In a retrospective analysis of 632 orthototopic liver transplant procedures performed between 1982 and 1997, the incidence of primary dysfunction (PDF) of the liver and its influence on organ survival were studied. Graft function during the first 3 postoperative days was categorized into four groups: (1) good (GOT max < 1000 U/l, spontaneous PT>> 50%, bile production>> 100 ml/day); (2) fair (GOT 1000-2500 U/l, clotting factor support < 2 days, bile < 100 ml/day); (3) poor (GOT>> 2500 U/l, clotting factor support>> 2 days, bile < 20 ml/day); (4) primary non-function (PNF; retransplantation required within 7 days). The aim of this study was to evaluate graft survival comparing organs with PDF (poor function) and PNF vs organs with initial good or fair function. After a median follow-up of 45 months, initially good and fair function of liver grafts resulted in a significantly better long-term graft survival compared with grafts with initially poor function or primary non-function (if re-transplanted) (P < 0.01). The Cox model revealed primary function as a highly significant factor in the prediction of long-term graft survival (P < 0.0001). We conclude that these results confirm the hypothesis that primary graft function is of major importance for the long-term survival of liver transplants. Patients with a poor primary function have the worst survival prognosis, which leads to the interpretation that these patients may be candidates for early retransplantation.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Advances in materials science and molecular biology followed rapidly from the ability to characterize atomic structure using single crystals. Structure determination is more difficult if single crystals are not available. Many complex inorganic materials that are of interest in nanotechnology have no periodic long-range order and so their structures cannot be solved using crystallographic methods. Here we demonstrate that ab initio structure solution of these nanostructured materials is feasible using diffraction data in combination with distance geometry methods. Precise, sub-ångström resolution distance data are experimentally available from the atomic pair distribution function (PDF). Current PDF analysis consists of structure refinement from reasonable initial structure guesses and it is not clear, a priori, that sufficient information exists in the PDF to obtain a unique structural solution. Here we present and validate two algorithms for structure reconstruction from precise unassigned interatomic distances for a range of clusters. We then apply the algorithms to find a unique, ab initio, structural solution for C60 from PDF data alone. This opens the door to sub-ångström resolution structure solution of nanomaterials, even when crystallographic methods fail.

OBJECTIVE

To quantify the variability of diaphragm motion during free-breathing radiotherapy of lung patients and its effect on treatment margins to account for geometric uncertainties.

METHODS

Thirty-three lung cancer patients were analyzed. Each patient had 5-19 cone-beam scans acquired during different treatment fractions. The craniocaudal position of the diaphragm dome on the same side as the tumor was tracked over 2 min in the projection images, because it is both easily visible and a suitable surrogate to study the variability of the tumor motion and its impact on treatment margins. Intra-acquisition, inter-acquisition, and inter-patient variability of the respiratory cycles were quantified separately, as were the probability density functions (PDFs) of the diaphragm position over each cycle, each acquisition, and each patient. Asymmetric margins were simulated using each patient PDF and compared to symmetric margins computed from a margin recipe.

RESULTS

The peak-to-peak amplitude variability (1 SD) was 3.3 mm, 2.4 mm, and 6.1 mm for the intra-acquisition, inter-acquisition, and inter-patient variability, respectively. The average PDF of each cycle was similar to the sin(4) function but the PDF of each acquisition was closer to a skew-normal distribution because of the motion variability. Despite large interfraction baseline variability, the PDF of each patient was generally asymmetric with a longer end-inhale tail because the end-exhale position was more stable than the end-inhale position. The asymmetry of the PDF required asymmetric margins around the time-averaged position to account for the position uncertainty but the average difference was 1.0 mm (range, 0.0-4.4 mm) for a sharp penumbra and an idealized online setup correction protocol.

CONCLUSIONS

The respiratory motion is more irregular during the fractions than between the fractions. The PDF of the respiratory motion is asymmetrically distributed. Both the intra-acquisition variability and the PDF asymmetry have a limited impact on dose distributions and inferred margins. The use of a margin recipe to account for respiratory motion with an estimate of the average motion amplitude was adequate in almost all patients.

Insulin-like peptides (ILPs) regulate numerous functions in insects including growth, development, carbohydrate metabolism and female reproduction. This paper reports the immunohistochemical localization of ILPs in brain neurons of Rhodnius prolixus and their intimate associations with the brain circadian clock system. In larvae, three groups of neurons in the protocerebrum are ILP-positive, and testis ecdysiotropin (TE) is co-localized in two of them. During adult development, the number of ILP groups increased to four. A blood meal initiates transport and release of ILPs, indicating that release is nutrient dependent. Both production and axonal transport of ILPs continue during adult development with clear cytological evidence of a daily rhythm that closely correlates with the daily rhythm of ILPs release from brains in vitro. The same phenomena were observed with TE previously. Double labeling for ILPs and pigment dispersing factor (PDF) (contained in the brain lateral clock cells, LNs) revealed intimate associations between axons of the ILP/TE cells and PDF-positive axons in both central brain and retrocerebral complex, revealing potential neuronal pathways for circadian regulation of ILPs and TE. Similar close associations were found previously between LN axons and axons of the brain neurons producing the neuropeptide prothoracicotropic hormone. Thus, the brain clock system controls rhythmicity in multiple brain neurohormones. It is suggested that rhythms in circulating ILPs and TE act in concert with known rhythms of circulating ecdysteroids in both larvae and adults to orchestrate the timing of cellular responses in diverse tissues of the animal, thereby generating internal temporal order within it.

The application of NMR spectroscopy to study the structure, dynamics and function of macromolecules requires the acquisition of several multidimensional spectra. The one-dimensional NMR time-response from the spectrometer is extended to additional dimensions by introducing incremented delays in the experiment that cause oscillation of the signal along "indirect" dimensions. For a given dimension the delay is incremented at twice the rate of the maximum frequency (Nyquist rate). To achieve high-resolution requires acquisition of long data records sampled at the Nyquist rate. This is typically a prohibitive step due to time constraints, resulting in sub-optimal data records to the detriment of subsequent analyses. The multidimensional NMR spectrum itself is typically sparse, and it has been shown that in such cases it is possible to use non-Fourier methods to reconstruct a high-resolution multidimensional spectrum from a random subset of non-uniformly sampled (NUS) data. For a given acquisition time, NUS has the potential to improve the sensitivity and resolution of a multidimensional spectrum, compared to traditional uniform sampling. The improvements in sensitivity and/or resolution achieved by NUS are heavily dependent on the distribution of points in the random subset acquired. Typically, random points are selected from a probability density function (PDF) weighted according to the NMR signal envelope. In extreme cases as little as 1% of the data is subsampled. The heavy under-sampling can result in poor reproducibility, i.e. when two experiments are carried out where the same number of random samples is selected from the same PDF but using different random seeds. Here, a jittered sampling approach is introduced that is shown to improve random seed dependent reproducibility of multidimensional spectra generated from NUS data, compared to commonly applied NUS methods. It is shown that this is achieved due to the low variability of the inherent sensitivity of the random subset chosen from a given PDF. Finally, it is demonstrated that metrics used to find optimal NUS distributions are heavily dependent on the inherent sensitivity of the random subset, and such optimisation is therefore less critical when using the proposed sampling scheme.

Pair distribution function (PDF) analysis was applied for structural characterization of the cobalt oxide water-splitting catalyst films using high energy X-ray scattering. The catalyst was found to be composed of domains consistent with a cobalt dioxide lattice sheet structure, possibly containing a Co(4)O(4) cubane-type "defect". The analysis identifies the film to consist of domains composed of 13-14 cobalt atoms with distorted coordination geometries that can be modeled by alteration in terminal oxygen atom positions at the domain edge. Phosphate is seen as a disordered component in the films. This work establishes an approach that can be applied to study the structure of in situ cobalt oxide water-splitting film under functional catalytic conditions.

Perception allows us to extract information about regularities in the environment. Observers can quickly determine summary statistics of a group of objects and detect outliers. The existing body of research has, however, not revealed how such ensemble representations develop over time. Moreover, the correspondence between the physical distribution of features in the external world and their potential internal representation as a probability density function (PDF) by the visual system is still unknown. Here, for the first time we demonstrate that such internal PDFs are built during visual search and show how they can be assessed with repetition and role-reversal effects. Using singleton search for an oddly oriented target line among differently oriented distractors (a priming of pop-out paradigm), we test how different properties of previously observed distractor distributions (mean, variability, and shape) influence search times. Our results indicate that observers learn properties of distractor distributions over and above mean and variance; in fact, response times also depend on the shape of the preceding distractor distribution. Response times decrease as a function of target distance from the mean of preceding Gaussian distractor distributions, and the decrease is steeper when preceding distributions have small standard deviations. When preceding distributions are uniform, however, this decrease in response times can be described by a two-piece function corresponding to the uniform distribution PDF. Moreover, following skewed distributions response times function is skewed in accordance with the skew in distributions. Indeed, internal PDFs seem to be specifically tuned to the observed feature distribution.

Helicobacter pylori (H. pylori) is a major causative factor for gastrointestinal illnesses, H. pylori peptide deformylase (HpPDF) catalyzes the removal of formyl group from the N-terminus of nascent polypeptide chains, which is essential for H. pylori survival and is considered as a promising drug target for anti-H. pylori therapy. Propolis, a natural antibiotic from honeybees, is reported to have an inhibitory effect on the growth of H. pylori in vitro. In addition, previous studies suggest that the main active constituents in the propolis are phenolic compounds. Therefore, we evaluated a collection of phenolic compounds derived from propolis for enzyme inhibition against HpPDF. Our study results show that Caffeic acid phenethyl ester (CAPE), one of the main medicinal components of propolis, is a competitive inhibitor against HpPDF, with an IC50 value of 4.02 μM. Furthermore, absorption spectra and crystal structural characterization revealed that different from most well known PDF inhibitors, CAPE block the substrate entrance, preventing substrate from approaching the active site, but CAPE does not have chelate interaction with HpPDF and does not disrupt the metal-dependent catalysis. Our study provides valuable information for understanding the potential anti-H. pylori mechanism of propolis, and CAPE could be served as a lead compound for further anti-H. pylori drug discovery.

This letter to the Editor aims to provide suggestions and recommendations for the management of urological conditions in times of COVID-19 crisis in Brazil and other low- and middle-income countries. It is important to highlight that one of the main characteristics of this pandemic is the oversaturation of the health system capacity, mostly due to a high demand for personal protective equipment (PPE), Hospital/ICU beds, as well as ventilators. In places with limited resources and where the health care systems are already saturated, such consideration is even more worrisome. Therefore, most worldwide authorities are recommending to avoid, as much as possible, patient's elective visits to hospitals, as well as a judicious use of the operating room in order to mitigate the strain put on the health system. While efforts should be directed to the care of COVID-19 patients, other conditions (especially urgencies and oncological cases) must continue to be assisted. Thus, through a panel of experts, we have prepared a practical guide for urologists based on the recommendations from the main Urologic Associations, as well as data from the literature to support the suggested management. We will try to follow the standard guideline recommendations from the American Urological Association (AUA) and European Association of Urology (EAU), with the aim of pursuing the best outcomes possible. However, some recommendations were based on the consensus of the panel, taking into consideration the reality of developing countries and the unprecedented situation caused by the COVID-19 crisis. Most importantly, all recommendations on this manuscript are based on the expectancy of a maximum 3-month duration of the crisis. If this period shall extended, these recommendations will be revised and updated. Available at. https://www.intbrazjurol.com.br/pdf/aop/COVID_19_Arie_et_al.pdf.

While reviewing the available literature, we noticed comorbidity of epilepsy and psychiatric disorders. Psychiatric disorders were observed more frequently in patients with high seizure frequency. There is significant prevalence of epilepsy comorbidity with depression, anxiety disorders, and to a lesser extent with bipolar disorders and other forms of psychosis. Suicidal risk factors, ideation and attempts in these patients as correlates of depression or as psychopathological features were associated to epileptic disease. This is confirmed by additional burden of epilepsy patients with psychic disorders (Ref. 70). Full Text (Free, PDF) www.bmj.sk.

An octadecapeptide capable of inducing pigment dispersion in the chromatophores of the fiddler crab Uca pugilator has been isolated from lyophilized heads of the lubber grasshopper Romalea microptera. This pigment-dispersing factor (PDF) was purified by gel filtration, ion-exchange chromatography, partition chromatography, and reversed-phase high performance liquid chromatography. Automated gas-phase sequencing, followed by the identification of the carboxyl-terminal amide, established the primary structure of this PDF as Asn-Ser-Glu-Ile-Ile-Asn-Ser-Leu-Leu-Gly-Leu-Pro-Lys-Leu-Leu-Asn-Asp-Ala- NH2. This structure was confirmed by chemical synthesis and by demonstrating that the synthetic and native PDF displayed identical chromatographic behavior and biological activity. The Romalea PDF is structurally related to the crustacean pigment-dispersing hormones (PDHs), which are also octadecapeptides. The sequence of grasshopper PDF shows 78% homology with beta-PDH (from the crabs U. pugilator and Cancer magister) and 50% homology with alpha-PDH (from the prawn Pandalus borealis). This study provides the first direct chemical evidence for the structural relatedness of insect PDF to the crustacean PDHs, thus identifying them as an authentic family of arthropod peptides.

The brain clock that drives circadian rhythms of locomotor activity relies on a multi-oscillator neuronal network. In addition to synchronizing the clock with day-night cycles, light also reformats the clock-driven daily activity pattern. How changes in lighting conditions modify the contribution of the different oscillators to remodel the daily activity pattern remains largely unknown. Our data in Drosophila indicate that light readjusts the interactions between oscillators through two different modes. We show that a morning s-LNv>> DN1p circuit works in series, whereas two parallel evening circuits are contributed by LNds and other DN1ps. Based on the photic context, the master pacemaker in the s-LNv neurons swaps its enslaved partner-oscillator-LNd in the presence of light or DN1p in the absence of light-to always link up with the most influential phase-determining oscillator. When exposure to light further increases, the light-activated LNd pacemaker becomes independent by decoupling from the s-LNvs. The calibration of coupling by light is layered on a clock-independent network interaction wherein light upregulates the expression of the PDF neuropeptide in the s-LNvs, which inhibits the behavioral output of the DN1p evening oscillator. Thus, light modifies inter-oscillator coupling and clock-independent output-gating to achieve flexibility in the network. It is likely that the light-induced changes in the Drosophila brain circadian network could reveal general principles of adapting to varying environmental cues in any neuronal multi-oscillator system.

Accurate and precise displacement estimation has been a hallmark of clinical ultrasound. Displacement estimation accuracy has largely been considered to be limited by the Cramer-Rao lower bound (CRLB). However, the CRLB only describes the minimum variance obtainable from unbiased estimators. Unbiased estimators are generally implemented using Bayes' theorem, which requires a likelihood function. The classic likelihood function for the displacement estimation problem is not discriminative and is difficult to implement for clinically relevant ultrasound with diffuse scattering. Because the classic likelihood function is not effective, a perturbation is proposed. The proposed likelihood function was evaluated and compared against the classic likelihood function by converting both to posterior probability density functions (PDFs) using a noninformative prior. Example results are reported for bulk motion simulations using a 6λ tracking kernel and 30 dB SNR for 1000 data realizations. The canonical likelihood function assigned the true displacement a mean probability of only 0.070 ± 0.020, whereas the new likelihood function assigned the true displacement a much higher probability of 0.22 ± 0.16. The new likelihood function shows improvements at least for bulk motion, acoustic radiation force induced motion, and compressive motion, and at least for SNRs greater than 10 dB and kernel lengths between 1.5 and 12λ.

Chronic renal failure (CRF) is often treated with peritoneal dialysis, although increased oxidative stress has been reported in such patients. The purpose of the current study was to analyze and compare oxidative stress and other compositional parameters in the saliva, serum and peritoneal dialytic fluid (PDF) of patients with chronic kidney disease (CKD), including predialysis CKD patients and end-stage renal disease (ESRD) patients treated with peritoneal dialysis. Twenty-three consenting patients participated in the current study. Saliva and serum samples collected from both groups and PDF from the dialysis patients were all examined for uric acid (UA), total antioxidant status, total protein and total albumin. The antioxidant enzyme peroxidase was examined both in saliva and serum, while the antioxidant enzyme superoxide dismutase (SOD) was examined solely in saliva. Various electrolytes were examined. Discrepancies were found between saliva and serum antioxidant status following peritoneal dialysis in ESRD patients. Oxidative stress was enhanced in the saliva but reduced in the serum. Significant changes in both oxidative-related and non-related parameters were demonstrated in saliva, serum and PDF. Salivary lactate dehydrogenase was substantially lower in the dialysis patients (by 92%, P = 0.02), as was the salivary UA concentration (by 22%, P = 0.05) and serum UA concentration (by 20%, P = 0.03). In contrast, salivary peroxidase and SOD were higher by 15% and 35%, respectively (P = 0.01), in these patients. We suggest monitoring salivary UA for assessing the baseline oral oxidative status of CRF and dialyzed patients.

BACKGROUND

Drug resistance in bacteria has become a global concern and the search for new antibacterial agents is urgent and ongoing. Endophytes provide an abundant reservoir of bioactive metabolites for medicinal exploitation, and an increasing number of novel compounds are being isolated from endophytic fungi. Ophiopogon japonicus, containing compounds with antibacterial activity, is a traditional Chinese medicinal plant used for eliminating phlegm, relieving coughs, latent heat in the lungs, and alleviating diabetes mellitus. We investigated the antimicrobial activities of 30 strains of O. japonicus.

METHODS

Fungal endophytes were isolated from roots and stems of O. japonicus collected from Chongqing City, southwestern China. Mycelial extracts (MC) and fermentation broth (FB) were tested for antimicrobial activity using peptide deformylase (PDF) inhibition fluorescence assays and MTT cell proliferation assays.

RESULTS

A total of 30 endophytic strains were isolated from O. japonicus; 22 from roots and eight from stems. 53.33% of the mycelial extracts (MC) and 33.33% of the fermentation broths (FB) displayed potent inhibition of PDF. 80% of MC and 33.33% of FB significantly inhibited Staphylococcus aureus. 70% of MC and 36.67% of FB showed strong activities against Cryptococcus neoformans. None showed influence on Escherichia coli.

CONCLUSIONS

The secondary metabolites of endophytic fungi from O. japonicus are potential antimicrobial agents.

OBJECTIVE

Fatigue is a problem experienced by many patients suffering from chronic diseases, including sarcoidosis patients. It has a substantial influence on patients' quality of life (QoL). It is, therefore, important to properly assess fatigue with a valid and reliable measure. The Fatigue Assessment Scale (FAS) is the only validated self-reporting instrument classifying fatigue in sarcoidosis. The aim of this review was to examine the psychometric properties of the FAS and the diseases and languages in which it has been used. Studies among sarcoidosis patients were also reviewed in terms of outcomes.

RESULTS

Studies were identified by searching the electronic bibliographic database Pubmed. Search terms used were: FAS and fatigue. Articles were included in the review if the FAS had been used to assess fatigue.

RESULTS

Since its introduction, the FAS was used in 26 different diseases or conditions, including stroke, neurologic disorders, rheumatoid arthritis, idiopathic pulmonary fibrosis and sarcoidosis. Its reliability and validity have proved to be good. Unidimensionality has been established. So far, the FAS is available in 20 languages and widely used in sarcoidosis. Digital versions as well as PDFs of various languages are available online (www.wasog.org).

CONCLUSIONS

The FAS has good psychometric qualities for the diseases in which it has been examined, including sarcoidosis, and can be used in clinical practice. Healthcare workers can use the FAS to assess fatigue in the management, follow-up and clinical care programmes for their patients consistently across countries, as well as in clinical research.

OBJECTIVE

To confirm the advantage of in situ reconstruction (ISR) over extra-anatomic reconstruction (EAR) for aortic graft infection and determine the most appropriate conduit including autogenous veins, cryopreserved allografts, and synthetic prosthesis (standard, rifampicin of silver polyesters).

METHODS

A meta-analysis was conducted with rate of mortality, graft occlusion, amputation, and reinfection. A meta-regression was performed with 4 factors: patients' age, presence of prosthetic-duodenal fistula (PDF), virulent organisms, or nonvirulent organisms.

RESULTS

In situ reconstruction over EAR seems to favor all events. For the 5 conduits used for ISR, according to operative mortality, age of the patients looks to have a positive correlation only for silver polyester and no conduit present any advantage in the presence of PDF. Reinfection seems to be not significantly different for the 5 conduits, and only autogenous veins appear to have a positive correlation with infecting organisms.

CONCLUSIONS

In situ reconstruction may be considered as first-line treatment. Our results suggest that silver polyesters appear to be most appropriate for older patients, and in order to limit reinfection, autogenous veins are probably the most suitable conduit.

Casein kinase 1, known as DOUBLETIME (DBT) in Drosophila melanogaster, is a critical component of the circadian clock that phosphorylates and promotes degradation of the PERIOD (PER) protein. However, other functions of DBT in circadian regulation are not clear, in part because severe reduction of dbt causes preadult lethality. Here we report the molecular and behavioral phenotype of a viable dbt(EY02910) loss-of-function mutant. We found that DBT protein levels are dramatically reduced in adult dbt(EY02910) flies, and the majority of mutant flies display arrhythmic behavior, with a few showing weak, long-period (∼32 h) rhythms. Peak phosphorylation of PER is delayed, and both hyper- and hypophosphorylated forms of the PER and CLOCK proteins are present throughout the day. In addition, molecular oscillations of the circadian clock are dampened. In the central brain, PER and TIM expression is heterogeneous and decoupled in the canonical clock neurons of the dbt(EY02910) mutants. We also report an interaction between dbt and the signaling pathway involving pigment dispersing factor (PDF), a synchronizing peptide in the clock network. These data thus demonstrate that overall reduction of DBT causes long and arrhythmic behavior, and they reveal an unexpected role of DBT in promoting synchrony of the circadian clock network.

BACKGROUND

Long-term heroin abuse is related to pathological changes in many organs mediated by oxidative stress (OS).

OBJECTIVE

Estimation of systemic OS and antioxidant capacity in heroin addiction and detoxification provides information about prooxidant/antioxidant homeostasis in heroin misuse and need for antioxidant supplementation.

METHODS

OS was evaluated by the measurement of plasma reactive oxygen metabolites using spectrophotometric method and plasma lipid peroxidation by its end product--malondyaldehyd using Tiobarbituric Acid Reactions Substances method. The extracellular antioxidant capacity was estimated using OXY-adsorbent test.

RESULTS

This cross-sectional study includes 68 patients: 46 heroin addicts (20 patients on chronic heroin abuse, 19 patients on conventional method of detoxification and 7 patients on opioid antagonist--naltrexone (and 22 patients as a control) group. Increased OS was found in the heroin group (d-ROMs 349.3 +/- 102.2 UCarr, MDA 4.0 +/- 0.4 micromol/L) compared to the group on detoxification (d-ROMs 230.2 +/- 96.4 UCarr; MDA 3.6 +/- 0.3 micromol/L) and control group (d-ROMs 264.1 +/- 30.9 UCarr; MDA 3.7 +/- 0.2 micromol/L). TAC was decreased in the heroin group (324.5 +/- 75.0 micromol HClO/ml) and restored during conventional detoxification (371.8 +/- 25.1 micromol HClO/ml), but not completely in the group with naltrexone treatment (335.6 +/- 16.9 micromol HClO/ml) compared with controls (395.4 +/- 35.6 micromol HClO/ml).

CONCLUSIONS

Long-term heroin abuse stimulates a progressive systemic oxidative stress which increases the extracellular antioxidants consumption and develops conditions for chronic heroin toxicity (Fig. 1, Tab. 4, Ref. 35). Full Text (Free, PDF) www.bmj.sk.

RNA-binding proteins mediate posttranscriptional functions in the circadian systems of multiple species. A conserved RNA recognition motif (RRM) protein encoded by the lark gene is postulated to serve circadian output and molecular oscillator functions in Drosophila and mammals, respectively. In no species, however, has LARK been eliminated, in vivo, to determine the consequences for circadian timing. The present study utilized RNA interference (RNAi) techniques in Drosophila to decrease LARK levels in clock neurons and other cell types in order to evaluate the circadian functions of the protein. Knockdown of LARK in timeless (TIM)- or pigment dispersing factor (PDF)-containing clock cells caused a significant number of flies to exhibit arrhythmic locomotor activity, demonstrating a requirement for the protein in pacemaker cells. There was no obvious effect on PER protein cycling in lark interference (RNAi) flies, but a knockdown within the PDF neurons was associated with increased PDF immunoreactivity at the dorsal termini of the small ventral lateral neuronal (s-LNv) projections, suggesting an effect on neuropeptide release. The expression of lark RNAi in multiple neurosecretory cell populations demonstrated that LARK is required within pacemaker and nonpacemaker cells for the manifestation of normal locomotor activity rhythms. Interestingly, decreased LARK function in the prothoracic gland (PG), a peripheral organ containing a clock required for the circadian control of eclosion, was associated with weak population eclosion rhythms or arrhythmicity.

Biallelic mutations in the RPE65 gene are associated with inherited retinal degenerations/dystrophies (IRD) and disrupt the visual cycle, leading to loss of vision. A new adenoviral vector-based gene therapy surgically delivered to retinal cells provides normal human RPE65 protein that can restore the visual cycle and some vision. To view this Bench to Bedside, open or download the PDF.

Pituitary cells have been used for the study of hormone synthesis, secretion, and regulation. However, the lack of human cell lines of pituitary origin has made such studies in humans very difficult. Activin, a member of the transforming growth factor-beta cytokine family, is secreted by the pituitary and serves, in addition to regulating hormone biosynthesis, as a regulator of cell growth and differentiation. In the human pituitary, folliculo-stellate cells secrete an activin-binding and -neutralizing protein, follistatin. However, the role of these cells in the autocrine/paracrine regulatory mechanisms of activin is poorly understood. We describe a human pituitary-derived folliculostellate cell line, designated PDFS, that was developed spontaneously from a clinically nonfunctioning pituitary macroadenoma. PDFS cells showed an epithelial-like morphology with long cytoplasmic processes. Electron microscopy revealed frequent intercellular junctions, including desmosomes, and cytogenetic analysis showed clonal characteristics with chromosomal abnormalities. These cells express vimentin and the nervous tissue-specific S-100 protein, specific markers of folliculostellate cells in the anterior pituitary, but no secretory pituitary cell markers. PDFS cells formed large colonies in an anchorage-independent transformation assay. They express follistatin and activin A and have an intact activin intracellular signaling pathway as determined by reporter assays. Therefore, this human cell line provides a useful model for studying the regulation of cell growth and cytokine production by factors endogenously produced in pituitary folliculostellate cells.

UNASSIGNED

Gout is a common type of inflammatory arthritis in patients seen by primary care physicians.

UNASSIGNED

To review evidence about treatment of acute gout attacks, management of hyperuricemia to prevent attacks, and discontinuation of medications for chronic gout in adults.

UNASSIGNED

Multiple electronic databases from January 2010 to March 2016, reference mining, and pharmaceutical manufacturers.

UNASSIGNED

Studies of drugs approved by the U.S. Food and Drug Administration and commonly prescribed by primary care physicians, randomized trials for effectiveness, and trials and observational studies for adverse events.

UNASSIGNED

Data extraction was performed by one reviewer and checked by a second reviewer. Study quality was assessed by 2 independent reviewers. Strength-of-evidence assessment was done by group discussion.

UNASSIGNED

High-strength evidence from 28 trials (only 3 of which were placebo-controlled) shows that colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids reduce pain in patients with acute gout. Moderate-strength evidence suggests that low-dose colchicine is as effective as high-dose colchicine and causes fewer gastrointestinal adverse events. Moderate-strength evidence suggests that urate-lowering therapy (allopurinol or febuxostat) reduces long-term risk for acute gout attacks after 1 year or more. High-strength evidence shows that prophylaxis with daily colchicine or NSAIDs reduces the risk for acute gout attacks by at least half in patients starting urate-lowering therapy, and moderate-strength evidence indicates that duration of prophylaxis should be longer than 8 weeks. Although lower urate levels reduce risk for recurrent acute attacks, treatment to a specific target level has not been tested.

UNASSIGNED

Few studies of acute gout treatments, no placebo-controlled trials of management of hyperuricemia lasting longer than 6 months, and few studies in primary care populations.

UNASSIGNED

Colchicine, NSAIDs, and corticosteroids relieve pain in adults with acute gout. Urate-lowering therapy decreases serum urate levels and reduces risk for acute gout attacks.

UNASSIGNED

Agency for Healthcare Research and Quality. (Protocol registration: http://effectivehealth-care.ahrq.gov/ehc/products/564/1992/Gout-managment-protocol-141103.pdf).