, however, a heterogeneous complex. Several new North American species have recently been described. The new species Sphaerosporithyrium mexicanum, Tubakia melnikiana and T. sierrafriensis, causing leaf spots on several oak species found in the North-Central Mexican state Aguascalientes and the North-Eastern Mexican state Nuevo León, are described, illustrated, and compared with similar species. Several additional new species are introduced, including Tubakia californica based on Californian collections on various species of the genera Chrysolepis, Notholithocarpus and Quercus, and T. dryinoides, T. oblongispora, T. paradryinoides, and Paratubakia subglobosoides described on the basis of Japanese collections. Tubakia suttoniana nom. nov., based on Dicarpella dryina, is a species closely allied to T. californica and currently only known from Europe. Tubakia dryina, type species of Tubakia, is epitypified, and the phylogenetic position and circumscription of Tubakia are clarified. A revised, supplemented key to the species of Tubakia and allied genera on the basis of conidiomata is provided.


Antinematode activity of Violacein and the role of the insulin/IGF-1 pathway in controlling violacein sensitivity in Caenorhabditis elegans.
The purple pigment violacein is well known for its numerous biological activities including antibacterial, antiviral, antiprotozoan, and antitumor effects. In the current study we identify violacein as the antinematode agent produced by the marine bacterium Microbulbifer sp. D250, thereby extending the target range of this small molecule. Heterologous expression of the violacein biosynthetic pathway in E. coli and experiments using pure violacein demonstrated that this secondary metabolite facilitates bacterial accumulation in the nematode intestine, which is accompanied by tissue damage and apoptosis. Nematodes such as Caenorhabditis elegans utilise a well-defined innate immune system to defend against pathogens. Using C. elegans as a model we demonstrate the DAF-2/DAF-16 insulin/IGF-1 signalling (IIS) component of the innate immune pathway modulates sensitivity to violacein-mediated killing. Further analysis shows that resistance to violacein can occur due to a loss of DAF-2 function and/or an increased function of DAF-16 controlled genes involved in antimicrobial production (spp-1) and detoxification (sod-3). These data suggest that violacein is a novel candidate antinematode agent and that the IIS pathway is also involved in the defence against metabolites from non-pathogenic bacteria.


[Congenital epiphyseal chondrodysplasia punctata. Study of 9 cases].
Clinical data of nine cases of chondrodysplasia punctata, eight males and one female are reported. Two males presented with rhizomelic form, characterized by severe symmetrical shortness of humeri and femora, marked metaphyseal changes, severe psychomotor retardation and cataracts. Consanguinity of parents in one of these cases was consistent with homozygote for an autosomal retarded physical development starting early in life. Cataracts were absent, and psychomotor development was normal except in two cases who were severely retarded. These two cases suffered also from congenital cardiomyopathy (one case of aortic coarctation and the other of severe pulmonary hypertension without shunts). These seven cases were diagnosed of Conradi-Hunermann type which is a mild form of disease.


Comparative effectiveness of angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers in patients with type 2 diabetes and retinopathy.
Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are effective treatments for diabetic retinopathy, but randomized trials and meta-analyses comparing their effects on macrovascular complications have yielded conflicting results. We compared the effectiveness of these drugs in patients with pre-existing diabetic retinopathy in a large population-based cohort. We conducted a propensity score-matched cohort study using Taiwan's National Health Insurance Research Database. We included adult patients prescribed an ACE inhibitor or ARB within 90 days after diagnosis of diabetic retinopathy between 2000 and 2010. Primary outcomes were all-cause death and major adverse cardiovascular events (myocardial infarction, ischemic stroke or cardiovascular death). Secondary outcomes were hospital admissions with acute kidney injury or hyperkalemia. We identified 11 246 patients receiving ACE inhibitors and 15 173 receiving ARBs, of whom 9769 patients in each group were matched successfully by propensity scores. In the intention-to-treat analyses, ARBs were similar to ACE inhibitors in risk of all-cause death (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.87-1.01) and major adverse cardiovascular events (HR 0.95, 95% CI 0.87-1.04), including myocardial infarction (HR 1.03, 95% CI 0.88-1.20), ischemic stroke (HR 0.94, 95% CI 0.85-1.04) and cardiovascular death (HR 1.01, 95% CI 0.88-1.16). They also did not differ from ACE inhibitors in risk of hospital admission with acute kidney injury (HR 1.01, 95% CI 0.91-1.13) and hospital admission with hyperkalemia (HR 1.01, 95% CI 0.86-1.18). Results were similar in as-treated analyses. Our study showed that ACE inhibitors were similar to ARBs in risk of all-cause death, major adverse cardiovascular events and adverse effects among patients with pre-existing diabetic retinopathy.


Tumor imaging and targeting potential of an Hsp70-derived 14-mer peptide.
We have previously used a unique mouse monoclonal antibody cmHsp70.1 to demonstrate the selective presence of a membrane-bound form of Hsp70 (memHsp70) on a variety of leukemia cells and on single cell suspensions derived from solid tumors of different entities, but not on non-transformed cells or cells from corresponding 'healthy' tissue. This antibody can be used to image tumors in vivo and target them for antibody-dependent cellular cytotoxicity. Tumor-specific expression of memHsp70 therefore has the potential to be exploited for theranostic purposes. Given the advantages of peptides as imaging and targeting agents, this study assessed whether a 14-mer tumor penetrating peptide (TPP; TKDNNLLGRFELSG), the sequence of which is derived from the oligomerization domain of Hsp70 which is expressed on the cell surface of tumor cells, can also be used for targeting membrane Hsp70 positive (memHsp70+) tumor cells, in vitro. The specificity of carboxy-fluorescein (CF-) labeled TPP (TPP) to Hsp70 was proven in an Hsp70 knockout mammary tumor cell system. TPP specifically binds to different memHsp70+ mouse and human tumor cell lines and is rapidly taken up via endosomes. Two to four-fold higher levels of CF-labeled TPP were detected in MCF7 (82% memHsp70+) and MDA-MB-231 (75% memHsp70+) cells compared to T47D cells (29% memHsp70+) that exhibit a lower Hsp70 membrane positivity. After 90 min incubation, TPP co-localized with mitochondrial membranes in memHsp70+ tumors. Although there was no evidence that any given vesicle population was specifically localized, fluorophore-labeled cmHsp70.1 antibody and TPP preferentially accumulated in the proximity of the adherent surface of cultured cells. These findings suggest a potential association between membrane Hsp70 expression and cytoskeletal elements that are involved in adherence, the establishment of intercellular synapses and/or membrane reorganization. This study demonstrates the specific binding and rapid internalization of TPP by tumor cells with a memHsp70+ phenotype. TPP might therefore have potential for targeting and imaging the large proportion of tumors (∼50%) that express memHsp70.


A comparison of palonosetron and dexamethasone for postoperative nausea and vomiting in orthopedic patients receiving patient-controlled epidural analgesia.
Postoperative nausea and vomiting (PONV) is one of the major concerns after anesthesia and surgery, and it may be more frequent in orthopedic patients receiving patient-controlled epidural analgesia (PCEA). The purpose of this study was to compare the effect of palonosetron and dexamethasone on the prevention of PONV in patients undergoing total joint arthroplasty and receiving PCEA. Patients scheduled for total hip or knee arthroplasty under spinal anesthesia/PCEA were randomly allocated to receive either intravenous palonosetron (0.075 mg, n = 50) or dexamethasone (5 mg, n = 50). Treatments were administered intravenously to the patients 30 min before the beginning of surgery. The total incidence of PONV and incidence in each time period, severity of nausea, need for rescue anti-emetics, pain score, and adverse effects during the first 48 h postoperatively were evaluated. The total incidence of PONV was lower in the palonosetron group compared with the dexamethasone group (18.4% vs. 36.7%, P = 0.042), but there were no statistically significant differences in incidence between the groups at all time points. No significant intergroup differences were observed in the severity of nausea, use of rescue anti-emetics, pain score, and adverse effects. Although there were no significant differences in the incidence of PONV between the treatment groups at all time points, intravenous palonosetron reduced the total incidence of PONV in orthopedic patients receiving PCEA compared with dexamethasone.


Late-onset bloodstream infections of Very-Low-Birth-Weight infants: data from the Polish Neonatology Surveillance Network in 2009-2011.
Late-Onset Bloodstream Infections (LO-BSI) continue to be one of the most important complications associated with hospitalization of infants born with very low birth weight (VLBW). The aims of this study were to assess the epidemiology of LO-BSI together with the risk factors and the distribution of causative pathogens at six Polish neonatal intensive care units that participated in the Polish Neonatology Surveillance Network from January 1, 2009 to December 31, 2011. The surveillance covered 1,695 infants whose birth weights were <1501 grams (VLBW) in whom LO-BSI was diagnosed >72 hours after delivery. Case LO-BSI patients were defined according to NeoKISS. Four hundred twenty seven episodes of LO-BSI were diagnosed with a frequency of 25.3% and an incidence density of 6.7/1000 patient-days (pds). Results of our multivariate analysis demonstrated that surgical procedures and lower gestational age were significantly associated with the risk of LO-BSI. Intravascular catheters were used in infants with LO-BSI significantly more frequently and/or for longer duration: Central venous cathters (CVC) (OR 1.29) and Peripheral venous catheters (PVC) (OR 2.8), as well as, the total duration of total parenteral nutrition (13 vs. 29 days; OR 1.81). Occurrence of LO-BSI was significantly associated with increased the length of mechanical ventilation (MV) (OR 2.65) or the continuous positive airway pressure (CPAP) (OR 2.51), as well as, the duration of antibiotic use (OR 2.98). The occurrence of more than one infection was observed frequently (OR 9.2) with VLBW with LO-BSI. Microorganisms isolated in infants with LO-BSI were dominated by Gram-positive cocci, and predominantly by coagulase-negative staphylococci (62.5%). Independent risk factor for LO-BSI in VLBV infants are: low gestational age and requirement for surgery. The incidence rates of LO-BSI especially CVC-BSI were higher in the Polish NICUs surveillance than those of other national networks, similar to the central- and peripheral utilization ratio.


Disentangling the Pelomedusa complex using type specimens and historical DNA (Testudines: Pelomedusidae).
Recent research has shown that the helmeted terrapin (Pelomedusa subrufa), a species that occurs throughout sub-Saharan Africa, in Madagascar and the southwestern Arabian Peninsula, consists of several deeply divergent genetic lineages. Here we examine all nominal taxa currently synonymized with Pelomedusa subrufa (Bonnaterre, 1789) and provide mitochondrial DNA sequences of type specimens or topotypic material for most taxa. Lectotypes are designated for Testudo galeata Schoepff, 1792, Pentonyx capensis Duméril & Bibron, 1835, Pelomedusa nigra Gray, 1863, Pelomedusa galeata var. disjuncta Vaillant & Grandidier, 1910, and Pelomedusa galeata damarensis Hewitt, 1935. For Pelomedusa gasconi Rochebrune, 1884, a taxon without preserved type material, a neotype is designated. Type material of Pentonix americana Cornalia, 1849, a nominal species without credible type locality, is lost and its identity remains questionable. Also the holotype of Pelomedusa galeata orangensis Hewitt, 1935 is lost, but its allocation to the only genetic lineage occurring in South Africa is unambiguous. Phylogenetic analyses of type sequences or topotypic material reveal that the remaining nominal taxa represent three of the nine previously identified lineages of Pelomedusa. Among these three lineages is the South African one. Type specimens of Pentonyx gehafie Rüppell, 1835 correspond to an additional distinct lineage. The present study provides a sound basis for a subsequent integrative taxonomic revision of the Pelomedusa complex.


The "Birmingham stitch"--avoiding slippage in laparoscopic gastric banding.
Slippage rates of 1.4-24 % are frequently quoted after adjustable gastric banding. This complication can be extremely serious and has contributed to many units offering more invasive interventions in the surgical management of morbid obesity. We present results of the first 1,140 Laparoscopic Bands performed in our unit. Between April 2003 and June 2007, 1140 consecutive patients, mean weight 121.5 kg (range 73-268 kg), mean body mass index (BMI) 44.3 kg/m(2) (range 35-88) underwent laparoscopic adjustable gastric banding (LAGB). An identical surgical technique of one gastropexy suture in addition to the two routine gastro-gastro tunnel sutures was used in all cases. Fluoroscopy-guided adjustments were performed at 3 and 6 months and fluoroscopic evaluations were performed later if clinically indicated. There was no mortality and only one major septic complication of gastric perforation 1 week postoperatively which was managed conservatively. The mean stay was 1.02 days (range 0-30 days). Excess percent BMI loss in these patients at 3, 6, 12, 18, 24, 30, and 36 months were 25.4%, 34.7%, 38.3%, 41.1%, 43.7%, 44.4%, and 58.9%, respectively. Slippage with urgent readmission occurred in one patient (0.08%) at 5 months. Two partial slippages were noticed at 12 and 18 months, respectively. One patient had the band removed and the other was treated by band deflation and repositioning 6 months later. These results demonstrate that in our unit, laparoscopic gastric band insertion is successful in producing weight loss and at the same time has a very low slippage and pouch dilatation rate. This difference is most probably secondary to operative technique.


Cold-adapted beta-galactosidase from the Antarctic psychrophile Pseudoalteromonas haloplanktis.
The beta-galactosidase from the Antarctic gram-negative bacterium Pseudoalteromonas haloplanktis TAE 79 was purified to homogeneity. The nucleotide sequence and the NH(2)-terminal amino acid sequence of the purified enzyme indicate that the beta-galactosidase subunit is composed of 1,038 amino acids with a calculated M(r) of 118,068. This beta-galactosidase shares structural properties with Escherichia coli beta-galactosidase (comparable subunit mass, 51% amino sequence identity, conservation of amino acid residues involved in catalysis, similar optimal pH value, and requirement for divalent metal ions) but is characterized by a higher catalytic efficiency on synthetic and natural substrates and by a shift of apparent optimum activity toward low temperatures and lower thermal stability. The enzyme also differs by a higher pI (7.8) and by specific thermodynamic activation parameters. P. haloplanktis beta-galactosidase was expressed in E. coli, and the recombinant enzyme displays properties identical to those of the wild-type enzyme. Heat-induced unfolding monitored by intrinsic fluorescence spectroscopy showed lower melting point values for both P. haloplanktis wild-type and recombinant beta-galactosidase compared to the mesophilic enzyme. Assays of lactose hydrolysis in milk demonstrate that P. haloplanktis beta-galactosidase can outperform the current commercial beta-galactosidase from Kluyveromyces marxianus var. lactis, suggesting that the cold-adapted beta-galactosidase could be used to hydrolyze lactose in dairy products processed in refrigerated plants.


Effects of dietary Ca2+ on erythrocyte Na(+)-transport systems in spontaneously hypertensive rats.
1. The purpose of this study was to determine the effect of dietary Ca2+ intake on blood pressure and erythrocyte Na+ transport in spontaneously hypertensive rats. 2. Spontaneously hypertensive rats and Wistar-Kyoto rats were fed diets with three different Ca2+ contents, 0.1% (low-Ca2+ diet), 0.6% (normal-Ca2+ diet) and 4.0% (high-Ca2+ diet), between 6 and 20 weeks of age. At 20 weeks of age, the levels of erythrocyte Na+ efflux, as well as Na+ and K+ contents in erythrocytes, were measured. 3. On the low-Ca2+ diet, spontaneously hypertensive rats showed an enhancement of hypertension. Conversely, on the high-Ca2+ diet, they showed an attenuation of the increase in blood pressure. Spontaneously hypertensive rats had a lower erythrocyte Na+ content and increased activity of the Na+ pump at higher levels of dietary Ca2+. Passive Na+ permeability and Na(+)-K+ co-transport were similar in spontaneously hypertensive rats on the low-, normal- and high-Ca2+ diets. There were no significant differences in blood pressure and in Na+ pump activity in WKY on the three different diets. 4. It is concluded that dietary Ca2+ might affect the regulation of blood pressure in spontaneously hypertensive rats by changing the activity of Na+ pump in the cell membrane.


Asthma and protracted bronchitis: who fares better during an acute respiratory infection?
Acute respiratory infections (ARI) are common in children, and symptoms range from days to weeks. The aim of this study was to determine if children with asthma have more severe ARI episodes compared with children with protracted bronchitis and controls. Parents prospectively scored their child's next ARI using the Canadian acute respiratory illness and flu scale (CARIFS) and a validated cough diary (on days 1-7, 10 and 14 of illness). Children were age- and season-matched. On days 10 and 14 of illness, children with protracted bronchitis had significantly higher median CARIFS when compared with children with asthma and healthy controls. On day 14, the median CARIFS were: asthma = 4.1 (interquartile range (IQR) 4.0), protracted bronchitis = 19.6 (IQR 25.8) and controls = 4.1 (IQR 5.25). The median cough score was significantly different between groups on days 1, 7, 10 and 14 (P < 0.001). A significantly higher proportion of children with protracted bronchitis (63%) were still coughing at day 14 in comparison with children with asthma (24%) and healthy controls (26%). Children with protracted bronchitis had the most severe ARI symptoms and higher percentage of respiratory morbidity at day 14 in comparison with children with asthma and healthy controls.


Co-Deposition of IgM and C3 May Indicate Unfavorable Renal Outcomes in Adult Patients with Primary Focal Segmental Glomerulosclerosis.
We aimed to investigate the effects of glomerular IgM and C3 deposition on outcomes of adult patients with primary focal segmental glomerulosclerosis (FSGS). In this retrospective analysis, 86 consecutive adult patients with biopsy-proven primary FSGS were stratified into 3 groups according to their histopathological features: IgM- C3-, IgM+ C3-, and IgM+ C3+. Primary outcome was defined as at least a 50% reduction in baseline estimated glomerular filtration rate (eGFR) or development of kidney failure, while complete or partial remission rates were secondary outcomes. Glomerular IgM deposits were found in 44 (51.1%) patients, 22 (25.5%) of which presented with accompanying C3 deposition. Patients in IgM+ C3+ group had higher level of proteinuria (5.6 g/24 h [3.77-8.5], p = 0.073), higher percentage of segmental glomerulosclerosis (20% [12.3-27.2], p = 0.001), and lower levels of eGFR (69 ± 37.2 mL/min/1.73 m2, p = 0.029) and serum albumin (2.71 ± 0.85 g/dL, p = 0.045) at the time of diagnosis. Despite 86.3% of patients in IgM+ C3+ group (19/22) received immunosuppressive treatment, the primary outcome was more common in patients in the IgM+ C3+ group compared with patients in IgM+ C3- and IgM- C3- groups (11 [50%] vs. 2 [9%] and 11 [26.1%] respectively [p = 0.010]). Complete or partial remission rates were lower in patients in the IgM+ C3+ group (5/22, 22.7%), as well (p = 0.043). Multivariate Cox regression analysis revealed that IgM and C3 co-deposition was an independent risk factor associated with primary outcome (hazard ratio 3.355, 95% CI 1.349-8.344, p = 0.009). Glomerular IgM and C3 co-deposition is a predictor of unfavorable renal outcomes in adult patients with primary FSGS.


Protein signaling and drug target activation signatures to guide therapy prioritization: Therapeutic resistance and sensitivity in the I-SPY 2 Trial.
Molecular subtyping of breast cancer is based mostly on HR/HER2 and gene expression-based immune, DNA repair deficiency, and luminal signatures. We extend this description via functional protein pathway activation mapping using pre-treatment, quantitative expression data from 139 proteins/phosphoproteins from 736 patients across 8 treatment arms of the I-SPY 2 Trial (ClinicalTrials.gov: NCT01042379). We identify predictive fit-for-purpose, mechanism-of-action-based signatures and individual predictive protein biomarker candidates by evaluating associations with pathologic complete response. Elevated levels of cyclin D1, estrogen receptor alpha, and androgen receptor S650 associate with non-response and are biomarkers for global resistance. We uncover protein/phosphoprotein-based signatures that can be utilized both for molecularly rationalized therapeutic selection and for response prediction. We introduce a dichotomous HER2 activation response predictive signature for stratifying triple-negative breast cancer patients to either HER2 or immune checkpoint therapy response as a model for how protein activation signatures provide a different lens to view the molecular landscape of breast cancer and synergize with transcriptomic-defined signatures.


Unilateral scrotal hernia repair in a ram lamb.
A hemilateral scrotal enlargement in a 5-month-old Hampshire ram lamb was diagnosed as a scrotal hernia. Surgical intervention revealed the herniation to involve only the omentum, with some testicular atrophy. The cause of this condition was thought to be trauma.


Assessing functional reorganization in visual cortex with simulated retinal lesions.
Macular degeneration (MD) causes central vision loss, removing input to corresponding representations in the primary visual cortex. There is disagreement concerning whether the cortical regions deprived of input can remain responsive, and the source of reported cortical responses is still debated. To simulate MD in controls, normally sighted participants viewed a bright central disk to adapt the retina, creating a transient 'retinal lesion' during a functional MRI experiment. Participants viewed blocks of faces, scrambled faces and uniform grey stimuli, either passively or whilst performing a one-back task. To assess the impact of the simulated lesion, participants repeated the paradigm using a more conventional mean luminance simulated scotoma without adaptation. Our results suggest our attempt to create a more realistic simulation of a lesion did not impact on responses in the representation of the simulated lesion. While most participants showed no evidence of stimulus-driven activation within the lesion representation, a few individuals (22%) exhibited responses similar to a participant with juvenile MD who completed the same paradigm (without adaptation). Reliability analysis showed that responses in the representation of the lesion were generally consistent irrespective of whether positive or negative. We provide some evidence that peripheral visual stimulation can also produce responses in central representations in controls while performing a task. This suggests that the 'signature of reorganization of visual processing', is not found solely in patients with retinal lesions, consistent with the idea that activity may be driven by unmasked top-down feedback.


Sexual arousal by dominance and submission in relation to increased reproductive success in the general population.
Sexual arousal by dominance and submissiveness was long considered a mental disorder. The origin of this sexual preference has not been clearly explained. This study scrutinizes the hypothesis that sexual arousal by hierarchical disparity is a manifestation of mating strategy by comparing number of offspring and self-reported attractiveness of the study participants. Our data were obtained from the general population via e-mail questionnaire (n=673, age 25-34 years and 35-44 years). Sexually dominant men aged 35-44 years had more biological male children. Both the sexually dominant men aged 35-44 years and sexually submissive women aged 35-44 years perceived themselves as being more attractive. Here we show that sexual arousal by dominance and submissiveness confers an increased capacity to pass on genes in the general population. We suggest that sexual arousal by dominance is likely to be the means by which the mating strategy is accomplished. Sexual arousal by dominance and submissiveness is a manifestation of mating strategy because such a behaviour results in an increased reproductive success and thus may lead to the preferential selection of individuals who prefer sexual arousal by hierarchical disparity. This fact explains why the high number of people is excited by sexual fantasies and activities connected to hierarchical disparity. This finding might open up novel insights into some reproductive medicine issues, as well as into such field as partnership therapy and partner violence.


Adjuvant chemotherapy for localised resectable soft tissue sarcoma in adults.
Individually, randomised trilas have not shown conclusively whether adjuvant chemotherapy benefits adult patients with localised resectable soft-tissue sarcoma. Adjuvant chemotherapy aims to lessen the recurrence of cancer after surgery with or without radiotherapy. The objective of this review was to assess the effects of adjuvant chemotherapy in adults with resectable soft tissue sarcoma after such local treatment. We searched the Cochrane Controlled Trials Register, UKCCCR Register of Cancer Trials, Physicians Data Query, EMBASE, MEDLINE and CancerLit. Randomised trials of adjuvant chemotherapy after local treatment in adults with localised resectable soft tissue sarcoma were included. Only trials in which accrual was completed by December 1992 were included. Individual patient data were obtained. Accuracy of data and quality of randomisation and follow-up of trials was assessed. Fourteen trials of doxorubicin-based adjuvant chemotherapy involving 1568 patients were included. Median follow-up was 9.4 years. For local recurrence-free interval the hazard ratio with chemotherapy was 0.73 (95% Confidence Interval 0.56-0.94). For distant recurrence-free interval it was 0.70 (95% CI 0.57-0.85). For overall recurrence-free survival it was 0.75 (95% CI 0.64-0.87). These correspond to significant absolute benefits of 6-10% at 10 years. For overall survival the hazard ratio of 0.89 (95% CI 0.76-1.03) was not significant but potentially represents an absolute benefit of 4% (95% CI -1 to 9) at 10 years. There was no consistent evidence of a difference in effect according to age, sex, stage, site, grade, histology, extent of resection, tumour size or exposure to radiotherapy. However, the strongest evidence of a beneficial effect on survival was shown in patients with sarcoma of the extremities. Doxorubicin-based adjuvant chemotherapy appears to significantly improve time to local and distant recurrence and overall recurrence-free survival in adults with localised resectable soft tissue sarcoma. There is some evidence of a trend towards improved overall survival.


Non-enzymatic modifications of prostaglandin H synthase 1 affect bifunctional enzyme activity - Implications for the sensitivity of blood platelets to acetylsalicylic acid.
Due to its ability to inhibit the blood platelet PGHS-1, acetylsalicylic acid (ASA, Aspirin(®)) is widely used as a preventive agent in atherothrombotic diseases. However, its beneficial effects seem to be lower in diabetic patients, suggesting that protein glycation may impair effective ASA-mediated acetylation process. On the other hand, it is proposed that ASA can prevent some of the late complications of diabetes by lowering the extent of glycation at protein free amino groups. The aim of this work was to evaluate the extents of non-enzymatic N-glycosylation (glycation) and acetylation of blood platelet PGHS-1 (COX-1) and the competition between glycation and acetylation was investigated in order to demonstrate how these two reactions may compete against platelet PGHS-1. When PGHS-1 was incubated with glycating/acetylating agents (glucose, Glu; 1,6-bisphosphofructose, 1,6-BPF; methylglyoxal, MGO, acetylsalicylic acid, ASA), the enzyme was modified in 13.4 ± 1.6, 5.3 ± 0.5, 10.7 ± 1.2 and 6.4 ± 1.1 mol/mol protein, respectively, and its activity was significantly reduced. The prior glycation/carbonylation of PGHS-1 with Glu, 1,6-BPF or MGO decreased the extent of acetylation from 6.4 ± 1.1 down to 2.5 ± 0.2, 3.6 ± 0.3 and 5.2 ± 0.2 mol/mol protein, respectively, but the enzyme still remained susceptible to the subsequent inhibition of its activity with ASA. When PGHS-1 was first acetylated with ASA and then incubated with glycating/carbonylating agents, we observed the following reductions in the enzyme modifications: from 13.4 ± 1.6 to 8.7 ± 0.6 mol/mol protein for Glu, from 5.3 ± 0.5 to 3.9 ± 0.3 mol/mol protein for 1,6-BPF and from 10.7 ± 1.2 to 7.5 ± 0.5 mol/mol protein for MGO, however subsequent glycation/carbonylation did not significantly affect PGHS-1 function. Overall, our outcomes allow to better understand the structural aspects of the chemical competition between glycation and acetylation of PGHS-1.