The oligomeric organization of the voltage-dependent anion-selective channel (VDAC) and its interactions with hexokinase play integral roles in mitochondrially mediated apoptotic signaling. Various small to large assemblies of VDAC are observed in mitochondrial outer membranes but they do not predominate in detergent solubilized VDAC samples. In this study, a cholesterol analogue, cholesteryl-hemisuccinate (CHS), was shown induce the formation of detergent soluble VDAC multimers. The various oligomeric states of VDAC induced by the addition of CHS were deciphered through an integrated biophysics approach using microscale thermophoresis, analytical ultracentrifugation and size exclusion chromatography-small angle X-ray scattering.
http://bit.ly/2G2Yr1T
Πέμπτη 31 Ιανουαρίου 2019
A cholesterol analogue induces an oligomeric reorganization of VDAC
Nanomechanics of diaminopurine-substituted DNA
2,6-diaminopurine (DAP) is a nucleobase analog of adenine. When incorporated into double-stranded DNA, it forms three hydrogen bonds with thymine. Rare in nature, DAP-substitution alters the physical characteristics of a DNA molecule without sacrificing sequence specificity. Here we show that in addition to stabilizing double-strand hybridization, DAP-substitution also changes the mechanical and conformational properties of dsDNA. Thermal melting experiments reveal that DAP-substitution raises melting temperatures without diminishing sequence-dependent effects.
http://bit.ly/2G0z7cM
Solvatochromic modeling of Laurdan for multiple polarity analysis of dihydro-sphingomyelin bilayer
The hydration properties of the interface between lipid bilayers and bulk water are important for determining membrane characteristics. Here, the emission properties of a solvent-sensitive fluorescence probe, 6-lauroyl-2-dimethylamino naphthalene (Laurdan), were evaluated in lipid bilayer systems composed of the sphingolipids, D-erythro-N-palmitoyl-sphingosylphosphorylcholine (PSM) and D-erythro-N-palmitoyl-dihydrosphingomyelin (DHPSM). The glycerophospholipids, 1-palmitoyl-2-palmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1-oleoyl-2-oleoyl-sn-glycero-3-phosphocholine (DOPC), were used as controls.
http://bit.ly/2GggelA
Synaptobrevin-2 C-terminal Flexible Region Regulates the Discharge of Catecholamine Through the Fusion Pore
The discharge of catecholamine molecules through the fusion pore is a regulated process, and understanding the role of the SNARE proteins during this process has been of great interest. These proteins facilitate the formation of the fusion pore, but it has been unclear whether their transmembrane domains regulate the flux of discharged catecholamines through direct interactions. Here, it is shown, using mutagenesis studies, that the transmembrane domain of the vesicular SNARE protein, synaptobrevin-2, does not directly interact with the discharged catecholamine, however it is suggested that synaptobrevin-2 transmembrane domain indirectly modulates the flux of catecholamine by interacting with the vesicle membrane.
http://bit.ly/2GkB4QP
The role of early bioelectric signals in the regeneration of planarian anterior/posterior polarity
Axial patterning during planarian regeneration relies on a transcriptional circuit that confers distinct positional information on the two ends of an amputated fragment. The earliest known elements of this system begin demarcating differences between anterior and posterior wounds by 6 hours post-amputation. However, it is still unknown what upstream events break the axial symmetry, allowing a mutual repressor system to establish invariant, distinct biochemical states at the anterior and posterior ends.
http://bit.ly/2G2uWwT
CcdB at pH 4 forms a partially unfolded state with a dry core
pH is an important factor that affects the protein structure, stability and activity. Here we probe the nature of the low pH structural form of the homodimeric CcdB protein (Controller of Cell Death B). Characterization of CcdB protein at pH 4 and 300K using circular dichroism spectroscopy, ANS binding and Trp solvation studies suggests that it forms a partially unfolded state with a dry core at equilibrium under these conditions. CcdB remains dimeric at pH 4 as shown by multiple techniques, such as SEC-MALS, analytical ultra-centrifugation and electron paramagnetic resonance.
http://bit.ly/2GclTJ4
Single-channel resolution of the interaction between C-terminal CaV1.3 isoforms and calmodulin
Voltage-dependent calcium CaV1.3 channels are involved in the control of cellular excitability and pacemaking in neuronal, cardiac and sensory cells. Various proteins interact with the alternatively spliced channel C-terminus regulating gating of CaV1.3 channels. Binding of a regulatory calcium-binding protein calmodulin (CaM) to the proximal C-terminus leads to the boosting of channel activity and promotes calcium-dependent inactivation (CDI). The C-terminal modulator domain (CTM) of CaV1.3 channels can interfere with the CaM binding, thereby inhibiting channel activity and CDI.
http://bit.ly/2G0B0Gl
Squamous cell carcinoma of the bladder: poor response to neoadjuvant chemotherapy
Abstract
Background
Squamous cell carcinoma (SCC) of the bladder is a rare, aggressive malignancy. Unlike urothelial cell carcinoma, SCC is resistant to chemotherapy and guidelines recommend radical cystectomy (RC) without neoadjuvant chemotherapy (NAC). We aimed to evaluate the current management and survival of patients with invasive SCC treated with or without NAC.
Methods
671 patients with invasive SCC bladder cancer from 2004 to 2015 in the National Cancer Data Base were identified. Patients were stratified by treatment with RC alone or NAC prior to RC (NAC + RC). Survival analysis was performed with Kaplan–Meier and Cox regression. Secondary outcomes included length of stay and readmission.
Results
Of 671 patients, 92.8% were treated with RC alone and 7.2% with NAC + RC. Cox regression for mortality was performed including age, Charlson score, clinical stage, and NAC. Increased risk of mortality was noted with increasing age (OR 1.01, p = 0.023) and Charlson score of 1–3 (HR 1.58–1.68, p < 0.05). NAC did not confer survival advantage (HR 1.17, p = 0.46). On Kaplan–Meier analysis, the overall survival was equivalent (log-rank p = 0.804). Hospital stay and readmission were similar between RC and NAC + RC groups.
Conclusions
Analysis of a national tumor registry suggests a lack of overall survival benefit for NAC with localized, muscle invasive SCC of the bladder. Further research directed at chemotherapy regimens for SCC is needed to optimize treatment and improve survival outcomes.
http://bit.ly/2MJcZnN
Complete resolution of erythrodermic psoriasis with first-line apremilast monotherapy
Erythrodermic psoriasis (EP) is the most serious type of psoriasis with high morbidity and mortality. First-line recommended therapies for EP, cyclosporine and infliximab have significant adverse effects. Cyclosporine increases the risk of hypertension, leucopenia, infections and renal failure. Infliximab increases the risk of reactivation of tuberculosis, hepatitis B and histoplasmosis, and increases risk for hepatitis, autoantibody formation, congestive heart failure, demyelinating disorders, pancytopenia, lymphoma and skin cancer. An effective drug with a much safer side effect profile will be of significant benefit in EP. The phosphodiesterase 4 inhibitor apremilast is U.S Food and Drug Administration (FDA) approved for plaque psoriasis and psoriatic arthritis. Adverse effects of apremilast reported are headache, nausea, diarrhoea, upper respiratory tract infection, potential for depression and weight loss. We report complete and long-standing resolution of EP with first-line apremilast monotherapy. Apremilast may be an effective option with comparatively minor side effects for EP.
http://bit.ly/2HHaaVm
Ectopic varices masquerading as lower gastrointestinal bleeding
A middle-aged woman previously in good health arrived to hospital with severe haemorrhagic shock. An abdominal and pelvic CT scan showed hepatomegaly, fluid in the sigmoid colon, perigastric and right sided pelvic varices without a clear source of bleeding. Urgent esophagogastroduodenoscopy excluded gastric varices and active upper gastrointestinal bleeding and the colonoscopy was inconclusive due to haemodynamic instability and massive bleeding which made it impossible to proceed with a full colonoscopy. An explorative laparotomy identified liver cirrhosis and bleeding from varices of the right fallopian tube which had formed a fistula with the caecum. A right hemicolectomy with a side to side anastomosis and a right sided salpingo-oophorectomy were carried out. The patient was thereafter transferred to the intensive care unit intubated, requiring massive fluid resuscitation and high doses of vasoactive agents. Nine days after hospital admission she was transferred to the surgical ward and followed up by a hepatologist.
http://bit.ly/2t1RfKR
Adipsic diabetes insipidus secondary to craniopharyngioma resection
Adipsic diabetes insipidus is an infrequent disease which may be associated with craniopharyngioma. It may be secondary to the tumour's extension, as well as to resection of the mass. We present the case of a 24-year-old woman with a history of delayed puberty and hypothyroidism, but no prior study reports. She consulted due to a headache with warning signs associated with altered visual acuity. Brain MRI was performed which showed signs of a non-adenomatous lesion with suprasellar and hypothalamic extension. Following transcranial surgery, she developed diabetes insipidus criteria, with absence of thirst documented during the hospitalisation. The histopathological findings confirmed the diagnosis of craniopharyngioma. The patient was treated with desmopressin and received recommendations regarding rehydration according to the quantification of losses, with electrolyte stabilisation.
http://bit.ly/2HLvo4t
Severe case of pneumonia with pleural effusion in an immunocompromised woman due to Fusobacterium necrophorum
Infections caused by fusobacteria have a wide clinical spectrum, and in certain patients, they can lead to severe systemic illness. We report the case of an immunocompromised young woman who presented with severe pneumonia complicated by parapneumonic pleural effusion, despite wide-spectrum antibiotic treatment. Fusobacterium necrophorum was isolated in the samples obtained after thoracentesis was performed. Apart from the pulmonary involvement, we could not identify the infectious focus, since the patient did not have poor dentition or Lemierre's syndrome. After an extended antibiotic regimen and placement of a chest tube, the patient fully recovered and was able to be discharged.
http://bit.ly/2t0VQga
Rare cause of lung atelectasis in a young woman
Pulmonary mucoepidermoid carcinoma is an extremely rare intrathoracic malignancy, comprising less than 1% of all lung tumours. These are very slow growing and are classified into low grade and high grade based on histological features. Surgical resection is the primary treatment with excellent outcomes, while chemotherapy or radiotherapy effectiveness is not known. Preoperative fluorine-18 fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) is useful for predicting tumour grade and postsurgical prognosis.
A clinical case of a 31-year-old woman who presented with dyspnoea on exertion, cough and wheezing is reported. Imaging studies revealed a mass involving the left lower lobe bronchus and atelectasis. 18F-FDG PET/CT showed uptake in the described mass with a maximum standardised uptake value of 9.7. Complete surgical resection was performed, and pathological examination revealed a high-grade mucoepidermoid carcinoma with tumour-free margins. Adjuvant chemotherapy was given and there is no evidence of tumour recurrence.
http://bit.ly/2HICtmd
Long-lasting response to afatinib that persisted after treatment discontinuation in a case of EGFR-mutated lung adenocarcinoma
It is unknown whether tyrosine kinase inhibitors targeting epidermal growth factor receptor (EGFR) can be discontinued in patients in whom EGFR-mutated lung cancer has well stabilised. We present a case of a 73-year-old Japanese woman with no history of smoking. Right pulmonary lower lobectomy, lymph node dissection and segmental resection of the right middle lobe were performed. Additionally, she underwent adjuvant chemotherapy for stage IIIB adenocarcinoma harbouring an EGFR exon 19 deletion. Afatinib was administered for liver metastases after 15 months. A complete response of metastatic disease was achieved for 2 years. However, afatinib was unavoidably discontinued due to splenectomy for the treatment of idiopathic thrombocytopenic purpura. Although afatinib was not resumed, due to the abscess formation as surgery complication, a drug-free complete response was sustained for over 18 months. The present case suggests that exceptional and durable responses to afatinib can be achieved in individual cases.
http://bit.ly/2HK9YEY
'Never say never: the first successful management of a type A aortic dissection in Liberia
The West African country of Liberia ranks as one of the lowest in the world in most measures of health. The diagnosis and management of complex surgical cases such as aortic dissection is extremely challenging, for reasons ranging from lack of diagnostic imaging capabilities to the high resources required for definitive surgical intervention. We present the first known successfully managed case of aortic dissection in the country's history and with it highlight the challenges faced and a number of lessons learned that are beneficial to anyone working in resource-limited environments.
http://bit.ly/2HEE7W2
Sunitinib in patients with pancreatic neuroendocrine tumors: update of safety data
Future Oncology, Ahead of Print.
http://bit.ly/2CTS6BC
Pediatric acute myeloid leukemia with t(7;21)(p22;q22)
Abstract
The t(7;21)(p22;q22) resulting in RUNX1‐USP42 fusion, is a rare but recurrent cytogenetic abnormality associated with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The prognostic significance of this translocation has not been well established due to the limited number of patients. Herein, we report three pediatric AML patients with t(7;21)(p22;q22). All three patients presented with pancytopenia or leukopenia at diagnosis, accompanied by abnormal immunophenotypic expression of CD7 and CD56 on leukemic blasts. One patient had t(7;21)(p22;q22) as the sole abnormality, whereas the other two patients had additional numerical and structural aberrations including loss of 5q material. Fluorescence in situ hybridization (FISH) analysis on interphase cells or sequential examination of metaphases showed the RUNX1 rearrangement and confirmed translocation 7;21. Genomic SNP microarray analysis, performed on DNA extracted from the bone marrow from the patient with isolated t(7;21)(p22;q22), showed a 32.2 Mb copy neutral loss of heterozygosity (cnLOH) within the short arm of chromosome 11. After 2‐4 cycles of chemotherapy, all three patients underwent allogeneic hematopoietic stem cell transplantation (HSCT). One patient died due to complications related to viral reactivation and graft‐versus‐host disease. The other two patients achieved complete remission after HSCT. Our data displayed the accompanying cytogenetic abnormalities including del(5q) and cnLOH of 11p, the frequent pathological features shared with other reported cases, and clinical outcome in pediatric AML patients with t(7;21)(p22;q22). The heterogeneity in AML harboring similar cytogenetic alterations may be attributed to additional uncovered genetic lesions.
This article is protected by copyright. All rights reserved.
http://bit.ly/2S2ON5w
Genomic alterations in breast cancer: Level of evidence for actionability according to ESMO Scale for Clinical Actionability of molecular Targets (ESCAT)
http://bit.ly/2Se4Tc0
Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001
http://bit.ly/2SheaA1
Diagnostic Reference Levels for Adult Nuclear Medicine Imaging Established from the National Survey in Korea
Abstract
Purpose
There is substantial need for optimizing radiation protection in nuclear medicine imaging studies. However, the diagnostic reference levels (DRLs) have not yet been established for nuclear medicine imaging studies in Korea.
Materials and Methods
The data of administered activity in 32 nuclear medicine imaging studies were collected from the Korean Society of Nuclear Medicine (KSNM) dose survey database from 2013 and 2014. Through the expert discussions and statistical analyses, the 75th quartile value (Q3) was suggested as the preliminary DRL values. Preliminary DRLs were subjected to approval process by the KSNM Board of Directors and KSNM Council, followed by clinical applications and performance rating by domestic institutes.
Results
DRLs were determined through 32 nuclear medicine imaging studies. The Q3 value was considered as appropriate selection as it was generally consistent with the most commonly administered activity. In the present study, the final version of initial DRL values for nuclear medicine imaging in Korean adults is described including various protocols of the brain and myocardial perfusion imaging.
Conclusion
The first DRLs for nuclear medicine imaging in Korean adults were confirmed. The DRLs will enable optimized radiation protection in the field of nuclear medicine imaging in Korea.
http://bit.ly/2SjlDyt
Activated YAP causes renal damage of type 2 diabetic nephropathy
OBJECTIVE: Yes-associated protein (YAP) is a critical factor of Hippo pathway. It can control organ size, regulate proliferation, differentiation, and apoptosis of cells, and mediate epithelial-mesenchymal transition and cell contact inhibition. It has gradually become a hot spot in the field of diabetic nephropathy (DN). Tea domain (TEAD) is a factor with a deoxyribose nucleic acid (DNA) binding domain, which combines with activated YAP to control the expression of their important target factor – connective tissue growth factor (CTGF).
PATIENTS AND METHODS: We have investigated the role of YAP in type 2 diabetic nephropathy and evaluated the correlation between YAP and the progress of type 2 diabetic nephropathy. We have detected the expression of YAP, TEAD and CTGF in normal people (n=10) and patients with DN (n=51) by immunohistochemical and immunofluorescence staining and evaluated the relationship among clinical, pathologic data and YAP expression in type 2 diabetic nephropathy.
RESULTS: In kidneys of type 2 diabetic nephropathy, YAP, TEAD and CTGF were highly expressed in the nucleus of glomerular podocytes. In those healthy kidneys, however, all three of the above factors were mainly expressed in cytoplasm. Furthermore, the high expression of YAP in DN had relevance to increasing systolic blood pressure (SBP) (r=0.484, p=0.019), blood urea nitrogen (BUN) (r=0.522, p=0.032), creatinine (Cr) (r=0.496, p=0.031), progression of DN stage (r=0.647, p=0.001) and progression of DN pathologic classification (r=0.298, p=0.033). In addition, decreasing serum albumin (SAlb) (r=-0.656, p=0.001) and estimated glomerular filtration rate (eGFR) (r=-0.607, p=0.006) were also correlated with the high expression of YAP in DN.
CONCLUSIONS: High expression of YAP, TEAD and CTGF in kidney tissues suggested that YAP played a significant role in the renal damage of type 2 diabetic nephropathy. YAP that is correlated with SBP, BUN, Cr, DN stage, DN pathologic classification, SAlb and eGFR, suggested that inhibition of the activity of YAP might have the effect in delaying DN progression.
L'articolo Activated YAP causes renal damage of type 2 diabetic nephropathy sembra essere il primo su European Review.
http://bit.ly/2UyLY9j
Long non-coding RNA Tubulin Alpha 4B (TUBA4B) inhibited breast cancer proliferation and invasion by directly targeting miR-19
OBJECTIVE: Long non-coding RNA (lncRNA) is a significant member of the non-coding RNA family. New evidence has shown that it plays a pivotal role in the processes of tumor genesis and development. According to previous verification, the lncRNA Tubulin Alpha 4B (TUBA4B) is a tumor-associated molecule, but how TUBA4B expresses and functions in breast cancer is still not clear.
PATIENTS AND METHODS: We conducted this study to examine what expression and biological role TUBA4B plays in breast cancer. The expression of TUBA4B was measured in breast cancer samples and cell lines. CCK8 assays and transwell assays were used for evaluating the effects of TUBA4B on breast cancer cell proliferation and invasion. Luciferase reporter assays were used for identifying the direct target of TUBA4B.
RESULTS: According to the results, TUBA4B was largely downregulated in breast cancer samples and cell lines. The functional analysis demonstrated that breast cancer cells proliferation and invasion could be inhibited by overexpression of TUBA4B. The results of Luciferase reporter assays indicated that TUBA4B directly targeted miR-19, which could rescue the effects of TUBA4B on breast cancer cells.
CONCLUSIONS: It is suggested that TUBA4B was downregulated in breast cancer and suppressed proliferation and invasion of breast cancer by targeting miR-19.
L'articolo Long non-coding RNA Tubulin Alpha 4B (TUBA4B) inhibited breast cancer proliferation and invasion by directly targeting miR-19 sembra essere il primo su European Review.
http://bit.ly/2WwU18q
RNA-seq analysis of diet-driven obesity and anti-obesity effects of quercetin glucoside or epigallocatechin gallate in Drosophila adults
OBJECTIVE: High-fat diet (HFD) feeding stimulates fat accumulation in mammals and Drosophila. In the present study, we examined whether simultaneous feeding of familiar anti-obesity drugs, quercetin glycosides (QG) and epigallocatechin gallate (EGCG), to Drosophila has the same suppressive effect on fat accumulation as previously reported in rats and mice. To understand the underlying molecular mechanisms of HFD diet-induced obesity and the suppression effect of the drugs, we performed transcriptome analyses.
MATERIALS AND METHODS: We induced extra fat accumulation by feeding Drosophila fly food containing 20% coconut oil and quantified the triglyceride accumulated in flies. The effects of anti-obesity drugs were also evaluated. We isolated total RNA from each sample and performed RNA-seq analyses and quantitive Real Time-Polymerase Chain Reaction (qRT-PCR) to investigate altered gene expression.
RESULTS: The mRNA levels of several genes involved in lipid metabolism, glycolysis/gluconeogenesis, and anti-oxidative stress changed in HFD-fed adults. Moreover, the levels altered in those fed an HFD with QG or EGCG. The qRT-PCR further confirmed the RNA-seq data, suggesting that the expression of five essential genes for lipid metabolism changed in HFD-fed flies and altered in the flies treated with anti-obesity drugs. The most remarkable alteration was observed in the dHSL gene encoding a lipase involved in lipid-storage after HFD feeding and HFD with QG or EGCG. These alterations are consistent with HFD-induced fat accumulation as well as the anti-obesity effects of the drugs in mammals, suggesting that the genes play an important role in anti-obesity effects.
CONCLUSIONS: These are the first reports to date of entire profiles of altered gene expression under the conditions of diet-induced obesity and its suppression by anti-obesity drugs in Drosophila.
L'articolo RNA-seq analysis of diet-driven obesity and anti-obesity effects of quercetin glucoside or epigallocatechin gallate in Drosophila adults sembra essere il primo su European Review.
http://bit.ly/2RuZPeM
Advancements in uterus transplant: new scenarios and future implications
Women suffering from Uterine Factor Infertility (UFI) arising from congenital conditions (e.g., Rokitansky-Kuster-Hauser syndrome) or hysterectomy can fulfill their wish to achieve motherhood only by resorting to surrogacy, which is, however, banned in most countries. Medical research has long been looking into uterus transplant (UTx), which may constitute a valuable alternative for such patients. Following decades of animal testing and clinical trials, several successful pregnancies have been carried to term. Yet UTx is still to be considered as an experimental procedure. The report's authors believe UTx has the potential to become a mainstream surgical practice, but for the time being, several ethical issues need to be weighed in before it does.
L'articolo Advancements in uterus transplant: new scenarios and future implications sembra essere il primo su European Review.
http://bit.ly/2Wxk2o1
Clip line traction method using locking‐clip technique for colorectal endoscopic submucosal dissection
Abstract
Appropriate traction is important for safe and efficient colorectal endoscopic submucosal dissection (ESD). Various traction methods are available. The optimal traction method should reasonably sustain the normal mucosa on the contralateral side of the lesion at an appropriate distance. We describe a novel method of clip line traction performed using a locking clip technique (LCT) to fix a conventional nylon line (2‐0 nylon) and clip to the root of the clip's tooth in an ESD (Video 1; Figures 1a‐d).
This article is protected by copyright. All rights reserved.
http://bit.ly/2WybaP6
Serum levels of histamine and diamine oxidase in multiple sclerosis.
| Related Articles |
Serum levels of histamine and diamine oxidase in multiple sclerosis.
Am J Clin Exp Immunol. 2018;7(6):100-105
Authors: Rafiee Zadeh A, Falahatian M, Alsahebfosoul F
Abstract
BACKGROUND: Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system, mostly affecting young adults. Diamine oxidase is an enzyme essential for histamine production. Histamine which is produced mostly by mast cells can have effects on different aspects of immune system via its different histamine receptors (H1R, H2R, H3R and H4R). The crucial role of diamine oxidase and histamine in immune balance has been documented in different studies and experiments both on MS patients and on experimental allergic encephalomyelitis (EAE). In this regard, we aimed to measure the level of histamine and diamine oxidase in the serum of MS patients.
METHODS: A total number of 50 relapsing-remitting MS (RRMS) patients and 41 age and sex matched controls were enrolled in this study. Assessments of serum levels of histamine and diamine oxidase enzyme were performed using enzyme-linked immune sorbent assay (ELISA).
RESULTS: The serum levels of histamine and diamine oxidase in RRMS patients were lower than healthy controls (P-value = 0.00, for both).
CONCLUSION: Our research team found significant low levels of histamine and diamine oxidase in RRMS patients; however the pathogenesis of this issue was unclear.
PMID: 30697467 [PubMed]
http://bit.ly/2HK9y1k
Pressure pain assessment may predict the outcome of spinal cord stimulation for refractory epilepsy.
| Related Articles |
Pressure pain assessment may predict the outcome of spinal cord stimulation for refractory epilepsy.
Am J Clin Exp Immunol. 2018;7(6):95-99
Authors: Feng L, Fan LH, Wu DZ
Abstract
It was well-documented that epilepsy and pain arise from an excitation-inhibition imbalance within neuronal networks. A previous meta-analysis of data from clinical trials showed an association between anticonvulsants and specific pain types, e.g. multiple sclerosis pain. Multiple multicentre randomized controlled trials have shown that antiepileptic drugs have a prominent role in the treatment of several types of pain, e.g. neuropathic pain. Many anticonvulsants have been introduced to better manage acute postoperative pain, with improvements in analgesic efficacy and safety. These data suggested that there existed the similar mechanisms of certain forms of epilepsy and pain, and the therapeutic mechanism of spinal cord stimulation for certain forms of epilepsy and pain may be involved in the melanocortinergic signaling, and the change in cerebral glucose metabolism. We hypothesized that pressure pain assessment may predict the outcome of spinal cord stimulation in refractory epilepsy.
PMID: 30697466 [PubMed]
http://bit.ly/2FWwWa0
p300 mediates muscle wasting in Lewis lung carcinoma
C/EBPβ is a key mediator of cancer-induced skeletal muscle wasting. However, the signaling mechanisms that activate C/EBPβ in the cancer milieu are poorly defined. Here we report cancer-induced muscle wasting requires the transcriptional co-factor p300 which is critical for the activation of C/EBPβ. Conditioned media from diverse types of tumor cells as well as recombinant HSP70 and HSP90 provoked rapid acetylation of C/EBPβ in myotubes, particularly at its Lys39 residue. Overexpression of C/EBPβ with mutated Lys39 impaired Lewis lung carcinoma (LLC)-induced activation of the C/EBPβ-dependent catabolic response, which included upregulation of E3 ligases UBR2 and atrogin1/MAFbx, increased LC3-II, and loss of muscle proteins both in myotubes and mouse muscle. Silencing p300 in myotubes or overexpressing a dominant negative p300 mutant lacking acetyltransferase activity in mouse muscle attenuated LLC tumor-induced muscle catabolism. Administration of pharmacological p300 inhibitor C646, but not PCAF/GCN5 inhibitor CPTH6, spared LLC tumor-bearing mice from muscle wasting. Furthermore, mice with muscle-specific p300 knockout were resistant to LLC tumor-induced muscle wasting. These data suggest that p300 is a key mediator of LLC tumor-induced muscle wasting whose acetyltransferase activity may be targeted for therapeutic benefit in this disease.
http://bit.ly/2WxdVjz
Systematic review with meta‐analysis: cholecystectomy for biliary dyskinesia—what can the gallbladder ejection fraction tell us?
Summary
Background
Gallbladder dyskinesia (gallbladder spasm, biliary dyskinesia or chronic acalculous cholecystitis) is a poorly defined entity which presents as biliary‐type pain without any identifiable organic pathology. Abnormal gallbladder ejection fraction (GBEF) is used by some to select those likely to benefit from cholecystectomy. The validity of this approach has been questioned.
Aim
To systematically review the literature and summarise the evidence surrounding the practice of cholecystectomy based on GBEF for gallbladder dyskinesia.
Methods
We conducted a systematic search of PubMed/MEDLINE and SCOPUS from 1980 to 2016 to identify the relevant literature.
Results
Twenty‐nine studies including 2891 patients were included in the final analysis. In comparing cholecystectomy with medical management, patients with a normal GBEF did not benefit from cholecystectomy; whereas those with low GBEF had a higher chance (RR, relative risk = 2.37) of symptomatic improvement following surgery. When those classified as "low" and "normal" GBEF were compared in terms of outcome following cholecystectomy, the rate of improvement following surgery was similar in the two groups (RR 1.09) which suggests a placebo effect of surgery.
Conclusions
While a low GBEF may provide some guidance in identifying those with gallbladder dyskinesia who may benefit from cholecystectomy, the available data are inconsistent and based on studies of poor quality which are often subject to bias and the impact of confounding factors. For these reasons, we conclude that the role of scintigraphy and cholecystectomy in the definition and management of this disorder remain unclear pending definitive study.
http://bit.ly/2S2uEfS
Photodynamic inactivation of planktonic cultures and Streptococcus mutans biofilms for prevention of white spot lesions during orthodontic treatment: An in vitro investigation
This study evaluated the efficacy of photodynamic inactivation (PDI) with hematoporphyrin IX (H) and modified hematoporphyrin IX (MH) at 10 μmol/L, using a blue light-emitting diode (LED), fluence of 75 J/cm,2 over planktonic cultures and biofilm of Streptococcus mutans (UA 159).
http://bit.ly/2CVKbEa
A rodent model using skeletal anchorage and low forces for orthodontic tooth movement
Nonhuman animal models have been used extensively to study orthodontic tooth movement (OTM). However, rodent models have disadvantages, including a reported reduction in bone volume during OTM. The purpose of this study was to determine the viability of a skeletal anchorage and the effect of low force (∼3 cN) on interradicular bone volume during OTM.
http://bit.ly/2D8wAtl
Residents' journal review
Proper control of the occlusal plane (OP) is an important criteria for success in surgical treatment of patients with double-jaw surgery. Alteration of the OP or rotation of the maxillomandibular complex around a predetermined point is a surgical technique that involves intentional manipulation of the OP by clockwise (CWR) or counterclockwise (CCWR) rotation. The purpose of this study was to evaluate the stability of CCWR double-jaw orthognathic surgery of hyperdivergent Class III patients. Patients were evaluated by means of lateral cephalometric analysis, and counterclockwise rotation was assessed according to the change in the angle of the OP to the Frankfort horizontal plane.
http://bit.ly/2CYopPY
Short-term cone-beam computed tomography evaluation of maxillary third molar changes after total arch distalization in adolescents
Our objectives were to evaluate changes in the position of maxillary third molars with cone-beam computed tomography images in adolescents after total arch distalization using a modified C-palatal plate (MCPP) and to compare them with the changes in a matched control group.
http://bit.ly/2CVKqPA
Vertical control of a Class II deep bite malocclusion with the use of orthodontic mini-implants
To improve the facial profile of a Class II patient with chin deficiency, orthodontists have traditionally used incisor retraction or jaw surgery. Recently, a new technique was introduced that uses orthodontic mini-implants to intrude the incisors and rotate the mandibular plane counterclockwise. In patients with deep bite, heavy anterior occlusal contact can make it difficult to use intrusion for profile improvement. This case report shows the successful treatment of a patient with Class II deep bite and chin deficiency by means of intrusion of the maxillary and mandibular dentition with multiple orthodontic mini-implants.
http://bit.ly/2D2ChZp
What I say versus what I do
So, you're an expert in a malpractice case; for which side is irrelevant. The legal issue is a simple one. Can you say that the doctor's care fell within the prevailing standard of care if you would have done it differently? Some courts allow an expert to be cross-examined on this point, and some don't. Let's take a look at how Indiana handles this matter and why.
http://bit.ly/2RZIv6F
Evaluation of facial soft tissue thickness in symmetric and asymmetric subjects with the use of cone-beam computed tomography
The aims of this study were to evaluate facial bilateral soft tissue thickness in symmetric and asymmetric subjects and to investigate whether soft tissue compensates for skeletal asymmetry.
http://bit.ly/2CX1mF9
What the world needs now …
Your newly minted diploma is ample representation of the culmination of your decades of hard work and sacrifice. You are excited to meet new colleagues in your city, to learn the faces behind their names, and to avail yourself for future patient referrals. So you begin calling each of their offices with the intention of making an appointment to introduce yourself and to bring a modest gift that represents your new office brand. All told, there are almost 4 dozen practitioners whose patients might benefit from your service.
http://bit.ly/2S1Dw5L
Comparison of root resorption after bone-borne and tooth-borne rapid maxillary expansion evaluated with the use of microtomography
Root resorption was compared between bone-borne and tooth tissue–borne rapid maxillary expansion patients with the use of microtomography.
http://bit.ly/2CVLvXy
Mandibular molar intrusion with mini-implants and the multiloop edgewise archwire technique
We sincerely compliment the authors on the publication of their case report, "Nonsurgical correction of a severe anterior open bite with mandibular molar intrusion using mini-implants and the multiloop edgewise archwire technique" in the April 2018 issue (Freitas BV, Abas Frazão MC, Dias L, Fernandes Dos Santos PC, Freitas HV, Bosio JA. Am J Orthod Dentofacial Orthop. 2018; 153:577-87). It was a pleasure reading the article, which mentioned a novel technique for the closure of open bite when the patient is unwilling to have surgery.
http://bit.ly/2D2Rxpw
Logically fallacious
Are we currently living in a post-truth world where facts no longer matter? In our society today, it would appear that this is the case. We see it every day in commercials that are trying to sell us something and in politics where our ideas and principals are being manipulated. It is all too common in everyday news programs, where bias toward one belief or another shapes the stories to persuade us into believing that which often is not the truth. Many of the opinions held by factions of the dental profession are presented as fact, when in reality they are factitious.
http://bit.ly/2RZIDDb
Influence of facial pattern in smile attractiveness regarding gingival exposure assessed by dentists and laypersons
The present study aimed to assess the influence of facial pattern in smile attractiveness on different levels of gingival exposure evaluated by dental specialists and laypersons.
http://bit.ly/2CYoenM
Searching the literature for studies for a systematic review. Part 1: Identifying search concepts in a question
Searching the literature for studies that meet the inclusion criteria is one of the first stages of a systematic review.1 A quality literature search is a systematic survey of the literature on a specific topic or clinical question. It goes beyond a cursory search of the literature to a series of steps that are well organized and planned before the search itself: selecting relevant databases, formulating a structured question, applying specific criteria before executing the search to reduce selection bias, creating a series of search queries using relevant keywords, and reviewing each result for suitability.
http://bit.ly/2RZI4t3
Autotransplantation of premolars and space closure in a patient with inflamed sinuses
Congenital absence of permanent teeth can be treated by means of dental implants and prosthetics. Tooth autotransplantation is an alternative in growing patients because continued eruption of the transplanted tooth and associated alveolar bone growth can be expected. This clinical report presents tooth autotransplantation in a 10-year-old boy with chronic maxillary rhinosinusitis, diagnosed by the department of otorhinolaryngology. The patient's mandibular second premolars were transplanted to a congenitally edentulous maxillary premolar region.
http://bit.ly/2D0SkHh
Removing plaque and tartar from teeth
The buildup of plaque and tartar on the teeth can cause bad breath, tooth decay, and gum disease. However, several simple home remedies can help treat and prevent plaque and tartar. Learn more here.
http://bit.ly/2HJzcTW
JAK/STAT signaling in stem cells and regeneration: from Drosophila to vertebrates [PRIMER]
The JAK/STAT pathway is a conserved metazoan signaling system that transduces cues from extracellular cytokines into transcriptional changes in the nucleus. JAK/STAT signaling is best known for its roles in immunity. However, recent work has demonstrated that it also regulates critical homeostatic processes in germline and somatic stem cells, as well as regenerative processes in several tissues, including the gonad, intestine and appendages. Here, we provide an overview of JAK/STAT signaling in stem cells and regeneration, focusing on Drosophila and highlighting JAK/STAT pathway functions in proliferation, survival and cell competition that are conserved between Drosophila and vertebrates.
http://bit.ly/2BnQ1hJ
Loss of SMAD4 promotes colorectal cancer progression by recruiting tumor-associated neutrophils via CXCL1/8-CXCR2 axis
Purpose:SMAD4 is a key transcriptional factor of TGF-b signaling, and acts as a tumor suppressor in colorectal cancer (CRC). In the present study, we explored the immunological effect of SMAD4 on the tumor microenvironment. Experimental Design: Using 99 clinical specimens and human CRC cell lines, we investigate the relationship between SMAD4 expression and neutrophil accumulation. We immunohistochemically analyzed expression of SMAD4, CXCL1, CXCL8, CXCR2 and other proteins with clinical specimens. Finally, we determined the serum levels of CXCL1 and CXCL8 in 125 CRC patients. Results: SMAD4 knockdown from human CRC cells up-regulated the expression of CXCL1 and CXCL8, which recruited neutrophils to CRC tumor via CXCR2. In turn, when neutrophils were exposed to the supernatant of SMAD4-negative CRC cells, they produced a large amount of CXCL1 and CXCL8 by themselves in vitro. In human clinical specimens, we found that neutrophil infiltration into the peritumoral stroma was more marked in SMAD4-negative CRC compared to that in SMAD4-positive CRC, and that both CXCL1 and CXCL8 were abundantly expressed in the tumor-infiltrating neutrophils. Neutrophils isolated from primary CRC expressed significantly higher levels of CXCL1 and CXCL8 than did those isolated from peripheral blood. Furthermore, tumor-infiltrating neutrophils expressed MMP2 and MMP9 in addition to ARG1 and IDO. Serum CXCL8 level was significantly higher in CRC patients, especially those at stage II/III, and statistical analysis indicated high CXCL8 level was associated with a shorter overall survival and relapse-free survival. Conclusions:Blockade of the CXCL1/8-CXCR2 axis could be a novel therapeutic approach against SMAD4-negative CRC.
http://bit.ly/2GeipWH
Transcriptional control of morphological properties of direction-selective T4/T5 neurons in Drosophila [RESEARCH ARTICLE]
In the Drosophila visual system, T4/T5 neurons represent the first stage of computation of the direction of visual motion. T4 and T5 neurons exist in four subtypes, each responding to motion in one of the four cardinal directions and projecting axons into one of the four lobula plate layers. However, all T4/T5 neurons share properties essential for sensing motion. How T4/T5 neurons acquire their properties during development is poorly understood. We reveal that the transcription factors SoxN and Sox102F control the acquisition of properties common to all T4/T5 neuron subtypes, i.e. the layer specificity of dendrites and axons. Accordingly, adult flies are motion blind after disruption of SoxN or Sox102F in maturing T4/T5 neurons. We further find that the transcription factors Ato and Dac are redundantly required in T4/T5 neuron progenitors for SoxN and Sox102F expression in T4/T5 neurons, linking the transcriptional programmes specifying progenitor identity to those regulating the acquisition of morphological properties in neurons. Our work will help to link structure, function and development in a neuronal type performing a computation that is conserved across vertebrate and invertebrate visual systems.
http://bit.ly/2Tps2FM
CDK5RAP3, a UFL1 substrate adaptor, is crucial for liver development [RESEARCH ARTICLE]
Protein modification by ubiquitin and ubiquitin-like proteins (UBLs) regulates numerous biological functions. The UFM1 system, a novel UBL conjugation system, is implicated in mouse development and hematopoiesis. However, its broad biological functions and working mechanisms remain largely elusive. CDK5RAP3, a possible ufmylation substrate, is essential for epiboly and gastrulation in zebrafish. Herein, we report a crucial role of CDK5RAP3 in liver development and hepatic functions. Cdk5rap3 knockout mice displayed prenatal lethality with severe liver hypoplasia, as characterized by delayed proliferation and compromised differentiation. Hepatocyte-specific Cdk5rap3 knockout mice suffered post-weaning lethality, owing to serious hypoglycemia and impaired lipid metabolism. Depletion of CDK5RAP3 triggered endoplasmic reticulum stress and activated unfolded protein responses in hepatocytes. We detected the in vivo interaction of CDK5RAP3 with UFL1, the defined E3 ligase in ufmylation. Notably, loss of CDK5RAP3 altered the ufmylation profile in liver cells, suggesting that CDK5RAP3 serves as a novel substrate adaptor for this UBL modification. Collectively, our study identifies CDK5RAP3 as an important regulator of ufmylation and suggests the involvement of ufmylation in mammalian development.
http://bit.ly/2BdopeN
Peri-arterial specification of vascular mural cells from naïve mesenchyme requires Notch signaling [RESEARCH ARTICLE]
Mural cells (MCs) are essential for blood vessel stability and function; however, the mechanisms that regulate MC development remain incompletely understood, in particular those involved in MC specification. Here, we investigated the first steps of MC formation in zebrafish using transgenic reporters. Using pdgfrb and abcc9 reporters, we show that the onset of expression of abcc9, a pericyte marker in adult mice and zebrafish, occurs almost coincidentally with an increment in pdgfrb expression in peri-arterial mesenchymal cells, suggesting that these transcriptional changes mark the specification of MC lineage cells from naïve pdgfrblow mesenchymal cells. The emergence of peri-arterial pdgfrbhigh MCs required Notch signaling. We found that pdgfrb-positive cells express notch2 in addition to notch3, and although depletion of notch2 or notch3 failed to block MC emergence, embryos depleted of both notch2 and notch3 lost mesoderm- as well as neural crest-derived pdgfrbhigh MCs. Using reporters that read out Notch signaling and Notch2 receptor cleavage, we show that Notch activation in the mesenchyme precedes specification into pdgfrbhigh MCs. Taken together, these results show that Notch signaling is necessary for peri-arterial MC specification.
http://bit.ly/2TkOtvE
The intestinal intermediate filament network responds to and protects against microbial insults and toxins [RESEARCH ARTICLE]
The enrichment of intermediate filaments in the apical cytoplasm of intestinal cells is evolutionarily conserved, forming a sheath that is anchored to apical junctions and positioned below the microvillar brush border, which suggests a protective intracellular barrier function. To test this, we used Caenorhabditis elegans, the intestinal cells of which are endowed with a particularly dense intermediate filament-rich layer that is referred to as the endotube. We found alterations in endotube structure and intermediate filament expression upon infection with nematicidal B. thuringiensis or treatment with its major pore-forming toxin crystal protein Cry5B. Endotube impairment due to defined genetic mutations of intermediate filaments and their regulators results in increased Cry5B sensitivity as evidenced by elevated larval arrest, prolonged time of larval development and reduced survival. Phenotype severity reflects the extent of endotube alterations and correlates with reduced rescue upon toxin removal. The results provide in vivo evidence for a major protective role of a properly configured intermediate filament network as an intracellular barrier in intestinal cells. This notion is further supported by increased sensitivity of endotube mutants to oxidative and osmotic stress.
http://bit.ly/2Beirum
Region-specific endodermal signals direct neural crest cells to form the three middle ear ossicles [RESEARCH ARTICLE]
Defects in the middle ear ossicles – malleus, incus and stapes – can lead to conductive hearing loss. During development, neural crest cells (NCCs) migrate from the dorsal hindbrain to specific locations in pharyngeal arch (PA) 1 and 2, to form the malleus-incus and stapes, respectively. It is unclear how migratory NCCs reach their proper destination in the PA and initiate mesenchymal condensation to form specific ossicles. We show that secreted molecules sonic hedgehog (SHH) and bone morphogenetic protein 4 (BMP4) emanating from the pharyngeal endoderm are important in instructing region-specific NCC condensation to form malleus-incus and stapes, respectively, in mouse. Tissue-specific knockout of Shh in the pharyngeal endoderm or Smo (a transducer of SHH signaling) in NCCs causes the loss of malleus-incus condensation in PA1 but only affects the maintenance of stapes condensation in PA2. By contrast, knockout of Bmp4 in the pharyngeal endoderm or Smad4 (a transducer of TGFβ/BMP signaling) in the NCCs disrupts NCC migration into the stapes region in PA2, affecting stapes formation. These results indicate that region-specific endodermal signals direct formation of specific middle ear ossicles.
http://bit.ly/2ToehXJ
IMP regulates Kuzbanian to control the timing of Notch signalling in Drosophila follicle cells [RESEARCH ARTICLE]
The timing of Drosophila egg chamber development is controlled by a germline Delta signal that activates Notch in the follicle cells to induce them to cease proliferation and differentiate. Here, we report that follicle cells lacking the RNA-binding protein IMP go through one extra division owing to a delay in the Delta-dependent S2 cleavage of Notch. The timing of Notch activation has previously been shown to be controlled by cis-inhibition by Delta in the follicle cells, which is relieved when the miRNA pathway represses Delta expression. imp mutants are epistatic to Delta mutants and give an additive phenotype with belle and Dicer-1 mutants, indicating that IMP functions independently of both cis-inhibition and the miRNA pathway. We find that the imp phenotype is rescued by overexpression of Kuzbanian, the metalloprotease that mediates the Notch S2 cleavage. Furthermore, Kuzbanian is not enriched at the apical membrane in imp mutants, accumulating instead in late endosomes. Thus, IMP regulates Notch signalling by controlling the localisation of Kuzbanian to the apical domain, where Notch cleavage occurs, revealing a novel regulatory step in the Notch pathway.
http://bit.ly/2BfeV2I
Distinct roles and requirements for Ras pathway signaling in visceral versus somatic muscle founder specification [RESEARCH ARTICLE]
Pleiotropic signaling pathways must somehow engender specific cellular responses. In the Drosophila mesoderm, Ras pathway signaling specifies muscle founder cells from among the broader population of myoblasts. For somatic muscles, this is an inductive process mediated by the ETS-domain downstream Ras effectors Pointed and Aop (Yan). We demonstrate here that for the circular visceral muscles, despite superficial similarities, a significantly different specification mechanism is at work. Not only is visceral founder cell specification not dependent on Pointed or Aop, but Ras pathway signaling in its entirety can be bypassed. Our results show that de-repression, not activation, is the predominant role of Ras signaling in the visceral mesoderm and that, accordingly, Ras signaling is not required in the absence of repression. The key repressor acts downstream of the transcription factor Lame duck and is likely a member of the ETS transcription factor family. Our findings fit with a growing body of data that point to a complex interplay between the Ras pathway, ETS transcription factors, and enhancer binding as a crucial mechanism for determining unique responses to Ras signaling.
http://bit.ly/2TkQ98A
Improving the visibility of developmental biology: time for induction and specification [SPOTLIGHT]
Developmental biology is a prominent field that has captured the imagination of many scientists. Over the years, research in the area has seen a steady number of amazing accomplishments, with peaks in activity following the development and application of new technologies. Although the field continues to flourish and produce excellent work, I have recently noticed difficulty with its perception and visibility. Having joined the developmental biology community during the early 1990s, and contributing since as a stem cell researcher, cancer biologist and an MD, I have a unique perspective on these challenges. Here, I discuss these issues and challenges and offer potential solutions for a field that is very important to me.
http://bit.ly/2BfeSE4
Characterization of Drosophila Nidogen/entactin reveals roles in basement membrane stability, barrier function and nervous system patterning [RESEARCH ARTICLE]
Basement membranes (BMs) are specialized layers of extracellular matrix (ECM) mainly composed of Laminin, type IV Collagen, Perlecan and Nidogen/entactin (NDG). Recent in vivo studies challenged the initially proposed role of NDG as a major ECM linker molecule by revealing dispensability for viability and BM formation. Here, we report the characterization of the single Ndg gene in Drosophila. Embryonic Ndg expression was primarily observed in mesodermal tissues and the chordotonal organs, whereas NDG protein localized to all BMs. Although loss of Laminin strongly affected BM localization of NDG, Ndg-null mutants exhibited no overt changes in the distribution of BM components. Although Drosophila Ndg mutants were viable, loss of NDG led to ultrastructural BM defects that compromised barrier function and stability in vivo. Moreover, loss of NDG impaired larval crawling behavior and reduced responses to vibrational stimuli. Further morphological analysis revealed accompanying defects in the larval peripheral nervous system, especially in the chordotonal organs and the neuromuscular junction (NMJ). Taken together, our analysis suggests that NDG is not essential for BM assembly but mediates BM stability and ECM-dependent neural plasticity during Drosophila development.
http://bit.ly/2TmNw60
Hippo signaling promotes lung epithelial lineage commitment by curbing Fgf10 and {beta}-catenin signaling [RESEARCH ARTICLE]
Organ growth and tissue homeostasis rely on the proliferation and differentiation of progenitor cell populations. In the developing lung, localized Fgf10 expression maintains distal Sox9-expressing epithelial progenitors and promotes basal cell differentiation in the cartilaginous airways. Mesenchymal Fgf10 expression is induced by Wnt signaling but inhibited by Shh signaling, and epithelial Fgf10 signaling activates β-catenin signaling. The Hippo pathway is a well-conserved signaling cascade that regulates organ size and stem/progenitor cell behavior. Here, we show that Hippo signaling promotes lineage commitment of lung epithelial progenitors by curbing Fgf10 and β-catenin signaling. Our findings show that both inactivation of the Hippo pathway (nuclear Yap) or ablation of Yap result in increased β-catenin and Fgf10 signaling, suggesting a cytoplasmic role for Yap in epithelial lineage commitment. We further demonstrate redundant and non-redundant functions for the two nuclear effectors of the Hippo pathway, Yap and Taz, during lung development.
http://bit.ly/2BcBXrg
Wnt produced by stretched roof-plate cells is required for the promotion of cell proliferation around the central canal of the spinal cord [RESEARCH ARTICLE]
Cell morphology changes dynamically during embryogenesis, and these changes create new interactions with surrounding cells, some of which are presumably mediated by intercellular signaling. However, the effects of morphological changes on intercellular signaling remain to be fully elucidated. In this study, we examined the effect of morphological changes in Wnt-producing cells on intercellular signaling in the spinal cord. After mid-gestation, roof-plate cells stretched along the dorsoventral axis in the mouse spinal cord, resulting in new contact at their tips with the ependymal cells that surround the central canal. Wnt1 and Wnt3a were produced by the stretched roof-plate cells and delivered to the cell process tip. Whereas Wnt signaling was activated in developing ependymal cells, Wnt activation in dorsal ependymal cells, which were close to the stretched roof plate, was significantly suppressed in embryos with roof plate-specific conditional knockout of Wls, which encodes a factor that is essential for Wnt secretion. Furthermore, proliferation of these cells was impaired in Wls conditional knockout mice during development and after induced spinal cord injury in adults. Therefore, morphological changes in Wnt-producing cells appear to generate new Wnt signal targets.
http://bit.ly/2TtEkwY
Genomic Resources for Goniozus legneri, Aleochara bilineata and Paykullia maculata, Representing Three Independent Origins of the Parasitoid Lifestyle in Insects
Parasitoid insects are important model systems for a multitude of biological research topics and widely used as biological control agents against insect pests. While the parasitoid lifestyle has evolved numerous times in different insect groups, research has focused almost exclusively on Hymenoptera from the Parasitica clade. The genomes of several members of this group have been sequenced, but no genomic resources are available from any of the other, independent evolutionary origins of the parasitoid lifestyle. Our aim here was to develop genomic resources for three parasitoid insects outside the Parasitica. We present draft genome assemblies for Goniozus legneri, a parasitoid Hymenopteran more closely related to the non-parasitoid wasps and bees than to the Parasitica wasps, the Coleopteran parasitoid Aleochara bilineata and the Dipteran parasitoid Paykullia maculata. The genome assemblies are fragmented, but complete in terms of gene content. We also provide preliminary structural annotations. We anticipate that these genomic resources will be valuable for testing the generality of findings obtained from Parasitica wasps in future comparative studies.
http://bit.ly/2RroKA5
Evaluation of InSeq To Identify Genes Essential for Pseudomonas aeruginosa PGPR2 Corn Root Colonization
The reciprocal interaction between rhizosphere bacteria and their plant hosts results in a complex battery of genetic and physiological responses. In this study, we used insertion sequencing (INSeq) to reveal the genetic determinants responsible for the fitness of Pseudomonas aeruginosa PGPR2 during root colonization. We generated a random transposon mutant library of Pseudomonas aeruginosa PGPR2 comprising 39,500 unique insertions and identified genes required for growth in culture and on corn roots. A total of 108 genes were identified as contributing to the fitness of strain PGPR2 on roots. The importance in root colonization of four genes identified in the TnSeq screen was verified by constructing deletion mutants in the genes and testing them for the ability to colonize corn roots singly or in competition with the wild type. All four mutants were affected in corn root colonization, displaying 5- to 100-fold reductions in populations in single inoculations, and all were outcompeted by the wild type by almost 100-fold after seven days on corn roots in mixed inoculations of the wild type and mutant. The genes identified in the screen had homology to genes involved in amino acid catabolism, stress adaptation, detoxification, signal transduction, and transport. INSeq technology proved a successful tool to identify fitness factors in P. aeruginosa PGPR2 for root colonization.
http://bit.ly/2WyjbDF
Changes in body weight, skeletal muscle and adipose tissue after gastrectomy: a comparison between proximal gastrectomy and total gastrectomy
The aim of this study was to clarify the advantage of proximal gastrectomy over total gastrectomy from a nutritional point of view. We analyse the changes in body weight and body composition after gastrectomy using a repeated measures analysis of variance.
Background
Proximal gastrectomy (PG) offers a well‐preserved digestive function after surgery, which may result in a better nutritional outcome in comparison to total gastrectomy (TG). The aim of this study was to clarify the advantage of PG over TG by evaluating the longitudinal changes in body weight (BW) and body composition after surgery.
Methods
A total of 112 patients undergoing PG with a reconstruction preserving food passage through the duodenum (n = 39) or TG with a reconstruction bypassing the duodenum (n = 73) for clinical stage IA gastric cancer were included. Changes in BW, psoas muscle and subcutaneous (SAT) and visceral adipose tissue were assessed before surgery, and at 1 and 3 years after surgery and were compared between the two groups.
Results
BW and SAT decreased significantly in both groups, but the rate of reduction was significantly lower in the PG group (P < 0.001 and P < 0.001, respectively). There were no significant differences between the groups with regard to skeletal muscle or visceral adipose tissue (P = 0.110 and 0.710, respectively), although they both significantly decreased throughout the course of the study.
Conclusions
The losses of BW and SAT were significantly smaller in the PG group. PG may be superior to TG in preserving BW and SAT in patients with clinical stage IA gastric cancer.
http://bit.ly/2BesijX
Vaginal microbiota transplantation for the treatment of bacterial vaginosis: A conceptual analysis
http://bit.ly/2G5LxjN
Effects of low-intensity and low-frequency ultrasound combined with tobramycin on biofilms of Extended-Spectrum Beta-Lactamases (ESBLs) Escherichia coli
http://bit.ly/2GetxTx
NCTN Assessment on Current Applications of Radiomics in Oncology
Radiomics is a fast-growing research area based on converting standard-of-care imaging into quantitative minable data and building subsequent predictive models to personalize treatment. It has been proposed as a study objective in clinical trial concepts and a potential biomarker for stratifying patients across interventional treatment arms. In recognizing the growing importance of radiomics in oncology a group of medical physicists and clinicians from NRG Oncology reviewed the current status of the field and identified critical issues, providing general assessment and early recommendations for incorporation in oncology studies.
http://bit.ly/2HKvw4l
Circadian rhythmicity as a predictor of quality of life in allogeneic hematopoietic cell transplant patients
Quality of life is increasingly recognized as an important outcome of cancer treatment. Previous studies have examined clinical predictors of quality of life, but with the increasing prevalence of wearable sensors that monitor sleep and activity patterns, further investigation into whether these behaviors are predictive of post-treatment quality of life is now feasible. Among patients receiving aggressive cancer treatment such as hematopoietic cell transplantation (HCT), analysis of circadian rhythms (24-hour patterns of sleep and activity) via wearable sensors is limited.
http://bit.ly/2DMkzel
Multidimensionality and Complexities of Fathering: A Critical Examination of Afro-Jamaican Fathers’ Perspectives
Abstract
Family socialization is integral to the development of well-adjusted children, and parenting by two parents provides important resources. For many families, children are socialized in contexts where their biological fathers are physically absent. Unfortunately, these children are regarded as fatherless in the literature and social commentary. Drawing on semi-structured interviews with 24 Afro-Jamaican fathers in a context with a high prevalence of single female-headed families, the current study explored fathers' perspectives on fathering presence/absence and their involvement. Thematic analysis from a social constructivist perspective revealed that children's experiences of being fathered are complex, involving biological and social fathering. Also, fatherlessness was regarded as the opposite of fathering whereby there was a lack of behavioral, affective, cognitive, and spiritual involvement. From fathers' own childhood experiences and being fathers themselves, they viewed the label as an inaccurate term. Rather, children may more likely experience levels of inadequate fathering or a lack of biological fathering. Moreover, complex factors including relationship dynamics and culture affect father involvement. The present findings highlight the need for policymakers and social activists to advocate for support programs for fathers and incentives to promote fathers' involvement rather than reinforcing inaccurate labels. Also, professionals working with families should promote social fathering.
http://bit.ly/2DNIfz9
Benefits of rhythm control and rate control in recent‐onset atrial fibrillation. the hermes‐af study
Abstract
Background
Although rhythm control has failed to demonstrate long‐term benefits over rate control in long‐standing episodes of atrial fibrillation (AF), there is little evidence concerning recent‐onset ones. We analyzed the benefits of rhythm and rate control in terms of symptoms alleviation and need for hospital admission in patients with recent‐onset AF.
Methods
This was a multicentre, observational, cross‐sectional study with prospective standardized data collection carried out in 124 Emergency Departments. Clinical variables, treatment effectiveness and outcomes (control of symptoms, final disposition) were analyzed in stable patients with recent‐onset AF consulting for AF‐related symptoms.
Results
Of 421 patients included, rhythm control was chosen in 352 patients (83.6%), global effectiveness of 84%. Rate control was performed in 69 patients (16.4%), and was achieved in 67 (97%) of them. Control of symptoms was achieved in 396 (94.1%) patients, and was associated with a heart rate after treatment ≤110 beats per minute (odds ratio [OR] 14.346, 95% confidence interval [CI] 3.90‐52.70, p<0.001) and a rhythm control strategy (OR 2.78, 95% CI 1.02‐7.61, p=0.046). Sixty patients (14.2%) were admitted: discharge was associated with a rhythm control strategy (OR 0.44, 95% CI 1.22‐4.76, p=0.031) and admission was associated with a heart rate >110 bpm after treatment (OR 0.03, 95% CI 0.008‐0.13, p<0.001) and acute heart failure (OR 9.45, 95% CI 2.91‐30.65, p<0.001).
Conclusion
In our study, recent‐onset AF patients in whom rhythm control was attempted in the Emergency Department had a high rate of symptoms' alleviation and a reduced rate of hospital admissions.
This article is protected by copyright. All rights reserved.
http://bit.ly/2Bc7NnZ
Construction and Use of an Electrical Stimulation Chamber for Enhancing Osteogenic Differentiation in Mesenchymal Stem/Stromal Cells In Vitro
http://bit.ly/2GdXtPp
Factors affecting quality of life in children and adolescents with hypermobile Ehlers‐Danlos syndrome/hypermobility spectrum disorders
Hypermobile Ehlers‐Danlos syndrome (hEDS) is a hereditary disorder of connective tissue, often presenting with complex symptoms can include chronic pain, fatigue, and dysautonomia. Factors influencing functional disability in the pediatric hEDS population are incompletely studied. This study's aims were to assess factors that affect quality of life in children and adolescents with hEDS. Individuals with hEDS between the ages 12–20 years and matched parents were recruited through retrospective chart review at two genetics clinics. Participants completed a questionnaire that included the Pediatric Quality of Life Inventory (PedsQL™), PedsQL Multidimentional Fatigue Scale, Functional Disability Inventory, Pain‐Frequency‐Severity‐Duration Scale, the Brief Illness Perception Questionnaire, measures of anxiety and depression, and helpful interventions. Survey responses were completed for 47 children and adolescents with hEDS/hypermobility spectrum disorder (81% female, mean age 16 years), some by the affected individual, some by their parent, and some by both. Clinical data derived from chart review were compared statistically to survey responses. All outcomes correlated moderately to strongly with each other. Using multiple regression, general fatigue and pain scores were the best predictors of the PedsQL total score. Additionally, presence of any psychiatric diagnosis was correlated with a lower PedsQL score. Current management guidelines recommend early intervention to prevent disability from deconditioning; these results may help identify target interventions in this vulnerable population.
http://bit.ly/2G0M0ng
Ectodermal dysplasias: Classification and organization by phenotype, genotype and molecular pathway
Abstract
An international advisory group met at the National Institutes of Health in Bethesda, Maryland in 2017, to discuss a new classification system for the ectodermal dysplasias (EDs) that would integrate both clinical and molecular information. We propose the following, a working definition of the EDs building on previous classification systems and incorporating current approaches to diagnosis: EDs are genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands. Genetic variations in genes known to be associated with EDs that affect only one derivative of the ectoderm (attenuated phenotype) will be grouped as non‐syndromic traits of the causative gene (e.g., non‐syndromic hypodontia or missing teeth associated with pathogenic variants of EDA "ectodysplasin"). Information for categorization and cataloging includes the phenotypic features, Online Mendelian Inheritance in Man number, mode of inheritance, genetic alteration, major developmental pathways involved (e.g., EDA, WNT "wingless‐type," TP63 "tumor protein p63") or the components of complex molecular structures (e.g., connexins, keratins, cadherins).
http://bit.ly/2GdUo1U
Probing The Structure And Dynamics Of Nucleosomes Using Atomic Force Microscopy Imaging
Here, we present a protocol to characterize nucleosome particles at the single-molecule level using static and time-lapse atomic force microscopy (AFM) imaging techniques. The surface functionalization method described allows for the capture of the structure and dynamics of nucleosomes in high-resolution at the nanoscale.
http://bit.ly/2HK6SRn
Simultaneous Electrocardiography Recording and Invasive Blood Pressure Measurement in Rats
http://bit.ly/2Sls83G
Oral Antibiotics Noninferior to IV for Bone, Joint Infection
THURSDAY, Jan. 31, 2019 -- For patients being treated for bone or joint infection, oral antibiotics are noninferior to intravenous antibiotics, according to a study published in the Jan. 31 issue of the New England Journal of Medicine. Ho-Kwong Li,...
http://bit.ly/2RYVt4B
Methotrexate Well Tolerated, Effective for Psoriasis in Chinese
THURSDAY, Jan. 31, 2019 -- Methotrexate is well tolerated and effective for psoriasis in a Chinese population and is more effective for those without psoriatic arthritis, according to a study published online Jan. 30 in JAMA Dermatology. Kexiang...
http://bit.ly/2S1MXC8
Symptom Combos Suggesting Laryngeal Cancer Identified
THURSDAY, Jan. 31, 2019 -- New symptom combinations that may indicate early symptoms of laryngeal cancer have been identified, according to a study published online Jan. 28 in the British Journal of General Practice. Elizabeth A. Shephard, Ph.D.,...
http://bit.ly/2CWGkXf
Liver Transplant Wait List May Not Prioritize High-Risk Patients
THURSDAY, Jan. 31, 2019 -- The current method for ranking patients on the liver transplantation wait list may not prioritize some of the sickest candidates, according to a study recently published online in Gastroenterology. Vinay Sundaram, M.D.,...
http://bit.ly/2CWwQeE
More High-Value Care Associated With Receipt of Primary Care
THURSDAY, Jan. 31, 2019 -- Receipt of primary care is associated with significantly more high-value care, slightly more low-value care, and a better health care experience, according to a study published online Jan. 28 in JAMA Internal...
http://bit.ly/2S0xJNJ
Management of MS in Pregnancy Reviewed in U.K. Guideline
THURSDAY, Jan. 31, 2019 -- It is important to discuss family planning and pregnancy proactively in women of childbearing age who have multiple sclerosis (MS), according to a review published online Jan. 5 in Practical Neurology. Ruth Dobson, Ph.D.,...
http://bit.ly/2CVq9JU
Medical Scribes Up Productivity for Emergency Medicine Doctors
THURSDAY, Jan. 31, 2019 -- Use of medical scribes in the emergency department improves physician productivity and reduces patient length of stay, according to a study published online Jan. 30 in The BMJ. Katherine Walker, M.B.Ch.B., from Cabrini...
http://bit.ly/2RXw5ME
Small Increase in HbA1c Seen With Switch to Human Insulin in T2DM
THURSDAY, Jan. 31, 2019 -- Switching from analogue to human insulin is associated with a small increase in hemoglobin A1c (HbA1c) levels, according to a study published in the Jan. 29 issue of the Journal of the American Medical Association. Jing...
http://bit.ly/2CXYg3X
Meta-Analysis: Small Weight Increase Seen for Breakfast Eaters
THURSDAY, Jan. 31, 2019 -- Eating breakfast may not be a good strategy for weight loss, according to research published online Jan. 30 in The BMJ. Katherine Sievert, from Monash University in Australia, and colleagues examined the effect of regular...
http://bit.ly/2RXXyOz
E-Cigarettes More Effective for Smoking Cessation
THURSDAY, Jan. 31, 2019 -- Electronic cigarettes are more effective for smoking cessation than nicotine replacement therapy, according to a study published online Jan. 30 in the New England Journal of Medicine. Peter Hajek, Ph.D., from the Queen...
http://bit.ly/2CUvMYS
Two-photon Imaging of Microglial Processes' Attraction Toward ATP or Serotonin in Acute Brain Slices
http://bit.ly/2MHhxuQ
Hybrid Printing for the Fabrication of Smart Sensors
http://bit.ly/2t03x6i
STING signalling protects against chronic pancreatitis by modulating Th17 response
Objective
Chronic pancreatitis (CP) is an inflammatory disease with progressive fibrosis leading to exocrine and endocrine dysfunction. Currently, there are no approved effective therapies for CP. Stimulator of interferon genes (STING) signalling is a key innate immune sensor of DNA. In this study, we evaluated the role of STING signalling in CP.
DesignWe used an experimental model of CP to test the effect of STING signalling in STING wild-type and knockout mice as well as bone marrow chimaeras (BMCs). STING was activated using a pharmacological agent. Since we found changes in Th17 cells, we used neutralising and control antibodies to determine the role of IL-17A. The effect of STING signalling was further explored in IL-17A generation and we examined the effect of IL-17A on pancreatic stellate cells (PSCs). Human pancreas from patients with CP and without CP were also stained for IL-17A.
ResultsSTING activation decreased CP-associated pancreatic inflammation and fibrosis, whereas absence of STING led to worsening of the disease. BMCs showed that leucocytes play an important role in STING signalling–mediated amelioration of experimental CP. STING deletion was associated with increased Th17 cell infiltration in the pancreas, whereas STING agonist limited this Th17 response. Importantly, anti-IL-17A antibody treatment mitigated the severity of CP in the absence of STING signalling. STING deficiency promoted Th17 polarisation and PSCs express functional IL-17 receptor by upregulating fibrosis genes. Compared with tumour margins, pancreas from patients with CP had significant increase in IL-17A+ cells.
ConclusionUnlike acute pancreatitis, STING activation is protective in CP. STING signalling is important in regulating adaptive immune responses by diminishing generation of IL-17A during CP and presents a novel therapeutic target for CP.
http://bit.ly/2MMYakg
Cancers, Vol. 11, Pages 162: PC 12 Pheochromocytoma Cell Response to Super High Frequency Terahertz Radiation from Synchrotron Source
Cancers, Vol. 11, Pages 162: PC 12 Pheochromocytoma Cell Response to Super High Frequency Terahertz Radiation from Synchrotron Source
Cancers doi: 10.3390/cancers11020162
Authors: Palalle G. Tharushi Perera Dominique R. T. Appadoo Samuel Cheeseman Jason V. Wandiyanto Denver Linklater Chaitali Dekiwadia Vi Khanh Truong Mark J. Tobin Jitraporn Vongsvivut Olha Bazaka Kateryna Bazaka Rodney J. Croft Russell J. Crawford Elena P. Ivanova
High frequency (HF) electromagnetic fields (EMFs) have been widely used in many wireless communication devices, yet within the terahertz (THz) range, their effects on biological systems are poorly understood. In this study, electromagnetic radiation in the range of 0.3–19.5 × 1012 Hz, generated using a synchrotron light source, was used to investigate the response of PC 12 neuron-like pheochromocytoma cells to THz irradiation. The PC 12 cells remained viable and physiologically healthy, as confirmed by a panel of biological assays; however, exposure to THz radiation for 10 min at 25.2 ± 0.4 °C was sufficient to induce a temporary increase in their cell membrane permeability. High-resolution transmission electron microscopy (TEM) confirmed cell membrane permeabilization via visualisation of the translocation of silica nanospheres (d = 23.5 ± 0.2 nm) and their clusters (d = 63 nm) into the PC 12 cells. Analysis of scanning electron microscopy (SEM) micrographs revealed the formation of atypically large (up to 1 µm) blebs on the surface of PC 12 cells when exposed to THz radiation. Long-term analysis showed no substantial differences in metabolic activity between the PC 12 cells exposed to THz radiation and untreated cells; however, a higher population of the THz-treated PC 12 cells responded to the nerve growth factor (NGF) by extending longer neurites (up to 0–20 µm) compared to the untreated PC12 cells (up to 20 µm). These findings present implications for the development of nanoparticle-mediated drug delivery and gene therapy strategies since THz irradiation can promote nanoparticle uptake by cells without causing apoptosis, necrosis or physiological damage, as well as provide a deeper fundamental insight into the biological effects of environmental exposure of cells to electromagnetic radiation of super high frequencies.
http://bit.ly/2Ur6fgM
Cancers, Vol. 11, Pages 157: Immunomagnetic-Enriched Subpopulations of Melanoma Circulating Tumour Cells (CTCs) Exhibit Distinct Transcriptome Profiles
Cancers, Vol. 11, Pages 157: Immunomagnetic-Enriched Subpopulations of Melanoma Circulating Tumour Cells (CTCs) Exhibit Distinct Transcriptome Profiles
Cancers doi: 10.3390/cancers11020157
Authors: Carlos Aya-Bonilla Elin Gray Jayapal Manikandan James Freeman Pauline Zaenker Anna Reid Muhammad Khattak Markus Frank Michael Millward Mel Ziman
Cutaneous melanoma circulating tumour cells (CTCs) are phenotypically and molecularly heterogeneous. We profiled the gene expression of CTC subpopulations immunomagnetic-captured by targeting either the melanoma-associated marker, MCSP, or the melanoma-initiating marker, ABCB5. Firstly, the expression of a subset of melanoma genes was investigated by RT-PCR in MCSP-enriched and ABCB5-enriched CTCs isolated from a total of 59 blood draws from 39 melanoma cases. Of these, 6 MCSP- and 6 ABCB5-enriched CTC fractions were further analysed using a genome-wide gene expression microarray. The transcriptional programs of both CTC subtypes included cell survival maintenance, cell proliferation, and migration pathways. ABCB5-enriched CTCs were specifically characterised by up-regulation of genes involved in epithelial to mesenchymal transition (EMT), suggesting an invasive phenotype. These findings underscore the presence of at least two distinct melanoma CTC subpopulations with distinct transcriptional programs, which may have distinct roles in disease progression and response to therapy.
http://bit.ly/2DLT70v
Establishment of a High-Yield Recombinant Adeno-Associated Virus/Human Bocavirus Vector Production System Independent of Bocavirus Nonstructural Proteins
Human Gene Therapy, Ahead of Print.
http://bit.ly/2Rt67f9
Pretreatment of rAAV-Mediated Expression of Myostatin Propeptide Lowers Type 2 Diabetes Incidence in C57BL/6 Mice on a High-Fat Diet
Human Gene Therapy, Ahead of Print.
http://bit.ly/2WwzII2
Ablation of Ischemic Ventricular Tachycardia Using a Multipolar Catheter and 3-dimensional Mapping System for High-density Electro-anatomical Reconstruction
With the following protocol, we provide an approach to Ventricular Tachycardia (VT) ablation using high density mapping with a multipolar catheter and 3D mapping system enhancing the success of the procedure.
http://bit.ly/2DKEfQ3
Physical and Chemical Compatibility of Extended-Release Triamcinolone Acetonide (TA-ER) with Common Local Anesthetics
Abstract
Introduction
Intra-articular (IA) corticosteroids are used extensively for the treatment of patients with knee osteoarthritis pain. In clinical practice, local anesthetics are frequently combined with corticosteroids prior to IA injection to provide rapid-onset analgesia. From this common practice there is no evidence to suggest that the addition of local anesthetics to corticosteroid preparations, including triamcinolone acetonide (TA), alters the physical properties or efficacy of the corticosteroid. Triamcinolone acetonide extended-release (TA-ER, formerly FX006) is a novel, microsphere-based TA formulation that demonstrated analgesic efficacy in phase 2 and 3 randomized controlled trials.
Methods
The current study assessed the compatibility of TA-ER and lidocaine, ropivacaine, and/or bupivacaine in vitro. The TA-ER and local anesthetic mixtures were assayed for changes in syringeability, pH, particle size, percentage free drug, purity, and appearance compared with TA-ER alone.
Results
By these measures, the combination of local anesthetics with TA-ER did not negatively impact the chemical or physical properties of TA-ER when compared to TA-ER controls.
Conclusion
These results demonstrate that lidocaine, bupivacaine, and ropivacaine are physically and chemically compatible with TA-ER, suggesting that local anesthetic solutions can be added to TA-ER preparations in clinical practice without adversely affecting TA-ER in vitro product characteristics.
Funding
Flexion Therapeutics, Inc.
http://bit.ly/2sWyclb
Doctoring and Hearing Loss
In treating hearing loss, I've found there's a particular tendency–especially in men losing their hearing in late middle age–for patients...
http://bit.ly/2RsViK3
Tonsillectomy: Tonsilliths, Pandas, and other great band names
I can't tell you how many times people at parties find out that I'm an ENT and have me look...
http://bit.ly/2Wut05q
Cost‐effectiveness of targeted screening for abdominal aortic aneurysm in siblings
Background
Population screening for abdominal aortic aneurysm (AAA) in 65‐year‐old men has been shown to be cost‐effective. A risk group with higher prevalence is siblings of patients with an AAA. This health economic model‐based study evaluated the potential cost‐effectiveness of targeted AAA screening of siblings.
Methods
A Markov model validated against other screening programmes was used. Two methods of identifying siblings were analysed: direct questioning of patients with an AAA (method A), and employing a national multigeneration register (method B). The prevalence was based on observed ultrasound data on AAAs in siblings. Additional parameters were extracted from RCTs, vascular registers, literature and ongoing screening. The outcome was cost‐effectiveness, probability of cost‐effectiveness at different willingness‐to‐pay (WTP) thresholds, reduction in AAA death, quality‐adjusted life‐years (QALYs) gained and total costs on a national scale.
Results
Methods A and B were estimated to reduce mortality from AAA, at incremental cost‐effectiveness ratios of €7800 (95 per cent c.i. 4627 to 12 982) and €7666 (5000 to 13 373) per QALY respectively. The probability of cost‐effectiveness was 99 per cent at a WTP of €23 000. The absolute risk reduction in AAA deaths was five per 1000 invited. QALYs gained were 27 per 1000 invited. In a population of ten million, methods A and B were estimated to prevent 12 and 17 AAA deaths, among 2418 and 3572 siblings identified annually, at total costs of €499 500 and €728 700 respectively.
Conclusion
The analysis indicates that aneurysm‐related mortality could be decreased cost‐effectively by applying a targeted screening method for siblings of patients with an AAA.
http://bit.ly/2DNDTIp
Cancers, Vol. 11, Pages 161: Synthetic Cannabinoids Influence the Invasion of Glioblastoma Cell Lines in a Cell- and Receptor-Dependent Manner.
Cancers, Vol. 11, Pages 161: Synthetic Cannabinoids Influence the Invasion of Glioblastoma Cell Lines in a Cell- and Receptor-Dependent Manner.
Cancers doi: 10.3390/cancers11020161
Authors: Hohmann Feese Greither Ghadban Jäger Dehghani Grabiec
The current treatment of glioblastoma is not sufficient, since they are heterogeneous and often resistant to chemotherapy. Earlier studies demonstrated effects of specific cannabinoid receptor (CB) agonists on the invasiveness of glioblastoma cell lines, but the exact mechanism remained unclear. Three human glioblastoma cell lines were treated with synthetic CB ligands. The effect of cannabinoids on microRNAs (miRs), Akt, and on the expression of proliferation and apoptosis markers were analyzed. Furthermore, in a model of organotypic hippocampal slice cultures cannabinoid mediated changes in the invasiveness were assessed. MicroRNAs and the activation of Akt which are related to cell migration, apoptosis, and proliferation were evaluated and found not to be associated with changes in the invasiveness after treatment with CB ligands. Also proliferation and/or apoptosis were not altered after treatment. The effects of cannabinoids on invasiveness could be blocked by the application of receptor antagonists and are likely mediated via CB1/CB2. In conclusion, our results suggest that cannabinoids can influence glioblastoma cell invasion in a receptor and cell type specific manner that is independent of proliferation and apoptosis. Thus, cannabinoids can potentially be used in the future as an addition to current therapy.
http://bit.ly/2TjYuJG
Ten years follow‐up retrospective study on implant survival rates and prevalence of peri‐implantitis in implant‐supported full‐arch rehabilitations
Abstract
Objectives
The aim of the present paper was to present medium‐ and long‐term data on implant survival and on the prevalence of peri‐implantitis in a cohort of patients treated with full‐arch rehabilitations.
Materials and methods
Clinical records of all patients treated with immediately loaded full‐arch rehabilitation in the Dental Clinic of the IRCCS Istituto Ortopedico Galeazzi in Milan, Italy supported by moderately rough implants were retrospectively examined to calculate survival curves for implant loss and for the occurrence of peri‐implantitis (both at implant‐ and at patient‐level). Regression methods were used to evaluate the correlation between the presence of periodontitis and smoking habits with the outcomes.
Results
A total of 384 implants placed in 77 patients (96 rehabilitations) were evaluated for a mean period of 8.0 years (range 1.0 ‐ 13.7 years) from loading. After 10 years the cumulative survival rate was 96.11% (95% CI 99.17% ‐ 93.05%) (84 implants) while the cumulative rate of implants free from peri‐implantitis was 86.92% (95% CI: 82.14%, 91.71%) (60.69% (95% CI: 44.19%, 77.19%) at patient‐level). The cumulative proportion of implants without peri‐implantitis after 10 years was significantly higher in mandible (89.76%, 95% CI: 84.49%, 95.03%) than in maxilla (81.71%, 95% CI: 71.91%, 91.51%) (P=0.028). No correlation was found between periodontal and smoking status and outcomes.
Conclusions
The study reported high 10‐year implant survival rate for full‐arch rehabilitations since implant loss was relatively rare. Peri‐implantitis was relatively frequent in the examined population although the number of subjects available for 10‐year evaluation was limited.
This article is protected by copyright. All rights reserved.
http://bit.ly/2Ghk9P3
Automating the Paris System for urine cytopathology—A hybrid deep‐learning and morphometric approach
Background
The Paris System for Urine Cytopathology (the Paris System) has succeeded in making the analysis of liquid‐based urine preparations more reproducible. Any algorithm seeking to automate this system must accurately estimate the nuclear‐to‐cytoplasmic (N:C) ratio and produce a qualitative "atypia score." The authors propose a hybrid deep‐learning and morphometric model that reliably automates the Paris System.
Methods
Whole‐slide images (WSI) of liquid‐based urine cytology specimens were extracted from 51 negative, 60 atypical, 52 suspicious, and 54 positive cases. Morphometric algorithms were applied to decompose images to their component parts; and statistics, including the NC ratio, were tabulated using segmentation algorithms to create organized data structures, dubbed rich information matrices (RIMs). These RIM objects were enhanced using deep‐learning algorithms to include qualitative measures. The augmented RIM objects were then used to reconstruct WSIs with filtering criteria and to generate pancellular statistical information.
Results
The described system was used to calculate the N:C ratio for all cells, generate object classifications (atypical urothelial cell, squamous cell, crystal, etc), filter the original WSI to remove unwanted objects, rearrange the WSI to an efficient, condensed‐grid format, and generate pancellular statistics containing quantitative/qualitative data for every cell in a WSI. In addition to developing novel techniques for managing WSIs, a system capable of automatically tabulating the Paris System criteria also was generated.
Conclusions
A hybrid deep‐learning and morphometric algorithm was developed for the analysis of urine cytology specimens that could reliably automate the Paris System and provide many avenues for increasing the efficiency of digital screening for urine WSIs and other cytology preparations.
http://bit.ly/2WtZBs6
De Novo PITX1 Expression Controls Bi-Stable Transcriptional Circuits to Govern Self-Renewal and Differentiation in Squamous Cell Carcinoma
Self-renewal and differentiation programs are critical determinants of tissue homeostasis and tumor growth. Sastre-Perona et al. identify a cancer-specific PITX1-, SOX2-, and TRP63-dependent transcriptional feed-forward circuit that governs self-renewal and squamous cell carcinoma growth as it inhibits KLF4-dependent differentiation.
http://bit.ly/2Rr0a25
EGFR-Aurka Signaling Rescues Polarity and Regeneration Defects in Dystrophin-Deficient Muscle Stem Cells by Increasing Asymmetric Divisions
Wang et al. found that EGFR-Aurka signaling in muscle stem cells acts to direct apicobasally oriented mitoses and asymmetric cell division. EGF treatment rescues the reduction of asymmetric divisions in dystrophin-deficient satellite cells in mdx mice, resulting in increased numbers of progenitors and enhanced regeneration.
http://bit.ly/2WrY1XP
Combination of MEK Inhibitor and the JAK2-STAT3 Pathway Inhibition for the Therapy of Colon Cancer
Abstract
The study aimed to investigate the reason of HCT116 cell resistance to MEK inhibitor, and the combination treatment effects of MEK inhibitor AZD6244 and JAK2/STAT3 inhibitor AG490 on colon cancer in vitro and in vivo, including cell viability, apoptosis, and explore the partial mechanisms focused on AZD6244 promoted the activation of JAK2-STAT3 pathways. In vitro, we examined the HCT116 cell viability by CCK8, cell apoptosis by flow cytometry; Western blot measured p-ERK, p-JAK2, p-STAT3 and STAT3 expression. In vivo, nude mice were subcutaneously injected by HCT116 cells. The tumor volume and weight were detected. HCT116 cell resistance to MEK inhibitor AZD6244, which inhibited the activation of ERK and promoted the activation of JAK2-STAT3 signaling. The combination treatment of AZD6244 and AG490 significantly inhibited cell viability and induced cell apoptosis, and completely inhibited the activation of ERK and JAK2-STAT3 signaling. Combination treatment of AZD6244 and AG490 had a stronger effect than that of AZD6244 as a monotherapy in vitro and in vivo. The treatment of AZD6244 on K-Ras mutations HCT116 cells promoted the activation of JAK2/STAT3 signaling. JAK2/STAT3 inhibitor AG490 synergistically increases effects of AZD6244 on colon cancer in vitro and in vivo. Collectively, these results provide a rationale for combining inhibitors of the JAK/STAT pathway and MEK inhibitors to reduce the potential impact of drug resistance.
http://bit.ly/2sWPLRZ
Opioid response in paediatric cancer patients and the Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene: an Italian study on 87 cancer children and a systematic review
Abstract
Background
Genetic polymorphisms in genes involved in pain modulation have been reported to be associated to opioid efficacy and safety in different clinical settings.
Methods
The association between COMT Val158Met polymorphism (rs4680) and the inter-individual differences in the response to opioid analgesic therapy was investigated in a cohort of 87 Italian paediatric patients receiving opioids for cancer pain (STOP Pain study). Furthermore, a systematic review of the association between opioid response in cancer patients and the COMT polymorphism was performed in accordance with the Cochrane Handbook and the Prisma Statement.
Results
In the 87 paediatric patients, pain intensity (total time needed to reach the lowest possible level) was significantly higher for G/G than A/G and A/A carriers (p-value = 0.042). In the 60 patients treated only with morphine, the mean of total dose to reach the same pain intensity was significantly higher for G/G than A/G and A/A carriers (p-value = 0.010). Systematic review identified five studies on adults, reporting that opioid dose (mg after 24 h of treatment from the first pain measurement) was higher for G/G compared to A/G and A/A carriers.
Conclusions
Present research suggests that the A allele in COMT polymorphism could be a marker of opioid sensitivity in paediatric cancer patients (STOP Pain), as well as in adults (Systematic Review), indicating that the polymorphism impact could be not age-dependent in the cancer pain context.
Trial registration
Registration number: CRD42017057831.
http://bit.ly/2BbB2r1
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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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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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