rSeqTU-A Machine-Learning Based R Package for Prediction of Bacterial Transcription Units.
A transcription unit (TU) is composed of one or multiple adjacent genes on the same strand that are co-transcribed in mostly prokaryotes. Accurate identification of TUs is a crucial first step to delineate the transcriptional regulatory networks and elucidate the dynamic regulatory mechanisms encoded in various prokaryotic genomes. Many genomic features, for example, gene intergenic distance, and transcriptomic features including continuous and stable RNA-seq reads count signals, have been collected from a large amount of experimental data and integrated into classification techniques to computationally predict genome-wide TUs. Although some tools and web servers are able to predict TUs based on bacterial RNA-seq data and genome sequences, there is a need to have an improved machine learning prediction approach and a better comprehensive pipeline handling QC, TU prediction, and TU visualization. To enable users to efficiently perform TU identification on their local computers or high-performance clusters and provide a more accurate prediction, we develop an R package, named rSeqTU. rSeqTU uses a random forest algorithm to select essential features describing TUs and then uses support vector machine (SVM) to build TU prediction models. rSeqTU (available at https://s18692001.github.io/rSeqTU/) has six computational functionalities including read quality control, read mapping, training set generation, random forest-based feature selection, TU prediction, and TU visualization.


Fibrinoid syndrome: a severe complication of vitrectomy surgery in diabetics.
Two hundred eighty consecutive vitrectomies in diabetic patients were studied retrospectively. In 15 eyes, interlacing fibrin-like strands appeared on the surface of the retina and behind the iris plane from two to 14 days postoperatively. One or two days later, a gelatinous mass formed in the center of the vitreous activity, leading to the development of tractional retinal detachment and rubeosis iridis with neovascular glaucoma. Large doses of systemic and topical corticosteroids reversed the fulminating course of this complication in six of 15 eyes. The combination of lens surgery or scleral buckling procedure with vitrectomy, and the presence of retinal detachment preoperatively seemed to predispose to this complication. It is possible that multiple surgical procedures performed during the same operation cause an increase in vascular permeability resulting in the formation of a gelatinous, fibrin-like material in the diabetic eye.


Polymerase chain reaction detection of Salmonella spp. in fecal samples of pet birds.
The aims of this study were 1) to determine the prevalence of Salmonella in clinically ill birds in aviaries in Ankara, Turkey, and 2) to compare conventional culture and polymerase chain reaction (PCR) for detection of Salmonella in feces from clinically ill pet birds. In the study, 185 fecal samples (feces and/or swabs) collected from the pet birds kept in the seven different aviaries in the city of Ankara were investigated for the existence of Salmonella spp. by bacterial isolation and PCR. The conventional isolation and identification methods were performed for Salmonella isolation from fecal cultures. Suspected colonies were confirmed with the Salmonella polyvalent O antiserum and serogrouped with Salmonella group-specific antiserum. PCR was performed after the fecal swabs were incubated for 18 hr in 10 ml of tetrathionate broth. Three (1.63%) out of 185 fecal samples were found to harbor Salmonella spp. by conventional identification tests and were found to belong to serogroup B. Five (2.7%) swab samples were found to harbor Salmonella DNA by PCR tests. As a conclusion, PCR following incubation of clinical samples in pre-enrichment broth seemed to be a fast and practicable method for Salmonella spp. diagnosis when compared to protracted labor-intensive conventional culture techniques.


Multiple sensitive periods in human visual development: evidence from visually deprived children.
Psychophysical studies of children deprived of early visual experience by dense cataracts indicate that there are multiple sensitive periods during which experience can influence visual development. We note three sensitive periods within acuity, each with different developmental time courses: the period of visually-driven normal development, the sensitive period for damage, and the sensitive period for recovery. Moreover, there are different sensitive periods for different aspects of vision. Relative to the period of visually driven normal development, the sensitive period for damage is surprisingly long for acuity, peripheral vision, and asymmetry of optokinetic nystagmus, but surprisingly short for global motion. A comparison of results from unilaterally versus bilaterally deprived children provides insights into the complex nature of interactions between the eyes during normal visual development.


A survey of patient dose and image quality factors for CT scanners in Victoria.
Image quality and dose parameters have been measured on most makes and models of CT scanners in Victoria. Image quality was assessed using a dose efficiency and imaging performance parameter (Q-value). Factors relating to patient dose were measured. Patient doses using CTDIw in mGy were determined for average size patients for the abdomen procedure. Guidance levels have been recommended for CT procedures in Victoria.


Racial Disparity in Postpartum Readmission due to Hypertension among Women with Pregnancy-Associated Hypertension.
Postpartum hypertension is a leading cause of readmission in the postpartum period. We aimed to examine the prevalence of racial/ethnic differences in postpartum readmission due to hypertension in women with antepartum pregnancy-associated hypertension. This was a multi-institutional retrospective cohort study of all women with antepartum pregnancy-associated hypertension diagnosed prior to initial discharge from January 2009 to December 2016. Antepartum pregnancy-associated hypertension, such as gestational hypertension, preeclampsia (with or without severe features), hemolysis, elevated liver enzyme, low platelet (HELLP) syndrome, and eclampsia was diagnosed based on American College of Obstetricians and Gynecologists Task Force definitions. Women with chronic hypertension and superimposed preeclampsia were excluded. Our primary outcome was postpartum readmission defined as a readmission due to severe hypertension within 6 weeks of postpartum. Risk factors including maternal age, gestational age at admission, insurance, race/ethnicity (self-reported), type of antepartum pregnancy-associated hypertension, marital status, body mass index (kg/m2), diabetes (gestational or pregestational), use of antihypertensive medications, mode of delivery, and postpartum day 1 systolic blood pressure levels were examined. Multivariable logistic regression models were performed to calculate adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs). Of 4,317 women with pregnancy-associated hypertension before initial discharge, 66 (1.5%) had postpartum readmission due to hypertension. Risk factors associated with postpartum readmission due to hypertension included older maternal age (aOR = 1.44; 95% CI: 1.20-1.73 for every 5 year increase) and non-Hispanic black race (aOR = 2.12; 95% CI: 1.16-3.87). In women with pregnancy-associated hypertension before initial discharge, non-Hispanic black women were at increased odds of postpartum readmission due to hypertension compared with non-Hispanic white women.


Embolus extravasation is an alternative mechanism for cerebral microvascular recanalization.
Cerebral microvascular occlusion is a common phenomenon throughout life that might require greater recognition as a mechanism of brain pathology. Failure to recanalize microvessels promptly may lead to the disruption of brain circuits and significant functional deficits. Haemodynamic forces and the fibrinolytic system are considered to be the principal mechanisms responsible for recanalization of occluded cerebral capillaries and terminal arterioles. Here we identify a previously unrecognized cellular mechanism that may also be critical for this recanalization. By using high-resolution fixed-tissue microscopy and two-photon imaging in living mice we observed that a large fraction of microemboli infused through the internal carotid artery failed to be lysed or washed out within 48 h. Instead, emboli were found to translocate outside the vessel lumen within 2-7 days, leading to complete re-establishment of blood flow and sparing of the vessel. Recanalization occurred by a previously unknown mechanism of microvascular plasticity involving the rapid envelopment of emboli by endothelial membrane projections that subsequently form a new vessel wall. This was followed by the formation of an endothelial opening through which emboli translocated into the perivascular parenchyma. The rate of embolus extravasation was significantly decreased by pharmacological inhibition of matrix metalloproteinase 2/9 activity. In aged mice, extravasation was markedly delayed, resulting in persistent tissue hypoxia, synaptic damage and cell death. Alterations in the efficiency of the protective mechanism that we have identified may have important implications in microvascular pathology, stroke recovery and age-related cognitive decline.


Current opinion on the management of iron deficiency anaemia in gastrointestinal diseases.
Iron deficiency is the most common cause of anaemia in the world. Despite frequently weak and masked clinical presentation of iron deficiency anaemia (IDA), this disease is very serious with complications leading to early mortality. In the developed countries IDA is predominantly diagnosed as the complication of another disease or as the result of major bleeding events. Diagnosis of IDA should be based on laboratory findings i.e. haemoglobin, mean corpuscular hemoglobin concentration and ferritin. Latter is the most sensitive marker for iron deficiency. Anaemia of chronic disease should be taken into an account as a potential differential diagnosis or coexisting state. For women in fertility age with IDA, gynaecological disorders should be ruled out first. Males and postmenopausal women with IDA should undergo upper, lower and in certain cases capsule endoscopy and/or enteroscopy to find a plausible cause of IDA. The ultimate goal of therapy is to find out and treat the primary cause of IDA. Iron body stores should be restored using either oral or parenteral iron preparations. The use of parenteral iron preparations in patients with gastrointestinal pathologies is often clinically substantiated for the treatment of IDA. Red blood cell transfusion should be administered in emergency cases only.


Pulmonary morphofunctional effects of acute myocardial infarction.
Acute myocardial infarction (AMI) may yield several respiratory changes. Nevertheless, no comprehensive pulmonary morphological/physiological correlation has been performed under this condition. The aims of the present investigation were: 1) to determine the respiratory parameters in an experimental model of coronary artery occlusion, 2) to relate these results to findings from lung histopathology, and 3) to evaluate the effects of propranolol used prior to AMI. Twenty-eight rats were anaesthetized and mechanically ventilated. In the control group (C), a suture line was passed around the left anterior descending coronary artery (LADCA). The infarct group (I) was similarly prepared but the LADCA was ligated and infarct resulted. In the control/propranolol (CP) and infarct/propranolol (IP) groups, propranolol was intravenously injected 5 min before surgery as performed in groups C and I, respectively. Lung static (EL,st) and dynamic (EL,dyn) elastances, airway resistance (RL,int), and viscoelastic/inhomogeneous pressure (deltaP2L) were determined before and 30, 60 and 120 min after surgery. In group I, EL,st, EL,dyn, RL,int and deltaP2L increased progressively throughout the experiment, and were higher than those found in groups C, CP and IP. All respiratory parameters but EL,st remained unaltered in group IP. Lung histopathological examination demonstrated alveolar, interstitial and intrabronchial oedema in group I. Group IP showed only interstitial oedema. Acute myocardial infarction yields lung resistive, elastic and viscoelastic changes. The last two results from alveolar and interstitial oedema, respectively. The previous use of propranolol diminishes respiratory changes.


Forensic animal DNA analysis using economical two-step direct PCR.
Wildlife forensic DNA analysis by amplification of a mitochondrial locus followed by DNA sequencing is routine, yet suffers from being costly and time-consuming. To address these disadvantages we report on a low-cost two-step direct PCR assay to efficiently analyze 12 forensically relevant mammalian sample types without DNA extraction. A cytochrome oxidase I degenerate-universal primer pair was designed and validated for the developed assay. The 12 sample types, which included bone, horn, feces, and urine, were amplified successfully by the assay using a pre-direct PCR dilution protocol. The average amplification success rate was as high as 92.5 % (n = 350), with an average PCR product concentration of 220.71 ± 180.84 ng/μL. Differences in amplification success rate and PCR product quantity between sample types were observed; however, most samples provided high quality sequences, permitting a 100 % nucleotide similarity to their respective species via BLAST database queries. The combination of PBS and Phire(®) Hot Start II DNA polymerase gave comparable amplification success rate and amplicon quantity with the proprietary commercial kits (P > 0.05, n = 350) but at considerably lower cost. The stability of the assay was tested by successfully amplifying samples that had been stored for up to 12 months. Our data indicate that this low-cost two-step direct amplification assay has the potential to be a valuable tool for the forensic DNA community.


Biological effects of power frequency electric and magnetic fields.
The Institute of Electrical and Electronics Engineers (IEEE) has made an analysis of six recent major scientific committee reports dealing with the biological effects of exposure to electric and magnetic fields associated with electric power distribution and utilization. The conclusions drawn from these committee reports are presented in this summary.


Effects of participatory workplace improvement program on stress-related biomarkers and self-reported stress among university hospital nurses: a preliminary study.
Although participatory workplace improvement programs are known to provide favorable effects on high stress occupations like nursing, no studies have confirmed its effect using biomarkers. The aim of this study was to determine whether a participatory workplace improvement program would decrease stress-related symptoms as evaluated by biomarkers and self-reported stress among hospital nurses. Three actions to alleviate job stress, which were determined through focus group interviews and voting, were undertaken for two months. A total of 31 female Japanese nurses underwent measurement of inflammatory markers, autonomic nervous activity (ANA), and perceived job stress (PJS) at three-time points; before the program (T1), within a week after the completion of the program (T2), and three months after the program (T3). A series of inflammatory markers (Interferon-γ, Interleukin (IL)-6, and IL-12/23p40) decreased significantly at T2, and IL-12/23p40 and IL-15 significantly decreased at T3 compared to T1, while ANA and PJS remained unchanged. Our participatory program exerted beneficial effects in reducing inflammatory responses, but not for ANA and PJS. Further investigations with a better study design, i.e., a randomized controlled trial, and a larger sample size are warranted to determine what exerted beneficial effects on inflammatory markers and why other outcomes remained unchanged.


Comparative study of the properties of the shoulder joint capsule with those of other joint capsules.
To compare the collagen structure of the shoulder joint with that of other joints, the collagen of shoulder, elbow, and hip joints was examined electron microscopically, electrophoretically, and by its response to mechanical stress. Collagen Types I, III, and V were common to joint capsules. Electron microscopy of shoulder and elbow joint capsules did not identify any structural difference. When subjected to a mechanical force, the shoulder joint showed a greater capacity to stretch than the elbow joint, and greater force was required to break the shoulder joint than the elbow joint.


Does incidental pride increase competency evaluation of others who appear careless? Discrete positive emotions and impression formation.
Emotion plays important and diverse roles across various social relations. Although the social functions of emotion have attracted increased attention, the effects of positive emotions such as pride on impression formation remain poorly understood. Drawing on social projection theory, this study examined how incidental experiences of pride influenced the impressions of those who made a blunder, along with two other characteristics: the person's warmth and competence. Participants were designated randomly to receive inductions of pride, awe, or a neutral emotion. Subsequently, they were asked to indicate their own impression of a person who had made a blunder and to rate their overall sense of that individual's warmth and competence. A laboratory experiment recruiting university students (Study 1, N = 79) demonstrated that pride, a positive emotion elicited by a self-relevant achievement, led to higher competency evaluations of others. However, a pre-registered online experiment in middle-aged adults (Study 2, N = 108) failed to replicate the effects of pride on competency evaluations of others. Furthermore, another pre-registered online experiment in younger adults (Study 3, N = 290) did not show successful manipulation of incidental emotions. These results suggest that strictly controlled experimental settings that induce robust incidental emotions might be better for demonstrating a strong pride effect on the evaluation of others.


Characterization of the Martian surface deposits by the Mars Pathfinder rover, Sojourner. Rover Team.
Sojourner, the Mars Pathfinder rover, discovered pebbles on the surface and in rocks that may be sedimentary-not volcanic-in origin. Surface pebbles may have been rounded by Ares flood waters or liberated by weathering of sedimentary rocks called conglomerates. Conglomerates imply that water existed elsewhere and earlier than the Ares flood. Most soil-like deposits are similar to moderately dense soils on Earth. Small amounts of dust are currently settling from the atmosphere.


On Neural Associative Memory Structures: Storage and Retrieval of Sequences in a Chain of Tournaments.
Associative memories enjoy many interesting properties in terms of error correction capabilities, robustness to noise, storage capacity, and retrieval performance, and their usage spans over a large set of applications. In this letter, we investigate and extend tournament-based neural networks, originally proposed by Jiang, Gripon, Berrou, and Rabbat (2016), a novel sequence storage associative memory architecture with high memory efficiency and accurate sequence retrieval. We propose a more general method for learning the sequences, which we call feedback tournament-based neural networks. The retrieval process is also extended to both directions: forward and backward-in other words, any large-enough segment of a sequence can produce the whole sequence. Furthermore, two retrieval algorithms, cache-winner and explore-winner, are introduced to increase the retrieval performance. Through simulation results, we shed light on the strengths and weaknesses of each algorithm.


En bloc resection of non-small cell lung cancer invading the thoracic inlet and intervertebral foramina.
In patients with non-small cell lung cancer invading the thoracic inlet, the transcervical approach does not permit removal of tumor in the intervertebral foramina. We report a variant that lifts this limitation. Through the transcervical approach, resectability was assessed and tumor-bearing structures were removed, leaving tumor-free margins. Standard upper lobectomy was performed, leaving the lobe in place. A posterior midline approach was used for multilevel unilateral laminectomy, nerve root division inside the spinal canal, and vertebral body division along the midline. The tumor was removed en bloc with the lung, ribs, and vessels through the posterior incision. Fixation of the spine was performed. Medical charts of patients treated with this technique between October 1994 and April 2001 were reviewed retrospectively. Seventeen patients (mean age 45 years) were treated. Resection of the upper lobe and T1 root was done in all 17 cases; 3- and 4-level hemivertebrectomies were done in 13 and 3 cases, respectively; 2-level total vertebral body resection and 2-level hemivertebrectomy were done in 1 case; and resections of the phrenic nerve and subclavian artery were done in 7 and 6 patients, respectively. There were no perioperative deaths or residual neurologic impairments. Postoperative complications were pneumonia (n = 6), cerebrospinal fluid leakage (n = 1), wound breakdown (n = 1), and bleeding necessitating reoperation (n = 1). The overall 3- and 5-year survivals were 39% and 20%, respectively. Non-small cell lung cancers invading the thoracic inlet and intervertebral foramina can be removed completely through a combined anterior transcervical and posterior midline approach, with good results.


Merkel cell carcinoma: combined surgery and radiation therapy.
Merkel cell carcinoma, first reported as "trabecular carcinoma" by Toker in 1972, is a dangerous, often fatal primary skin tumor. The current authors report eight patients, only one of whom is considered to have a totally successful clinical outcome. Two patients died and one was preterminal with widespread disease in 10 to 20 months. Two others had recurrence or metastases within a year, and two patients died early of intercurrent disease after first developing regional lymph node involvement. Review of 139 patients reported in the literature indicates local recurrence in 30 per cent, regional lymph node metastases in 50 per cent, and death from neoplasm in 18 per of the cases. All patients in the present series received radiation therapy with encouraging response. The tumor was quite radiosensitive, and in only one instance was there recurrence within an irradiated field. Wide surgical excision with prompt postoperative irradiation to the local site and regional lymphatics is the therapy of choice in early lesions. Regional lymphadenectomy is recommended whenever nodal involvement is suspected. Currently, an aggressive combined surgical and radio-therapeutic approach to this dangerous neoplasm appears warranted, although further data may show that early and routine use of radiotherapy in Merkel cell carcinoma could obviate the necessity for extensive operative procedures.


Multispecies microbial mutualisms on coral reefs: the host as a habitat.
Reef-building corals associate with a diverse array of eukaryotic and noneukaryotic microbes. Best known are dinoflagellates in the genus Symbiodinium ("zooxanthellae"), which are photosynthetic symbionts found in all reef-building corals. Once considered a single species, they are now recognized as several large, genetically diverse groups that often co-occur within a single host species or colony. Variation among Symbiodinium in host identities, tolerance to stress, and ability to colonize hosts has been documented, but there is little information on the ecology of zooxanthellar free-living stages and how different zooxanthellae perform as partners. Other microbial associates of reef corals are much less well known, but studies indicate that individual coral colonies host diverse assemblages of bacteria, some of which seem to have species-specific associations. This diversity of microbial associates has important evolutionary and ecological implications. Most mutualisms evolve as balanced reciprocations that allow partners to detect cheaters, particularly when partners are potentially diverse and can be transmitted horizontally. Thus, environmental stresses that incapacitate the ability of partners to reciprocate can destabilize associations by eliciting rejection by their hosts. Coral bleaching (the loss of zooxanthellae) and coral diseases, both increasing over the last several decades, may be examples of stress-related mutualistic instability.


Nature-Inspired Unconventional Approaches to Develop 3D Bioceramic Scaffolds with Enhanced Regenerative Ability.
Material science is a relevant discipline in support of regenerative medicine. Indeed, tissue regeneration requires the use of scaffolds able to guide and sustain the natural cell metabolism towards tissue regrowth. This need is particularly important in musculoskeletal regeneration, such as in the case of diseased bone or osteocartilaginous regions for which calcium phosphate-based scaffolds are considered as the golden solution. However, various technological barriers related to conventional ceramic processing have thus far hampered the achievement of biomimetic and bioactive scaffolds as effective solutions for still unmet clinical needs in orthopaedics. Driven by such highly impacting socioeconomic needs, new nature-inspired approaches promise to make a technological leap forward in the development of advanced biomaterials. The present review illustrates ion-doped apatites as biomimetic materials whose bioactivity resides in their unstable chemical composition and nanocrystallinity, both of which are, however, destroyed by the classical sintering treatment. In the following, recent nature-inspired methods preventing the use of high-temperature treatments, based on (i) chemically hardening bioceramics, (ii) biomineralisation process, and (iii) biomorphic transformations, are illustrated. These methods can generate products with advanced biofunctional properties, particularly biomorphic transformations represent an emerging approach that could pave the way to a technological leap forward in medicine and also in various other application fields.


Cost-effectiveness of cinacalcet hydrochloride for hemodialysis patients with severe secondary hyperparathyroidism in Japan.
Cinacalcet effectively reduces elevated levels of parathyroid hormone (PTH) in patients with secondary hyperparathyroidism (SHPT), even those with severe disease for whom parathyroidectomy can be the treatment of choice. The objective of this study was to estimate the cost-effectiveness of cinacalcet treatment in hemodialysis patients with severe SHPT in Japan. Cost-effectiveness analysis. Patients with severe SHPT (intact PTH >500 pg/mL) who were receiving hemodialysis in Japan. A Markov model was constructed from the health care system perspective in Japan. Patients were followed up over their lifetime. Dialysis costs were not included in the base case. Cinacalcet as an addition to conventional treatment compared to conventional treatment alone. In both arms, patients underwent parathyroidectomy if intact PTH level was >500 pg/mL for 6 months and they were eligible for surgery. Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). ICERs for cinacalcet for those who were eligible for surgery and those who were not were $352,631/QALY gained and $21,613/QALY gained, respectively. Sensitivity and scenario analyses showed that results were fairly robust to variations in model parameters and assumptions. In the probabilistic sensitivity analysis, cinacalcet was cost-effective in only 0.9% of simulations for those eligible for surgery, but in more than 99.9% of simulations for those ineligible for surgery, if society would be willing to pay $50,000 per additional QALY. Data for the long-term effect of cinacalcet on patient-level outcomes are limited. The model predicted rates for clinical events using data for the surrogate biochemical end points. The use of cinacalcet to treat severe SHPT is likely to be cost-effective for only those who cannot undergo parathyroid surgery for medical or personal reasons.


Visual-spatial sequence learning and memory in trained musicians.
Previous research has shown that musicians have enhanced visual-spatial abilities and sensorymotor skills. As a result of their long-term musical training and their experience-dependent activities, musicians may learn to associate sensory information with fine motor movements. Playing a musical instrument requires musicians to rapidly translate musical symbols into specific sensory-motor actions while also simultaneously monitoring the auditory signals produced by their instrument. In this study, we assessed the visual-spatial sequence learning and memory abilities of long-term musicians. We recruited 24 highly trained musicians and 24 nonmusicians, individuals with little or no musical training experience. Participants completed a visual-spatial sequence learning task as well as receptive vocabulary, nonverbal reasoning, and short-term memory tasks. Results revealed that musicians have enhanced visual-spatial sequence learning abilities relative to nonmusicians. Musicians also performed better than nonmusicians on the vocabulary and nonverbal reasoning measures. Additional analyses revealed that the large group difference observed on the visualspatial sequencing task between musicians and nonmusicians remained even after controlling for vocabulary, nonverbal reasoning, and short-term memory abilities. Musicians' improved visualspatial sequence learning may stem from basic underlying differences in visual-spatial and sensorymotor skills resulting from long-term experience and activities associated with playing a musical instrument.


Sorafenib enhances the antitumor effects of chemoradiation treatment by downregulating ERCC-1 and XRCC-1 DNA repair proteins.
Head and neck squamous cell carcinoma remains a challenging clinical problem because of the persisting high rate of local and distant failure due to the acquisition of chemo- and radioresistance. In this study, we examined if treatment with sorafenib, a potent inhibitor of Raf kinase and VEGF receptor, could reverse the resistant phenotype in tumor and tumor-associated endothelial cells, thereby enhancing the therapeutic efficacy of currently used chemoradiation treatment. We used both in vitro and in vivo models to test the efficacy of sorafenib either as a single agent or in combination with chemoradiation. Sorafenib, as a single agent, showed antitumor and angiogenesis properties, but the effects were more pronounced when used in combination with chemoradiation treatment. Sorafenib significantly enhanced the antiproliferative effects of chemoradiation treatment by downregulating DNA repair proteins (ERCC-1 and XRCC-1) in a dose-dependent manner. In addition, combination treatment significantly inhibited tumor cell colony formation, tumor cell migration, and tumor cell invasion. Combination treatment was also very effective in inhibiting VEGF-mediated angiogenesis in vitro. In a severe combined immunodeficient mouse xenograft model, combination treatment was very well tolerated and significantly inhibited tumor growth and tumor angiogenesis. Interestingly, following combination treatment, low-dose sorafenib treatment alone was highly effective as a maintenance regimen. Taken together, our results suggest a potentially novel strategy to use sorafenib to overcome chemo- and radioresistance in tumor and tumor-associated endothelial to enhance the effectiveness of the chemoradiation therapy.


[Effect of an antioxidant on vascular wall cell apoptosis markers after reconstructive operations].
This study was aimed at determining Bcl-2 and Bax proteins expression before and after reconstructive-repairing operations in patients with atherosclerosis obliterans of lower extremities and at assessing the effect of an antioxidant (vitamin E at a dose of 100 mg once daily for 1 month after surgery) on the dynamics of changes of Bcl-2 and Bax proteins in the postoperative period. The study included a total of 60 patients with stage III-IV lower limb atherosclerosis obliterans. All patients underwent reconstructive-repairing operations on the arteries of the aortofemoral segment. After surgery the patients were divided into two groups. Group A included 30 patients who during 1 month received additionally to basic therapy vitamin E at a daily dose of 100 mg. Group B was composed of 30 patients receiving basic therapy alone according to the National guidelines of managing patients with peripheral artery disease. All patients before, on POD 1, and 1 month after surgery were subjected to venous blood test aimed at determining Bcl-2 and Bax apoptosis proteins expression by means of enzyme-linked immunosorbent assay. In patients of groups A and B, the baseline level of Bcl-2 protein (4.75 and 4.2 ng/ml, respectively) was comparable with that in apparently healthy volunteers (5.3 ng/ml). The baseline levels of Bax protein in patients of the operated groups (26.9 and 26.0 ng/ml, respectively) were increased compared with the values in healthy volunteers (16.5 ng/ml). On POD 1 there was increased expression of Bax protein in Group A and B patients to 39.4 and 30.2 ng/ml, respectively. One month after surgery, Group B patients demonstrated a decrease in the Bcl-2 values below the baseline level - 1.1 ng/ml (p=0.003), with the Bax level continuing to increase - 36 ng/ml (p=0.004). In turn, Group A patients after 1 month were found to have increased levels of the Bcl-2 protein - 5.75 ng/ml, with the Bax level returning to the baseline values - 27.4 ng/ml. In stage III and IV lower limb obliterating atherosclerosis, the level of the Bax proapoptoric protein was higher than that in healthy volunteers. On POD 1, there occurred increased expression of the pro-apoptotic protein Bax and activation of apoptosis markers. On the background of using vitamin E at a dose of 100 mg once daily for 1 month, there was a decrease in level of the Bax propapoptotic protein (p=0.003) and an increase in level of the anti-apoptotic Bcl-2 protein level (p=0.0007).


Passive Brain-Computer Interfaces for Enhanced Human-Robot Interaction.
Brain-computer interfaces (BCIs) have long been seen as control interfaces that translate changes in brain activity, produced either by means of a volitional modulation or in response to an external stimulation. However, recent trends in the BCI and neurofeedback research highlight passive monitoring of a user's brain activity in order to estimate cognitive load, attention level, perceived errors and emotions. Extraction of such higher order information from brain signals is seen as a gateway for facilitation of interaction between humans and intelligent systems. Particularly in the field of robotics, passive BCIs provide a promising channel for prediction of user's cognitive and affective state for development of a user-adaptive interaction. In this paper, we first illustrate the state of the art in passive BCI technology and then provide examples of BCI employment in human-robot interaction (HRI). We finally discuss the prospects and challenges in integration of passive BCIs in socially demanding HRI settings. This work intends to inform HRI community of the opportunities offered by passive BCI systems for enhancement of human-robot interaction while recognizing potential pitfalls.


Holistic feedback approach with video and peer discussion under teacher supervision.
High quality feedback is vital to learning in medical education but many students and teachers have expressed dissatisfaction on current feedback practices. Lack of teachers' insight into students' feedback requirements may be a key, which might be addressed by giving control to the students with student led feedback practices. The conceptual framework was built on three dimensions of learning theory by Illeris and Vygotsky's zone of proximal development and scaffolding. We introduced a feedback session with self-reflection and peer feedback in the form of open discussion on video-recorded student performances under teacher's guidance. The aims of this qualitative study were to explore students' perception on this holistic feedback approach and to investigate ways of maximising effective feedback and learning. Semi-structured interviews were used to gather data which were evaluated using a thematic analytical approach. The participants were third year medical students of Imperial College London on clinical placements at Hillingdon Hospital. Video based self-reflection helped some students to identify mistakes in communication and technical skills of which they were unaware prior to the session. Those who were new to video feedback found their expected self-image different to that of their actual image on video, leading to some distress. However many also identified that mistakes were not unique to themselves through peer videos and learnt from both model performances and from each other's mistakes. Balancing honest feedback with empathy was a challenge for many during peer discussion. The teacher played a vital role in making the session a success by providing guidance and a supportive environment. This study has demonstrated many potential benefits of this holistic feedback approach with video based self-reflection and peer discussion with students engaging at a deeper cognitive level than the standard descriptive feedback.


Superiority of metastatic lymph node ratio to the 7th edition UICC N staging in gastric cancer.
To compare and evaluate the appropriate prognostic indicators of lymph node basic staging in gastric cancer patients who underwent radical resection. A total of 1042 gastric cancer patients who underwent radical resection and D2 lymphadenectomy were staged using the 6th and 7th edition International Union Against Cancer (UICC) N staging methods and the metastatic lymph node ratio (MLNR) staging. Homogeneity, discriminatory ability, and gradient monotonicity of the various staging methods were compared using linear trend χ(2), likelihood ratio χ(2) statistics, and Akaike information criterion (AIC) calculations. The area under the curve (AUC) was calculated to compare the predictive ability of the aforementioned three staging methods. Optimal cut-points of the MLNR were calculated as MLNR0 (0), MLNR1 (0.01-0.30), MLNR2 (0.31-0.50), and MLNR3 (0.51-1.00). In univariate, multivariate, and stratified analyses, MLNR staging was superior to the 6th and 7th edition UICC N staging methods. MLNR staging had a higher AUC, higher linear trend and likelihood ratio χ(2) scores and lower AIC values than the other two staging methods. MLNR staging predicts survival after gastric cancer more precisely than the 6th and 7th edition UICC N classifications and should be considered as an alternative to current pathological N staging.


Peripheral circulation of the prion infectious agent in transgenic mice expressing the ovine prion protein gene in neurons only.
For prion diseases, even if a large body of evidence indicates that both the lymphoreticular system (LRS) and peripheral nerves are involved in scrapie neuroinvasion, the processes by which prions invade the central nervous system are only partially understood. Transgenic Tg(OvPrP4) mice, which express the ovine prion protein (PrP) gene under the rat neuron-specific enolase promoter on a knockout background, were used to study prion extracerebral circulation after scrapie prions were inoculated via the intracerebral (ic) and the intraperitoneal (ip) route. Surprisingly, PrP(Sc) was detected in the spleens of mice inoculated ic with prions. Moreover, the absence of the ovine PrP(C) in nonneural tissue at the periphery did not stop neuroinvasion after ip challenge. Additionally, pilot studies performed in Tg(OvPrP4) mice that had undergone splenectomy before ic prion inoculation showed that the time course of the disease is delayed. Given that these mice express the ovine PrP gene in neuronal cells but not in nonnervous tissue, our results suggest that PrP(C) expressed by cells of the LRS are not necessary for neuroinvasion or for their ability to accumulate PrP(Sc) and emphasize the importance of extracerebral circulation of PrP(C) or PrP(Sc) for the development of the disease.


Introduction to the Special LDLensRad Focus Issue.
Recent epidemiological and experimental animal data, as well as reanalyses of data previously accumulated, indicate that the lens of the eye is more radiosensitive than was previously thought. This has resulted in a reduction of the occupational lens dose limit within the European Union countries, Japan and elsewhere. This Commentary introduces the work done by the LDLensRad Consortium contained within this Focus Issue, towards advancement of understanding of the mechanisms of low dose radiation cataract.


Improving oxidation stability of 2D MXenes: synthesis, storage media, and conditions.
Understanding and preventing oxidative degradation of MXene suspensions is essential for fostering fundamental academic studies and facilitating widespread industrial applications. Owing to their outstanding electrical, electrochemical, optoelectronic, and mechanical properties, MXenes, an emerging class of two-dimensional (2D) nanomaterials, show promising state-of-the-art performances in various applications including electromagnetic interference (EMI) shielding, terahertz shielding, electrochemical energy storage, triboelectric nanogenerators, thermal heaters, light-emitting diodes (LEDs), optoelectronics, and sensors. However, MXene synthesis using harsh chemical etching causes many defects or vacancies on the surface of the synthesized MXene flakes. Defective sites are vulnerable to oxidative degradation reactions with water and/or oxygen, which deteriorate the intrinsic properties of MXenes. In this review, we demonstrate the nature of oxidative degradation of MXenes and highlight the recent advancements in controlling the oxidation kinetics of MXenes with several promising strategic approaches, including careful control of the quality of the parent MAX phase, chemical etching conditions, defect passivation, dispersion medium, storage conditions, and polymer composites.


Neonatal bilirubin triage with transcutaneous meters: when is a blood draw necessary?
To find the optimal transcutaneous bilirubin (TcB) screening level in term neonates that minimizes the discomfort of phlebotomy, while protecting the child from harm and controlling costs. All available TcB and total serum bilirubin (TSB) measurements taken between 27 and 51 hours of life from a cohort of term newborns were analyzed in a retrospective chart review. TcB cutoffs between 6 and 12 mg/dL were evaluated for their negative predictive values (NPVs) for high risk (HR) and for the combination of high-intermediate risk and HR on the Bhutani TSB risk nomogram. One thousand seventy-one full-term newborns were entered into the study. Of 601 newborns with TcB < 7 mg/dL, none were HR by TSB. Of newborns with a TcB of < 8 mg/dL, 1 in 759 was HR. The NPVs for screening levels of 7 and 8 mg/dL were of 100% and 99.9%, respectively, for HR and 99% and 97.60%, respectively, for high-intermediate/HR. A cutoff at 12 mg/dL had NPVs of 99.3% for HR, with 7 neonates, and 92.7% for high-intermediate/HR, with 76 infants of 1041. In our center, term infants with a TcB of < 8 mg/dL may be safely discharged without a follow-up TSB, with the understanding that -1/1000 infants may be at HR for developing severe hyperbilirubinemia. Practices with universal follow-up may safely choose cutoffs up to 12 mg/dL. An institution's degree of comfort and confidence in follow-up of the newborn cohort will guide the choice of an appropriate TcB cutoff requiring a TSB.


The pathogenesis of climacteric syndrome and principle of acupuncture treatment based on TCM theory about brain.
The brain is the sea of marrow, stores the cerebral spirit and dominates all the life activities of the human body, which are the basic TCM knowledge about the brain. Based on this knowledge, the pathogenesis of climacteric syndrome is considered as consumption and deficiency of kidney-essence, and incoordination between the brain and kidney. The principle of acupuncture treatment should be soothing the mind and tonifying the kidney.


Epidemiological Approaches to Understanding the Link Between Type 2 Diabetes and Dementia.
Diabetes and dementia are two diseases that increased dramatically in most societies in direct proportion to increases in average life expectancy. The two conditions are strongly associated and there is much hope that understanding this association will unlock the enigma that is the pathogenesis of dementia. Previous studies suggest that type 2 diabetes is a risk factor for all-cause dementia, vascular dementia and Alzheimer's disease. However these estimates may not necessarily have taken into account the overlap in dementia pathologies or the competing risk of death. Although the link between diabetes and vascular disease is intuitive, it is now becoming clear that type 2 diabetes is also associated with reduced brain volumes and with progression of brain atrophy, apparently independent of its relation with cerebrovascular disease. This raises the possibility that type 2 diabetes may also contribute to neurodegeneration, and particularly tau pathology. Prospective studies that record extensive multimodal in-vivo biomarkers and conduct rigorous postmortem neuropathological examination are certainly required to tease apart these complex pathways. However monitoring cognitive outcomes from current observational studies and randomized clinical trials of new diabetes treatments could be equally valuable in reducing the dementia epidemic.


39·0°C versus 38·5°C ear temperature as fever limit in children with neutropenia undergoing chemotherapy for cancer: a multicentre, cluster-randomised, multiple-crossover, non-inferiority trial.
Fever in neutropenia is the most frequent complication of chemotherapy for cancer. The temperature limit defining fever used clinically varies. A higher limit can avoid unnecessary diagnoses in patients spontaneously recovering from fever. This trial primarily aimed to determine if a limit of 39·0°C ear temperature is non-inferior to 38·5°C regarding safety. This cluster-randomised, multiple crossover, non-blinded, non-inferiority trial was done in six Swiss Paediatric Oncology Group centres (clusters) in Switzerland. Patients (aged 1 to <18 years) with any malignancy and treated with myelosuppressive chemotherapy expected to last 2 months or more were repeatedly randomly assigned (1:1), at the cluster level, to either monthly 39·0°C or 38·5°C ear temperature limits for diagnosis of fever in neutropenia. Diagnosis below the randomised limit was allowed for clinical reasons. Such a diagnosis implied emergency hospitalisation, examinations (including blood culture), as-needed antipyretics, and empirical intravenous broad-spectrum antibiotics. The primary outcome was the rate of fever in neutropenia with safety relevant events (SRE) per chemotherapy year; we also assessed efficacy in terms of rate of fever in neutropenia. The non-inferiority margin was 1·33 for safety, and for effiacy, the superiority margin was 1·00. This trial is registered at ClinicalTrials.gov, number NCT02324231. 269 patients were recruited between April 28, 2016, to Aug 27, 2018, until the trial was stopped for success after the second interim analysis. Patients were repeatedly randomly assigned, with 1210 (48%) of 2547 randomisation periods and 92 (47%) of 195 chemotherapy years randomised to 39·0°C. SREs were diagnosed in 72 (20%) of 360 fever in neutropenia episodes (zero deaths, 16 intensive care unit admissions, 22 cases of severe sepsis, and 56 cases of bacteraemia). In 92 chemotherapy years randomised to the 39·0°C fever limit, 151 episodes of fever with neutropenia were diagnosed (1·64 per year), including 22 (15%) with SRE (0·24 per year). In 103 chemotherapy years randomised to 38·5°C, 209 episodes were diagnosed (2·03 per year), including 50 (24%) with SRE (0·49 per year). The mixed Poisson regression rate ratio (RR) of fever in neutropenia with SRE in 39·0°C versus 38·5°C was 0·56 (95% upper confidence bound 0·72). The corresponding RR of fever in neutropenia was 0·83 (95% upper confidence bound 0·98). In children with neutropenia and chemotherapy for cancer, 39·0°C ear temperature was safe and seemed efficacious. For Switzerland and comparable settings, 39·0°C can be recommended as new evidence-based standard fever limit except for patients with acute myeloid leukaemia or haematopoietic stem cell transplantation. Swiss Cancer League (KLS-3645-02-2015).


Aspects of stomatognathic system before and after adenotonsillectomy.
To verify the speech therapy aspects of the stomatognathic system, including phonoarticulatory structures (lips, tongue, and soft palate) and swallowing, respiratory, speech, and phonation (vocal quality and resonance) functions, before and after undergoing adenotonsillectomy. The study included 22 children, 17 males and 5 females, aged between 5 and 10 years, suffering from hypertrophy of palatine and adenoid tonsils, with surgical indication for adenotonsillectomy and with no previous speech therapy. The speech-language pathology evaluation was performed before surgery and during the period between 1 and 6 months after adenotonsillectomy. It consisted of an evaluation of structures (lips, tongue, and soft palate) and of swallowing (liquid), respiration (mode), speech, and phonation (voice quality and resonance) functions. To evaluate vocal quality and resonance, 15 participants with the postoperative evaluation carried out in a period from 1 to 2 months were considered. There were differences regarding nasal respiratory mode, lips closed at rest posture, changed tongue tonus, adequate mobility of the soft palate, changed tongue posture during liquid swallowing, and absence of interposition compensatory mechanism of lips in swallowing. Reduction in the frequency of distortion processes was also found. With regard to speech, little improvement in vocal quality and resonance was seen. Following adenotonsillectomy, some structures and functions can spontaneously readapt or improve. However, most children needed to be referred to speech therapy for readapting stomatognathic structures and the assessed functions.


Efficacy and safety of rituximab in the treatment of connective tissue disease-related interstitial lung disease.
Interstitial lung disease (ILD) represents a severe pulmonary complication of connective tissue diseases, rheumatoid arthritis (RA), and antineutrophil cytoplasmic antibody-associated vasculitis. Treatment of ILD, mainly based on immunosuppression, remains challenging. Rituximab (RTX), a monoclonal antibody binding to CD20, is considered a valuable therapeutic choice in cases of refractory ILD. Here, we review the available efficacy and safety data on the use of RTX in the treatment of rheumatic disease-related ILD. Despite controversial efficacy data, RTX seems to be able to stabilize or improve ILD related to RA and antisynthetase syndrome and in established and severe ILD complicating systemic sclerosis. Fewer data are available regarding ILD related to Sjögren syndrome, systemic lupus erythematosus, and antineutrophil cytoplasmic antibody-associated vasculitis. To date, few prospective studies are available and randomized trials are still ongoing with the purpose of exploring the role of RTX in this condition, including the supposed relationship between efficacy and ILD radiologic patterns and safety data, up to now derived mainly from RA studies. Despite an overall acceptable safety profile, concerns remain regarding an increased infectious disease risk in patients with ILD as well as possible lung toxicity and the increased rate of immune-mediated reactions in patients with connective tissue diseases. In conclusion, RTX is a relevant therapeutic option for rheumatic disease-related ILD despite the existing uncertainties; ongoing trials are expected to clarify its use.


Looking at a baby's heart through the lens of the mother's blood.
Congenital heart disease (CHD) comprises several cardiovascular abnormalities existing from birth. Cardiac defects range from minor asymptomatic lesions to potentially life-threatening situations. Early fetal echocardiography, the gold standard for the in-utero diagnosis of CHD, is inaccurate at identifying defects in pulmonary veins and atrioventricular valves or lesions that occur later or progress during pregnancy. In this issue of EMBO Molecular Medicine, Yin et al report new proteomic data on maternal blood samples and a novel bioinformatic and artificial intelligence approach for the early diagnosis and screening of CHD.


Psychological and sociodemographic predictors of premature discontinuation of a 1-year multimodal outpatient weight-reduction program: an attrition analysis.
Attrition rates of up to 77% have been reported in conservative weight-reduction programs for the treatment of obesity. In view of the cost of such programs to the health system, there is a need to identify the variables that predict premature discontinuation of treatment. Previous studies have focused mainly on somatic and sociodemographic parameters. The prospective influence of psychological factors has not been systematically investigated to date. A total of 164 patients (138 of whom were women) with a mean age of 45 years and a mean body mass index of 39.57 participated in a 1-year outpatient weight-reduction program at the Charité - Universitätsmedizin Berlin University Hospital. The program included movement therapy, dietary advice, psychoeducational and behavioral interventions, relaxation procedures, and consultations with a specialist in internal medicine and a psychologist. Patients also underwent regular laboratory and psychological testing. The results were evaluated using a t-test, χ(2)-test, and logistic regression analysis. Seventy-one of the 164 patients (61 women, mean age = 43 years, mean body mass index = 39.53) withdrew before the end of the program (attrition rate = 43.3%). While there were no differences between the somatic and metabolic characteristics of those who withdrew and those who remained, the sociodemographic and psychological factors had some relevance. In particular, "expectation of self-efficacy" (Fragebogen zu Selbstwirksamkeit, Optimismus und Pessimismus [SWOP]), "not working," "tiredness" (Berliner Stimmungsfragebogen [BSF]), "pessimism" (SWOP) and "positive reframing" (Brief-COPE) were found to play a role in whether participants subsequently dropped out of the treatment. "Support coping" (Brief-COPE) and "older age" prior to the start of treatment were identified as variables that promoted treatment adherence. The results are discussed in light of previous findings and with regard to whether the modules of the weight-reduction program should be adapted.


The availability of computed tomography for pulmonary staging in colorectal cancer.
Chest computed tomography is performed frequently for the preoperative pulmonary staging in colorectal cancers (CRCs) regardless of the result of chest x-ray (CXR) due to its high sensitivities and specificities. The advancement of CT technology detects more indeterminate lung lesions that may require further investigations, referrals and follow-up. The aim of this study was to suggest a guideline for performing chest CT for preoperative pulmonary staging in colorectal cancer. We performed a retrospective analysis of the records of patients who had chest CT preformed without the evidence of metastasis on CXR for preoperative pulmonary staging. Of 21 patients with metastatic nodules on chest CT, 23.8% showed pulmonary metastasis on positron emission tomography, 47.6% showed extrapulmonary metastasis on preoperative evaluation and 61.9% showed elevated serum carcinoembryonic antigen level above 10 ng/mL. These results showed significant value compared to patients without metastatic nodules. But, in analyzing patients with or without indeterminate nodules in the three contents listed above, there was no significance. In the patients with CRC who show normal CXR and exhibit positivity in PET, preoperative extrapulmonary metastasis and elevated serum CEA level above 10 ng/mL preoperatively, chest CT would be helpful in preoperative staging.


Effects of household chaos and parental responsiveness on child executive functions: a novel, multi-method approach.
Executive functions can be adversely affected by contextual risks in the home environment including chaos and parenting challenges. Furthermore, household chaos negatively influences parenting practices. Few studies, however, have examined the role of parenting in the association between household chaos and child executive functions. Using a sample of 128 school-aged children (mean = 61.9 months, SD = 2.0, range 58-68 months) and their mothers, the present study examined direct and indirect effects (via parental responsiveness) of household chaos on child executive functioning. Multi-measures were used including performance-based assessments, behavioural observations, questionnaires, and video-home tours. Household chaos had both a direct effect on child executive functions (β = - .31, 95% CI [- .58, - .04]) and an indirect effect (β = - .05, 95% [- .13, - .01]) via parental responsiveness. Further, the indirect effect was only significant for household instability. These findings indicate that parental responsiveness may be compromised by household chaos, with implications for the executive functions of school-aged children. Preventative strategies are needed to improve the stability in the home and strengthen parenting practices.


Two topical calcineurin inhibitors for the treatment of atopic dermatitis in pediatric patients: a meta-analysis of randomized clinical trials.
Two new topical immunomodulators, pimecrolimus cream and tacrolimus ointment for atopic dermatitis (AD) in pediatric patients, have provided alternatives to topical corticosteroids without the associated adverse events. To evaluate the efficacy and safety of tacrolimus ointment and pimecrolimus cream for the treatment of AD in pediatric patients. MEDLINE, Embase, the CNKI and Cochrane Library databases were searched up to December 2008. Additional data sources were manual searches of abstract proceedings and personal contact with investigators and pharmaceutical companies. Two investigators assessed the quality of trials with unified tables independently. Disagreements on validity assessment were resolved through discussion or consultation with the third author. Quality analysis of methodology was evaluated according to the Jadad scale, including randomization, blinding and patients' discontinuation. Twenty trials involving 6288 infants and children with AD met the inclusion criteria. More patients using tacrolimus had a good response than those in control groups including vehicle, 1% hydrocortisone acetate and 1% pimecrolimus, the corresponding OR were (4.56; 95%CI: 2.80 to 7.44), (3.92; 95% CI: 2.96 to 5.20) and (1.58; 95% CI: 1.18 to 2.12). The effect difference between 0.03% tacrolimus and 0.1% tacrolimus ointments was not statistically significant (OR = 0.90; 95% CI: 0.55 to 1.48). The incidence of adverse events of tacrolimus ointment or pimecrolimus cream was similar to the vehicle. The major adverse events were burning and pruritus. Both tacrolimus ointment and pimecrolimus cream are safe and effective in the treatment of AD in pediatric patients. Tacrolimus ointments were superior to pimecrolimus cream.


A small molecule chaperone rescues keratin-8 mediated trafficking of misfolded podocin to correct genetic Nephrotic Syndrome.
Podocin is a key membrane scaffolding protein of the kidney podocyte essential for intact glomerular filtration. Mutations in NPHS2, the podocin-encoding gene, represent the commonest form of inherited nephrotic syndrome (NS), with early, intractable kidney failure. The most frequent podocin gene mutation in European children is R138Q, causing retention of the misfolded protein in the endoplasmic reticulum. Here, we provide evidence that podocin R138Q (but not wild-type podocin) complexes with the intermediate filament protein keratin 8 (K8) thereby preventing its correct trafficking to the plasma membrane. We have also identified a small molecule (c407), a compound that corrects the Cystic Fibrosis Transmembrane Conductance Regulator protein defect, that interrupts this complex and rescues mutant protein mistrafficking. This results in both the correct localization of podocin at the plasma membrane and functional rescue in both human patient R138Q mutant podocyte cell lines, and in a mouse inducible knock-in model of the R138Q mutation. Importantly, complete rescue of proteinuria and histological changes was seen when c407 was administered both via osmotic minipumps or delivered orally prior to induction of disease or crucially via osmotic minipump two weeks after disease induction. Thus, our data constitute a therapeutic option for patients with NS bearing a podocin mutation, with implications for other misfolding protein disorders. Further studies are necessary to confirm our findings.


Preiser disease after repeated local glucocorticoid injections: A case report.
Preiser disease or avascular necrosis (AVN) of the scaphoid causes intolerable wrist pain and malalignment of the carpal bones. In previously reported cases, patients have had a history of steroid use for systemic illness such as autoimmune hemolytic anemia, systemic lupus erythematosus, or renal transplantation, or have had other risk factors, such as smoking, alcoholism, or infection. In particular, systemic glucocorticoid therapy has been most commonly associated with the disease. Although there are reports of AVN of the scaphoid induced by systemic glucocorticoids, no prior report has associated AVN of the carpal bones with repeated local injections of glucocorticoids. We present a case in which it was strongly suspected that AVN of the scaphoid was induced by repeated local glucocorticoid injections. The patient had no history of excessive alcohol use, smoking, or trauma, except for local repeated steroid injections. Initially, she had diagnosed with de Quervain's disease and was treated by repeated local glucocorticoid injections followed by surgery for de Quervain's disease. Five years after surgery for de Quervain's disease, the patient presented at our hospital with sudden onset of intolerable pain in her right wrist without a history of trauma. In spite of nonsurgical treatment with rest, immobilization, analgesia, and surgery, her wrist pain was not improved. After further repeated local steroid injections in her wrist, radiographs, and magnetic resonance imaging of her wrist showed the AVN of the scaphoid. Surgery was performed and the fragmented proximal scaphoid and the entire lunate were resected. The diagnosis was confirmed according to the histopathological examination of the proximal scaphoid bone, which showed the characteristic of AVN of the scaphoid. At follow-up evaluation, radiographs of the right wrist showed no progression of osteoarthritis. The patient had no tenderness or residual pain at the wrist and had no desire to pursue additional surgery. We have presented a case with AVN of the scaphoid, which was strongly suspected to be associated with the repeated local steroid injections. Further studies are required to more fully elucidate the association between AVN of the scaphoid and repeated local steroid injections.


An Open Effectiveness Trial of a Multimodal Inpatient Treatment for Depression and Anxiety Among Adults With Serious Mental Illness.
This prospective open effectiveness trial examined symptom change trajectories and rates of remission from depression and anxiety in an intensive multimodal inpatient treatment for adults with serious mental illness (SMI). Patient baseline characteristics were examined as mediators/moderators of treatment response. Adult inpatients with SMI (N = 994) completed an average of 39 days of inpatient treatment. Latent growth curve (LGC) methods were used to model symptom trajectories, estimating expected remission based on individual patterns of change observed across the sample. Absolute reductions in symptoms were substantial, with large effect size improvements for both depression (d = 1.21, 95% CI [1.13, 1.29]) and anxiety (d = 1.13, 95% CI [1.05, 1.21]). For those presenting with elevated depressive symptoms (Patient Health Questionnaire-Depression ≥ 5.0; 87.5% of the sample), 46.9% evidenced remission from admission to discharge. Among patients presenting with significant anxiety (Patient Health Questionnaire-Generalized Anxiety Disorder Screener ≥ 5.0; 84.5% of the sample), 50.0% evidenced remission from admission to discharge. Mediation analyses revealed that depression and anxiety severity decreased more rapidly with increasing age and initial levels of experiential avoidance. Rates of remission of depression and anxiety were greater than anticipated in this large cohort of adult SMI inpatients and may be related to intensity and length of hospitalization.


Earthquake Shaking and Damage to Buildings: Recent evidence for severe ground shaking raises questions about the earthquake resistance of structures.
Ground shaking close to the causative fault of an earthquake is more intense than it was previously believed to be. This raises the possibility that large numbers of buildings and other structures are not sufficiently resistant for the intense levels of shaking that can occur close to the fault. Many structures were built before earthquake codes were adopted; others were built according to codes formulated when less was known about the intensity of near-fault shaking. Although many building types are more resistant than conventional design analyses imply, the margin of safety is difficult to quantify. Many modern structures, such as freeways, have not been subjected to and tested by near-fault shaking in major earthquakes (magnitude 7 or greater). Damage patterns in recent moderate-sized earthquakes occurring in or adjacent to urbanized areas (17), however, indicate that many structures, including some modern ones designed to meet earthquake code requirements, cannot withstand the severe shaking that can occur close to a fault. It is necessary to review the ground motion assumed and the methods utilized in the design of important existing structures and, if necessary, to strengthen or modify the use of structures that are found to be weak. New structures situated close to active faults should be designed on the basis of ground motion estimates greater than those used in the past. The ultimate balance between risk of earthquake losses and cost for both remedial strengthening and improved earthquake-resistant construction must be decided by the public. Scientists and engineers must inform the public about earthquake shaking and its effect on structures. The exposure to damage from seismic shaking is steadily increasing because of continuing urbanization and the increasing complexity of lifeline systems, such as power, water, transportation, and communication systems. In the near future we should expect additional painful examples of the damage potential of moderate-sized earthquakes in urban areas. Over a longer time span, however, we can significantly reduce the risk to life and property from seismic shaking through better land utilization, improved building codes and construction practices, and at least the gradual replacement of poor buildings by more resistant buildings. Progress toward reducing risk from seismic shaking through better building design is slowed by deficiencies in our knowledge about the nature of damaging ground motion and the failure mechanisms in structures. For example, lacking observational data, seismologists must rely on simplified theoretical and numerical models of the earthquake process to estimate near-fault ground motion, especially for earthquakes as large as magnitude 7 and 8. Because such models have not been adequately tested against data, their reliability is unknown. Engineers lack detailed information about failure processes in structures during an earthquake. Although many structures have been instrumented to measure their response to an earthquake, few records have been obtained from buildings that actually sustained significant structural damage and few structures are properly instrumented to measure all the modes of deformation that are likely to contribute to failure. Moreover, the fact that many structures have withstood ground motion more intense than that assumed in their design indicates that conventional methods of design do not take into account important contributions to earthquake resistance by nonstructural elements and by the ability of structural elements to deform inelastically without necessarily causing failure of the structure. It is fortunate when such reserve resistance exists, but better understanding of the sources of reserve strength is needed to determine how large a margin of safety they confer and how they might be affected by changes in construction practices and materials with time. In the next few years we look forward to significant advances in knowledge and to more effective application of what is already known, largely because of substantial funding of research related to seismic engineering by the National Science Foundation (18). The increasing number of strong-motion seismographs operating in seismically active regions (19) will likely provide for the first time a number of records of damaging levels of ground motion. Significant effort is being directed toward obtaining near-fault records, although many probable sites of future large earthquakes remain inadequately instrumented, especially outside the conterminous United States. New and more complete information on building response and damage mechanisms will be obtained by improved instrumentation of structures and through laboratory investigations of failure in structures and structural elements. Further developments in computer technology and in computer modeling techniques will permit more realistic simulations of the seismic response of soils and structures that take into account their inelastic behavior and their strain-dependent properties. Earthquake design codes will continually be revised to better utilize existing knowledge concerning the nature of strong ground motion and the dynamic behavior of buildings during earthquakes and to incorporate new knowledge and also experiences gained from future earthquakes. We believe that application of new knowledge, improvements in earthquake-resistant design and construction, and remedial strengthening or replacement of weak existing structures can significantly reduce our current level of exposure to earthquake hazards.


Increased concentrations of bone sialoprotein in joint fluid after knee injury.
To detect evidence for localised changes in bone matrix metabolism after joint trauma and in post-traumatic osteoarthritis by quantification of bone sialoprotein in joint fluid and serum after knee injury in a cross sectional study. Samples of knee joint fluid and serum were obtained from volunteers with normal knees (n = 19), patients with rupture of the anterior cruciate ligament isolated or combined with tear of a meniscus (n = 114), and patients with isolated meniscus lesions (n = 80). Concentrations of bone sialoprotein were determined by ELISA. Concentrations of other markers of joint tissue metabolism in these samples were determined in previous investigations. The median concentrations of bone sialoprotein in joint fluid from healthy volunteers was 122 ng ml-1 (range 41 to 183). Concentrations of bone sialoprotein were increased in both injury groups compared with the reference group (median for cruciate ligament injury 146 ng ml-1, range 72 to 339; median for meniscus injury 166 ng ml-1, range 75 to 376). After injury, bone sialoprotein increased quickly and remained increased for six months. Bone sialoprotein in joint fluid was increased only in samples from joints with normal or nearly normal (fibrillated) cartilage, and was within reference range in joints with radiographic signs of osteoarthritis. Bone sialoprotein concentrations in joints with cruciate ligament injury were positively correlated with levels of aggrecan and cartilage oligomeric matrix protein fragments, and with levels of stromelysin-1 and tissue inhibitor of metalloproteinase-1. The ratios between the concentrations of bone sialoprotein in joint fluid and serum were > 1 in the majority of the cruciate ligament injury cases. The release of significant amounts of bone sialoprotein into joint fluid in connection with acute joint trauma may be associated with injury to, and active remodelling of, the cartilage-bone interface and subchondral bone. The findings are consistent with dramatic shifts in cartilage, bone, and synovial metabolism following joint injury. Bone sialoprotein concentrations in synovial fluid may be a useful marker of subchondral injury and remodelling following joint injury.


Activating the Wnt/β-Catenin Pathway for the Treatment of Melanoma--Application of LY2090314, a Novel Selective Inhibitor of Glycogen Synthase Kinase-3.
It has previously been observed that a loss of β-catenin expression occurs with melanoma progression and that nuclear β-catenin levels are inversely proportional to cellular proliferation, suggesting that activation of the Wnt/β-catenin pathway may provide benefit for melanoma patients. In order to further probe this concept we tested LY2090314, a potent and selective small-molecule inhibitor with activity against GSK3α and GSK3β isoforms. In a panel of melanoma cell lines, nM concentrations of LY2090314 stimulated TCF/LEF TOPFlash reporter activity, stabilized β-catenin and elevated the expression of Axin2, a Wnt responsive gene and marker of pathway activation. Cytotoxicity assays revealed that melanoma cell lines are very sensitive to LY2090314 in vitro (IC50 ~10 nM after 72hr of treatment) in contrast to other solid tumor cell lines (IC50 >10 uM) as evidenced by caspase activation and PARP cleavage. Cell lines harboring mutant B-RAF or N-RAS were equally sensitive to LY2090314 as were those with acquired resistance to the BRAF inhibitor Vemurafenib. shRNA studies demonstrated that β-catenin stabilization is required for apoptosis following treatment with the GSK3 inhibitor since the sensitivity of melanoma cell lines to LY290314 could be overcome by β-catenin knockdown. We further demonstrate that in vivo, LY2090314 elevates Axin2 gene expression after a single dose and produces tumor growth delay in A375 melanoma xenografts with repeat dosing. The activity of LY2090314 in preclinical models suggests that the role of Wnt activators for the treatment of melanoma should be further explored.


Best practices in free energy calculations for drug design.
Free energy calculations are increasingly of interest for computing biophysical properties of novel small molecules of interest in drug design, such as protein-ligand binding affinities and small molecule partition coefficients. However, these calculations are also notoriously difficult to implement correctly. In this article, we review standard methods for computing free energy differences via simulation, discuss current best practices, and examine potential pitfalls for computational researchers without extensive experience in such calculations. We include a variety of examples and tips for how to set up and conduct these calculations, including applications to relative binding affinities and absolute binding free energies.


Early on-treatment prediction of response to peginterferon alfa-2a for HBeAg-negative chronic hepatitis B using HBsAg and HBV DNA levels.
Peginterferon alfa-2a results in a sustained response (SR) in a minority of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). This study investigated the role of early on-treatment serum hepatitis B surface antigen (HBsAg) levels in the prediction of SR in HBeAg-negative patients receiving peginterferon alfa-2a. HBsAg (Architect from Abbott) was quantified at the baseline and during treatment (weeks 4, 8, 12, 24, 36, and 48) and follow-up (weeks 60 and 72) in the sera from 107 patients who participated in an international multicenter trial (peginterferon alfa-2a, n = 53, versus peginterferon alfa-2a and ribavirin, n = 54). Overall, 24 patients (22%) achieved SR [serum hepatitis B virus (HBV) DNA level < 10,000 copies/mL and normal alanine aminotransferase levels at week 72]. Baseline characteristics were comparable between sustained responders and nonresponders. From week 8 onward, serum HBsAg levels markedly decreased in sustained responders, whereas only a modest decline was observed in nonresponders. However, HBsAg declines alone were of limited value in the prediction of SR [area under the receiver operating characteristic curve (AUC) at weeks 4, 8, and 12 = 0.59, 0.56, and 0.69, respectively]. Combining the declines in HBsAg and HBV DNA allowed the best prediction of SR (AUC at week 12 = 0.74). None of the 20 patients (20% of the study population) in whom a decrease in serum HBsAg levels was absent and whose HBV DNA levels declined less than 2 log copies/mL exhibited an SR (negative predictive value = 100%). At week 12 of peginterferon alfa-2a treatment for HBeAg-negative CHB, a solid stopping rule was established with a combination of declines in serum HBV DNA and HBsAg levels from the baseline. Quantitative serum HBsAg in combination with HBV DNA enables on-treatment adjustments of peginterferon therapy for HBeAg-negative CHB.


Regulation of the expression of death receptors and their ligands by melatonin in haematological cancer cell lines and in leukaemia cells from patients.
Incorporation of new therapeutic agents remains as a major challenge for treatment of patients with malignant haematological disorders. Melatonin is an indolamine without relevant side effects. It has been shown previously to exhibit synergism with several chemotherapeutic drugs in Ewing sarcoma cells by potentiating the extrinsic pathway of apoptosis. It also sensitizes human glioma cells against TRAIL by increasing DR5 expression. Here, we report the induction of cell death by melatonin in several human malignant haematological cell lines through the activation of the extrinsic pathway of apoptosis. Such activation was mediated by the increase in the expression of the death receptors Fas, DR4 and DR5 and their ligands Fas L and TRAIL, with a remarkable rise in the expression of Fas and Fas L. The cytotoxic effect and the increase in Fas and Fas L were dependent on Akt activation. Results were corroborated in blasts from bone marrow and peripheral blood of acute myeloid leukaemia patients, where melatonin induced cell death and increased both Fas and Fas L expressions. We conclude that melatonin may be considered as a potential antileukaemic agent and its therapeutic use, either alone or in combination with current chemotherapeutic drugs, should be taken into consideration for further research.


Exploring the interconnectedness of fatigue, depression, anxiety and potential risk and protective factors in cancer patients: a network approach.
Researchers have extensively studied fatigue, depression and anxiety in cancer patients. Several risk and protective factors have been identified for these symptoms. As most studies address these constructs, independently from other symptoms and potential risk and protective factors, more insight into the complex relationships among these constructs is needed. This study used the multivariate network approach to gain a better understanding of how patients' symptoms and risk and protective factors (i.e. physical symptoms, social withdrawal, illness cognitions, goal adjustment and partner support) are interconnected. We used cross-sectional data from a sample of cancer patients seeking psychological care (n = 342). Using network modelling, the relationships among symptoms of fatigue, depression and anxiety, and potential risk and protective factors were explored. Additionally, centrality (i.e. the number and strength of connections of a construct) and stability of the network were explored. Among risk factors, the relationship of helplessness and physical symptoms with fatigue stood out as they were stronger than most other connections in the network. Among protective factors, illness acceptance was most centrally embedded within the network, indicating it had more and stronger connections than most other variables in the network. The network identified key connections with risk factors (helplessness, physical symptoms) and a key protective factor (acceptance) at the group level. Longitudinal studies should explore these risk and protective factors in individual dynamic networks to further investigate their causal role and the extent to which such networks can inform us on what treatment would be most suitable for the individual cancer patient.


Dengue viruses in the Caribbean. Twenty years of dengue virus isolates from the Caribbean Epidemiology Centre.
The first isolate of a dengue virus in the Americas was obtained in Trinidad and Tobago in 1953, and several dengue virus isolates were obtained in subsequent years. However, the systematic isolation and typing of dengue viruses in support of virus surveillance and outbreak investigations did not start until the creation of the Caribbean Epidemiology Centre (CAREC) in 1975. Since then, over two thousand viral isolates have been obtained and typed from many countries in the English and Dutch-speaking Caribbean. In this communication, virological data from 17 countries between 1977 and 1996 are presented and analyzed together for the first time with available epidemiological data. Types 1, 2 and 4 were isolated over the period, and geographic and temporal patterns in the distribution of the most prevalent strains are presented. The historical surveillance data is critically assessed. A temporal correlation with reported dengue incidence and rainfall data in Trinidad and Tobago is reported. Recent changes in epidemiological patterns are described, including reference to two large later outbreaks. Risk assessment of complicated forms of dengue virus infections in the Caribbean has been attempted, with some success. The importance of ongoing systematic surveillance is discussed.


The mitochondrial cyanide-resistant oxidase: structural conservation amid regulatory diversity.
Mitochondria from all plants, many fungi and some protozoa contain a cyanide-resistant, alternative oxidase that functions in parallel with cytochrome c oxidase as the terminal oxidase on the electron transfer chain. Characterization of the structural and potential regulatory features of the alternative oxidase has advanced considerably in recent years. The active site is proposed to contain a di-iron center belonging to the ribonucleotide reductase R2 family and modeling of a four-helix bundle to accommodate this active site within the C-terminal two-thirds of the protein has been carried out. The structural features of this active site are conserved among all known alternative oxidases. The post-translational regulatory features of the alternative oxidase are more variable among organisms. The plant oxidase is dimeric and can be stimulated by either alpha-keto acids or succinate, depending upon the presence or absence, respectively, of a critical cysteine residue found in a conserved block of amino acids in the N-terminal region of the plant protein. The fungal and protozoan alternative oxidases generally exist as monomers and are not subject to organic acid stimulation but can be stimulated by purine nucleotides. The origins of these diverse regulatory features remain unknown but are correlated with sequence differences in the N-terminal third of the protein.


Variation among alfalfa somaclones in copy number of repeated DNA sequences.
Repeated DNA sequences of alfalfa (Medicago sativa L.) somaclonal variants were analyzed to determine if changes in copy number had occurred during tissue culture. DNA clones containing highly repeated nuclear sequences from the diploid line HG2 (2x = 16) were slot blotted and probed with labeled DNAs from HG2 and several somaclones of HG2. Two DNA clones that differed visually in hybridization intensity among the plant DNAs and one clone that had constant hybridization intensity were selected and used as probes on Southern blots and slot blots containing equal quantities of DNAs from HG2 and 15 régénérants. Statistically significant differences were detected in the copy number of two anonymous DNA sequences initially selected as variable and in the copy number of sequences homologous to pea ribosomal DNA. Based on Southern blot analysis, these sequences appeared to be arranged as tandem repeats. The cloned sequence initially selected as stable did not vary significantly in copy number and it appeared to be arranged as a dispersed repeat. Both increases and decreases in copy number of repeated sequences were observed in plants from successive regeneration cycles. Results from this study indicate that specific repeated nuclear DNA sequences have changed copy number in plants regenerated from tissue culture.


In vitro laser scanning confocal microscopy and unsupervised segmentation: Quantification of cytosolic calcium and RNA distribution in hypoxic neurons.
The mimicry of neurodegenerative diseases in vitro can be observed through the induction of chronic hypoxia, and the impact of this stress is monitored using multiplexed imaging techniques. While laser scanning confocal microscopy (LSCM) is a valuable tool for observing single neurons under degenerative conditions, accurately quantifying RNA distribution and cell size by deep learning tools remains challenging due to the lack of annotated training datasets. To address this, we propose a framework that combines 3D tracking of RNA distribution and cell size identification using unsupervised image segmentation. Additionally, we quantified the calcium level in neurons using fluorescent microscopy using unsupervised image segmentation. First, we performed imaging of neuronal morphology using differential interference contrast (DIC) optics and RNA/calcium level imaging using fluorescent microscopy. Next, we performed k-means clustering-based cell segmentation. The results show that our framework can distinguish between distinct neuronal states under control and chronic hypoxic conditions. The analysis reveals that hypoxia induces a significant increase in cytosolic calcium level, reduction in neuron diameter, and alterations in RNA distribution.Clinical Relevance- The proposed framework is crucial to study the neurodegeneration process and evaluating the efficacy of neuroprotective drugs through image analysis.


Resting state functional connectivity of five neural networks in bipolar disorder and schizophrenia.
Bipolar disorder (BPD) and schizophrenia (SCZ) share clinical characteristics and genetic contributions. Functional dysconnectivity across various brain networks has been reported to contribute to the pathophysiology of both SCZ and BPD. However, research examining resting-state neural network dysfunction across multiple networks to understand the relationship between these two disorders is lacking. We conducted a resting-state functional connectivity fMRI study of 35 BPD and 25 SCZ patients, and 33 controls. Using previously defined regions-of-interest, we computed the mean connectivity within and between five neural networks: default mode (DM), fronto-parietal (FP), cingulo-opercular (CO), cerebellar (CER), and salience (SAL). Repeated measures ANOVAs were used to compare groups, adjusting false discovery rate to control for multiple comparisons. The relationship of connectivity with the SANS/SAPS, vocabulary and matrix reasoning was investigated using hierarchical linear regression analyses. Decreased within-network connectivity was only found for the CO network in BPD. Across groups, connectivity was decreased between CO-CER (p<0.001), to a larger degree in SCZ than in BPD. In SCZ, there was also decreased connectivity in CO-SAL, FP-CO, and FP-CER, while BPD showed decreased CER-SAL connectivity. Disorganization symptoms were predicted by connectivity between CO-CER and CER-SAL. Our findings indicate dysfunction in the connections between networks involved in cognitive and emotional processing in the pathophysiology of BPD and SCZ. Both similarities and differences in connectivity were observed across disorders. Further studies are required to investigate relationships of neural networks to more diverse clinical and cognitive domains underlying psychiatric disorders.


A conserved gene structure and expression regulation of miR-433 and miR-127 in mammals.
MicroRNAs play essential roles in many cellular processes. However, limited information is available regarding the gene structure and transcriptional regulation of miRNAs. We explored the gene cluster encoding miR-433/127 in mammalian species using bioinformatics and in vitro "gene" expression approaches. Multiple sequence alignments (MSA) showed that the precursors of miR-433 and of miR-127 exhibited 95% and 100% similarity, respectively, in human, chimpanzee, horse, dog, monkey, rat, cow, and mouse. MSA of the promoter sequences of miR-433 and of miR-127 revealed lower sequence similarity among these mammalian species. However, the distance between miR-433 and miR-127 was strikingly similar, which was between 986 and 1007 bp and the position of transcription factor (TF) binding motifs, including estrogen related receptor response element (ERRE), was well conserved. Transient transfection assays showed that promoters of miR-433 and of miR-127 from human, rat, and dog were activated by estrogen related receptor gamma (ERRgamma) and inhibited by small heterodimer partner (SHP). ChIP assays confirmed the physical association of ERRgamma with the endogenous promoters of miR-433 and miR-127. In vitro over-expression of the human, rat, or dog miR-433/127 loci in cells, using an expression vector containing miR-433/127 and their promoter regions, markedly induced a differential expression of both primary and mature miR-433 and miR-127, indicating that miR-433 and miR-127 were possessed from their independent promoters. Our studies for the first time demonstrate a conserved gene structure and transcriptional regulation of miR-433 and miR-127 in mammals. The data suggest that the miR-433/127 loci may have evolved from a common gene of origin.


[Psychedelics in the treatment of depression, anxiety, and obsessive-compulsive disorder].
There is a need for new, effective treatments for patients with (treatment-resistant) depressive disorders, anxiety disorders and obsessive-compulsive disorder (ocd). At the same time, there is renewed interest in psychedelics for the treatment of psychiatric disorders.
 AIM: To provide an overview of results from past and current research into psychedelics in the treatment of depression, anxiety disorders and ocd.
 METHOD: Literature search in Medline and PubMed databases, supplemented with cross-references and results from recent studies.
 RESULTS: There is a considerable evidence base for the atypical psychedelic ketamine. Ketamine has a rapid, beneficial effect on depression and suicidality; longer-term effects are less clear. Research into classical psychedelics for the treatment of depression and anxiety disorders is currently limited to a few small (open label) studies, although positive outcomes are reported even after a single administration, with potentially longer lasting benefits. Studies must be repeated in larger and more diverse groups of patients.
 CONCLUSION: Further research into efficacy, therapeutic mechanisms and intervention models is very worthwhile; for the benefit of patients, but also to provide a deeper insight into the psychotherapeutic and neurobiological mechanisms that play a role in (the treatment of) common mental disorders.


Delayed CSF lavage for arteriographic and morphological vasospasm after experimental SAH.
Irrigation of the subarachnoid space after aneurysmal subarachnoid hemorrhage (SAH) has been reported to alleviate subsequent arterial vasospasm. The authors have investigated the effect of lavage of the cerebrospinal fluid (CSF) space in the two-hemorrhage canine model of vasospasm. Twelve dogs had basilar cistern lavage with 120 cc of artificial CSF 24 hours after each of two SAH's, and 12 control dogs had two sequential SAH's without intervening lavage of clot. The amount of clot on the ventral brain stem was evaluated at sacrifice and was graded from 0 (no clot) to 4 (maximum clot) to assess the adequacy of clot removal. Dogs that had undergone lavage had a median grade of 1 (range Grade 0 to 2); control dogs had a median grade of 2 (range Grade 1 to 3.5, p less than 0.001. Wilcoxon rank sum test), indicating significant reduction of gross clot by lavage. The neurological findings were graded from 0 to 5, based on meningismus, ataxia, paresis, and cranial nerve deficits. No significant differences in neurological grade were found on any day between the two groups. Satisfactory angiograms were obtained before and 7 days after hemorrhage and were controlled for blood pressure and blood gases; these showed significant spasm in both groups. There was a mean reduction (+/- standard deviation) of 21.6% +/- 16.2% in basilar artery diameter in control dogs, compared to a 28.8% +/- 15.1% reduction in dogs with lavage (difference not significant, t-test). There was a strong, but insignificant, trend toward reduction of endothelial desquamation in the basilar and middle cerebral arteries in dogs with lavage compared to control animals (p = 0.06). Corrugation and tearing of the elastica, thickened intima, intimal fibroplasia, vacuolization of the endothelial or smooth-muscle cells, and presence of blood cells in the adventitia occurred similarly in both groups. It appears that cisternal lavage 24 hours after hemorrhage in this model has no effect on the angiographic, neurological, or most morphological sequelae of SAH, in spite of evidence for removal of clot as seen at sacrifice. Any postulated interaction of clot and vessel resulting in chronic vasospasm must occur before this time. Evaluation of the effect of much earlier lavage (for instance, 1 hour after hemorrhage) may elucidate the point at which vasospasm is instigated after SAH, and help in determining what factors cause vasospasm.


Transcriptomic Characterization of Bradyrhizobium diazoefficiens Bacteroids Reveals a Post-Symbiotic, Hemibiotrophic-Like Lifestyle of the Bacteria within Senescing Soybean Nodules.
The transcriptional activity of Bradyrhizobium diazoefficens isolated from soybean nodules was monitored over the period from symbiosis to late plant nodule senescence. The bacteria retained a near constant level of RNA throughout this period, and the variation in genes demonstrating increased, decreased, and/or patterned transcriptional activity indicates that the bacteria are responding to the changing environment within the nodule as the plant cells progress from an organized cellular structure to an unorganized state of internal decay. The transcriptional variation and persistence of the bacteria suggest that the bacteria are adapting to their environment and acting similar to hemibiotrophs, which survive both as saprophytes on live plant tissues and then as necrophytes on decaying plant tissues. The host plant restrictions of symbiosis make B. diazoefficiens a highly specialized, restricted hemibiotroph.


Prevalence and predictors of concomitant low sexual desire/interest and new-onset erectile dysfunction - a picture from the everyday clinical practice.
Prevalence and risk factors of concomitant primary low sexual desire/interest (LSD/I) and subsequent new-onset erectile dysfunction (ED) in men have been only partially investigated. We looked at the sociodemographic and clinical predictors of the concomitant condition of primary LSD/I - defined as the reduction in the usual level of SD/I which precedes ED or another sexual dysfunction - and new-onset ED (LSD/I + ED) in a cohort of consecutive Caucasian-European patients seeking their first medical help for sexual dysfunction at a single outpatient clinic in the everyday clinical practice setting. Data from 439 sexually active patients were analysed. Health-significant comorbidities were scored with the Charlson Comorbidity Index (CCI). Patients' LSD/I were evaluated according to the findings of a comprehensive sexual history. Moreover, patients completed the International Index of Erectile Function (IIEF). Descriptive statistics and logistic regression models tested the prevalence and predictors of LSD/I + ED as compared with ED only. Of the 439 men, LSD/I + ED was observed in 33 (4.2%) individuals. One of three men with LSD/I + ED was younger than 40 years. Patients complaining of LSD/I + ED or ED alone did not differ in terms of hormonal milieu. No significant differences emerged between groups in terms of sexual orientation, rates of stable sexual relationships, educational status, recreational habits and comorbid sexual dysfunctions. Patients with LSD/I + ED had significantly lower IIEF-sexual desire and IIEF-overall satisfaction scores than ED-only individuals (all p ≤ 0.003). At multivariable analysis younger age and severe CCI scores emerged as independent predictors of LSD/I + ED (all p ≤ 0.04). These findings showed that primary LSD/I is concomitant with new-onset ED in less than 5% of men seeking first medical help. Younger age and severe CCI emerged as independent predictors of LSD/I + ED. Patients with both conditions reported an impaired overall sexual satisfaction.