Joy C Edlin<br />May 7, 2018; 2018:bcr-2017-223704-bcr-2017-223704<br />Images in...
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Σάββατο 2 Ιουνίου 2018
Risk of operating on the wrong site: how to avoid a never event
LOXO-292 Reins In RET-Driven Tumors [News in Brief]
Responses seen across a range of RET alterations and cancer types in phase I trial.
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Influence of Creatine Supplementation on Apoptosis Markers after Downhill Running in Middle-Aged Men: A Crossover Randomized, Double-Blind, and Placebo-Controlled Study
Objective Strenuous exercise can induce apoptosis in a variety of tissues. We investigated the effects of creatine loading on apoptosis markers after downhill running. Design Twenty-two middle-aged men were randomly assigned to either a creatine or a placebo group. Crossover design, double-blind controlled supplementation was performed using 20 g/d-1 of creatine or maltodextrin for seven days. Downhill running (12% incline) at 70% of HRmax for 40 min was performed on the 8th day. Blood samples were taken on the day prior to supplementation, after supplementation and after running. Results There were no significant changes in the caspase-3 and -9, p53, Bax and IGF-1 concentrations from pre- to post- supplementation in both groups of creatine and placebo (p > 0.05). There were significant increases (p 0.05). Bcl-2 was unchanged in the placebo group, but substantially increased (p 0.05). Lactate levels increased similarly in both groups (p
https://ift.tt/2HhEQXI
https://ift.tt/2HhEQXI
Fatigue after aneurysmal subarachnoid hemorrhage is highly prevalent in the first year post onset and related to low physical fitness: A longitudinal study
Objective To investigate whether low physical fitness and inactive and sedentary lifestyles play a role in the severity of fatigue in patients with aneurysmal subarachnoid hemorrhage (a-SAH). Design Prospective one-year follow-up study, including a total of 52 patients with a-SAH. Outcome measures included the Fatigue Severity Scale -score, peak oxygen uptake (V[Combining Dot Above]O2peak), isokinetic knee muscle strength (peak torque), physical activity (%24h period) and sedentary behavior (% waking hours), and were evaluated at six and twelve months post onset. Results Fatigue was highly prevalent in the first year, and reported by 48% of the patients at six months and by 52% at twelve months post a-SAH. Fatigue was associated with the knee extension (p
https://ift.tt/2J4MpH4
https://ift.tt/2J4MpH4
An Empirical Study of Visitors’ Experience at Kuching Orchid Garden with Mobile Guide Application
This empirical study was conducted to measure visitors' experiences with a mobile guide application at Kuching Orchid Garden (KOG). A between-group experimental design with 114 participants was conducted to test three groups; a group using the mobile guide application as an information aid, a control group (with no information aid), and a group using pamphlets to explore the KOG. The Museum Experience Scale (MES) was used to evaluate visitors' experience for all participants, whilst the Multimedia Guide Scale (MMGS) was used to evaluate the visitors' experience with the mobile guide group. The most notable result from the Museum Experience Scale (MES) showed an impact on the visitors in terms of knowledge and learning when using the mobile guide application. However, the study found that enhancing visitors experience goes beyond simply providing interactive technologies in public settings to aid with information delivery. A limitation was providing relevant information in a timely and seamless manner due to inaccuracies of mapping between physical and digital environments. Future works should consider beacons and other Bluetooth low energy (BLE) technology to address the issues with location based devices. It is also important to highlight that the use of one's own device had a significant impact on learnability and control of the device, thus suggesting that the BYOD concept should be widely used in informal educational settings implementing mobile guide applications. The use of MES and MMGS informs future researches with an understanding of the different dimensions of visitors' experiences with mobile guide technology in public spaces to inform mobile application development that may further boost visitors' engagement, emotional connection, and meaningful experience.
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Outcome of gastrointestinal graft-versus-host disease according to the treatment response
Abstract
The optimal treatment strategy for gastrointestinal graft-versus-host disease (GI-GVHD) after allogeneic hematopoietic cell transplantation remains to be established. We retrospectively analyzed 68 cases of GI-GVHD at our institution between 2007 and 2017. The survival outcomes were significantly inferior in patients who did not respond to the first-line treatment (1-year overall survival 27.3 vs 69.2%, P = 0.0017; non-relapse mortality 50.0 vs 18.6%, P = 0.026). After subsequent treatments, 18 patients were refractory to all steroid-based treatments such as steroid pulse therapy and oral beclomethasone dipropionate (BDP). However, these steroid-refractory cases showed a gradual increase in the response rate after the initial diagnosis of steroid refractoriness. This result may be explained by the problem of evaluating the response based solely on the volume of diarrhea, i.e., severe mucosal damage due to refractory GI-GVHD may require a long recovery and sometimes be complicated with other diseases. In conclusion, patients with GI-GVHD who failed to respond to the first-line treatment had inferior survival. However, later improvement may be observed without additional immunosuppressant other than steroid among patients who initially do not respond to steroid therapy. It is important to repeat colonoscopy in patients with refractory GI-GVHD to monitor the activity of GVHD.
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Analysis and expression of the carotenoid biosynthesis genes from Deinococcus wulumuqiensis R12 in engineered Escherichia coli
Deinococcus wulumuqiensis R12 is a red-pigmented extremophilic microorganism with powerful antioxidant properties that was isolated from radiation-contaminated soil in Xinjiang Uyghur Autonomous Region of China. ...
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Practical guidelines for clinical magnetoencephalography – Another step towards best practice
The first successful recordings of electrical activity from the human brain using scalp EEG were performed nearly a century ago (Berger, 1929). Its clinical relevance, particularly for epilepsy, was realized and established within a few years. Since then, scalp EEG has found many applications in neurological and neuropsychiatric disorders (Schomer et al., 2018). However, the limitations of EEG were already acknowledged in these early years, notably by one of its pioneers, Edgar Adrian, who wrote "With present methods the skull and the scalp are too much in the way, and we need some new physical method to read through them" (Adrian, 1944).
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High voltage 14 Hz hippocampal discharges on stereotactic EEG underlying 14&6 Hz positive bursts on scalp EEG
14&6 Hz positive bursts are one of the well-known benign EEG variants (Lombroso et al., 1966). They are maximally expressed in adolescents. The peak age of prominent 14&6 Hz ranges from 13 to 15 years. Gibbs and Gibbs (Gibbs and Gibbs, 1951) first reported 14&6 Hz positive bursts and indicated thalamic or hypothalamic epilepsy. However, currently they are believed to be a benign EEG variant because they are frequently seen in a wide range of neurological disorders including epilepsy and normal individuals (Lombroso et al., 1966).
https://ift.tt/2xEcpUq
Hepatocellular Carcinoma Tumor Dose Response following 90Y-radioembolization with glass microspheres using 90Y-SPECT/CT based Voxel Dosimetry
To investigate hepatocellular carcinoma (HCC) tumor dose-response characteristics based on voxel-level absorbed doses (D) and biological effective doses (BED) using quantitative 90Y-SPECT/CT after 90Y-radioembilization with glass-microspheres. We also investigated the relationship between normal liver D and toxicities.
https://ift.tt/2LVH7LN
Automated instead of manual treatment planning? A plan comparison based on dose-volume statistics and clinical preference
Automated planning aims to improve the efficiency of the treatment planning process as well as the final plan quality. We compared automated plans to manual plans for 56 patients based on clinical objectives, DVH metrics and a blind clinical assessment by three experienced radiation oncologists. We observed a statistically significant reduction in OAR dose while maintaining PTV coverage for the automated plans. Clinically, however, the automated plans were not always preferred over their manual counterparts.
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Does Point-of-Care Ultrasonography Improve Clinical Outcomes in Emergency Department Patients With Undifferentiated Hypotension? An International Randomized Controlled Trial From the SHoC-ED Investigators
Point-of-care ultrasonography protocols are commonly used in the initial management of patients with undifferentiated hypotension in the emergency department (ED). There is little published evidence for any mortality benefit. We compare the effect of a point-of-care ultrasonography protocol versus standard care without point-of-care ultrasonography for survival and clinical outcomes.
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Carcinosarcoma of the parotid gland with abdominal metastasis: a case report and review of literature
Abstract
Background
Carcinosarcoma of the salivary gland is a rare aggressive malignant tumor, composed of a mixture of carcinomatous and sarcomatous components. The most common metastatic sites include the lungs, bones, and central nervous system.
Case presentation
This report describes a rare case of carcinosarcoma of the parotid gland with an osteosarcoma as sarcomatous component in a 72-year-old man who had a history of low anterior resection for rectal cancer. Six months after parotidectomy, he presented abdominal pain as a symptom of abdominal metastasis by the sarcomatous component. At that time, the possibility of abdominal metastasis was overlooked because of the history of abdominal surgery. After several days of conservative treatment, emergency laparotomy was done. However, he died of acute respiratory distress syndrome.
Conclusions
Awareness of the possibility of abdominal metastasis by salivary carcinosarcoma may help in managing patients with a history of abdominal surgery.
https://ift.tt/2JqjfS2
Opioid Use After Discharge in Postoperative Patients: A Systematic Review
Background: Over the past 2 decades, there has been an increase in opioid use and subsequently, opioid deaths. The amount of opioid prescribed to surgical patients has also increased. The aim of this systematic review was to determine postdischarge opioid consumption in surgical patients compared with the amount of opioid prescribed. Secondary outcomes included adequacy of pain control and disposal methods for unused opioids. Objective: The objective of this study is to characterize postdischarge opioid consumption and prescription patterns in surgical patients. Methods: A systematic search in MEDLINE and EMBASE identified 11 patient survey studies reporting on postdischarge opioid use in 3525 surgical patients. Results: The studies reported on a variety of surgical operations, including abdominal surgery, orthopedic procedures, tooth extraction, and dermatologic procedures. The majority of patients consumed 15 pills or less postdischarge. The proportion of used opioids ranged from 5.6% to 59.1%, with an outlier of 90.1% in pediatric spinal fusion patients. Measured pain scores of those taking opioids ranged between 2 and 5 out of 10 and the majority of patients were satisfied with their pain control. Seventy percent of patients kept the excess opioids. Where planned disposal methods were reported, between 4% and 59% of patients planned proper disposal. Conclusion: This study suggests that surgical patients are using substantially less opioid than prescribed. There is a lack of awareness regarding proper disposal of leftover medication, leaving excess opioid that may be used inappropriately by the patient or others. Education for providers and clinical practice guidelines that provide guidance on prescription of outpatient of opioids are required.https://ift.tt/2FTs0OH
Dissection of Enhancer Function Using Multiplex CRISPR-based Enhancer Interference in Cell Lines
This protocol describes the steps needed to design and perform multiplexed targeting of enhancers with the deactivating fusion protein SID4X-dCas9-KRAB, also known as enhancer interference (Enhancer-i). This protocol enables the identification of enhancers that regulate gene expression and facilitates the dissection of relationships between enhancers regulating a common target gene.
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An Invasive Method for the Activation of the Mouse Dentate Gyrus by High-frequency Stimulation
https://ift.tt/2Hi3kAo
Hemoglobin concentration does not impact 3-month outcome following acute ischemic stroke
There is uncertainty regarding the effect of anemia and red blood cell transfusion on functional outcome following acute ischemic stroke. We studied the relationship of hemoglobin parameters and red cell trans...
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Generation of Scaffold-free, Three-dimensional Insulin Expressing Pancreatoids from Mouse Pancreatic Progenitors In Vitro
https://ift.tt/2Hf8YTF
Ex Vivo Calcium Imaging for Visualizing Brain Responses to Endocrine Signaling in Drosophila
This paper describes a protocol for ex vivo calcium imaging of the Drosophila brain. In this method, natural or synthetic compounds can be applied to the buffer to test their ability to activate particular neurons in the brain.
https://ift.tt/2kJzzzz
Application of End-to-end Anastomosis in Robotic Central Pancreatectomy
The robotic central pancreatectomy with end-to-end anastomosis is feasible and safe for tumor in the pancreatic neck and proximal portion of pancreatic body. The operative techniques of this operation are presented.
https://ift.tt/2LS1ERv
Ablation of a Neuronal Population Using a Two-photon Laser and Its Assessment Using Calcium Imaging and Behavioral Recording in Zebrafish Larvae
Here, we present a protocol to ablate a genetically labeled subpopulation of neurons by a two-photon laser from Zebrafish larvae.
https://ift.tt/2xIkOGC
Association between delayed gastric emptying and upper gastrointestinal symptoms: a systematic review and meta-analysis
Background
The relationship between delayed gastric emptying and upper GI symptoms (UGI Sx) is controversial.
ObjectiveTo assess association between gastric emptying and UGI Sx, independent of treatment.
DesignWe performed a systematic review and meta-analysis of the literature from 2007 to 2017, review of references and additional papers identified by content expert. We included studies evaluating the association between gastric emptying and nausea, vomiting, early satiety/postprandial fullness, abdominal pain and bloating. Covariate analyses included optimal gastric emptying test method, gastric emptying type (breath test or scintigraphy) and patient category. Meta-regression compared the differences based on type of gastric emptying tests.
ResultsSystematic review included 92 gastric emptying studies (26 breath test, 62 scintigraphy, 1 ultrasound and 3 wireless motility capsule); 25 of these studies provided quantitative data for meta-analysis (15 scintigraphy studies enrolling 4056 participants and 10 breath test studies enrolling 2231 participants). Meta-regression demonstrated a significant difference between optimal and suboptimal gastric emptying test methods when comparing delayed gastric emptying with nausea and vomiting. On evaluating studies using optimal gastric emptying test methodology, there were significant associations between gastric emptying and nausea (OR 1.6, 95% CI 1.4 to 1.8), vomiting (OR 2.0, 95% CI 1.6 to 2.7), abdominal pain (OR 1.5, 95% CI 1.0 to 2.2) and early satiety/fullness (OR 1.8, 95% CI 1.2 to 2.6) for patients with UGI Sx; gastric emptying and early satiety/fullness in patients with diabetes; gastric emptying and nausea in patients with gastroparesis.
ConclusionsThe systematic review and meta-analysis supports an association between optimally measured delayed gastric emptying and UGI Sx.
https://ift.tt/2LiZI3w
Functional abdominal pain and discomfort (IBS) is not associated with faecal microbiota composition in the general population
We read with interest the study by Simrén et al1 addressing the correlation between GI symptoms and functional GI disorders (eg, irritable bowel syndrome (IBS)) and the comment by Hadizadeh et al2 reporting abdominal pain sensation to be associated with an altered faecal microbiota composition. Hadizadeh et al2 propose from their study on 159 individuals that their results may allow to develop novel tools for diagnosis and management of IBS and dyspepsia. We tried to replicate their findings in the population-based Study of Health in Pomerania (SHIP-Trend)3 using stool samples from 906 volunteers to analyse faecal microbiota composition and diversity by 16S rRNA gene sequencing as previously described.4 Twenty participants were excluded for incomplete phenotypic data or antibiotic treatment at sample collection. Of the remaining 886 individuals (age: 51 years (40–61), median (first to third quartiles); female: 56.4%), 172 (19.4%) reported...
https://ift.tt/2JsgQ9K
Gut microbiota metabolites, amino acid metabolites and improvements in insulin sensitivity and glucose metabolism: the POUNDS Lost trial
Objective
Alterations in gut microbiota have been linked to host insulin resistance, diabetes and impaired amino acid metabolism. We investigated whether changes in gut microbiota-dependent metabolite of trimethylamine N-oxide (TMAO) and its nutrient precursors (choline and L-carnitine) were associated with improvements in glucose metabolism and diabetes-related amino acids in a weight-loss diet intervention.
DesignWe included 504 overweight and obese adults who were randomly assigned to one of four energy-reduced diets varying in macronutrient intake. The 6-month changes () in TMAO, choline and L-carnitine levels after the intervention were calculated.
ResultsGreater decreases in choline and L-carnitine were significantly (p<0.05) associated with greater improvements in fasting insulin concentrations and homeostasis model assessment of insulin resistance (HOMA-IR) at 6 months. The reduction of choline was significantly related to 2-year improvements in glucose and insulin resistance. We found significant linkages between dietary fat intake and TMAO for changes in fasting glucose, insulin and HOMA-IR (pinteraction <0.05); a greater increase in TMAO was related to lesser improvements in the outcomes among participants who consumed a high-fat diet. In addition, L-carnitine and choline were significantly related to changes in amino acids (including branched-chain and aromatic amino acids). Interestingly, the associations of TMAO, choline and L-carnitine with diabetes-related traits were independent of the changes in amino acids.
ConclusionOur findings underscore the importance of changes in TMAO, choline and L-carnitine in improving insulin sensitivity during a weight-loss intervention for obese patients. Dietary fat intake may modify the associations of TMAO with insulin sensitivity and glucose metabolism.
Trial registration numberhttps://ift.tt/2LiZzx0
Ocular Kinematics Measured by In Vitro Stimulation of the Cranial Nerves in the Turtle
https://ift.tt/2J76cFW
The effect of conscious intention to act on the Bereitschaftspotential
Abstract
The current study investigated the effect of conscious intention to act on the Bereitschaftspotential. Situations in which the awareness of acting is minimally expressed were generated by asking 16 participants to press a button after performing a mental imagery task based on animal pictures (automatic condition). The affective responses induced by the pictures were controlled by selecting the animals according to different valences, threatening and neutral. The Bereitschaftspotential associated with the button presses was compared to the observed when similar movements were performed under the basic instructions of the self-paced movement paradigm (willed condition). Enhanced Bereitschaftspotential amplitudes were observed in the willed condition with respect to the automatic condition. This effect was manifested as a negative slope at medial frontocentral sites during the last 500 ms before movement onset. The valence of the pictures did not affect the motor preparatory potentials. The results suggest that significant part of the NS' subcomponent of the readiness potential is associated with the attention to—and, presumably, awareness of—intention to move, possibly reflecting cortical activation from supplementary motor areas. Secondarily, our findings supports that the feeling of threat does not influence the Bereitschaftspotential associated with automatic movements. Regarding methodological issues, the behavioural model of spontaneous voluntary movements proposed in automatic condition can benefit investigations on purely motor (or non-cognitive) subcomponents of the Bereitschaftspotential.
https://ift.tt/2LgCgnh
Effects of 2-day calorie restriction on cardiovascular autonomic response, mood, and cognitive and motor functions in obese young adult women
Abstract
Although long-term energy restriction has been widely investigated and has consistently induced improvements in health and cognitive and motor functions, the responses to short-duration calorie restriction are not completely understood. The purpose of this study was to investigate the effects of a 2-day very low-calorie diet on evoked stress, mood, and cognitive and motor functions in obese women. Nine obese women (body fatness > 32%) aged 22–31 years were tested under two randomly allocated conditions: 2-day very low-calorie diet (511 kcal) and 2-day usual diet. The perceived stressfulness of the diet, cardiovascular autonomic response, and cognitive and motor performances were evaluated before and after each diet. The subjective stress rating of the calorie-restricted diet was 41.5 ± 23.3. Calorie restriction had no detectable effects on the heart rate variability indices, mood, grip strength, or psychomotor functions. By contrast, calorie restriction increased (p < 0.05) spatial processing and visuospatial working memory accuracy, and decreased (p < 0.05) accuracy of cognitive flexibility. In conclusion, our results demonstrate that although a 2-day calorie restriction evoked moderate stress in obese women, cardiovascular autonomic function was not affected. Calorie restriction had complex effects on cognition: it declined cognitive flexibility, and improved spatial processing and visuospatial working memory, but did not affect mood or motor behavior.
https://ift.tt/2Jo92pe
Hyperfibrinogenemia is a poor prognostic factor in diffuse large B cell lymphoma
Abstract
Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphomas worldwide. Previous studies indicated that hyperfibrinogenemia was a poor predictor in various tumors. The purpose of our study was to evaluate the prognostic effect of hyperfibrinogenemia in DLBCL. Data of 228 patients, who were diagnosed with DLBCL in our hospital between May 2009 and February 2016, were analyzed retrospectively. The Kaplan-Meier method and Cox regression were performed to find prognostic factors associated with progression-free survival (PFS) and overall survival (OS). Receiver operator characteristic (ROC) curve and the areas under the curve were used to evaluate the predictive accuracy of predictors. Comparison of characters between groups indicated that patients with high National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) score (4–8) and advanced stage (III–IV) were more likely to suffer from hyperfibrinogenemia. The Kaplan-Meier method revealed that patients with hyperfibrinogenemia showed inferior PFS (P < 0.001) and OS (P < 0.001) than those without hyperfibrinogenemia. Multivariate analysis showed that hyperfibrinogenemia was an independent prognostic factor associated with poor outcomes (HR = 1.90, 95% CI: 1.15–3.16 for PFS, P = 0.013; HR = 2.65, 95% CI: 1.46–4.79 for OS, P = 0.001). We combined hyperfibrinogenemia and NCCN-IPI to build a new prognostic index (NPI). The NPI was demonstrated to have a superior predictive effect on prognosis (P = 0.0194 for PFS, P = 0.0034 for OS). Hyperfibrinogenemia was demonstrated to be able to predict poor outcome in DLBCL, especially for patients with advanced stage and high NCCN-IPI score. Adding hyperfibrinogenemia to NCCN-IPI could significantly improve the predictive effect of NCCN-IPI.
https://ift.tt/2HfQoe3
A dominant variant in the PDE1C gene is associated with nonsyndromic hearing loss
Abstract
Identification of genes with variants causing non-syndromic hearing loss (NSHL) is challenging due to genetic heterogeneity. The difficulty is compounded by technical limitations that in the past prevented comprehensive gene identification. Recent advances in technology, using targeted capture and next-generation sequencing (NGS), is changing the face of gene identification and making it possible to rapidly and cost-effectively sequence the whole human exome. Here, we characterize a five-generation Chinese family with progressive, postlingual autosomal dominant nonsyndromic hearing loss (ADNSHL). By combining population-specific mutation arrays, targeted deafness genes panel, whole exome sequencing (WES), we identified PDE1C (Phosphodiesterase 1C) c.958G>T (p.A320S) as the disease-associated variant. Structural modeling insights into p.A320S strongly suggest that the sequence alteration will likely affect the substrate-binding pocket of PDE1C. By whole-mount immunofluorescence on postnatal day 3 mouse cochlea, we show its expression in outer (OHC) and inner (IHC) hair cells cytosol co-localizing with Lamp-1 in lysosomes. Furthermore, we provide evidence that the variant alters the PDE1C hydrolytic activity for both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Collectively, our findings indicate that the c.958G>T variant in PDE1C may disrupt the cross talk between cGMP-signaling and cAMP pathways in Ca2+ homeostasis.
https://ift.tt/2LTPSpx
How do you know if you have a cracked tooth?
Cracks in teeth vary in severity. Some are mild and invisible, while others are significant and cause a lot of pain. Dentists judge the extent of damage by inspecting the tooth and taking X-rays. Here, we describe how to tell if a tooth is cracked and when one needs removing. We also explore other treatment options.
https://ift.tt/2sAMBmb
Cancers, Vol. 10, Pages 177: Frequency of EBV LMP-1 Promoter and Coding Variations in Burkitt Lymphoma Samples in Africa and South America and Peripheral Blood in Uganda
Cancers, Vol. 10, Pages 177: Frequency of EBV LMP-1 Promoter and Coding Variations in Burkitt Lymphoma Samples in Africa and South America and Peripheral Blood in Uganda
Cancers doi: 10.3390/cancers10060177
Authors: Liao Liu Lei Li Chin Tsai Bhatia Gutierrez Epelman Biggar Nkrumah Neequaye Ogwang Reynolds Lo Mbulaiteye
Epstein-Barr virus (EBV) is linked to several cancers, including endemic Burkitt lymphoma (eBL), but causal variants are unknown. We recently reported novel sequence variants in the LMP-1 gene and promoter in EBV genomes sequenced from 13 of 14 BL biopsies. Alignments of the novel sequence variants for 114 published EBV genomes, including 27 from BL cases, revealed four LMP-1 variant patterns, designated A to D. Pattern A variant was found in 48% of BL EBV genomes. Here, we used PCR-Sanger sequencing to evaluate 50 additional BL biopsies from Ghana, Brazil, and Argentina, and peripheral blood samples from 113 eBL cases and 115 controls in Uganda. Pattern A was found in 60.9% of 64 BL biopsies evaluated. Compared to PCR-negative subjects in Uganda, detection of Pattern A in peripheral blood was associated with eBL case status (odds ratio [OR] 31.7, 95% confidence interval: 6.8–149), controlling for relevant confounders. Variant Pattern A and Pattern D were associated with eBL case status, but with lower ORs (9.7 and 13.6, respectively). Our results support the hypothesis that EBV LMP-1 Pattern A may be associated with eBL, but it is not the sole associated variant. Further research is needed to replicate and elucidate our findings.
https://ift.tt/2LRSmFg
Relationships between sunitinib plasma concentration and clinical outcomes in Japanese patients with metastatic renal cell carcinoma
Abstract
Background
The aim was to investigate the relationships between total sunitinib plasma concentrations (sunitinib plus its active metabolite; N-desethyl sunitinib) and clinical outcomes in Japanese patients with metastatic renal cell carcinoma (mRCC).
Methods
Twenty patients with mRCC were enrolled following treatment with sunitinib. To assess safety, the total sunitinib concentration range up to discontinuation of treatment and dosage reduction associated with adverse events within 6 weeks from initiating administration were analyzed. The longest administered sunitinib dosage was defined as the maintenance dose, and the relationship between total sunitinib concentration at the maintenance dosage and sunitinib efficacy was investigated.
Results
Total sunitinib concentration was significantly higher in patients who discontinued treatment or had dosage reduction due to adverse events within 6 weeks after initiation of sunitinib than in patients who continued treatment with the initial dosage. The time to treatment failure, progression-free survival, and overall survival were better in patients with total sunitinib concentrations < 50 ng/mL than in those with concentrations ≥ 50 ng/mL.
Conclusions
The present study demonstrated that the effective range of total sunitinib concentration in Japanese patients with mRCC was lower than 50–100 ng/mL which was previously reported. These results indicate that therapeutic drug monitoring could maintain the therapeutic effect of sunitinib while minimizing adverse events by personalizing sunitinib dosages for Japanese patients with mRCC.
https://ift.tt/2JdEfbD
Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development
Abstract
The post-translational modification of proteins through the addition of UFM1, also known as ufmylation, plays a critical developmental role as revealed by studies in animal models. The recent finding that biallelic mutations in UBA5 (the E1-like enzyme for ufmylation) cause severe early-onset encephalopathy with progressive microcephaly implicates ufmylation in human brain development. More recently, a homozygous UFM1 variant was proposed as a candidate aetiology of severe early-onset encephalopathy with progressive microcephaly. Here, we establish a locus for severe early-onset encephalopathy with progressive microcephaly based on two families, and map the phenotype to a novel homozygous UFM1 mutation. This mutation has a significantly diminished capacity to form thioester intermediates with UBA5 and with UFC1 (the E2-like enzyme for ufmylation), with resulting impaired ufmylation of cellular proteins. Remarkably, in four additional families where eight children have severe early-onset encephalopathy with progressive microcephaly, we identified two biallelic UFC1 mutations, which impair UFM1-UFC1 intermediate formation with resulting widespread reduction of cellular ufmylation, a pattern similar to that observed with UFM1 mutation. The striking resemblance between UFM1- and UFC1-related clinical phenotype and biochemical derangements strongly argues for an essential role for ufmylation in human brain development. The hypomorphic nature of UFM1 and UFC1 mutations and the conspicuous depletion of biallelic null mutations in the components of this pathway in human genome databases suggest that it is necessary for embryonic survival, which is consistent with the embryonic lethal nature of knockout models for the orthologous genes.https://ift.tt/2Lbktha
Variables affecting functional outcome in floating knee injuries
Publication date: Available online 1 June 2018
Source:Injury
Author(s): Mahesh Suresh Kulkarni, Monappa Naik Aroor, Sandeep Vijayan, Saurabh Shetty, Sujit Kumar Tripathy, Sharath K Rao
BackgroundThe surgical outcome of floating knee injuries is difficult to predict. The high-velocity nature of the injury, complex fracture pattern and associated soft tissue/ visceral injuries may have some impact on the functional outcome. The present study evaluates the variables affecting the clinical and radiological outcomes of floating knee injuries.Materials and methodsThe clinical, radiological and functional outcome (Karlstrom and Olegrud criteria) of 89 patients with 90 floating knee injuries were evaluated at the end of one year who were managed in our level 1 trauma center between January 2013 and December 2016. The details of the injury, fracture pattern, management and complications were collected retrospectively from their records.ResultsThere were 81 (91.1%) males and 8 (8.9%) females with mean age of 34.34 ± 12.28 years. The mean time for tibia and femur union was 9.52 (±6.6) and 10.5 (±7.37) months. There was significant delay (p < 0.005) in time taken for union in segmental femur fractures (14.3 ± 9.6 months) compared to nonsegmental femur fractures (8.68 ± 5.18 months). Such significant difference in time taken for union was not seen in tibial segmental (10.6 ± 4.62 months) and nonsegmental fractures (9.05 ± 7.27 months). As per the Karlstrom and Olegrud criteria, there were 22 (24.4%) excellent, 26 (28.9%) good, 24 (26.7%) fair and 11 (12.2%) poor outcome. There were 15 patients with malunited tibia, 6 with malunited femur, 10 with limb length discrepancy and 39 with knee stiffness. 28 (33.3%) patients underwent major additional procedures such as bone grafting, re-fixation or bone transport or tendon transfer. It was observed that open tibia fracture, segmental fracture, intra-articular fracture, additional surgical procedures, initial external-fixator (ex-fix) application were significantly associated with development of knee stiffness, limb shortening, malalignment and unsatisfactory (Karlstrom and Olegrud fair to poor) functional outcome.ConclusionOpen tibial fractures, segmental fractures, intraarticular involvement, additional surgical procedures and initial external fixator application are the poor prognostic indicators of floating knee injuries.
https://ift.tt/2sqZ8JX
Adaptations to marine versus terrestrial low temperature environments as revealed by comparative genomic analyses of the genus Psychrobacter
Abstract
While cold-adapted bacteria isolated from marine or terrestrial low temperature environments share many similarities, cold-adapted bacteria from terrestrial environments usually grow over a broader range of temperatures suggesting different constraints of these two low temperature environments. The diversity of habitats from which Psychrobacter have been isolated (e.g. cold marine environments, frozen soils, permafrost, and humans) provides a unique opportunity to examine habitat specific adaptations while reducing phylogenetic effects. Here, comparative genomic analyses of 26 strains of Psychrobacter revealed several clusters with characteristics that correlated with habitat. Marine and terrestrial Psychrobacter have amino acid composition typical of psychrophiles (e.g. fewer proline and lysine, more acidic) when compared to Psychrobacter strains associated with warm hosts, and have many potentially cold-adapted core genes (e.g. ClpX, DsbC, GroEL/GroES and MutS2). Marine and terrestrial Psychrobacter share many genes (e.g. FadB) not found in warm host Psychrobacter which had their own distinct gene content (e.g. collagenase-like protease). Furthermore, terrestrial Psychrobacter were differentiated from marine Psychrobacter by the use of different cold adaptations and more hydrophobic and aliphatic proteins. These data suggest that terrestrial and marine Psychrobacter evolved from a mesophilic ancestor and are accumulating adaptations for low temperatures as well as for their respective habitats.https://ift.tt/2soGjHm
Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström’s Macroglobulinemia
New England Journal of Medicine, Ahead of Print.
https://ift.tt/2J9bHzH
Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström’s Macroglobulinemia
https://ift.tt/2J9bHzH
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
