Low molecular weight heparin has been extensively evaluated for the prevention of preeclampsia in high-risk pregnant women, however, the results from these trials have been conflicting. This review discusses the potential mechanisms of action of low molecular weight heparin for the prevention of severe preeclampsia, how to optimize the selection of high-risk women for participation in future trials and the importance of trial standardization.
Oncotype Dx (ODx) is a multigene assay that is prognostic and predictive in estrogen receptor (ER) positive early breast cancer. ODx recurrence score (RS) is reported to be histologic grade dependent. Relationship of RS with breast cancer histologic subtypes is unknown. This study was designed to assess the relationship of histologic subtype with RS. Histologic grade dependence of RS was also investigated.
Results of consecutive ODx tests (1/2007–7/2016) from two institutions were reviewed. Histologic subtypes (in: Lakhani et al., WHO classification, IARC Press, Lyon, 2012), combined Nottingham histologic grade, age and tumor size were recorded from pathology reports. Univariate and multivariate analysis was performed to investigate the relationship between RS and ODx risk categories and histologic subtypes, grade, age and tumor size.
RS was grade dependent. RS of grade 1 and grade 2 tumors were significantly lower than grade 3 tumors. There was no high-risk grade 1 tumor. In favorable histologic subtypes there was no high-risk tumor. Mean RS of grade 1 lobular tumors was significantly higher than grade 1 ductal tumors. Using newer ODx cut-offs, 5 grade 1 tumors were reclassified as high risk (RS > 25) and grade 3 lobular tumors showed significantly higher rate of reclassification as high-risk than grade 3 ductal tumors. In a multivariate analysis, only grade showed a significant positive correlation with RS. Adding dichotomous histologic subtyping (favorable vs. non-favorable) to grade further improved correlation with RS.
The Oncotype Dx result is impacted by histologic grade and histologic subtype. Tumors with favorable histologic subtypes and histologic grade 1 tumors do not have high-risk RS. High RS in a grade 1 tumor or in a tumor with favorable histology is unusual that warrants further investigation. Invasive lobular carcinomas rarely show high-risk RS. Histologic grade and histologic subtype should be considered while ordering ODx testing.
Severe neutropenia is a common dose-limiting side effect of adjuvant breast cancer chemotherapy. We aimed to test the hypothesis that weak circadian rhythm is associated with an increased risk of neutropenia using a cohort study.
We consecutively recruited 193 breast cancer patients who received adjuvant chemotherapy (5-fluorouracil, epirubicin, and cyclophosphamide followed by docetaxel; doxorubicin and cyclophosphamide; docetaxel and cyclophosphamide). Participants wore a wrist actigraph continuously for 168 h at the beginning of chemotherapy. Values of percent rhythm and double amplitude below medians represented weak circadian rhythm. Mesor measured the mean activity level and acrophase symboled the peak time of the rhythm. We used Cox proportional hazard regression model to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of grade 4 neutropenia and febrile neutropenia in relation to actigraphy-derived parameters.
Low levels of percent rhythm (HR:2.59, 95% CI 1.50–4.72), double amplitude (HR:2.70, 95% CI 1.51–4.85), and mesor (HR: 2.48, 95% CI 1.44–4.29) were positively associated with the risk of grade 4 neutropenia during chemotherapy. Low levels of percent rhythm (HR: 2.41, 95% CI 1.02–5.69) and double amplitude (HR:2.49, 95% CI 1.05–5.90) were also associated with increased risks of febrile neutropenia. The HRs for acrophase were not statistically significant.
This study provides the first epidemiological evidence that increased risks of grade 4 neutropenia and febrile neutropenia are associated with weak circadian rhythm among adjuvant breast cancer patients. The results suggest that circadian rhythm might be one potential target for the prevention of chemotherapy-induced neutropenia among cancer patients.
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Peroral endoscopic myotomy (POEM) is a revolutionary treatment for achalasia.1-3 It involves creating a submucosal tunnel directly to the stomach side; theoretically, a straight tunnel can be obtained by creating it perpendicular to the inner annulus muscle. Clinically, this is not always easy; therefore, we introduced a new method for controlling the submucosal tunnel direction in which a small-diameter endoscope is inserted along with the main endoscope. This allows us to check the illumination of the main scope in the submucosal layer, which can be particularly useful when treating a sigmoid-type anomaly with a highly flexed esophagus.
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Benign Prostatic Hyperplasia (BPH) affects, worldwide, 50% of 60-year-old men. The Peruvian plant red maca (Lepidium meyenii) inhibits BPH in rodents. This study aimed to determine the effects of methanolic red maca extract and its n-butanol and aqueous fractions on expression of androgen and oestrogen receptors in rats with testosterone enanthate-induced BPH. Thirty-six rats in six groups were studied. Control group received 2 mL of vehicle orally and 0.1 mL of propylene glycol intramuscularly. The second group received vehicle orally and testosterone enanthate (TE) (25 mg/0.1 mL) intramuscularly in days 1 and 7. The other four groups were BPH-induced with TE and received, during 21 days, 3.78 mg/mL of finasteride, 18.3 mg/mL methanol extract of red maca, 2 mg/mL of n-butanol fraction, or 16.3 mg/mL of aqueous fraction from red maca. Treatments with red maca extract and its n-butanol but not aqueous fraction reduced prostate weight similar to finasteride. All maca treated groups restored the expression of ERβ, but only the aqueous fraction increased androgen receptors and ERα. In conclusion, butanol fraction of red maca reduced prostate size in BPH by restoring expression of ERβ without affecting androgen receptors and ERα. This effect was not observed with aqueous fraction of methanolic extract of red maca.
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Total glucosides of paeony (TGP) have been confirmed to be hepatoprotective. However, the underlying mechanism is largely unclear. In this study, we investigated the metabolic profiles of urine and serum in rats with carbon tetrachloride- (CCl4-) induced experimental liver injury and TGP administration by using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). The vehicle or a single dose of TGP was intragastrically administered to Wistar rats once a day for 14 consecutive days. To induce ALI, 50% CCl4 was injected intraperitoneally into these rats 2 hours after the last time administration of saline of TGP at the 14th day. The results indicated that TGP administration could protect rats from CCl4-induced ALI and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation, as well as hepatocyte apoptosis and inflammation. Furthermore, metabolomics analysis showed that TGP treatment significantly attenuated CCl4-triggered deregulation of multiple metabolites in both urine and serum, including glycine, alanine, proline, and glutamine. Metabolite set enrichment and pathway analyses demonstrated that amino acid cycling and glutathione metabolism were two main pathways involved in CCl4-induced experimental liver injury and TGP administration. Taken together, these findings revealed that regulation of metabolites potentially plays a pivotal role in the protective effect of TGP on ALI.
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BACKGROUND:
In September 2011, the government of Ontario implemented payment incentives to encourage the delivery of community-based psychiatric care to patients after discharge from a psychiatric hospital admission and to those with a recent suicide attempt. We evaluated whether these incentives affected supply of psychiatric services and access to care.
METHODS:We used administrative data to capture monthly observations for all psychiatrists who practised in Ontario between September 2009 and August 2014. We conducted interrupted time-series analyses of psychiatrist-level and patient-level data to evaluate whether the incentives affected the quantity of eligible outpatient services delivered and the likelihood of receiving follow-up care.
RESULTS:Among 1921 psychiatrists evaluated, implementation of the incentive payments was not associated with increased provision of follow-up visits after discharge from a psychiatric hospital admission (mean change in visits per month per psychiatrist 0.0099, 95% confidence interval [CI] –0.0989 to 0.1206; change in trend 0.0032, 95% CI –0.0035 to 0.0095) or after a suicide attempt (mean change –0.0910, 95% CI –0.1885 to 0.0026; change in trend 0.0102, 95% CI 0.0045 to 0.0159). There was also no change in the probability that patients received follow-up care after discharge (change in level –0.0079, 95% CI –0.0223 to 0.0061; change in trend 0.0007, 95% CI –0.0003 to 0.0016) or after a suicide attempt (change in level 0.0074, 95% CI –0.0094 to 0.0366; change in trend 0.0006, 95% CI –0.0007 to 0.0022).
INTERPRETATION:Our results suggest that implementation of the incentives did not increase access to follow-up care for patients after discharge from a psychiatric hospital admission or after a suicide attempt, and the incentives had no effect on supply of psychiatric services. Further research to guide design and implementation of more effective incentives is warranted.
BACKGROUND:
Knowing when physicians retire and how they practise in the pre-retirement years is important information for health human resource planning. We identified patterns of retirement for physicians in British Columbia and the determinants of when and how physicians retire.
METHODS:For this population-based retrospective cohort study, we used administrative data to examine activity levels and to identify retirements among BC's practising physicians. We included all physicians who were at least 50 years of age as of March 2006 and who had received payments for clinical services in at least 1 year between 2005/06 and 2011/12. We defined retirement as a permanent drop in monthly payments to less than $1667/month ($20 000/yr). We examined the patterns and timing of retirement by age, sex, specialty and location using linear and logistic regression models.
RESULTS:Of the 4572 physicians who met the inclusion criteria, 1717 (37.6%) retired during the study period. The average age at retirement was 65.1 (standard deviation 7.8) years. Controlling for other demographic and practice characteristics, we found that women and physicians working in rural areas retired earlier, by 4.1 (95% confidence interval [CI] –4.9 to –3.2) years and 2.3 (95% CI –3.4 to –1.1) years, respectively. We found no difference in retirement age by specialty. We identified 4 patterns of pre-retirement activity: slow decline, rapid decline, maintenance and increasing activity. About 40% of physicians (440/1107) reduced their activity levels by at least 10% in the 3 years preceding retirement.
INTERPRETATION:During the study period, physicians in BC — particularly women and those in rural areas — retired earlier than indicated by licensure and survey data. Many physicians reduced their practice activity in the pre-retirement years. These trends indicate that forecasts relying on licensure "head counts" are likely overestimating current and future physician supply.
This project was undertaken to examine the association between dietary intake of soy or cruciferous vegetables and breast cancer treatment-related symptoms among Chinese-American (CA) and Non-Hispanic White (NHW) breast cancer survivors.
This cross-sectional study included 192 CA and 173 NHW female breast cancer survivors (stages 0–III, diagnosed between 2006 and 2012) recruited from two California cancer registries, who had completed primary treatment. Patient-reported data on treatment-related symptoms and potential covariates were collected via telephone interviews. Dietary data were ascertained by mailed questionnaires. The outcomes evaluated were menopausal symptoms (hot flashes, night sweats, vaginal dryness, vaginal discharge), joint problems, fatigue, hair thinning/loss, and memory problems. Associations between soy and cruciferous vegetables and symptoms were assessed using logistic regression. Analyses were further stratified by race/ethnicity and endocrine therapy usage (non-user, tamoxifen, aromatase inhibitors).
Soy food and cruciferous vegetable intake ranged from no intake to 431 and 865 g/day, respectively, and was higher in CA survivors. Higher soy food intake was associated with lower odds of menopausal symptoms (≥ 24.0 vs. 0 g/day, OR 0.51, 95% CI 0.25, 1.03), and fatigue (≥ 24.0 vs. 0 g/day, OR 0.43, 95% CI 0.22, 0.84). However, when stratified by race/ethnicity, associations were statistically significant in NHW survivors only. Compared with low intake, higher cruciferous vegetable intake was associated with lower odds of experiencing menopausal symptoms (≥ 70.8 vs. < 33.0 g/day, OR 0.50, 95% CI 0.25, 0.97) in the overall population.
In this population of breast cancer survivors, higher soy and cruciferous vegetable intake was associated with less treatment-related menopausal symptoms and fatigue.
In this study, lipid degradation during the processing of salt-fermented Antarctic krill paste was studied by evaluating changes in physicochemical parameters, lipid content, and fatty acid composition, phospholipase (phospholipase A1 [PLA1], phospholipase A2 [PLA2], phospholipase C [PLC] and phospholipase D [PLD]) and lipase activities. Triacylglycerols (TAGs) were an important source of free fatty acids (FFAs) in Antarctic krill paste, causing an increase in FFA content in the early stage of processing, while phospholipids were intensely hydrolyzed during the mid-late stages. Lipase activities remained constant, while PLA2 and PLD activities increased during all stages of processing. The relative activities of PLA2 and PLC highly correlated with a decline in phosphatidylcholine (PC) and an increase in lysophosphatidylcholine (LPC). A high correlation was also observed between relative PLD activity and increased phosphatidic acid (PA). These results suggest that lipase, PLA2, and PLD contribute to the degradation of lipids during the processing of salt-fermented Antarctic krill paste.
Practical applications: Due to their abundance of Antarctic krill, fermentation technology can be applied to transform them into a popular condiment. The present study aimed to investigate changes in lipid composition throughout krill salt-fermentation, and to evaluate their potential effects on fermented krill product. Knowledge of lipase activities during processing is essential to improve the quality of the end products and to further elucidate the complicated mechanisms of lipid degradation.
Flaxseed oil and quercetin have received extensive attention in food industry. However, their poor solubility in water and stability are major limitations for their application in functional foods. In this work, we encapsulated flaxseed oil and quercetin into submicron emulsions by high pressure homogenization method to overcome their shortcomings in application. The loading of flaxseed oil in submicron emulsions was 10% and the solubility of quercetin in water was increased by at least 1300 folds. In vitro antioxidant study indicated that the addition of flaxseed oil could increase the antioxidant activity of quercetin. During in vitro digestion, the smaller the particle size of submicron emulsions, the faster the digestive rate of flaxseed oil and the higher the bio-accessibility of quercetin. Furthermore, accelerated oxidation study revealed that quercetin could protect flaxseed oil effectively. Besides, metallic ions stability study illustrated that the influence of Na+ on the emulsion stability was smaller than that of Ca2+ and high Ca2+ concentration could lead to stratification of the submicron emulsions. The storage stability showed that the prepared submicron emulsions could be stored for eight weeks at three different temperatures. Hence, submicron emulsion could be a promising vehicle for delivery of flaxseed oil and quercetin.
Practical applications: Submicron emulsions can be used to improve the water solubility and bioavailability of lipophilic nutrients. The combination of flaxseed oil and quercetin in submicron emulsions could compensate for their individual shortcomings in application and exert synergistic beneficial actions on human health. Furthermore, this technology is easy in operation and can be realized in industry. Flaxseed oil and quercetin co-loaded submicron emulsions could be applied in milk and liquid beverages in food industry.
Lowe syndrome (LS) is a very rare disorder of phosphatidylinositol metabolism, which manifests with a complex phenotype comprising a clinical triad encompassing major abnormalities of the eyes, the kidneys, and the central nervous system. We are reporting a 23-year-old Egyptian male with a severe phenotype of LS with a minimal kidney disease. Direct sequencing of the OCRL gene detected a p.His375Arg mutation in the catalytic domain of the protein. The patient suffered from bilateral congenital cataracts and glaucoma, striking growth deficiency, severe psychomotor disability, a severe osteopathy, and seizures, but only minimal renal dysfunction. Although the biological mechanisms underlying the pathophysiology of LS manifestations is yet unclear, it has been proposed that growth delay and osteopathy are linked to a renal dysfunction. This report, however, argues this association and suggests that kidney dysfunction may partially explain the growth deficiency and bone abnormalities, but other still undefined factors might have a potential impact.
Array comparative genomic hybridization is essential in the investigation of chromosomal rearrangements associated with epilepsy, intellectual disability, and dysmorphic features. In many cases deletions, duplications, additional marker chromosomes, and ring chromosomes originating from chromosome 15 lead to abnormal phenotypes. We present a child with epilepsy, cardiac symptoms, severely delayed mental and growth development, behavioral disturbances and characteristic dysmorphic features showing a ring chromosome 15 and a small supernumerary marker chromosome. Array CGH detected a 1 Mb deletion of 15q26.3 in a ring chromosome 15 and a 2.6 Mb copy number gain of 15q11.2 corresponding to a small supernumerary marker chromosome involving proximal 15q. Our findings add to previously published results of 15q11q13 duplications and 15q26 terminal deletions. Based on our study we can support the previous reported limited information about the role of SELS, SNRPA1, and PCSK6 genes in the development of the heart morphology. On the other hand, we found that the copy number loss of our patient did not involve the IGF1R gene which is often associated with growth retardation (short stature and decreased weight). We hypothesize that haploinsufficiency of the 15q26 genomic region distal to IGF1R gene might be related to growth disturbance; however, presence of the ring chromosome 15 itself could also be responsible for the growth delay.
SLC25A1 mutations are associated with combined D,L-2-hydroxyglutaric aciduria (DL- 2HGA; OMIM #615182), characterized by muscular hypotonia, severe neurodevelopmental dysfunction and intractable seizures. SLC25A1 encodes the mitochondrial citrate carrier (CIC), which mediates efflux of the mitochondrial tricarboxylic acid (TCA) cycle intermediates citrate and isocitrate in exchange for cytosolic malate. Only a single family with an SLC25A1 mutation has been described in which mitochondrial respiratory chain dysfunction was documented, specifically in complex IV. Five infants of two consanguineous Bedouin families of the same tribe presented with small head circumference and neonatal-onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development culminating in early death. Ventricular septal defects (VSD) were demonstrated in three patients. Blood and CSF lactate were elevated with normal levels of plasma amino acids and free carnitine and increased 2-OH-glutaric acid urinary exertion. EEG was compatible with white matter disorder. Brain MRI revealed ventriculomegaly, thin corpus callosum with increased lactate peak on spectroscopy. Mitochondrial complex V deficiency was demonstrated in skeletal muscle biopsy of one infant. Homozygosity mapping and sequencing ruled out homozygosity of affected individuals in all known complex V-associated genes. Whole exome sequencing identified a novel homozygous SLC25A1 c.713A>G (p.Asn238Ser) mutation, segregating as expected in the affected kindred and not found in 220 control alleles. Thus, SLC25A1 mutations might be associated with mitochondrial complex V deficiency and should be considered in the differential diagnosis of mitochondrial respiratory chain defects.
KAT6B sequence variants have been identified in both patients with the Say–Barber–Biesecker–Young–Simpson syndrome (SBBYSS) and in the genitopatellar syndrome (GPS). In SBBYSS, they were reported to affect mostly exons 16–18 of KAT6B, and the predicted mechanism of pathogenesis was haploinsufficiency or a partial loss of protein function. Truncating variants in KAT6B leading to GPS appear to cluster within the proximal portion of exon 18, associated with a dominant-negative effect of the mutated protein, most likely. Although SBBYSS and GPS have been initially considered allelic disorders with distinctive genetic and clinical features, there is evidence that they represent two ends of a spectrum of conditions referable as KAT6B-related disorders. We detected a de novo truncating variant within exon 7 of KAT6B in a 8-year-old female who presented with mild intellectual disability, facial dysmorphisms highly consistent with SBBYSS, and skeletal anomalies including exostosis, that are usually considered component manifestations of GPS. Following the clinical diagnosis driven by the striking facial phenotype, we analyzed the KAT6B gene by NGS techniques. The present report highlights the pivotal role of clinical genetics in avoiding clear-cut genotype-phenotype categories in syndromic forms of intellectual disability. In addition, it further supports the evidence that a continuum exists within the clinical spectrum of KAT6B-associated disorders.
We here describe novel compound heterozygous missense variants, NM_133443:c.[400C>T] and NM_133443:[1435G>A], in the glutamic-pyruvic transaminase 2 (GPT2) gene in a large consanguineous family with two affected siblings diagnosed with microcephaly intellectual disability and developmental delay (IDD). In addition to these clinical phenotypes, the male sibling has spastic paraplegia, and the female sibling has epilepsy. Their four extended family members have IDD and microcephaly. Both of these variants, c.400C>T (p.R134C) and c.1435G>A (p.V479M), reside in the pyridoxal phosphate-dependent aminotransferase domain. The missense variants affect highly conserved amino acids and are classified to be disease-causing by meta-SVM. The candidate variants were not found in the Exome Aggregation Consortium (ExAC) dataset or in dbSNP. Both GPT2 variants have an allele frequency of 0% (0/ ∼ 600) in the whole-exome sequenced Turkish cohort. Upon Sanger sequencing, we confirmed these mutations in all affected family members and showed that the index patient and his affected sister inherited one mutant allele from each unaffected parent. To the best of our knowledge, this is the first family in which a novel compound heterozygous variant in the GPT2 gene was identified.
Smith–Lemli–Opitz syndrome (SLOS) is a metabolic disorder caused by an inborn error of cholesterol synthesis that affects the development of many organ systems. Malformations in the central nervous system typically involve midline structures and reflect abnormal growth and differentiation of neurons and supporting cells. Despite these defects in central nervous system development, brain tumor formation has only rarely been reported in association with SLOS. We present three individuals with SLOS and lesions in the basal ganglia or brainstem detected by MRI that were concerning for tumor formation. However, the individuals' clinical and neurological course remained stable, and the lesions regressed after several years. These lesions have similarities to spongiotic changes observed in individuals with neurofibromatosis type 1 (NF1). Notably, impaired activity of small GTPases is present in both SLOS and NF1, perhaps giving mechanistic insight into the formation of these lesions.
This study introduces an innovative stepwise vascular control technique to address the high risk of massive bleeding from main hepatic veins and the retro-hepatic inferior vena cava during hepatectomy involving hepatocaval confluence.
From January 2010 to July 2016, 80 patients underwent stepwise vascular occlusion during complex liver resection involving hepatocaval confluence. Relevant clinical data were collected and compared with those obtained in parallel studies. The protocol has been registered in the Protocol Registration and Results System as protocol NCT02996006.
All 80 patients underwent portal triad (PT), infra-hepatic inferior vena cava (IIVC) and supra-hepatic inferior vena cava (SIVC) preparation for occlusion in that order; PT, PT + SIVC and PT + IIVC + SIVC occlusions were performed during liver resection for six, 42 and 32 patients, respectively. The PT, IIVC and SIVC clamping times were 12.9 ± 2.5, 9.1 ± 2.1 and 5.1 ± 1.4 min, respectively. The mean blood loss was 504.1 ± 234.5 mL. Sixteen patients received blood transfusions. Haemodynamic parameters remained stable. No patients had life-threatening complications or died (Clavien-Dindo grade IV or V). Compared with other techniques used in parallel studies, this technique has the advantage of decreased blood loss in less warm ischaemia time.
For complex hepatectomy involving hepatocaval confluence, this newly described stepwise vascular control technique was efficacious and feasible for controlling intraoperative bleeding.
Tabebuia species (Bignoniaceae) have long been used in folk medicine as anti-inflammatory, antirheumatic, antimicrobial, and antitumor. The aim of this study was to investigate if aqueous extract from the leaves (AEL) of Tabebuia roseoalba (Ridl.) Sandwith, Bignoniaceae, and its constituents could be useful to decrease serum uric acid levels and restrain the gout inflammatory process. HPLC analysis identified caffeic acid and chlorogenic acid in AEL. Antihyperuricemic effects and inhibition of liver XOD (xanthine oxidoreductase) by AEL and identified compounds were evaluated in hyperuricemic mice. Anti-inflammatory activity was evaluated on MSU (monosodium urate) crystal-induced paw edema. In addition, AEL antioxidant activity in vitro was evaluated. AEL, caffeic, and chlorogenic acids were able to reduce serum uric acid levels in hyperuricemic mice probably through inhibition of liver xanthine oxidase activity and significantly decreased the paw edema induced by MSU crystals. AEL showed significant antioxidant activity in all evaluated assays. The results show that the AEL of Tabebuia roseoalba can be a promising agent for treatment for gout and inflammatory diseases. We suggest that caffeic and chlorogenic acids may be responsible for the activities demonstrated by the species.
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To evaluate the association between increased exposure to airborne fine particulate matter (PM2.5) during the periconception period with risk of congenital anomalies.
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Here we present an adaptation of the passive CLARITY and 3D reconstruction method for visualization of the ovarian vasculature and follicular capillaries in intact mouse ovaries.
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Although there has been considerable research activity in the treatment of Hodgkin's lymphoma since advanced stages of the disease became curable with combination chemotherapy in the 1960s, the most significant advances have involved the maintenance of a particular level of antitumor efficacy while…
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Large B-cell lymphomas, including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma, are treated with combination chemoimmunotherapy at diagnosis. Patients who have a relapse with chemotherapy-sensitive disease may be treated with high-dose…
http://ift.tt/2yVYck9
Diffuse large B-cell lymphoma, the most common non-Hodgkin's lymphoma, is successfully treated in about two thirds of patients with rituximab-based immunochemotherapy. When current frontline immunochemotherapy fails, high-dose chemotherapy with autologous stem-cell transplantation can lead to…
http://ift.tt/2ycc1ra
More than 7 years have passed since the regression of advanced lymphoma was first reported in a patient who had undergone the infusion of T cells engineered to express a chimeric antigen receptor (CAR) targeting the CD19 antigen expressed on the surface of both normal and malignant B cells.…
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Here, we describe a simple tail vein blood sampling method in non-anesthetized rats using a vacuum extraction tube system. This method reduces the risk of direct exposure to blood and simplifies taking multiple samples from a single venipuncture.
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The large observation study once again demonstrates the harm of a liberal approach to fluid administration in patients with sepsis
EMCrit by Paul Marik.
More than 7 years have passed since the regression of advanced lymphoma was first reported in a patient who had undergone the infusion of T cells engineered to express a chimeric antigen receptor (CAR) targeting the CD19 antigen expressed on the surface of both normal and malignant B cells.…
http://ift.tt/2yWsX8S
Large B-cell lymphomas, including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma, are treated with combination chemoimmunotherapy at diagnosis. Patients who have a relapse with chemotherapy-sensitive disease may be treated with high-dose…
http://ift.tt/2yVYck9
Outcomes for patients with advanced-stage Hodgkin's lymphoma have improved dramatically over the past half century. Although regional differences exist, the most commonly used frontline regimen — doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) — has not been modified since its original…
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Diffuse large B-cell lymphoma, the most common non-Hodgkin's lymphoma, is successfully treated in about two thirds of patients with rituximab-based immunochemotherapy. When current frontline immunochemotherapy fails, high-dose chemotherapy with autologous stem-cell transplantation can lead to…
http://ift.tt/2ycc1ra
Amylases catalyze the hydrolysis of starch, a vegetable polysaccharide abundant in nature. These enzymes can be utilized in the production of syrups, alcohol, detergent, pharmaceutical products, and animal feed formulations. The aim of this study was to optimize the production of amylases by the filamentous fungus Gongronella butleri by solid-state fermentation and to evaluate the catalytic properties of the obtained enzymatic extract. The highest amylase production, 63.25 U g−1 (or 6.32 U mL−1), was obtained by culturing the fungus in wheat bran with 55% of initial moisture, cultivated for 96 h at 25°C. The enzyme presented optimum activity at pH 5.0 and 55°C. The amylase produced was stable in a wide pH range (3.5–9.5) and maintained its catalytic activity for 1 h at 40°C. Furthermore, the enzymatic extract hydrolyzed starches from different vegetable sources, presenting predominant dextrinizing activity for all substrates evaluated. However, the presence of glucose was observed in a higher concentration during hydrolysis of corn starch, indicating the synergistic action of endo- and exoamylases, which enables the application of this enzymatic extract to produce syrups from different starch sources.
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Cardiovascular disease (CVD) is the most common cause of death in the world. Recent studies have shown an association between adrenal insufficiency (AI) and increased cardiovascular risk (CVR). Patients with AI receive glucocorticoid (GC) replacement therapy which can lead to varying levels of blood cortisol. It was shown that these imbalances in blood cortisol may lead to a higher prevalence of coronary heart disease, major adverse coronary events, and increased mortality. GC substitution is essential in the treatment of AI without which the disease has been shown to be fatal. The most frequently used GC formula for replacement therapy is hydrocortisone (HC). There is no uniform opinion on hydrocortisone replacement therapy. Alternative GC such as prednisolone is also in use. Overreplacement of GC may lead to adverse effects including obesity, high blood pressure, and hyperglycaemia. Outcome may vary between primary and secondary AI mainly due to differences in the renin-angiotensin-aldosterone system (RAAS). Furthermore, decreased blood levels of cortisol may lead to a compensatory secretion of inflammatory mediators such as Interleukin-1 (IL-1), Interleukin-6 (IL-6), and/or tumor-necrosis factor (TNF). Physicians and patients should be properly educated about the increased risk of CVD in patients with AI.
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We develop a strategy for haplotype analysis of PCR products that contained two adjacent heterozygous loci using sequencing with specific primers, allele-specific primers, and ddNTP-blocked primers. To validate its feasibility, two sets of PCR products, including two adjacent heterozygous SNPs, UGT1A16 (rs4148323) and UGT1A128 (rs8175347), and two adjacent heterozygous SNPs, K1637K (rs11176013) and S1647T (rs11564148), were analyzed. Haplotypes of PCR products, including UGT1A16 and UGT1A128, were successfully analyzed by Sanger sequencing with allele-specific primers. Also, haplotypes of PCR products, including K1637K and S1647T, could not be determined by Sanger sequencing with allele-specific primers but were successfully analyzed by pyrosequencing with ddNTP-blocked primers. As a result, this method is able to effectively haplotype two adjacent heterozygous PCR products. It is simple, fast, and irrespective of short read length of pyrosequencing. Overall, we fully hope it will provide a new promising technology to identify haplotypes of conventional PCR products in clinical samples.
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Objective. This study applied Liu-He-Dan (LHD) to treat the infective wounds of rabbits to explore the mechanism of LHD in promoting wound healing. Method. Five circular infective incisions were generated on the back of each rabbit. Wound dressings were performed every day since postoperative day 1. Ten rabbits were euthanized on days 3, 7, 14, and 21. Each specimen was divided into two parts, one was used for detecting interleukin-1 beta (IL-1β), and the other one was used for detecting basic fibroblast growth factor (bFGF). Result. The content of IL-1β in the model group was higher than those in the other groups (). The content of IL-1β in the treatment group was lower than the other groups on days 14 and 21. The expression of bFGF in treatment group is significant on days 3, 7, and 14, compared with traditional Chinese medicine group and model group. The expression of bFGF has no significant difference with Western group. Conclusion. The research approved that LHD could specifically suppress the expression of IL-1β and upregulate the expression of bFGF in the wound, decreasing the release of inflammatory factor of the infective wounds and promoting the healing of the infective wounds.
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Background. In the current study, we investigated midterm results of a new rotating hinge total knee arthroplasty (EnduRo prosthesis), which uses a new bearing material (CFR PEEK). Methods. We prospectively analysed data of 50 patients with a minimum follow-up of 5 years. In 24 (48%) patients, a primary implantation was performed and 26 (52%) were revision cases. Clinical and radiographic examinations were performed preoperatively as well as postoperatively after 3 and 12 months and annually thereafter. The Knee Society Score (KSS), WOMAC, Oxford Knee Score (OKS), and range of motion (ROM) were used for clinical assessment. Results. KSS, WOMAC, OKS, and ROM significantly improved between the preoperative and the follow-up investigations. The overall survival rate with revision for any reason as an endpoint was 77.9% after five years. The number of complications was significantly higher in the revision group (). Conclusion. The EnduRo prosthesis provides highly satisfying clinical and functional results in severe primary as well as in revision cases. Implant-associated complications were rare. However, in cases of revision surgery, the risk for complications was considerably high, mostly related to previous joint infections and poor soft tissue quality.
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Objective. The opinions about the application of pulse oximetry in diagnosis of congenital heart disease (CHD) were debatable. We performed this meta-analysis to confirm the diagnostic role of pulse oximetry screening for CHD. Methods. Relevant articles were searched in the databases of Pubmed, Embase, Google Scholar, and Chinese National Knowledge Infrastructure (CNKI) up to April 2017. Data was processed in the MetaDiSc 1.4 software. Pooled sensitivity and specificity with 95% confidence interval (95% CI) were calculated to explain the diagnostic role of pulse oximetry screening for CHD. % or indicated significant heterogeneity. Area under curve (AUC) of summary receiver operating characteristics (SROC) was calculated to assess its diagnostic accuracy. The robustness of overall results was evaluated by sensitivity analysis. Publication bias was evaluated by Deek's funnel plot. Results. 22 eligible articles were selected. Pooled sensitivity and specificity were 0.69 (0.67–0.72) and 0.99 (0.99-0.99), respectively. The corresponding AUC was 0.9407, suggesting high diagnostic accuracy of pulse oximetry screening for CHD. Sensitivity analysis demonstrated that the pooled results were robust. Deek's funnel plot seemed to be symmetrical. Conclusions. Pulse oximetry screening could be used to diagnose CHD. It shows high diagnosis specificity and accuracy.
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Publication date: Available online 9 December 2017
Source:Injury
Author(s): Aliasghar A. Kiadaliri, Björn E. Rosengren, Martin Englund
PurposeTo assess fracture-related mortality among adults (aged ≥20years) in southern Sweden using multiple causes of death approach.MethodsAll death certificates (n=201 488) in adults recorded in the region of Skåne from 1998 to 2014 were examined. We identified fracture-related deaths and computed mortality rates by sex, age group, and fracture site. Temporal trends were evaluated using joinpoint regression and associated causes were identified by age- and sex-adjusted observed/expected ratios.ResultsFractures were mentioned on 6 226 (3.1%) death certificates, with majority of these occurred among women (60%) and those aged≥80years (77%). While hip was the most common site overall (61% of all fracture-related deaths), skull was the most common site in people <60years (60% of all fracture-related deaths). Proportion of death certificates mentioning fracture was stable in women but increased by 0.4% (95% CI: 0.1 to 0.6) in men between 1998–2002 and 2010–2014. The mean age at death was higher in death certificates mentioning fracture than those without and this gap widened over time. The mean age-standardized fracture-related mortality rate was 18.8 (14.0) per 100 000 person-year in men (women) and declined by 1.5% (1.3%) per year during 1998–2014. Injuries (84.6%) and cardiovascular disorders (64.6%) were the most common comorbidities on death certificates mentioning fracture.ConclusionsFracture is a contributing cause of death in more than 3% of all deaths in southern Sweden with hip in lead among older and skull fracture among younger people. There was a slight increase in proportion of deaths associated with fracture in men but not women during the study period.
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Publication date: Available online 9 December 2017
Source:Injury
Author(s): Beatrice Sanna, Brandon Michael Henry, Jens Vikse, Bendik Skinningsrud, Jakub R. Pękala, Jerzy A. Walocha, Roberto Cirocchi, Krzysztof A. Tomaszewski
PurposeCorona mortis is a highly variable vascular connection between the obturator and external iliac or inferior epigastric arteries or veins located behind the superior pubic ramus in the retropubic space (space of Retzius). Due to the significant variation in this collateral circulation, detailed anatomical knowledge of the corona mortis is vital to enhance the prevention of possible iatrogenic errors in hernia repair and other pubic surgical procedures. The aim of our meta-analysis was to provide comprehensive data on the prevalence, anatomical characteristics, and ethnic variations of the corona mortis vessel.MethodsAn extensive search was conducted through the major electronic databases to identify eligible articles. Data extracted included investigative method, prevalence of the corona mortis vessels among hemi-pelvises (overall, arterial only, venous only, and combined), distance from the corona mortis to pubic symphysis, and assessment of gender, side, laterality, and ethnicity subgroups.ResultsA total of 21 studies (n=2,184 hemi-pelvises) were included in the meta-analysis. The overall prevalence of the corona mortis in hemi-pelvises is high (49.3%). A venous corona mortis is more prevalent than an arterial corona mortis (41.7% vs. 17.0%). The corona mortis is more common in Asia (59.3%) than in Europe (42.8%) and North America (44.3%).ConclusionsAs a corona mortis is present in a about half of all hemi-pelvises, it is important to consider the possibilities of its presence when undertaking surgical procedures and plan accordingly to avoid injuries. All surgeons operating in the retropubic region should have a thorough understanding of the anatomical characteristics and surgical implications of a corona mortis.
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Objective. Breast cancer, the most common malignancy in women, comprises 18% of all female cancers. Mastectomy is an essential intervention to save lives, but it can destroy one's body image, causing both physical and psychological trauma. Reconstruction is an important step in restoring patient quality of life after the mutilating treatment. Material and Methods. Tissue expanders and implants are now commonly used in breast reconstruction. Autologous reconstruction allows a better aesthetic result; however, many patients prefer implant reconstruction due to the shorter operation time and lack of donor site morbidity. Moreover, this reconstruction strategy is safe and can be performed in patients with multiple health problems. Tissue-expander reconstruction is conventionally performed as a two-stage procedure starting immediately after mammary gland removal. Results. Mastectomy is a destructive but essential intervention for women with breast cancer. Tissue expansion breast reconstruction is a safe, reliable, and efficacious procedure with considerable psychological benefits since it provides a healthy body image. Conclusion. This article focuses on this surgical technique and how to achieve the best reconstruction possible.
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Background. Cathepsin D has been recently implicated in insulin resistance and cardiovascular disease. This study was designed to investigate the relationship between cathepsin D and newly diagnosed type 2 diabetes. Methods. Circulating cathepsin D levels and metabolic variables were measured in 98 cases and 98 controls. Myocardial performance index "Tei index" that reflects both left ventricular systolic and diastolic function was measured with Doppler echocardiography in cases. Results. Newly diagnosed type 2 diabetes demonstrated significantly higher circulating cathepsin D concentrations than controls (median level: 227 ng/ml versus 174 ng/ml, ). In newly diagnosed type 2 diabetes, a significant correlation was found between cathepsin D levels and HOMA-IR (homeostatic model assessment of insulin resistance) (, ). In contrast, no significant correlation was found between cathepsin D levels and clinical parameters in the control group (all ). Interestingly, correlation analysis revealed a positive association between cathepsin D levels and Tei index in type 2 diabetes (, ). Conclusions. Increased levels of circulating cathepsin D are closely linked with the presence of type 2 diabetes, and cathepsin D might serve as a novel biomarker for cardiac dysfunction in newly diagnosed type 2 diabetes.
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The close relationship between atopic dermatitis (AD) and infective endocarditis (IE) has been implicated. Staphylococcus aureus colonization is frequently seen observed in AD patients' skin lesions. Although a case of IE due to S. aureus bacteremia in an AD patient has been sporadically reported, a case of S. aureus bacteremia complicated by psoas abscess and IE has not been previously reported. A 42-year-old man with a history of AD presented to our hospital complaining of fever, fatigue, chills, lower right back pain, and poor appetite for a week. His blood cultures showed growth of S. aureus. On day 3, the patient presented acute cardiac failure and was diagnosed with IE based on echocardiogram examination. Since the patient's cardiac failure did not respond to medication, an emergency surgery was performed on the fourth day of hospitalization. The patient underwent successful surgical treatment of the heart lesions and subsequent percutaneous drainage of psoas abscess and received intensive antibiotics, which successfully improved his condition. Our report emphasizes awareness of the association between AD and invasive S. aureus infections.
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In view of recent increase of brain computer interface (BCI) based applications, the importance of efficient classification of various mental tasks has increased prodigiously nowadays. In order to obtain effective classification, efficient feature extraction scheme is necessary, for which, in the proposed method, the interchannel relationship among electroencephalogram (EEG) data is utilized. It is expected that the correlation obtained from different combination of channels will be different for different mental tasks, which can be exploited to extract distinctive feature. The empirical mode decomposition (EMD) technique is employed on a test EEG signal obtained from a channel, which provides a number of intrinsic mode functions (IMFs), and correlation coefficient is extracted from interchannel IMF data. Simultaneously, different statistical features are also obtained from each IMF. Finally, the feature matrix is formed utilizing interchannel correlation features and intrachannel statistical features of the selected IMFs of EEG signal. Different kernels of the support vector machine (SVM) classifier are used to carry out the classification task. An EEG dataset containing ten different combinations of five different mental tasks is utilized to demonstrate the classification performance and a very high level of accuracy is achieved by the proposed scheme compared to existing methods.
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New England Journal of Medicine, Ahead of Print.
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New England Journal of Medicine, Ahead of Print.
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Objective. We aimed to evaluate the therapeutic effects and long-term effects of YKF and dissect the potential mechanisms. Materials and Methods. IPF rats were given YKF, prednisone, or pirfenidone, respectively, from day 1 to day 42, followed by a 28-day nonintervention interval through day 70. Forced vital capacity (FVC), histopathology, hydroxyproline (HYP) contents, lung coefficient, blood inflammatory cell populations, inflammatory cytokine levels of the lung tissues, and the expression of proteins involved in nuclear factor- (NF-) B signaling pathway were evaluated on days 7, 14, 28, 42, and 70. Results. HYP contents, Ashcroft scores, lung coefficient, and pulmonary fibrosis blood cell populations increased significantly in IPF rats, while FVC declined. All the above-mentioned parameters were improved in treatment groups from day 7 up to day 70, especially in YKF group. The mRNA and protein expressions of tumor necrosis factor- (TNF-) α significantly decreased, while interferon- (IFN-) γ significantly increased, and phosphorylations of cytoplasm inhibitor of nuclear factor kappa-B kinase β (IKKβ), inhibitor of nuclear factor kappa-B α (IκBα), and NF-κB were obviously downregulated in YKF group from day 7 to day 70. Conclusion. YKF has beneficial protective and long-term effects on pulmonary fibrosis by anti-inflammatory response and alleviating fibrosis.
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New England Journal of Medicine, Ahead of Print.
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New England Journal of Medicine, Ahead of Print.
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IL15 and IL7 are two cytokines essential for T cell development and homeostasis. In order to improve the antitumor activity by Newcastle Disease Virus (NDV)-modified tumor vaccine, we generated a recombinant NDV co-expressing IL15 and IL7 (LX/IL(15+7)) by incorporation of a 2A self-processing peptide into IL15 and IL7 using reverse genetics. B16 cells infected with LX/IL(15+7) expressed both IL15 and IL7 stably. The cytotoxicity assay showed that murine melanoma cells modified with LX/IL(15+7) could significantly enhance the antitumor immune response in vitro. Then, the antitumor effects of tumor vaccine modified with recombinant virus were tested in the murine tumor models. We observed strong antitumor responses induced by LX/IL(15+7)-modified tumor cells both in prophylaxis and therapeutic models. Although the tumor-infiltrating CD4+ T cells and CD8+ T cells were both increased, the antitumor activity of the tumor vaccine modified with LX/IL(15+7) was dependent on CD8+ T cells. Taken together, our data strongly indicated that tumor vaccine modified with NDV strain LX/IL(15+7) is a promising agent for cancer immunotherapy.
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C-MYC stimulates cell proliferation through the suppression of cyclin-dependent kinase (CDK) inhibitors including P15 (CDKN2B) and P21 (CDKN1A). It also activates E-box-mediated transcription of various target genes including telomerase reverse transcriptase (TERT) that is involved in cellular immortality and tumorigenesis. Transforming growth factor-beta 1 (TGF-β1)-stimulated clone 22 (TSC-22/TSC22D1) encodes a highly conserved leucine zipper protein that is induced by various stimuli, including TGF-β. TSC-22 inhibits cell growth in mammalian cells and in Xenopus embryos. However, underlying mechanisms of growth inhibition by TSC-22 remain unclear. Here, we show that TSC-22 physically interacts with c-MYC to inhibit the recruitment of c-MYC on the P15 (CDKN2B) and P21 (CDKN1A) promoters, effectively inhibiting c-MYC-mediated suppression of P15 (CDKN2B) and also P21 (CDKN1A) promoter activities. On the other hand, TSC-22 enhances c-MYC-mediated activation of the TERT promoter. Additionally, the expression of TSC-22 in embryonic stem cells inhibits cell growth without affecting its pluripotency-related gene expression. These results indicate that TSC-22 differentially regulates c-MYC-mediated transcriptional activity to regulate cell proliferation.
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Chronic inflammation has a crucial role in cancer development and the progression of various tumors, including pancreatic ductal adenocarcinoma (PDAC). The arachidonate cascade is a major inflammatory pathway that produces several metabolites, such as prostaglandin E2 (PGE2). The enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) degrades prostaglandin and is frequently decreased in several types of cancer; however, the molecular mechanisms of 15-PGDH suppression are unclear. The current study was conducted to elucidate the molecular mechanisms and clinical significance of 15-PGDH suppression in PDAC. Here, we showed that interleukin-1 beta (IL-1β), a pro-inflammatory cytokine, down-regulates 15-PGDH expression in PDAC cells and that IL-1β expression was inversely correlated with 15-PGDH levels in frozen PDAC tissues. We also found that activated macrophages produced IL-1β and reduced 15-PGDH expression in PDAC cells. Furthermore, the number of CD163-positive tumor-associated macrophages (TAMs) was shown to be inversely correlated with 15-PGDH levels in PDAC cells by immunohistochemical staining of 107 PDAC samples. Finally, we demonstrated that low 15-PGDH expression was significantly associated with advanced tumors, presence of lymph node metastasis and nerve invasion, and poor prognosis in PDAC patients. Our results indicate that IL-1β derived from TAMs suppresses 15-PGDH expression in PDAC cells, resulting in poor prognosis of PDAC patients.
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