Combined oral contraceptive pills for treatment of acne.
Acne is a common skin disorder among women. Although no uniform approach to the management of acne exists, combination oral contraceptives (COCs), which contain an estrogen and a progestin, often are prescribed for women. To determine the effectiveness of combined oral contraceptives (COCs) for the treatment of facial acne compared to placebo or other active therapies. In January 2012, we searched for randomized controlled trials of COCs and acne in the computerized databases of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, POPLINE, and LILACS. We also searched for clinical trials in ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP) (Aug 2011). For the initial review, we wrote to researchers to seek any unpublished or published trials that we might have missed. We considered randomized controlled trials reported in any language that compared the effectiveness of a COC containing an estrogen and a progestin to placebo or another active therapy for acne in women. We extracted data on facial lesion counts, both total and specific (i.e., open or closed comedones, papules, pustules and nodules); acne severity grades; global assessments by the clinician or the participant, and discontinuation due to adverse events. Data were entered and analyzed in RevMan. For continuous data, we calculated the mean difference (MD) and 95% confidence interval (CI). For dichotomous data, we calculated the Peto odds ratio (OR) and 95% CI. The review includes 31 trials with 12,579 participants. Of 24 comparisons made, 6 compared a COC to placebo, 17 different COCs, and 1 compared a COC to an antibiotic. Of nine placebo-controlled trials with data for analysis, all showed COCs reduced acne lesion counts, severity grades and self-assessed acne compared to placebo. A levonorgestrel-COC group had fewer total lesion counts (MD -9.98; 95% CI -16.51 to -3.45), inflammatory and non-inflammatory lesion counts, and were more likely to have a clinician assessment of clear or almost clear lesions and participant self-assessment of improved acne lesions. A norethindrone acetate COC had better results for clinician global assessment of no acne to mild acne (OR 1.86; 95% CI 1.32 to 2.62). In two combined trials, a norgestimate COC showed reduced total lesion counts (MD-9.32; 95% CI -14.19 to -4.45), reduced inflammatory lesion and comedones counts, and more with clinician assessment of improved acne. For two combined trials of a drospirenone COC, the investigators' assessment of clear or almost clear skin favored the drospirenone group (OR 3.02; 95% CI 1.99 to 4.59). In one trial, the drospirenone-COC group showed greater (more positive) percent changes for total lesion count (MD 29.08; 95% CI 3.13 to 55.03), inflammatory and non-inflammatory lesion counts, and papule and closed comedone counts. A dienogest-COC group had greater percentage decreases in total lesion count (MD -15.30; 95% CI -19.98 to -10.62) and inflammatory lesion count, and more women assessed with overall improvement of facial acne. A CMA-COC group had more 'responders,' those with 50% or greater decrease in facial papules and pustules (OR 2.31; 95% CI 1.50 to 3.55)Differences in the comparative effectiveness of COCs containing varying progestin types and dosages were less clear, and data were limited for any particular comparison. COCs that contained chlormadinone acetate or cyproterone acetate improved acne better than levonorgestrel. A COC with cyproterone acetate showed better acne outcomes than one with desogestrel, but the studies produced conflicting results. Likewise, levonorgestrel showed a slight improvement over desogestrel in acne outcomes, but results were not consistent. A drospirenone COC appeared to be more effective than norgestimate or nomegestrol acetate plus 17β-estradiol but less effective than cyproterone acetate. This update yielded six new trials but no change in conclusions. The six COCs evaluated in placebo-controlled trials are effective in reducing inflammatory and non-inflammatory facial acne lesions. Few important and consistent differences were found between COC types in their effectiveness for treating acne. How COCs compare to alternative acne treatments is unknown since only one trial addressed this issue. The use of standardized methods for assessing acne severity would help in synthesizing results across trials as well as aid in interpretation.


Left ventricular isovolumic flow sequence during sinus and paced rhythms: new insights from use of high-resolution Doppler and ultrasonic digital particle imaging velocimetry.
We sought to clarify the role of isovolumic intervals during a cardiac cycle by in vivo visualization of left ventricular (LV) intracavitary flow dynamics. Asynchronous LV deformation during isovolumic contraction (IVC) and isovolumic relaxation (IVR) might represent a transient feature of myocardial wall mechanics that reverses the direction of blood flow. In 10 beating porcine hearts, the changes in LV intracavitary flow were recorded at baseline and after LV epicardial and right atrial pacing with high-resolution Doppler and contrast echocardiography. Two-dimensional vector flow fields were generated offline from B-mode contrast images with particle imaging velocimetry. During IVC, flow from the LV apex accelerated toward the base, whereas blood from the base was redirected toward the outflow through formation of an anterior vortex. Conversely, during IVR, flow was initially directed toward the apex and then briefly reversed toward the base. Epicardial pacing from the LV base altered the stages of flow redirection during the pre-ejection period and delayed mitral valve closure (28 +/- 14 ms vs. 61 +/- 13 ms, p < 0.001) and aortic valve opening (77 +/- 18 ms vs. 111 +/- 18 ms, p = 0.004). Isovolumic intervals are not periods of hemodynamic stasis but, rather, phases with dynamic changes in intracavitary flow. Experimentally induced aberrant epicardial electrical activation alters stages of flow redirection and prolongs the pre-ejection period. Normal electromechanical activation through the His-Purkinje system in mammalian hearts maintains an inherent synchrony with the sequence of intracavitary flow redirection.


Metal-Ligand Interactions in Scandium Complexes with Radiopharmaceutical Applications.
The radioisotopes of scandium (43Sc, 44Sc, and 47Sc) are potential candidates for use in imaging and therapy both separately and as elementally matched pairs for radiotheranostics. In the present study the bonding interactions of Sc3+ with 18 hepta- to decadentate ligands are compared using density functional theory (DFT) calculations. The bonding analysis is based on the natural bond orbital (NBO) model. The main contributions to the bonding were assessed using natural energy decomposition analysis (NEDA). Most of the ligands have anionic character (charges from 2- to 8-); thus the electrical term determines the major differences in the interaction energies. However, interesting features were found in the covalent contributions manifested by the ligand → Sc3+ charge transfer (CT) interactions. Significant differences could be observed in the energetic contributions of the N and O donors to the total CT.


Use of Rho kinase Inhibitors in Ophthalmology: A Review of the Literature.
The use of Rho Kinase (ROCK) inhibitors as therapeutic agents in ophthalmology has been a topic of discussion for several years, particularly in the realm of glaucoma, Fuchs' endothelial dystrophy, and diabetic retinopathy. In this review, the authors provide a detailed and comprehensive overview of the published literature on the use of Rho kinase inhibitors for the aforementioned purposes. A thorough search of several databases was conducted to find sufficient literature on ROCK inhibitors. This research found strong evidence demonstrating that inhibition of Rho kinase significantly decreases IOP, increases healing of the corneal endothelium, and decreases progression of diabetic retinopathy. The main side effect of ROCK inhibitors is conjunctival hyperemia that is often present in more than half of the patients in certain formulations. Additional clinical trials investigating the reviewed treatment options of Rho kinase inhibitors are necessary to further validate previous findings on the topic. Nonetheless, it is clear that Rho kinase inhibitors have the potential to be another potent therapeutic option for several chronic diseases in ophthalmology.


Teledebriefing: connecting learners to faculty members.
Simulation has become widespread among medical educators. Although simulation facilities are available at most teaching institutions, the number of qualified instructors to facilitate post-simulation debriefing is inadequate, resulting in sub-par educational experiences for learners. Efforts to broaden medical curricula to include simulation have been successful. An integral component of simulation-based education is the debriefing stage, in which learning and reflection are believed to be greatest. To be maximally effective, debriefing should be performed by faculty members who have both expertise in the subject matter and a strong grasp of debriefing principles. Unfortunately, the debriefing portion of simulation exercises is often performed in a sub-par fashion because many simulation centres do not have access to trained debriefers. As a result, the overall experience of simulation training programmes is reduced, and the exercises have much less educational benefit to the learner. This article outlines a novel use of videoconferencing technology for debriefing learners at remote locations, which we term teledebriefing. This can be accomplished in a cost-effective and straightforward manner using basic equipment: a smartphone and a television. Many simulation centres do not have access to trained debriefers Teledebriefing can create a mutually beneficial faculty instructor network between institutions. By connecting clinical educators from geographically distant areas or from specialties not available locally, learners are exposed to faculty that can provide content expertise and high-quality debriefing during simulation exercises. Evaluating the effectiveness and feasibility of teledebriefing is warranted.


Effect of written information on physicians' knowledge of drug prices.
Fifty-four residents in internal medicine and primary care medicine were surveyed before and after receiving a prescription drugs price guide booklet to determine whether providing written price information to the residents would improve their knowledge of drug costs. Results indicated that the pricing information did not improve the residents' knowledge of drug costs. It was also found that neither the residents' concern with the importance of drug cost nor their personal assessment of their knowledge of drug cost influenced their incorporation of drug price information into their professional data base.


Stochastic model of self-regulation decision making exemplified by decisions concerning hypoglycemia.
The following sequence-internal condition --> symptom perception --> appraisal --> decision-models various symptom-based self-regulation processes. A formal mathematical model describes the first three steps by continuous variables and the decisions at the fourth step by binary variables. The stochastic transitions between the sequential steps are quantified by transition probabilities. The model is illustrated by blood glucose level estimation and detection and treatment of hypoglycemia in 78 patients with insulin-dependent diabetes mellitus. These patients made 50 to 70 data collection trials over 3 to 4 weeks recording perceived symptoms, cognitive-motor performance, subjective estimates of blood glucose, decisions about treatment of hypoglycemia, and driving. A statistical estimation of the model's parameters demonstrates the utility of this approach for understanding the awareness, detection, and treatment of hypoglycemia as a process of symptom-based decision making.


Non-replicating deletion mutants of brome mosaic virus RNA-2 interfere with viral replication.
Naturally occurring defective interfering RNAs (DI-RNAs) and satellite RNAs greatly reduce the accumulation of their helper virus in vivo, but often modulate symptom expression in an unpredictable manner. Deletion mutants Nc/S, Na/M and Sa/Nc + M/S, derived from brome mosaic virus (BMV) RNA-2, failed to replicate when co-inoculated with BMV RNAs-1 and -2 to barley protoplasts. However, the inoculum RNA corresponding to these deletion mutants was extremely stable and could have been mistaken for plus-strand progeny had minus-strand progeny analysis been omitted. These results accentuate the need for such tests in evaluating the ability of mutant viral sequences to replicate. One of the mutants, Nc/S, effectively interfered with the accumulation of BMV RNAs-1 and -2 in barley protoplasts. This non-replicating interfering RNA was termed NRI RNA-2 Nc/S. When present with RNAs-1 and -2 at low inoculum amounts (1 microgram), NRI RNA-2 Nc/S reduced replication of RNA-2, the parental RNA, by 63% and preferentially interfered with minus-strand RNA accumulation. At higher levels (4 micrograms), it completely displaced replication of both RNAs-1 and -2. Mutations eliminating translation of a truncated p2a protein from NRI RNA-2 Nc/S did not alleviate the interference effect, demonstrating that a defective replicase protein was not responsible for the decreased accumulation of genomic RNA. At an NRI RNA: genomic RNA inoculum molar ratio of 1:1, NRI RNA-2 Nc/S reduced the accumulation of all helper virus RNAs by 55%. Since this reduction was seen for both wild-type RNA-3 and delta SGP RNA-3, a deletion mutant of RNA-3 that lacks the subgenomic promoter necessary for coat protein expression, it was evident that the effective interference mediated by NRI RNA-2 Nc/S was not mitigated by encapsidation. The ability of the NRI RNAs to mimic satellite DI RNAs in depressing helper virus replication suggests that their expression in transgenic plants may provide a new and widely applicable approach for inducing resistance to viral infection.


Molecular phylogeny of Sydowiellaceae--resolving the position of Cainiella.
Cainiella is an ascomycete genus associated with arctic alpine plants. The systematic position of Cainiella has long been unclear, with current classifications placing the genus in either Sordariales or Xylariales. Our molecular results, based on mtSSU, ITS and nLSU rDNA data, clearly show that the genus belongs in the Sydowiellaceae (Diaporthales). The study also includes new sequences of Sydowiellaceae and contributes to a better knowledge of the phylogenetic relationships of that family.


Giant negative T waves after treatment of severe hyperkalaemia.
We present the case of a 79-year-old female with severe hyperkalaemia and severe prerenal insufficiency due to dehydration and nephrotoxic medications, including spironolactone. The ECG showed AV nodal rhythm and tented T waves. After treatment with fluids, insulin, polystyrene sulphonate and sodium bicarbonate, the serum potassium level and kidney function normalised. Several days later, she developed QT prolongation with giant negative T waves without signs of ischaemia. In this report, we review the effect of hyperkalaemia on cardiac ion channel function and the associated changes on the ECG. In addition, the causes and mechanisms of giant negative T waves are discussed.


Media Use Among Students From Different Health Curricula: Survey Study.
Mobile devices such as smartphones, tablets, and laptop computers enable users to search for information and communicate with others at any place and any time. Such devices are increasingly being used at universities for teaching and learning. The use of mobile devices by students depends, among others, on the individual media literacy level and the curricular framework. The objective of this study was to explore whether there were differences in media use in students from various curricula at the Faculty of Health, Witten/Herdecke University. During the 2015-16 winter term, a survey was conducted at the Faculty of Health, Witten/Herdecke University, in which a total of 705 students (out of 1091 students; response rate: 705/1091, 64.61%) from 4 schools participated voluntarily: medicine (346/598), dentistry (171/204), psychology (142/243), and nursing science (46/46). The questionnaire developed for the study included 132 questions on 4 topics: (1) electronic and mobile devices (19 questions), (2) communication and organization of learning (45 questions), (3) apps/programs/websites/media (34 questions), and (4) media literacy (34 questions). The questionnaire was distributed and anonymously completed during in-class courses. Students from all 4 schools had at least two electronic devices, with smartphones (97.4%, 687/705) and laptops (94.8%, 669/705) being the most common ones. Students agreed that electronic devices enabled them to effectively structure the learning process (mean 3.16, SD 0.62) and shared the opinion that university teaching should include imparting media literacy (mean 2.84, SD 0.84). Electronic device ownership was the highest among medical students (mean 2.68, SD 0.86) and medical students were the only ones to use a tutorial (36.1%, 125/346). Dental students most widely used text messages (mean 3.41, SD 0.49) and social media (mean 2.57, SD 1.10) to organize learning. Psychology students considered mobile devices to be most ineffective (mean 2.81, SD 0.83). Nursing science students used emails (mean 3.47, SD 0.73) and desktop computers (39%, 18/46) most widely. The results show that almost all students use electronic learning (e-learning) tools. At the same time, different profiles for different degree programs become apparent, which are to be attributed to not only the varying curricula and courses but also to the life circumstances of different age groups. Universities should, therefore, pay attention to the diverse user patterns and media literacy levels of students when planning courses to enable successful use of e-learning methods.


A revealed preference analysis to develop composite scores approximating lung allocation policy in the U.S.
The patient ranking process for donor lung allocation in the United States is carried out by a classification-based, computerized algorithm, known as the match system. Experts have suggested that a continuous, points-based allocation framework would better serve waiting list candidates by removing hard boundaries and increasing transparency into the relative importance of factors used to prioritize candidates. We applied discrete choice modeling to match run data to determine the feasibility of approximating current lung allocation policy by one or more composite scores. Our study aimed to demystify the points-based approach to organ allocation policy; quantify the relative importance of factors used in current policy; and provide a viable policy option that adapts the current, classification-based system to the continuous allocation framework. Rank ordered logistic regression models were estimated using 6466 match runs for 5913 adult donors and 534 match runs for 488 pediatric donors from 2018. Four primary attributes are used to rank candidates and were included in the models: (1) medical priority, (2) candidate age, (3) candidate's transplant center proximity to the donor hospital, and (4) blood type compatibility with the donor. Two composite scores were developed, one for adult and one for pediatric donor allocation. Candidate rankings based on the composite scores were highly correlated with current policy rankings (Kendall's Tau ~ 0.80, Spearman correlation > 90%), indicating both scores strongly reflect current policy. In both models, candidates are ranked higher if they have higher medical priority, are registered at a transplant center closer to the donor hospital, or have an identical blood type to the donor. Proximity was the most important attribute. Under a points-based scoring system, candidates in further away zones are sometimes ranked higher than more proximal candidates compared to current policy. Revealed preference analysis of lung allocation match runs produced composite scores that capture the essence of current policy while removing rigid boundaries of the current classification-based system. A carefully crafted, continuous version of lung allocation policy has the potential to make better use of the limited supply of donor lungs in a manner consistent with the priorities of the transplant community.


Cross-dressed CD8α+/CD103+ dendritic cells prime CD8+ T cells following vaccination.
Activation of naïve cluster of differentiation (CD)8(+) cytotoxic T lymphocytes (CTLs) is a tightly regulated process, and specific dendritic cell (DC) subsets are typically required to activate naive CTLs. Potential pathways for antigen presentation leading to CD8(+) T-cell priming include direct presentation, cross-presentation, and cross-dressing. To distinguish between these pathways, we designed single-chain trimer (SCT) peptide-MHC class I complexes that can be recognized as intact molecules but cannot deliver antigen to MHC through conventional antigen processing. We demonstrate that cross-dressing is a robust pathway of antigen presentation following vaccination, capable of efficiently activating both naïve and memory CD8(+) T cells and requires CD8α(+)/CD103(+) DCs. Significantly, immune responses induced exclusively by cross-dressing were as strong as those induced exclusively through cross-presentation. Thus, cross-dressing is an important pathway of antigen presentation, with important implications for the study of CD8(+) T-cell responses to viral infection, tumors, and vaccines.


Index assignment for progressive transmission of full-search vector quantization.
The authors study codeword index assignment to allow for progressive image transmission of fixed rate full-search vector quantization (VQ). They develop three new methods of assigning indices to a vector quantization codebook and formulate these assignments as labels of nodes of a full-search progressive transmission tree. The tree is used to design intermediate codewords for the decoder so that full-search VQ has a successive approximation character. The binary representation for the path through the tree represents the progressive transmission code. The methods of designing the tree that they apply are the generalized Lloyd algorithm, minimum cost perfect matching from optimization theory, and a method of principal component partitioning. Their empirical results show that the final method gives intermediate signal-to-noise ratios (SNRs) that are close to those obtained with tree-structured vector quantization, yet they have higher final SNRs.


Should Facebook advertisements promoting a physical activity smartphone app be image or video-based, and should they promote benefits of being active or the app attributes?
Social media provides a convenient platform for health campaigns. However, practitioners designing such campaigns are faced with a number of decisions regarding advertising formats and appeals. This study set out to compare the effectiveness of two advertising formats (image vs. video) and two advertising appeals (benefits of being active vs. app attributes and features) for promoting a physical-activity smartphone app. The advertising experiment was conducted on Facebook and employed a 2 × 2 full-factorial experimental design, examining two advertising formats: image versus video and two advertising appeals: benefit versus attribute. Outcome measures were advertisement cost (number of viewers reached according to the amount spent) and consumer engagement (rates of advertisement click-through and app downloads). Chi-Square analysis revealed that advertisement cost was found to differ according to the type of advertising format used, with image advertisements achieving a greater audience reach than video advertisements (χ 2(1) = 905.292, p < .001). Consumer engagement also differed according to advertising format and appeal: images achieved high rates of advertisement click-through (2.7% vs. 1.9%; χ 2(1) = 196.9, p < .001) and app downloads (0.6% vs. 0.5%; χ 2(1) = 4.0, p = .044) compared with videos. Furthermore, benefit appeal advertisements were more effective than attribute appeals, yielding a greater rate of advertisement click-through (2.8% vs. 1.8%; χ 2(1) = 282.2, p < .001) and app downloads (0.7% vs. 0.4%; χ 2(1) =106.0, p < .001). Overall, image advertisements were seen to be the most cost-effective and engaging. Advertisements employing a benefit appeal achieved greater consumer engagement than and attribute appeal advertisements.


Supporting well-being in retirement through meaningful social roles: systematic review of intervention studies.
The marked demographic change toward greater proportions of older people in developed nations poses significant challenges for health and social care. Several studies have demonstrated an association between social roles in later life and positive health and well-being outcomes. After retiring from work, people may lose roles that provide purpose and social contacts. The outcomes of interventions to promote social roles in retirement have not been systematically reviewed. We examined three research questions: (1) What kinds of intervention have been developed to promote social roles in retirement? (2) How much have they improved perceived roles? (3) Have these roles improved health or well-being? We included those studies that evaluated the provision of social roles; used a control or comparison group; targeted healthy retirement-transition adults who were living in the community; provided an abstract written in English; took place in a highly developed nation; and reported social role, health, or well-being outcomes. We searched eight electronic databases and combined the results with hand searches. Through our searches, we identified 9,062 unique publications and eleven evaluative studies of acceptable quality, which reported seven interventions that met our inclusion criteria. These interventions varied in year of inception and scope, but only two were based outside North America. The studies rarely reported the quality or meaning of roles. Only three studies used random allocation, thus limiting inferences of causality from these studies. Interventions providing explicit roles and using supportive group structures were somewhat effective in improving one or more of the following: life satisfaction, social support and activity, physical health and activity, functional health, and cognition. Social role interventions may improve health and well-being for people in retirement transition. Future research should improve the quality of intervention and assessment and look at which interventions are most effective and acceptable in facilitating social roles for diverse older populations.


Sipuleucel-T (Provenge) autologous vaccine approved for treatment of men with asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer.
Sipuleucel-T (Provenge) (Sip-T) is first -in class as a therapeutic autologous vaccine approved for the treatment of men with asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer. This product is the culmination of decades of basic immunological and prostate cancer investigations and 13 y of clinical trial investigations. Sip-T represents a paradigm shift in cancer therapeutics and represents the first approved autologous therapeutic cancer vaccine, which has demonstrated a survival benefit. The potential benefit of this product is the excellent risk to benefit ratio, which will allow for the combination of this approach with other more toxic therapies. The favorable risk to benefit will also afford the opportunity for trials investigating this product earlier in the disease state and in combination with local therapies. The ability to target more localized or lower volume disease will maximize the therapeutic benefit over a longer period of time. The novelty of the platform of this approach could be used to treat any cancer with a tumor-specific cell surface target. The main product of Sip-T is the re-infusion of a patient's antigen presenting cells from leukapheresis after ex-vivo exposure to a chimeric protein of human GM-CSF and PAP. In metastatic CRPC patients three infusions of these activated cells over a month lead to statistically significant 4.1 mo increase in median survival and a 22.5% reduction in risk of death. The main side effect from this re-infusion of activated immune cells is a "flu-like" syndrome that includes chills, fatigue, fevers, back pain, nausea, joints aches and headaches in decreasing order of frequency. Immune monitoring during the clinical trials also demonstrated a specific cellular and antibody immune response, suggesting the proposed mechanism of adoptive immunotherapy to PAP was behind this survival benefit. This product also serves as a proof of principle for targeted immunotherapy for others cancers with defined cell surface markers. In summary, the approval of Sip-T based on a survival benefit and very tolerable safety profile will 1) enhance our ability to care for men with advanced prostate cancer, 2) allow for further investigations of this approach in combination with others therapies with different mechanisms of action and non-overlapping toxicities, and 3) allow further investigations earlier in the course of the disease.


Intraoperative 186Re-liposome radionuclide therapy in a head and neck squamous cell carcinoma xenograft positive surgical margin model.
Positive surgical margins in advanced head and neck squamous cell carcinoma (HNSCC) have a well-documented association with an increased risk of locoregional recurrence and significantly poorer survival. Traditionally, unresectable tumor is treated with postoperative radiotherapy and/or chemotherapy. However, these therapeutic options can delay treatment and increase toxicity. The potential value of intraoperative injection of liposomal therapeutic radionuclides as a locoregional, targeted therapy in unresectable advanced HNSCC was assessed in a nude rat xenograft positive surgical margin model. The therapeutic effects of beta-emission rhenium-186 (186Re) carried by liposomes into the tumor remnants in a nude rat squamous cell carcinoma xenograft model were studied. Following the partial resection of tumor xenografts, the animals were intratumorally injected with 186Re-labeled or unlabeled (control) neutrally charged or positively charged 100-nm-diameter liposomes. Tumor size, body weight, hematology, and toxicity were monitored for 35 days posttherapy. The neutral (n = 4) and cationic (n = 4) liposome control groups showed an increase in tumor growth of 288.0 +/- 37.3% and 292.2 +/- 133.7%, respectively, by day 15. The 186Re-neutral-liposome group (n = 8) and the 186Re-cationic-liposome group (n = 8) presented with an average final tumor volume of 25.6 +/- 21.8% and 28.5 +/- 32.2%, respectively, at the end of the study (day 35). All groups showed consistent increases in body weight. No significant systemic toxicity was observed in any of the animals. With excellent tumor suppression and minimal side-effect profile, the intraoperative use of liposomal therapeutic radionuclides may play a role in the management of positive surgical margins in advanced HNSCC.


Microhabitat characteristics of the critically endangered big-headed turtle Platysternon megacephalum.
Understanding the microhabitat requirements of an animal is vital for ensuring the success of targeted conservation and microhabitat restoration measures. The big-headed turtle (Platysternon megacephalum) is a freshwater species that is distributed across Southeast Asia. Owing to the human threats posed by illegal pet trade and overharvesting for food and medicinal purposes, the species has undergone rapid decline. However, in Hainan, their microhabitat characteristics are still unknown, which is neither conducive to the conservation of the species nor to the establishment of the Hainan Tropical Rainforest National Park. This study examined the microhabitat characteristics of P. megacephalum using sample plot methods in the Diaoluo Mountain area of Hainan Tropical Rainforest National Park. Our results indicated that P. megacephalum prefers stream microhabitats with rocky substrates, several caves, and a high diversity of food sources. Microhabitat characteristics did not differ significantly between adults and juveniles. Our results suggest that protecting microhabitats and main food sources is important for the conservation of P. megacephalum. Our findings provide a reference for the protection of this species in Jianfeng Ridge, Yingge Ridge, and other areas in Hainan Tropical Rainforest National Park.


Applying Risk Prediction Models to Optimize Lung Cancer Screening: Current Knowledge, Challenges, and Future Directions.
Risk prediction models may be useful for facilitating effective and high-quality decision-making at critical steps in the lung cancer screening process. This review provides a current overview of published lung cancer risk prediction models and their applications to lung cancer screening and highlights both challenges and strategies for improving their predictive performance and use in clinical practice. Since the 2011 publication of the National Lung Screening Trial results, numerous prediction models have been proposed to estimate the probability of developing or dying from lung cancer or the probability that a pulmonary nodule is malignant. Respective models appear to exhibit high discriminatory accuracy in identifying individuals at highest risk of lung cancer or differentiating malignant from benign pulmonary nodules. However, validation and critical comparison of the performance of these models in independent populations are limited. Little is also known about the extent to which risk prediction models are being applied in clinical practice and influencing decision-making processes and outcomes related to lung cancer screening. Current evidence is insufficient to determine which lung cancer risk prediction models are most clinically useful and how to best implement their use to optimize screening effectiveness and quality. To address these knowledge gaps, future research should be directed toward validating and enhancing existing risk prediction models for lung cancer and evaluating the application of model-based risk calculators and its corresponding impact on screening processes and outcomes.


Effective Synergy of Sorafenib and Nutrient Shortage in Inducing Melanoma Cell Death through Energy Stress.
Skin melanoma is one of the most aggressive and difficult-to-treat human malignancies, characterized by poor survival rates, thus requiring urgent novel therapeutic approaches. Although metabolic reprogramming has represented so far, a cancer hallmark, accumulating data indicate a high plasticity of cancer cells in modulating cellular metabolism to adapt to a heterogeneous and continuously changing microenvironment, suggesting a novel therapeutic approach for dietary manipulation in cancer therapy. To this aim, we exposed melanoma cells to combined nutrient-restriction/sorafenib. Results indicate that cell death was efficiently induced, with apoptosis representing the prominent feature. In contrast, autophagy was blocked in the final stage by this treatment, similarly to chloroquine, which also enhanced melanoma cell sensitization to combined treatment. Energy stress was evidenced by associated treatment with mitochondrial dysfunction and glycolysis impairment, suggesting metabolic stress determining melanoma cell death. A reduction of tumor growth after cycles of intermittent fasting together with sorafenib treatment was also observed in vivo, reinforcing that the nutrient shortage can potentiate anti-melanoma therapy. Our findings showed that the restriction of nutrients by intermittent fasting potentiates the effects of sorafenib due to the modulation of cellular metabolism, suggesting that it is possible to harness the energy of cancer cells for the treatment of melanoma.


High throughput in silico identification and characterization of Plasmodium falciparum PRL phosphatase inhibitors.
Kinases and phosphatases are involved in many essential processes in Plasmodium lifecycle. Among the identified 67 Plasmodium falciparum phosphatases, Phosphatase of Regenerating Liver (PRL) family protein homolog, PfPRL, is an essential parasite tyrosine phosphatase. PfPRL is shown to be prenylated, secreted, and involved in the host invasion process. In the present study, a structure-based high throughput in silico screening of PfPRL binders, using ChEMBL-NTD compounds lead to the identification of nine compounds based on binding energy, Lipinski rule of five, and QED score. The most of the shortlisted compounds are known to inhibit parasite growth at a concentration (EC50) ≤2 μm in in vitro P. falciparum culture assays. MD simulations were carried out on the shortlisted nine potential enzyme-inhibitor complexes to analyze specificity, stability, and to calculate the free binding energies of the complexes. The study identifies PfPRL as one of the potential drug targets for selected ChEMBL-NTD compounds that may be exploited as a scaffold to develop novel antimalarials.


An individual patient-based meta-analysis of tamoxifen versus ovarian ablation as first line endocrine therapy for premenopausal women with metastatic breast cancer.
We performed a meta-analysis of randomized trials comparing tamoxifen to ovarian ablation carried out either by surgery or irradiation as first-line hormonal therapy for pre-menopausal women with metastatic breast cancer. Patients in all trials included were required to have measurable disease and to be currently menstruating or within 1 year of cessation of menses, and to have estrogen receptor (ER) positive or unknown disease (ER negative women were admitted to one of the studies). Individual patient data were obtained from the four studies identified and the results updated to June 1992. A total of 220 eligible patients were enrolled in the four trials. There was no difference in overall response rate between tamoxifen and oophorectomy across the four trials (p = 0.94, Mantel-Haenszel test). The odds reduction for progression was 14% +/- 12% and for mortality 6% +/- 13% in favour of tamoxifen, results which were not statistically significant (p = 0.32 and 0.72, respectively). Although the design of all four studies included a cross-over to the other therapy, only 54/111 patients receiving ovarian ablation and 34/109 patients receiving tamoxifen as primary therapy actually crossed over to the other arm at the time of disease progression. Response to initial treatment with tamoxifen was predictive of subsequent response to ovarian ablation (p < 0.05), and response to initial therapy with ovarian ablation was predictive of subsequent response to tamoxifen (p < 0.05). Support curves based on log-likelihood ratios revealed that this meta-analysis provides moderate evidence rejecting a 14% advantage for ovarian ablation compared to tamoxifen in terms of odds of disease progression. A 25% advantage for ovarian ablation with respect to odds of death is also rejected with moderate evidence. We conclude that the efficacy of tamoxifen appears to be similar to that of ovarian ablation by surgery or irradiation as first-line therapy for premenopausal, ER positive metastatic breast cancer, and is unlikely to be substantially inferior.


AKR1A1 Variant Associated With Schizophrenia Causes Exon Skipping, Leading to Loss of Enzymatic Activity.
Schizophrenia is a heterogeneous psychiatric disorder characterized by positive symptoms such as hallucinations and delusions, negative symptoms such as anhedonia and flat affect, and cognitive impairment. Recently, glucuronate (GlucA) levels were reported to be significantly higher in serum of patients with schizophrenia than those in healthy controls. The accumulation of GlucA is known to be related to treatment-resistant schizophrenia, since GlucA is known to promote drug excretion by forming conjugates with drugs. However, the cause of GlucA accumulation remains unclear. Aldo-keto reductase family one member A1 (AKR1A1) is an oxidoreductase that catalyzes the reduction of GlucA. Genetic loss of AKR1A1 function is known to result in the accumulation of GlucA in rodents. Here, we aimed to explore genetic defects in AKR1A1 in patients with schizophrenia, which may result in the accumulation of GlucA. We identified 28 variants of AKR1A1 in patients with schizophrenia and control subjects. In particular, we identified a silent c.753G > A (rs745484618, p. Arg251Arg) variant located at the first position of exon 8 to be associated with schizophrenia. Using a minigene assay, we found that the c.753G > A variant induced exon 8 skipping in AKR1A1, resulting in a frameshift mutation, which in turn led to truncation of the AKR1A1 protein. Using the recombinant protein, we demonstrated that the truncated AKR1A1 completely lost its activity. Furthermore, we showed that AKR1A1 mRNA expression in the whole blood cells of individuals with the c.753G > A variant tended to be lower than that in those without the variants, leading to lower AKR activity. Our findings suggest that AKR1A1 carrying the c.753G > A variant induces exon skipping, leading to a loss of gene expression and enzymatic activity. Thus, GlucA patients with schizophrenia with the c.753G > A variant may show higher GlucA levels, leading to drug-resistant schizophrenia, since drug excretion by GlucA is enhanced.


The Effects of Acute Low-Volume HIIT and Aerobic Exercise on Leukocyte Count and Redox Status.
A single bout of exercise can result in inflammatory responses, increased oxidative stress and upregulation of enzymatic antioxidant mechanisms. Although low-volume high-intensity interval training (HIIT) has become popular, its acute responses on the above mechanisms have not been adequately studied. The present study evaluated the effects of HIIT on hematological profile and redox status compared with those following traditional continuous aerobic exercise (CET). Twelve healthy young men participated in a randomized crossover design under HIIT and CET. In HIIT session, participants performed four 30-sec sprints on a cycle-ergometer with 4 min of recovery against a resistance of 0.375 kg/kg of body mass. CET consisted of 30-min cycling on a cycle-ergometer at 70% of their VO2max. Blood was drawn at baseline, immediately post, 24h, 48h and 72h post-exercise and was analyzed for complete blood count and redox status (thiobarbituric acid reactive substances, [TBARS]; protein carbonyls, [PC]; total antioxidant capacity, [TAC]; catalase and uric acid). White blood cells (WBC) increased after both exercise protocols immediately post-exercise (HIIT: 50% and CET: 31%, respectively). HIIT increased (+22%) PC post-exercise compared to baseline and CET (p < 0.05). HIIT increased TAC immediately post-exercise (16%) and at 24h post-exercise (11%, p < 0.05), while CET increased TAC only post-exercise (12%, p < 0.05) compared to baseline, and TAC was higher following HIIT compared to CET (p < 0.05). Both HIIT and CET increased uric acid immediately post- (21% and 5%, respectively, p < 0.05) and 24h (27% and 5%, respectively, p < 0.05) post-exercise and the rise was greater following HIIT (p < 0.05). There were no significant changes (p > 0.05) for TBARS and catalase following either exercise protocol. Low-volume HIIT is associated with a greater acute phase leukocyte count and redox response than low-volume CET, and this should be considered when an exercise training program is developed and complete blood count is performed for health purposes.


bZIP transcription factor PubZIP914 enhances production of fatty acid-derived volatiles in pear.
'Nanguo' pear emitted a rich aroma when entirely ripe. The six-carbon (C6) volatiles, including the aldehydes, 2-hexenal, and hexanal, as well as their corresponding alcohols and esters which are derived from lipoxygenase pathway are the important volatile components in 'Nanguo' pears. However, the transcriptional regulation mechanism of aroma synthesis of 'Nanguo' pears remains largely unknown. bZIP transcription factors (TFs) mediate different developmental processes in plants. In this study, we identified and characterized a bZIP TF that is highly expressed and induced in 'Nanguo' pear fruits at the mature stage. The content of fatty acid-derived volatiles increased significantly in transgenic pears and tomatoes of PubZIP914 overexpression. Meanwhile, PubZIP914 could regulate PuLOX3.1 by binding directly to PuLOX3.1 promoter. The results of this study provide evidence demonstrating how bZIP transcription factors regulate fatty acid-derived volatiles biosynthesis during pear fruit ripening.


Host records and geographical distribution of Corynosoma magdaleni, C. semerme and C. strumosum (Acanthocephala: Polymorphidae).
A literature survey was conducted to investigate the host and geographical distribution patterns of three Corynosoma species (Acanthocephala: Polymorphidae), viz. C. magdaleni, C. semerme and C. strumosum. All three species appear to be restricted to the Northern Hemisphere. Occurrence records of C. magdaleni are limited to the Northern Atlantic coasts, while C. semerme has a circumpolar distribution. The geographical range of Corynosoma strumosum encompasses the distributions of the other two species, but also extends into warmer southern regions. Some Corynosoma populations are living with their definitive hosts in very isolated locations, such as in the brackish Baltic Sea or different freshwater lakes (e.g. Lake Saimaa). All three species have a heteroxenous life cycle, comprising a peracaridan intermediate host, a fish paratenic host and a mammalian definitive host. Occasionally, an acanthocephalan may enter an accidental host, from which it is unable to complete its life cycle. The host records reported here are categorised by type, i.e. intermediate, paratenic, definitive or accidental. While most of the definitive hosts are shared amongst the three Corynosoma species, C. strumosum showed the broadest range of paratenic hosts, which reflects its more extensive geographical distribution. One aim of this study and extensive literature summary is to guide future sampling efforts and therewith contribute to throw more light on the on-going species and morphotype discussion for this interesting parasite species.


Effects of maternal genotypic identity and genetic diversity of the red mangrove Rhizophora mangle on associated soil bacterial communities: A field-based experiment.
Loss of plant biodiversity can result in reduced abundance and diversity of associated species with implications for ecosystem functioning. In ecosystems low in plant species diversity, such as Neotropical mangrove forests, it is thought that genetic diversity within the dominant plant species could play an important role in shaping associated communities. Here, we used a manipulative field experiment to study the effects of maternal genotypic identity and genetic diversity of the red mangrove Rhizophora mangle on the composition and richness of associated soil bacterial communities. Using terminal restriction fragment length polymorphism (T-RFLP) community fingerprinting, we found that bacterial community composition differed among R. mangle maternal genotypes but not with genetic diversity. Bacterial taxa richness, total soil nitrogen, and total soil carbon were not significantly affected by maternal genotypic identity or genetic diversity of R. mangle. Our findings show that genotype selection in reforestation projects could influence soil bacterial community composition. Further research is needed to determine what impact these bacterial community differences might have on ecosystem processes, such as carbon and nitrogen cycling.


Outcomes of renal transplants from spousal donors: 25 years of experience at our center.
Many transplantation teams have attempted renal transplants from living unrelated kidney donors, as well as from cadaveric and living related kidney donors. In this study, we evaluated the results for renal transplants from spousal donors at our center. We retrospectively analyzed renal transplant patients from spousal donors from 1983 to 2008. A total of 25 patients who underwent a cadaveric donor renal transplant from 1983 to 2008 were also studied as a control group. Patients were evaluated regarding patient and graft survival at 1 and 5 years of follow-up. Acute rejection, delayed graft function, infections, and late complications were recorded. Thirty-eight male, spousal transplant recipients (group 1), 21 female, spousal transplant recipients (group 2), and 25 cadaveric donor transplant recipients were included this study. Graft survival rates were 96% in group 1 and 100% in group 2 (p=0.76) at 1-year follow-up. Patient survival rates in group 1 and 2 were both 100% at 1-year follow-up. Graft survival rates were 80% in group 1 and 100% in group 2 (p=0.12) at 5-year follow-up. Patient survival rates were 90% in group 1 and 100% in group 2 (p=0.56) at 5-year follow-up. Acute rejection rates were 10% (group 1) and 33% (group 2) (p=0.03); delayed graft function rates were 0% (group 1) and 10% (group 2) (p=0.05); infection rates were 16% (group 1) and 5% (group 2) (p=0.21) as early period posttransplant complications. Results for transplants between spouses in our groups were comparable to those previously reported in the literature. Acute rejection rates were mildly higher in female recipients than in the male recipients due to pre-sensitization arising from previous pregnancies; however long-term patient and graft survival rates were not significantly different between female and male recipients.


Ileal microvillar protein villin is tyrosine-phosphorylated and associates with PLC-gamma1. Role of cytoskeletal rearrangement in the carbachol-induced inhibition of ileal NaCl absorption.
In ileal absorptive cells, carbachol inhibits NaCl absorption and its component brush border Na+/H+ exchanger, acting via basolateral membrane receptors. This carbachol effect involves (i) activation of brush border phosphatidylinositol 4,5-bisphosphate-specific phospholipase C (PLC) activity and brush border but not basolateral membrane translocation of PLC-gamma1 (Khurana, S., Kreydiyyeh, S., Aronzon, A., Hoogerwerf, W. A., Rhee, S. G., Donowitz, M., and Cohen, M. E. (1996) Biochem. J. 313, 509-518); and (ii) brush border tyrosine kinase(s) because mucosal but not serosal addition of the tyrosine kinase inhibitor genistein prevents the carbachol-induced inhibition of NaCl absorption and brush border Na+/H+ exchange. In the present work we identify a pool of villin (a brush border actin-binding protein) in the microvillus membrane fraction of rabbit ileum; this pool of villin is tyrosine-phosphorylated and associates with brush border membrane PLC-gamma1. Villin is present both in the Triton X-100-soluble and -insoluble fractions of the brush border. The Triton X-100-soluble pool is approximately 4-fold smaller than the brush border pool of villin that is present in the Triton X-100-insoluble fraction. Only the villin present in the Triton X-100-soluble fraction of ileal villus brush border associates with PLC-gamma1 and is tyrosine-phosphorylated. Carbachol increases the tyrosine phosphorylation of villin rapidly (as early as 30 s) and transiently. Carbachol also increases the amount of tyrosine-phosphorylated villin that associates with PLC-gamma1. These studies demonstrate that carbachol effects on NaCl absorption are accompanied by an increase in brush border PLC-gamma1 association with villin and an increase in tyrosine phosphorylation of villin. To study the role of cytoskeletal rearrangement in carbachol-induced inhibition of NaCl absorption, we used the F-actin stabilizing drug jasplakinolide. Jasplakinolide prevents the carbachol inhibition of ileal NaCl absorption. This suggests that F-actin severing is necessary for carbachol to inhibit ileal villus NaCl absorption. Since villin is known to sever actin, these studies suggest a role for villin in the signaling cascade that begins at the basolateral membrane with carbachol binding to its receptor and ends at the apical membrane in inhibition of NaCl absorption.


Maternal vitamin D deficiency and fetal programming--lessons learned from humans and mice.
Cardiovascular disease partially originates from poor environmental and nutritional conditions in early life. Lack of micronutrients like 25 hydroxy vitamin D3 (25OHD) during pregnancy may be an important treatable causal factor. The present study explored the effect of maternal 25OHD deficiency on the offspring. We performed a prospective observational study analyzing the association of maternal 25OHD deficiency during pregnancy with birth outcomes considering confounding. To show that vitamin D deficiency may be causally involved in the observed associations, mice were set on either 25OHD sufficient or insufficient diets before and during pregnancy. Growth, glucose tolerance and mortality was analyzed in the F1 generation. The clinical study showed that severe 25OHD deficiency was associated with low birth weight and low gestational age. ANCOVA models indicated that established confounding factors such as offspring sex, smoking during pregnancy and maternal BMI did not influence the impact of 25OHD on birth weight. However, there was a significant interaction between 25OHD and gestational age. Maternal 25OHD deficiency was also independently associated with low APGAR scores 5 minutes postpartum. The offspring of 25OHD deficient mice grew slower after birth, had an impaired glucose tolerance shortly after birth and an increased mortality during follow-up. Our study demonstrates an association between maternal 25OHD and offspring birth weight. The effect of 25OHD on birth weight seems to be mediated by vitamin D controlling gestational age. Results from an animal experiment suggest that gestational 25OHD insufficiency is causally linked to adverse pregnancy outcomes. Since birth weight and prematurity are associated with an adverse cardiovascular outcome in later life, this study emphasizes the need for novel monitoring and treatment guidelines of vitamin D deficiency during pregnancy.


A case of phrynoderma in a patient with Crohn's disease.
Phrynoderma is a type of follicular hyperkeratosis associated with nutritional deficiencies. It is rarely seen in developed countries, although cases have been reported in patients with severe malnutrition or malabsorption secondary to various causes. This report describes a 19-year-old patient with poorly controlled Crohn's disease and malnutrition who developed the characteristic hyperkeratotic papules and plaques on his trunk and extremities in the setting of low serum vitamin A levels. To our knowledge, there are no reports of phrynoderma associated with Crohn's disease. It is likely that our patient's low vitamin A level and subsequent phrynoderma was the result of increased Crohn's disease activity and malnutrition.


Protease-activated alpha-2-macroglobulin can inhibit amyloid formation via two distinct mechanisms.
α(2)-Macroglobulin (α(2)M) is an extracellular chaperone that inhibits amorphous and fibrillar protein aggregation. The reaction of α(2)M with proteases results in an 'activated' conformation, where the proteases become covalently-linked within the interior of a cage-like structure formed by α(2)M. This study investigates, the effect of activation on the ability of α(2)M to inhibit amyloid formation by Aβ(1-42) and I59T human lysozyme and shows that protease-activated α(2)M can act via two distinct mechanisms: (i) by trapping proteases that remain able to degrade polypeptide chains and (ii) by a chaperone action that prevents misfolded clients from continuing along the amyloid forming pathway.


Enzyme-mediated binding of tyrosine to brome-mosaic-virus ribonucleic acid.
Incubation of tyrosine with the RNA from brome-mosaic-virus under conditions favourable for aminoacylation of tRNA resulted in binding of tyrosine to the viral RNA. Sucrose-density-gradient centrifugation showed that tyrosine binds to three and probably to all four of the viral RNA components. The bound amino acid was readily released in mild alkaline solutions. Of 20 amino acids tested, only tyrosine was found to bind. The maximum extent of binding observed was 0.58mol of tyrosine/mol of brome-mosaic-virus RNA.


Neutrophil to Lymphocyte Ratio and C-Reactive Protein as Two Predictive Tools of Anastomotic Leak in Colorectal Cancer Open Surgery.
To assess the prognostic value of postoperative C-reactive protein (CRP) and neutrophil to lymphocyte ratio (NLR) in the development of anastomotic leak (AL) in patients after surgery for colorectal cancer (CRC). Patients operated on for CRC between 2010 and 2014 were enrolled into the study. The sensitivity, specificity, positive predictive value (PPV) and negative predictive values (NPVs) were calculated for the CRP and NLR measured on the 4th postoperative day (POD). Among 724 patients, AL was diagnosed in 33 (4.6%). The accuracy of CRP in the detection of AL using area under curve was 0.83 with the optimal cut-off value of 180 mg/L, sensitivity 75%, specificity 91%, PPV 52% and NPV 87%. Also, NLR on POD4 was higher in the AL group: 9.03 ± 4.13 vs. 4.45 ± 2.25; p = 0.0012; sensitivity 69%, specificity 78%, PPV 49%, NPV 88% at cut-off point of 6.5. Moreover, CRP and NLR on POD4 were significantly higher in patients who died in the postoperative period: 239 ± 24 mg/L vs. 199 ± 41 mg/L; p = 0.034 and 10.71 ± 2.08 vs. 8.65 ± 4.67; p = 0.029, respectively). CRP and NLR on POD4 possess the ability to predict the development of AL and postoperative mortality after CRC operation. Based on our results, high NPV might be indicative of patients with low risk of AL in their postoperative period.


Neurogenic obesity and systemic inflammation following spinal cord injury: A review.
Spinal Cord Injury (SCI) results in physiological changes that markedly reduces whole-body metabolism, resulting in neurogenic obesity via adipose tissue accumulation. Adipose tissue has been implicated in the release of proinflammatory adipokines that lead to chronic, systemic inflammation, and evidence suggests these adipokines contribute to the pathogeneses of metabolic diseases that often accompany obesity. In this review, we propose the concept of neurogenic obesity through paralysis-induced adiposity as the primary source of systemic inflammation and metabolic dysfunction reported in chronic SCI. We also briefly discuss how exercise in SCI can attenuate the negative consequences of obesity-induced inflammation and its comorbidities. A MEDLINE, PubMed, Google Scholar, and ClinicalKey search was performed using the following search terms: obesity, adiposity, adipose tissue, proinflammatory adipokines, proinflammatory cytokines, metabolic dysfunction, exercise, physical activity, and spinal cord injury. All papers identified were full-text, English language papers. The reference list of identified papers was also searched for additional papers. Research suggests that obesity in SCI results in a state of chronic, systemic inflammation primarily through proinflammatory adipokines secreted from excess adipose tissue. The reduction of adipose tissue through the use of diet and exercise demonstrates promise to combat neurogenic obesity, inflammation, and cardiometabolic dysfunction in SCI. Proinflammatory adipokines may serve as biomarkers for the development of obesity-related complication in SCI. Mechanistic and interventional studies on neurogenic obesity-induced inflammation in chronic SCI are warranted.


Isolation and sequence analysis of three cloned cDNAs for rabbit liver proteins that are related to rabbit cytochrome P-450 (form 2), the major phenobarbital-inducible form.
We have isolated from rabbit liver three cDNA clones of 1400-1800 base pairs that hybridize selectively to RNA from animals treated with phenobarbital. The nucleotide sequences of the cDNAs have been determined. In the protein coding region the nucleotide sequences of two of the cDNAs are 88% homologous, and the third cDNA is about 72-74% homologous to the other two. All three are 55-60% homologous to rat liver cytochrome P-450b cDNA. The amino acid sequences derived from the cDNA sequences are about 50% homologous to those of rat liver cytochrome P-450b and rabbit liver cytochrome P-450 (form 2). The degree of homology differs substantially in different regions of the protein. The hydrophobicity profiles of these five mammalian cytochromes P-450 are very similar and contain up to eight regions of hydrophobicity that are long enough to span a membrane. These results indicate that these three cDNAs code for rabbit liver cytochromes P-450 which are different from any rabbit liver cytochrome P-450 for which amino acid sequence information is published. These cDNAs are part of a family of genes that are related to rabbit liver cytochrome P-450 (form 2) and rat liver cytochrome P-450b which are the major phenobarbital-inducible forms. The divergence of amino acid sequence between the rat and rabbit forms and the divergence of nucleotide sequences of silent sites in the two most closely related rabbit forms suggest that cytochromes P-450 have a relatively high rate of amino acid divergence compared to many other vertebrate proteins.


Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia.
Targeted therapies including the engineered afucosylated anti-CD20 monoclonal antibody obinutuzumab, Bruton's tyrosine kinase inhibitor ibrutinib, and B-cell lymphoma protein 2 inhibitor venetoclax have demonstrated significant clinical activity in chronic lymphocytic leukemia (CLL) and, based on their complementary mechanisms, are ideal for combination. However, combining venetoclax with other active agents raises safety concerns, as it may increase the risk for tumor lysis syndrome. To minimize this risk, we designed and implemented a fixed-duration regimen using sequentially administered obinutuzumab followed by ibrutinib (cycle 2) and venetoclax (cycle 3), for a total of fourteen 28-day cycles. This phase 1b study included 12 patients with relapsed or refractory CLL. We tested 3 dose levels of venetoclax and identified the doses of all 3 agents approved by the US Food and Drug Administration for use in the combination. Adverse events were consistent with known toxicities of the individual agents, with hematologic adverse events being most frequent. No clinically significant tumor lysis syndrome occurred. The overall response rate was 92% (95% confidence interval, 62%-100%), with 42% (5/12) achieving a complete remission or complete remission with incomplete marrow recovery. There were 6 patients with no detectable CLL in both the blood and bone marrow at the end of treatment. We found this regimen to be safe and tolerable in CLL, and capable of inducing deep responses, justifying future study in our ongoing phase 2 cohorts of relapsed or refractory and treatment-naive patients, as well as larger phase 3 trials currently in planning. This trial was registered at www.clinicaltrials.gov as #NCT02427451.


Effects of HMG-CoA reductase inhibition on hepatic expression of key cholesterol-regulatory enzymes and receptors in nephrotic syndrome.
Hypercholesterolemia is one of the major manifestations of nephrotic syndrome. We have previously shown that nephrotic hypercholesterolemia is associated with and, in part, due to dysregulation of hepatic HMG-CoA reductase, acyl-CoA:cholesterol acyltransferase (ACAT) and cholesterol 7alpha-hydroxylase, as well as lecithin:cholesterol acyltransferase (LCAT), low-density lipoprotein (LDL) receptor and high-density lipoprotein (HDL) receptor deficiencies. This study was carried out to discern the effect of inhibition of HMG-CoA reductase on expression of the key enzymes and receptors involved in cholesterol metabolism in the liver. Rats with puromycin-induced nephrotic syndrome were treated with either a statin (rosuvastatin 20 mg/kg/day) or placebo for 2 weeks. Placebo-treated normal rats served as controls. Gene expression, protein abundance and/or activities of relevant receptors and enzymes were quantified. The untreated nephrotic rats showed heavy proteinuria, hypoalbuminemia, hypercholesterolemia, elevated total cholesterol:HDL cholesterol ratio and normal creatinine clearance. This was associated with severe reductions in hepatic LDL receptor, hepatic HDL receptor and plasma LCAT concentration, marked upregulation of hepatic ACAT, and unchanged cholesterol 7alpha-hydroxylase (rate-limiting step in cholesterol catabolism). Statin administration for 2 weeks ameliorated hepatic LDL receptor and HDL receptor deficiencies and significantly lowered plasma cholesterol, LDL cholesterol, total cholesterol:HDL cholesterol ratio and proteinuria. HMG-CoA reductase inhibition improved hepatic LDL and HDL receptor deficiencies, and ameliorated the associated hyperlipidemia in the nephrotic rats.


Iron-dependent regulation of transferrin receptor expression in Trypanosoma brucei.
Transferrin is an essential growth factor for African trypanosomes. Here we show that expression of the trypanosomal transferrin receptor, which bears no structural similarity with mammalian transferrin receptors, is regulated by iron availability. Iron depletion of bloodstream forms of Trypanosoma brucei with the iron chelator deferoxamine resulted in a 3-fold up-regulation of the transferrin receptor and a 3-fold increase of the transferrin uptake rate. The abundance of expression site associated gene product 6 (ESAG6) mRNA, which encodes one of the two subunits of the trypanosome transferrin receptor, is regulated 5-fold by a post-transcriptional mechanism. In mammalian cells the stability of transferrin receptor mRNA is controlled by iron regulatory proteins (IRPs) binding to iron-responsive elements (IREs) in the 3'-untranslated region (UTR). Therefore, the role of a T. brucei cytoplasmic aconitase (TbACO) that is highly related to mammalian IRP-1 was investigated. Iron regulation of the transferrin receptor was found to be unaffected in Deltaaco::NEO/Deltaaco::HYG null mutants generated by targeted disruption of the TbACO gene. Thus, the mechanism of post-transcriptional transferrin receptor regulation in trypanosomes appears to be distinct from the IRE/IRP paradigm. The transferrin uptake rate was also increased when trypanosomes were transferred from medium supplemented with foetal bovine serum to medium supplemented with sera from other vertebrates. Due to varying binding affinities of the trypanosomal transferrin receptor for transferrins of different species, serum change can result in iron starvation. Thus, regulation of transferrin receptor expression may be a fast compensatory mechanism upon transmission of the parasite to a new host species.


Development of osmoregulatory tissues in the Lake van fish (Alburnus tarichi) during larval development.
Lake Van is one of the largest alkaline lakes worldwide and Lake Van Fish (Alburnus tarichi Güldenstädt, 1814) is the only vertebrate species inhabiting it. Lake Van Fish is an anadromous species that migrates to the streams (salinity 0.02%, pH 8.42) flowing into Lake Van (salinity 0.22%, pH 9.8) during the spawning period (April-July). Following spawning, fish return to Lake Van while larvae remain in fresh water. This study examined the development of osmoregulatory organs and the distribution of ionocytes in Lake Van Fish larvae adapting to the highly alkaline water characterizing the lake. Ionocytes were marked immunohistochemically and observed in whole mounts with immunofluorescence staining using the Na+/K+ ATPase antibody. Ionocytes were first identified in the yolk sac membrane and skin, and then in the gills, digestive tract, and kidneys of larvae. The number of ionocytes on yolk sac membrane and skin decreased during larval development, indicating ionocytes on these tissues have a role in larvae osmoregulation. Larvae hatched from eggs in stream waters die when transferred to Lake Van water but survived in lake water diluted with deionized water. Thus, larvae need to go through certain alterations at the cellular and organ levels in order to adapt to the conditions of Lake Van water, indicating they do not enter this lake immediately after hatching.


Adult cervical intramedullary teratoma: first reported immature case.
Intramedullary teratomas, particularly adult cervicothoracic lesions, are extremely rare. Up to now only 6 cases of intramedullary cervical teratomas have been reported in adults, and all of these were histologically mature. The authors present the case of a 35-year-old man with progressive myelopathic symptoms who was admitted through an outpatient clinic and was surgically treated. The characteristics, diagnosis, epidemiology, and treatment of cervical intramedullary teratomas in adults are also reviewed. Postoperative MR imaging showed that the tumor had been near totally removed, and severely adherent tissue remained ventrocranially with tiny focal enhancement on follow-up MR imaging. Pathological examinations revealed immature teratoma without any malignant component. Adjuvant therapy was not performed. Although no change in neurological findings and symptoms was apparent postoperatively, lesion regrowth was demonstrated on MR imaging 4 months after surgery. At 8 months postoperatively, myelopathic symptoms had developed and a huge intramedullary tumor recurred according to MR imaging. This case is the seventh reported instance of intramedullary cervical teratoma in an adult, and the first case report of the immature type with malignant features.


Resurrection of the Follow-Back Method to Study the Transdiagnostic Origins of Psychosis.
There has been a major drive in research trying to understand the onset of psychosis. Clinical-high risk (CHR) studies focus on opportunistic help-seeking samples with non-psychotic disorders and a degree of psychosis admixture of variable outcome, but it is unlikely that these represent the population incidence of psychotic disorders. Longitudinal cohort studies of representative samples in the general population have focused on development and outcome of attenuated psychotic symptoms, but typically have low power to detect transition to clinical psychotic disorder. In this issue of Schizophrenia Bulletin, Cupo and colleagues resurrect a time-honored method to examine psychosis onset: the epidemiological follow-back study, modernizing it to fit the research framework of the early intervention era. The authors set out to investigate the hypothesis that psychotic disorder represents the poorest outcome fraction of initially non-psychotic, common mental disorders and present compelling findings, unifying previous opportunistic CHR and representative cohort-based work.


Practising family history: 'identity' as a category of social practice.
Research on family history argues it performs the task of anchoring a sense of 'self' through tracing ancestral connection and cultural belonging, seeing it as a form of storied 'identity-work'. This paper draws on a small-scale qualitative study to think further on the identity-work of family history. Using practice theory, and a disaggregated notion of 'identity', it explores how the storying of family histories relates to genealogy as a leisure hobby, a form of historical research, and an information-processing activity; and examines the social organization of that narrativity, where various practical engagements render certain kinds of genealogical information more, or less, 'storyable'. Key features of 'identity-work' in family history, such as the construction of genealogy as a personal journey of discovery and identification with particular ancestors, emerge as a consequence of the procedures of family history, organized as a set of practical tasks. The paper explores 'identity-work' as a consequence of people's engagement in specific social practices which provide an internal logic to their actions, with various components of 'identity' emerging as categories of practice shaped within, and for, use. Focusing on 'identity' as something produced when we are engaged in doing other things, the paper examines how the practical organization of 'doing other things' helps produce 'identity' in particular ways.


More to Lose? Noise-Risk Perceptions of Young Adults with Hearing Impairment.
This study investigated the attitudes and behaviors of young adults with hearing impairment (HI), in relation to leisure noise. It was hypothesized that young people with HI would have more negative perceptions of noise exposure than their peers with nonimpaired (normal) hearing (NH) and would engage more frequently in self-protective behaviors. Questionnaires were administered as part of a larger study of young Australians with: (1) preadult onset HI and (2) NH. Data from adults (age range 18 to 24 years; n = 79 with HI, n = 131 with NH) were selected for the current analysis. Attitudes data for HI and NH groups were compared using chi-square tests, and the reported use of hearing aids and personal hearing protectors (PHPs) in leisure environments was quantified. Most participants with HI and NH regarded leisure noise as a health hazard but rated their own noise-injury risk as lower than that of their peer group. The use of PHPs was low overall, and many participants with HI reported using hearing aids (switched on) during noisy leisure activities. An equal and substantial proportion of participants with HI and NH reported dislike and avoidance of loud activities. Systematic noise management in leisure environments would address noise-injury risk and also enhance social participation.


ASGART: fast and parallel genome scale segmental duplications mapping.
Segmental Duplications (SDs) are DNA fragments longer than 1 kbp, distributed within and between chromosomes and sharing more than 90% identity. Although they hold a significant role in genomic fluidity and adaptability, many key questions about their intrinsic characteristics and mutability remain unsolved due to the persistent difficulty of sequencing highly duplicated genomic regions. The recent development of long and linked-read NGS technologies will increase the need to search for SDs in genomes newly sequenced with these technics. The main limitation of SD analysis will soon be the availability of efficient detection software, to retrieve and compare SD genomic component between species or lineages. In this paper, we present the open-source ASGART, 'A Segmental duplications Gathering And Refining Tool', developed to search for segmental duplications (SDs) in any assembled sequence. We have tested and benchmarked ASGART on five models organisms. Our results demonstrate ASGART's ability to extract SDs from any genome-wide sequence, regardless of genomic size or organizational complexity and quicker than any other software available. The online version of ASGART is available at http://asgart.irit.fr. The source code of ASGART is available both on the ASGART website and at https://github.com/delehef/asgart. Supplementary data are available at Bioinformatics online.


Health care accreditation surveyor styles typology.
This paper aims to investigate how health care accreditation surveyors enact their role with a view to identifying a surveyor styles typology. This study was conducted in two phases. First, observational research was used to examine the conduct of a small survey team during the 2005 accreditation survey of a rural health service in Australia. The survey team was from the Australian Council on Healthcare Standards (ACHS), the major health care accreditation agency in Australia. Second, the emerging typology was reviewed by an expert panel of ACHS surveyors. A typology comprising three unique surveyor styles is identified--interrogator; explorer; and discusser. Additionally, a further style, the questioner, is hypothesised. RESEARCH LIMITATION/IMPLICATIONS: The typology has application for development by accreditation agencies to be used with surveyors as a self-reflection tool to improve learning and development. The knowledge gained about surveyors' styles can be used to match more effectively survey teams to organisations seeking accreditation. Further research is necessary to confirm these styles and examine whether other styles are apparent. This study is an important step in examining the conduct of surveyors and opening up health care accreditation surveyor inter-rater reliability for further investigation.


Optimization of human tendon tissue engineering: peracetic acid oxidation for enhanced reseeding of acellularized intrasynovial tendon.
Tissue engineering of human flexor tendons combines tendon scaffolds with recipient cells to create complete cell-tendon constructs. Allogenic acellularized human flexor tendon has been shown to be a useful natural scaffold. However, there is difficulty repopulating acellularized tendon with recipient cells, as cell penetration is restricted by a tightly woven tendon matrix. The authors evaluated peracetic acid treatment in optimizing intratendinous cell penetration. Cadaveric human flexor tendons were harvested, acellularized, and divided into experimental groups. These groups were treated with peracetic acid in varying concentrations (2%, 5%, and 10%) and for varying time periods (4 and 20 hours) to determine the optimal treatment protocol. Experimental tendons were analyzed for differences in tendon microarchitecture. Additional specimens were reseeded by incubation in a fibroblast cell suspension at 1 × 10(6) cells/ml. This group was then analyzed for reseeding efficacy. A final group underwent biomechanical studies for strength. The optimal treatment protocol comprising peracetic acid at 5% concentration for 4 hours produced increased scaffold porosity, improving cell penetration and migration. Treated scaffolds did not show reduced collagen or glycosaminoglycan content compared with controls (p = 0.37 and p = 0.65, respectively). Treated scaffolds were cytotoxic to neither attached cells nor the surrounding cell suspension. Treated scaffolds also did not show inferior ultimate tensile stress or elastic modulus compared with controls (p = 0.26 and p = 0.28, respectively). Peracetic acid treatment of acellularized tendon scaffolds increases matrix porosity, leading to greater reseeding. It may prove to be an important step in tissue engineering of human flexor tendon using natural scaffolds.


National Study of Off-label Proton Pump Inhibitor Use Among New Zealand Infants in the First Year of Life (2005-2012).
Off-label prescribing of proton pump inhibitors (PPIs) to infants to treat symptoms attributed to gastroesophageal reflux disease (GERD) is widely reported, despite evidence that PPIs are no more effective than placebo in relieving those symptoms. To initiate discussion about appropriate prescribing of these drugs for infants, we describe the characteristics of PPI use among infants in New Zealand. In this population-based study we used routinely collected dispensing data to identify all children born between 2005 and 2012 who were dispensed a government-subsidized PPI (omeprazole, lansoprazole, pantoprazole) before their first birthday. Unique patient identifiers were used to link administrative datasets containing patient-level demographic, dispensing, and health information. In total, 22,643 children were dispensed a study PPI before their first birthday. The prevalence of infant PPI use as a proportion of all live births increased from 2.4% for children born in 2005 to 5.2% for children born in 2012. Overall, 71.6% of infants were dispensed a PPI by 3 months of age, and 8.7% received a PPI within the first month of life. Before PPI initiation, only 7.0% of infants had a hospital-based diagnosis of GERD (with or without esophagitis), and 4.7% of infants had a hospital-based diagnosis of one or more known or suspected GERD risk factors. Off-label prescribing of PPIs to New Zealand infants was relatively common and increased over the study period. The appropriateness of PPI treatment should be questioned, as the majority of infants who received these drugs were not diagnosed with severe GERD.


Knockdown of TRAF4 expression suppresses osteosarcoma cell growth in vitro and in vivo.
Tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4) is an adapter molecule that is overexpressed in certain cancers. TRAF4 is overexpressed in osteosarcoma tissues and osteosarcoma cells. Using the technique of RNA interference, the expression of TRAF4 in the human osteosarcoma Saos-2 cell line was shown to be downregulated. The proliferation, cell cycle arrest and apoptosis ability of Saos‑2 cells were examined, as was tumor development in a xenograft mouse model. The results showed that the TRAF4 knockdown exerts inhibitory effects on the proliferation ability of Saos-2 cells and tumor development in a xenograft mouse model. Simultaneously, it was found that TRAF4 knockdown led to cell cycle arrest in the G1 phase and promoted Saos-2 cell apoptosis. Following TNF-α treatment, the expression of nuclear factor κB was significantly reduced in the TRAF4‑small interfering RNA group. These results indicate that TRAF4 regulated osteosarcoma cell growth in vitro and in vivo, and offers a candidate molecular target for osteosarcoma prevention and therapy.


Tumours of the testis. A report of 128 cases.
The records of 128 patients treated between 1960 and 1971 at the University Hospital, Lund, because of tumour of the testis were analysed in respect of age at onset of the tumour, symptoms, histology, diagnosis, treatment and survival rate. Teratoma occured in 67 cases, in the majority at the age of 20-30 years. Treatment consisted in orchiectomy, lymphadenectomy, administration of cytostatics and radiation alone or combined, depending upon the histology and spread of the tumour. The 5-year survival rate was 40%. Sixty-one patients had seminoma, most of which appeared between 30 and 40 years of age. The patients were treated with orchiectomy and radiation. The 5-year survival rate was 82%.


Regional population collapse followed initial agriculture booms in mid-Holocene Europe.
Following its initial arrival in SE Europe 8,500 years ago agriculture spread throughout the continent, changing food production and consumption patterns and increasing population densities. Here we show that, in contrast to the steady population growth usually assumed, the introduction of agriculture into Europe was followed by a boom-and-bust pattern in the density of regional populations. We demonstrate that summed calibrated radiocarbon date distributions and simulation can be used to test the significance of these demographic booms and busts in the context of uncertainty in the radiocarbon date calibration curve and archaeological sampling. We report these results for Central and Northwest Europe between 8,000 and 4,000 cal. BP and investigate the relationship between these patterns and climate. However, we find no evidence to support a relationship. Our results thus suggest that the demographic patterns may have arisen from endogenous causes, although this remains speculative.


Is the regulation of the center of mass maintained during leg movement under microgravity conditions?
1. Investigations on stance regulation have already suggested that the body's center of mass is the variable controlled by the CNS to maintain equilibrium. The aim of this study was to determine how the center of mass of the body is regulated when leg movements are made under different gravitoinertial force conditions. 2. Kinematic and electromyographic (EMG) recordings were made during both straight-and-level flight (earth-normal gravity condition, nG) and periods of weightlessness in parabolic flight (microgravity condition, microG). The standing subjects were restrained to the floor (kept from floating away in microG) and were instructed to raise one leg laterally to an angle of 45 degrees as fast as possible. 3. Two modes of center of mass (CM) control were identified during leg movement in nG: a "shift mode" and a "stabilization mode." The shift mode served to transfer the CM toward the supporting side before the leg raising, and it preceded the phase of single limb support. The stabilization mode took place after the CM shift was completed and was aimed at stabilizing the CM during raising of the leg. In this phase, the movement of the raising leg is counterbalanced by a lateral inclination of the trunk in the opposite direction. As a consequence, CM position did not change with respect to the position reached before the leg raising, and its projection on the ground remained within the support area delineated by the stance foot. 4. Under microG, the CM position did not change before the leg raising. Moreover, gastrocnemius medialis activity observed in the moving leg under nG, preceding the initiation of the body weight transfer toward the supporting leg, was greatly reduced. While the leg is raising, the simultaneous and opposite lateral trunk movement was still present in microG. 5. Results suggest that the body weight transfer corresponding to the shift mode, might depend on the gravity constraints, whereas the stabilization mode, which remains unchanged in microG, might be a motor stereotype that does not depend on the gravity conditions.


Effect of intra-articular dexmedetomidine on postoperative analgesia after arthroscopic knee surgery.
Alpha-2-adrenergic agonists have peripheral analgesic effects. We have assessed the potential analgesic effect of dexmedetomidine after intra-articular administration in arthroscopic knee surgery. Sixty patients undergoing arthroscopic knee surgery were randomly assigned into three groups in a double-blind placebo controlled study. The control group received i.v. and intra-articular saline, the intra-articular group received i.v. saline and intra-articular dexmedetomidine, and the i.v. group received i.v. dexmedetomidine and intra-articular saline. Haemodynamic changes, pain visual analogue scale (VAS), sedation score, the time to first postoperative analgesic request, and the total postoperative analgesic use during the first 24 h were evaluated. Dexmedetomidine administration resulted in a significant reduction in pain scores for 6 h after operation in the intra-articular group but only for 1 h in the i.v. group. The time to first postoperative analgesic request was longer in the intra-articular group [312.0 (SD 120.7) min] compared with the control group [71.0 (50.1) min] and the i.v. group [102.1 (54.4) min] (P<0.001). Total diclofenac requirement was significantly lower in the intra-articular group [90.0 (46.2) mg] than in the control group [165.0 (52.2) mg] and in the i.v. group [129.3 (54.3) mg] (P<0.05). Intra-articular dexmedetomidine enhanced postoperative analgesia after arthroscopic knee surgery, with an increased time to first analgesic request and a decreased need for postoperative analgesia.


[Ultrastructure of Candida utilis in continuous culture with various concentrations of the carbon source introduced by different technics].
The object of the work was to study changes in the ultrastructure of Candida utilis cells induced by increasing concentrations of glucose during chemostat cultivation and continuous cultivation with glucose pulse feeding. The results indicate that the cell structure and metabolism change vectorially with an increase of glucose concentration regardless of how glucose was added. An increase of the input glucose concentration is followed by an increase in the periplasmic space, the content of glycogen, the length and diameter of mitochondria, and the size of the nucleus. However, in the case of glucose pulse feeding, the above changes in the cell structure occur at a considerably lower input concentration as compared to the chemostat culture. Under these conditions, microtubuli are assembled in the cytoplasm in response to the glucose stimulus.


Differential effects of lidocaine and tramadol on modified nerve impulse by 4-aminopyridine in rats.
We have used the sucrose gap method to measure the effects of drugs on the electrophysiological properties of rat sciatic nerves. The results showed that 4-aminopyridine produced a slight conduction block, prolonged the duration of action potential, enhanced the hyperpolarizing afterpotential, and elicited a hump that followed the action potential. In the presence of 4-aminopyridine, the impulse-blocking activity of lidocaine and tramadol was enhanced. Both lidocaine and tramadol effectively depressed the delayed depolarization generated by 4-aminopyridine. While tramadol decreased the activity-evoked hyperpolarizing afterpotentials, lidocaine completely removed them. These findings indicate that lidocaine may be more effective in blocking the Na(+) channels than tramadol. Tramadol may be more effective on the delayed rectifier K(+) channels than lidocaine.


Tolerogenic vaccines for Multiple sclerosis.
Tolerogenic vaccines represent a new class of vaccine designed to re-establish immunological tolerance, restore immune homeostasis, and thereby reverse autoimmune disease. Tolerogenic vaccines induce long-term, antigen-specific, inhibitory memory that blocks pathogenic T cell responses via loss of effector T cells and gain of regulatory T cell function. Substantial advances have been realized in the generation of tolerogenic vaccines that inhibit experimental autoimmune encephalomyelitis in a preclinical setting, and these vaccines may be a prequel of the tolerogenic vaccines that may have therapeutic benefit in Multiple Sclerosis. The purpose here is to provide a snapshot of the current concepts and future prospects of tolerogenic vaccination for Multiple Sclerosis, along with the central challenges to clinical application.


Targeted metagenomics reveals extensive diversity of the denitrifying community in partial nitritation anammox and activated sludge systems.
The substantial presence of denitrifiers has already been reported in partial nitritation anammox (PNA) systems using the 16S ribosomal RNA (rRNA) gene, but little is known about the phylogenetic diversity based on denitrification pathway functional genes. Therefore, we performed a metagenomic analysis to determine the distribution of denitrification genes and the associated phylogeny in PNA systems and whether a niche separation between PNA and conventional activated sludge (AS) systems exists. The results revealed a distinct abundance pattern of denitrification pathway genes and their association to the microbial species between PNA and AS systems. In contrast, the taxonomic analysis, based on the 16S rRNA gene, did not detect notable variability in denitrifying community composition across samples. In general, narG and nosZa2 genes were dominant in all samples. While the potential for different stages of denitrification was redundant, variation in species composition and lack of the complete denitrification gene pool in each species appears to confer niche separation between PNA and AS systems. This study suggests that targeted metagenomics can help to determine the denitrifying microbial composition at a fine-scale resolution while overcoming current biases in quantitative polymerase chain reaction approaches due to a lack of appropriate primers.


Comparison of desipramine and citalopram treatments for depression in Parkinson's disease: a double-blind, randomized, placebo-controlled study.
Depression is one of the most common psychiatric disturbances in Parkinson's disease (PD). Recent reviews have highlighted the lack of controlled trials and the ensuing difficulty in formulating recommendations for antidepressant use in PD. We sought to establish whether antidepressants provide real benefits and whether tricyclic and selective serotonin reuptake inhibitor (SSRI) antidepressants differ in their short-term efficacy, because the time to onset of therapeutic benefit remains an important criterion in depression. The short-term efficacy (after 14 and 30 days) of two antidepressants (desipramine, a predominantly noradrenergic reuptake inhibitor tricyclic and citalopram, a SSRI) was assessed in a double-blind, randomized, placebo- controlled study of 48 nondemented PD patients suffering from major depression. After 14 days, desipramine prompted an improvement in the Montgomery Asberg Depression Rating Scale (MADRS) score, compared with citalopram and placebo. Both antidepressants produced significant improvements in the MADRS score after 30 days. Mild adverse events were twice as frequent in the desipramine group as in the other groups. A predominantly noradrenergic tricyclic antidepressant induced a more intense short-term effect on parkinsonian depression than did an SSRI. However, desipramine's lower tolerability may outweigh its slight short-term clinical advantage.


DNA methylation of hMLH1 correlates with the clinical response to cisplatin after a surgical resection in Non-small cell lung cancer.
Our previous study demonstrated that promoter methylation of human mutL homolog 1 (hMLH1) is involved in determining sensitivity to cisplatin in NSCLC A549/DDP cell line, The present study was designed to determine whether DNA methylation of hMLH1 affects the prognosis of non-small cell lung cancer patients who received cisplatin-based adjuvant chemotherapy. Methylation status of hMLH1 was examined by nested methylation-specific PCR (nested MSP) in 84 archived NSCLC surgically resected tissue specimens from patients receiving cisplatin-based adjuvant chemotherapy. Univariate and multivariate analysis were used to investigate the relationship between hMLH1 methylation status and the clinical prognosis of the patients mentioned above. In the cohort of 84 NSCLC cases, 80 tissue samples were successfully amplified by nested MSP. Among them, 36 samples (45%) were identified to be methylated. Moreover, hMLH1 methylation was not associated with age, gender, smoking status, T stage, histology and differentiation, but correlated with lymphatic metastasis (P=0.021). Multivariate logistic regression analysis showed that hMLH1 methylation may function as a significant independent prognostic factor for tumor recurrence in NSCLC patients treated with adjuvant cisplatin (HR 3.114, 95% CI 1.032-9.399; P=0.044). However, Kaplan-Meier method (P=0.093) and multivariate Cox regression analysis (P=0.598) revealed that hMLH1 methylation was not associated with the survival of these patients. To conclude, the cisplatin-based adjuvant chemotherapy is more beneficial for NSCLC patients without hMLH1 methylation. hMLH1 methylation may have a potential to become a biomarker of individualized therapy for NSCLC patients.


Comparative survey of psychiatrists' prescription preferences: New York and Texas.
The present survey compares the treatment preferences of New York and Texas psychiatrists using a questionnaire report of a single psychiatric case. The characteristics of this approach enable the investigator to hold and symptoms and syndromes of the patient constant. All clinicians respond to identical stimuli. What varies naturally, then, is the judgment of the clinician in developing his treatment procedure, thereby enabling estimation of the degree of standardization in treatment preferences. Three hundred twelve psychiatrists from New York and 133 from Texas provided data for comparative purposes. On the first admission 41% of the New York respondents and 24% of the Texas psychiatrists preferred a regimen that included more than one drug. When a combination of drugs was selected, chlorpromazine-trifluoperazine was preferred. But ten other specific combinations also were selected. Most were of potent neuroleptics, but some included antidepressant-neuroleptic combinations. None of the variables included in the study provided tangible systematic variance for these treatment preferences. A year and a half after first admission, followed by treatment in and out of hospital, the patient's clinical course continued to deteriorate. At this point more than 50% of the respondents in each state selected a regimen that included a minimum of two drugs. As many as 24 different combinations were selected for this single case. Nineteen percent of the New York respondents and 13% of the Texas respondents selected a regimen that included three or more psychoactive medications. The existence of these treatment preferences requires a more basic understanding of treatment preferences, for these seems to be no basis for them.


Biochemistry and physiology of anabolic hormones used for improvement of meat production.
A number of hormones are involved in endocrine regulation of growth. In general, these hormones enhance body protein accretion and metabolise fat stores resulting in increased lean growth rates. Most practical importance was obtained by sex hormones (oestrogens and androgens), beta-agonists and growth hormone - whether legally or illegally. Efficiency of growth promotion ranges between 0% and +20% depending on the prerequisites such as species, breed, gender, age, reproductive status, body score or feeding of the animals. Oestrogens and androgens mediate their activity via intracellular receptors - directly in muscular tissue as well as indirectly via stimulation of growth hormone from the hypophysis and other growth factors from liver plus several further organs. In addition, mineral absorption in the gut is improved. The outstanding efficiency of trenbolone is based on its androgenic plus antiglucocorticoid activity. Melengestrolacetate is thought to act indirectly via stimulation of endogenous ovarian oestradiol in non-pregnant heifers. The necessary dosages and residue formations depend on the pharmacokinetic parameters of each substance and extrapolations between compounds are hardly possible. Growth hormone and beta2-agonists use independent pathways for growth promotion not related to steroid biochemistry.