Developmental Psychobiology, EarlyView.
https://ift.tt/2Lj3Y3P
Δευτέρα 21 Μαΐου 2018
Prenatal predatory stress in a wild species of subterranean rodent: Do ecological stressors always have a negative effect on the offspring?
A Case of Pelvic Abscess Caused by Edwardsiella tarda followed by Laparoscopic Resection of a Hematoma Derived from Caesarean Section
Edwardsiella tarda (E. tarda) infections are rare and can be fatal. We report a case of an E. tarda abscess which developed in the hematoma originally derived from a caesarean section. A 24-year-old gravida 1 woman was admitted to our hospital with a complaint of abdominal pain. Approximately one month before her admission, pelvic hematoma had developed derived from caesarean section. Followed by the failure of conservative management, she underwent laparoscopic surgery to remove the hematoma 6 days before her admission. On computed tomography examination, we found that the abscess with a diameter of 9 cm was located in the right pelvic space. We punctured the abscess and identified E. tarda in the abscess. We continued administering antibiotics, but her symptoms, including fever and abdominal pain, became worse, and the abscess enlarged. We performed laparotomy drainage and ileocecal resection on the 10th posthospitalization day. After drainage surgery, the patient's condition improved gradually, and the patient was discharged uneventfully. There are no reports in patients of E. tarda infection during the perinatal period. E. tarda infection can be a life-threatening illness even in immunocompetent patients. In the case of E. tarda infection, intensive care and surgical procedures should be considered.
https://ift.tt/2IydZfw
FDA OKs Doptelet for Liver Disease Patients Undergoing Procedures
MONDAY, May 21, 2018 -- Doptelet (avatrombopag) has been approved by the U.S. Food and Drug Administration to treat adults with chronic liver disease who are slated to have a medical or dental procedure. Doptelet was evaluated in a pair of clinical...
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Cancers, Vol. 10, Pages 150: Determining the Radiation Enhancement Effects of Gold Nanoparticles in Cells in a Combined Treatment with Cisplatin and Radiation at Therapeutic Megavoltage Energies
Cancers, Vol. 10, Pages 150: Determining the Radiation Enhancement Effects of Gold Nanoparticles in Cells in a Combined Treatment with Cisplatin and Radiation at Therapeutic Megavoltage Energies
Cancers doi: 10.3390/cancers10050150
Authors: Celina Yang Kyle Bromma Wonmo Sung Jan Schuemann Devika Chithrani
Combined use of chemotherapy and radiation therapy is commonly used in cancer treatment, but the toxic effects on normal tissue are a major limitation. This study assesses the potential to improve radiation therapy when combining gold nanoparticle (GNP) mediated radiation sensitization with chemoradiation compared to chemoradiation alone. Incorporation of GNPs with 2 Gy, 6 MV (megavoltage) radiation resulted in a 19 ± 6% decrease in survival of MDA-MB-231 cells. Monte-Carlo simulations were performed to assess dosimetric differences in the presence of GNPs in radiation. The results show that physics dosimetry represents a small fraction of the observed effect. The survival fraction of the cells exposed to GNPs, cisplatin, and radiation was 0.16 ± 0.007, while cells treated with cisplatin and radiation only was 0.23 ± 0.011. The presence of GNPs resulted in a 30 ± 6% decrease in the survival, having an additive effect. The concentration of the GNPs and free drug used for this study was 0.3 and 435 nM, respectively. These concentrations are relatively lower and achievable in an in vivo setting. Hence, the results of our study would accelerate the incorporation of GNP-mediated chemoradiation into current cancer therapeutic protocols in the near future.
https://ift.tt/2GFm6Bg
"All my relations": experiences and perceptions of Indigenous patients connecting with Indigenous Elders in an inner city primary care partnership for mental health and well-being [Research]
BACKGROUND:
Mental health services in urban settings generally have not been adapted to serve the needs of Indigenous patients. We explored how patients' encounters with Indigenous Elders affected their overall mental health and well-being to identify therapeutic mechanisms underlying improvement.
METHODS:We conducted qualitative interviews of participants enrolled in a 6-month prospective mixed-methods evaluation of a program for mental health and well-being that featured the inclusion of Elders in the direct care of Indigenous patients in an inner city primary care clinic. Individual semistructured interviews were conducted to explore patients' experiences and perceptions of their participation in the Elders program.
RESULTS:We included 37 participants from at least 20 different First Nations. All but 1 participant described substantial benefits from their encounters with Elders, and none reported being negatively affected. Five overarching themes were identified: experiencing healing after prolonged periods of seeking and desperation; strengthening cultural identity and belonging; developing trust and opening up; coping with losses; and engaging in ceremony and spiritual dimensions of care as a resource for hope.
INTERPRETATION:Our evaluation illustrates that the Elders program was perceived by participants to have a broad range of positive impacts on their care and well-being. Although this study was based on experiences at a single urban clinic, these findings support the Truth and Reconciliation Commission of Canada's calls to action regarding the inclusion of Elders as a strategy to improve care of Indigenous patients in Canadian health care systems.
https://ift.tt/2s1VKUV
Excessive Erythrocytosis and Cardiovascular Risk in Andean Highlanders
High Altitude Medicine &Biology, Ahead of Print.
https://ift.tt/2KMhaNd
Comparison of anti-HBV regimen with or without adefovir on hepatocellular carcinoma development of Chronic hepatitis B patients with compensated cirrhosis: a retrospective cohort study
Abstract
Background
The impact of different anti-virus regimens on prognosis of Chronic hepatitis B (CHB) related cirrhosis remains to be explored. We aim to investigate whether CHB-related HCC patients receiving nucleoside analogue regimen or not have a different prognosis.
Methods
242 CHB-related compensated cirrhosis patients from 2008 June to 2011 December were included in our study and attributed into groups based on their anti-virus regimens containing adefovir (ADV) or not. The clinical parameters and virological response between ADV-containing regimen group and non-ADV containing regimen groups were reviewed and compared. The risk of hepatocellular carcinoma (HCC) development were analyzed and compared between two groups.
Results
127 patients received anti-virus regimen containing ADV and 115 patients received anti-virus regimen without ADV. The cumulative risk of HCC development among patients treated with ADV-contained therapy was significantly lower than that observed in patients with non-ADV-contained therapy (p<0.05). Multivariate analysis indicated that ADV-containing regimen treatment was significantly associated with lower probability of HCC development, (hazard ratio, 0.18; 95% confidence interval range, 0.07-0.45, p<0.05).
Conclusion
Both anti-virus regimens were effective in reducing serum HBV DNA. Regimen containing ADV decreased the incidence of HCC development in CHB patients with compensated cirrhosis.
https://ift.tt/2LgGY5c
Peg-manipulation capabilities of middle-aged adults have a greater influence on pegboard times than those of young and old adults
Abstract
Declines in manual dexterity are frequently quantified as the time it takes to complete the grooved pegboard test. The test requires individuals to manipulate 25 pegs, one at a time, by removing them from a well and inserting them into a prescribed hole. The manipulation of each peg involves four phases: selection, transport, insertion, and return. The purpose of our study was to compare the times to complete the four phases of peg manipulation and the forces applied to the pegboard during peg insertion as young, middle-aged, and old adults performed the grooved pegboard test. The relative significance of the peg-manipulation attributes for 30 young (24.0 ± 4.4 years), 15 middle-aged (46.5 ± 6.5 years), and 15 old (70.4 ± 4.0 years) adults was assessed with a multiple-regression analysis. The grooved pegboard test was performed on a force plate. Pegboard times for the old adults (81 ± 17 s) were longer than those for young (56 ± 7 s) and middle-aged (58 ± 11 s) adults. Regression analysis indicated that the explanatory variables for the pegboard times of young (R2 = 0.33) and middle-aged (R2 = 0.78) adults were the times for the peg insertion and return phases, whereas the predictors for old adults (R2 = 0.49) were the times for the peg selection and transport phases. The relative influence of peg-manipulation capabilities on a pegboard test of manual dexterity was greater for middle-aged adults than for young and old adults.
https://ift.tt/2KHFQ9Q
Modulation the crosstalk between tumor-associated macrophages and non-small cell lung cancer to inhibit tumor migration and invasion by ginsenoside Rh2
Abstract
Background
Tumor-associated macrophages (TAMs) play a critical role in modulating the tumor microenvironment and promote tumor metastases. Our studies have demonstrated that ginsenoside Rh2 (G-Rh2), a monomeric compound extracted from ginseng, is a promising anti-tumor agent in lung cancer cells. However, it remains unclear whetherG-Rh2 can modulate the differentiation of TAMs and its interaction with tumor microenvironment. In this study, we investigated how G-Rh2 regulates the phenotype of macrophages and affects the migration of non-small cell lung cancer (NSCLC) cells.
Methods
Murine macrophage-like RAW264.7 cells and human THP-1 monocyte were differentiated into M1 and M2 subsets of macrophages with different cytokines combination, which were further identified by flow cytometry with specific biomarkers. M2 macrophages were sorted out to co-culture with NSCLC cell lines, A549 and H1299. Wound healing assay was performed to examine the cell migration. Expression levels of matrix metalloproteinases 2 and 9 (MMP-2, − 9) and vascular endothelial growth factor-C (VEGF-C) were measured by RT-qPCR and western blot, and the release of VEGF in the supernatant was measured by a VEGF ELISA kit. Finally, modulation of TAMs phenotype and VEGF expression by G-Rh2 was examined in vivo.
Results
We demonstrated that M2 subset of macrophages alternatively differentiated from RAW264.7 or THP-1cells promote migration of NSCLC cells. Further examinations revealed that NSCLC significantly increased the release of VEGF to the media and elevated the expression levels of VEGF at mRNA and protein levels after being co-cultured with M2 macrophages. Similar alterations in MMP-2 and MMP-9 were observed in NSCLC after being co-cultured. Of note,G-Rh2 had a potential to effectively convert M2 phenotype to M1 subset of macrophages. Importantly, G-Rh2 had a preference to decrease the expression levels of VEGF, MMP2, and MMP9 in co-cultured lung cancer cells, over than those in lung cancer cells without co-culturing. Consistently, G-Rh2 reduced M2 macrophage marker CD206 and VEGF expression levels in vivo.
Conclusions
All of these results suggested that M2 subset macrophages drive lung cancer cells with more aggressive phenotypes. G-Rh2 has a potential to convert TAMs from M2 subset to M1 in the microenvironment and prevents lung cancer cell migration, suggesting the therapeutic effects of G-Rh2onlung cancer.
https://ift.tt/2IAWCXv
Outcomes of oesophageal self‐dilation for patients with refractory benign oesophageal strictures
Alimentary Pharmacology &Therapeutics, EarlyView.
https://ift.tt/2xaI7bR
The Impact of Hospital Costing Methods on Cost-Effectiveness Analysis: A Case Study
Abstract
Background
Several methods exist to cost hospital contacts when estimating the cost effectiveness of a new intervention. However, the implications of choosing a particular approach remain unclear. We compare the use of the three main diagnosis-related group (DRG)-based national unit costs in England to determine whether choice of approach can impact on economic evaluation results.
Methods
A cost-utility model was developed to compare secondary fracture prevention models of care for hip fracture patients, using data from large primary and hospital care administrative datasets in England. A healthcare and personal social services payer perspective was adopted, and utilities were informed by a meta-regression. Hospital resource use was valued using three DRG-based unit costs, and regression-based costing models were developed using data from 13,906 patients to inform the model health states.
Results
Finished consultant episode (FCE)-level reference costs resulted in the highest costs on admission (£9075) and in the year of the fracture (£14,440). Relative to FCE-level costs, spell-level tariffs led to the lowest total hospital care costs per patient within 1 year of fracture (− £3691) compared with spell-level reference costs (− £2106). At a £20,000/quality-adjusted life-year threshold, using spell-level reference costs or spell-level tariffs, the introduction of a nurse-led fracture liaison service model of care was the cost-effective alternative. However, using FCE-level reference costs, usual care was the cost-effective option.
Conclusions
Our results show that, conditional on the set of national unit costs adopted, the costs of hip fracture may vary considerably and different decisions may be reached regarding the introduction of new healthcare interventions.
https://ift.tt/2ken1Qb
Carbapenem-non-Susceptible Haemophilus influenzae with Penicillin-Binding Protein 3 containing Amino Acid Insertion [PublishAheadOfPrint]
Prevalence of β-lactamase-negative ampicillin-resistant Haemophilus influenzae (BLNAR) has become a clinical concern. In BLNAR, amino acid substitutions in penicillin-binding protein 3 (PBP3) are relevant to the β-lactam resistance. Carbapenem-non-susceptible H. influenzae isolates have been rarely reported. Through antimicrobial susceptibility testing and nucleotide sequence analysis of ftsI, encoding PBP3, and utilizing a collection of H. influenzae clinical isolates in our laboratory, we obtained a carbapenem-non-susceptible clinical isolate (NUBL1772) that possessed an altered PBP3 containing V525_N526insM. The aim of this study was to reveal the effect of altered PBP3 containing V525_N526insM on reduced carbapenem susceptibility. After generating recombinant strains with altered ftsI, we performed antimicrobial susceptibility testing and competitive binding assays with fluorescent penicillin (Bocillin FL) and carbapenems. Elevated carbapenem MICs were found for the recombinant strain harboring the entire ftsI gene of NUBL1772. The recombinant PBP3 of NUBL1772 also exhibited reduced binding to carbapenem. These results demonstrate that altered PBP3 containing V525_N526insM influences reduced carbapenem susceptibility. The revertant mutant lacking the V525_N526insM exhibited lower MICs of carbapenem than NUBL1772, suggesting that this insertion affects reduced carbapenem susceptibility. MICs of β-lactam for NUBL1772 was higher than those for the recombinant possessing ftsI of NUBL1772. NUBL1772 harbored AcrR with early termination, resulting in low-level transcription of acrB and high efflux pump activity. These findings suggest that the disruption of AcrR also contributes to the reduced carbapenem susceptibility found in NUBL1772. Our results provide the first evidence that the altered PBP3 containing V525_N526insM is responsible for reduced susceptibility to carbapenem in H. influenzae.
https://ift.tt/2IEG14Y
Molecular Analysis of a blaIMP-1-Harboring Class 3 Integron in Multidrug-Resistant Pseudomonas fulva [PublishAheadOfPrint]
A multidrug-resistant (MDR) Pseudomonas fulva was isolated in 2006 from a urine sample. The isolate harbored the blaIMP-1 gene, which was located in a chromosomal Tn402-like class 3 integron as a gene cassette array of aacA31-fosE-blaIMP-1. Two mutations in gyrA and one mutation in parC were detected in quinolone resistance-determining regions (QRDRs). We report a full-length, novel blaIMP-1-carrying class 3 integron. This integron and together with mutations in QRDRs could have influenced the MDR phenotypes.
https://ift.tt/2IA5JvD
Replacement by site-saturation mutagenesis of residue 119 in NDM-1 metallo-{beta}-lactamase: a kinetic study [PublishAheadOfPrint]
NDM-1 is a subclass B1 metallo-β-lactamase which exhibits a broad activity spectrum against β-lactam antibiotics. In this study we report the kinetic study of six Q119X variants obtained by site-directed mutagenesis on NDM-1. All Q119X variants were able to hydrolyze very efficiently carbapenems, penicillins and 1st, 2nd, 3rd and 4th generation cephalosporins. In particular, Q119E, Q119Y, Q119V and Q119K mutants showed an improvement of kcat/Km towards penicillins respect to NDM-1. The catalytic efficiency of Q119K variant is about 65- and 70-fold higher than that of NDM-1 for benzylpenicillin and carbenicillin, respectively. The Q119K and Q119Y enzymes have kcat/Km values for ceftazidime of about 25- and 89-fold higher than NDM-1.
https://ift.tt/2x2xk35
Clonal spread in Candida glabrata bloodstream isolates and fluconazole resistance affected by prolonged exposure: a 12-year single-center study in Belgium [PublishAheadOfPrint]
Candida glabrata is a major cause of candidemia in immunocompromised patients and is characterized by a high-level of fluconazole resistance. In the present study, acquisition of antifungal resistance and potential clonal spread of C. glabrata were explored at a single center over a 12-year period by analyzing 187 independent clinical C. glabrata bloodstream isolates. One strain was found to be micafungin resistant due to a mutation in the FKS2 gene. Fluconazole resistance remained stable throughout the period and was observed in 20 (10.7%) of the isolates. Analysis of the antifungal consumption data revealed that recent prior exposure to fluconazole increased the risk to be infected by a resistant strain. In particular, the duration of the treatment was significantly longer for patients infected by a resistant isolate while total and mean daily doses received did not impact the acquisition of resistance in C. glabrata. No link between genotype and resistance was found. However, multilocus variable-number tandem-repeat analyses indicated a potential intra-hospital spread of some isolates between patients. These isolates shared the same genetic profile and infected patients were hospitalized in the same unit during an overlapping period. Finally, quantitative real-time PCR analyses showed that, unlike other ABC efflux pumps, CgCDR1 was significantly more expressed in resistant strains, suggesting that it would be more involved in FLC resistance. Our study provides additional evidence that a proper administration of fluconazole is required to limit resistance and that strict hand hygiene is necessary to avoid possible spreading of C. glabrata isolates between patients.
https://ift.tt/2Livu1i
Translation elongation factor 4 (LepA) contributes to tetracycline susceptibility by stalling elongating ribosomes [PublishAheadOfPrint]
Even though elongation factor 4 (EF4) is the third most conserved protein in bacteria, its physiological functions remain largely unknown and its proposed molecular mechanisms are conflicting among previous studies. In the present study we show that growth of an Escherichia coli strain is more susceptible to tetracycline than its EF4 knockout strain. In consistence with previous studies, our results suggested that EF4 affects ribosome biogenesis when tetracycline is present. Through ribosome profiling analysis, we discovered that EF4 causes 1-nucleotide shifting of ribosomal footprints on mRNA when cells have been exposed to tetracycline. In addition, when tetracycline is present, EF4 inhibits the elongation of protein synthesis, which leads to the accumulation of ribosomes in the early segment of mRNA. Together, when cells are exposed to tetracycline, EF4 alters both ribosome biogenesis and the elongation phase of protein synthesis.
https://ift.tt/2x75vXI
Plasma and Intrapulmonary Concentrations of Cefepime and Zidebactam following Intravenous Administration of WCK 5222 to Healthy Adult Subjects [PublishAheadOfPrint]
WCK 5222 is a combination of cefepime and the novel beta-lactam enhancer zidebactam being developed for the treatment of serious Gram-negative infections. The objective of this study was to compare plasma (total), epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of cefepime and zidebactam in healthy adult subjects. The WCK 5222 dosing regimen was 2 grams cefepime/1 gram zidebactam administered as a 1-hour intravenous infusion every 8 hours for a total of 7 doses. Subjects were assigned to one bronchoalveolar lavage (BAL) sampling time at 0.5, 1.25, 3, 6, 8 or 10 hours after the seventh dose. Noncompartmental pharmacokinetic parameters were determined from serial plasma concentrations collected over an 8-hour and 10-hour interval following the first and seventh doses, respectively. Penetration ratios were calculated from the AUC0–8 for plasma, ELF and AM using mean and median concentrations at each BAL sampling time. Plasma Cmax and AUC of cefepime and zidebactam increased by 8% to 9% after the seventh versus first dose of WCK 5222. The respective AUC0-8 values based on mean concentrations for cefepime and zidebactam in ELF were 127.9 and 52.0 mg·h/liter, and 87.9 and 13.2 mg·h/liter in AM. The ELF to total plasma penetration ratios of cefepime and zidebactam based on mean AUC0-8 values were 0.39 and 0.38, respectively. The AM to total plasma ratios were 0.27 and 0.10, respectively. The observed plasma, ELF and AM concentrations of cefepime and zidebactam support studies of WCK 5222 for treatment of pneumonia caused by susceptible pathogens.
https://ift.tt/2IEQIZi
Interaction of Bacterial Phenazines with Colistimethate in Bronchial Epithelial Cells [PublishAheadOfPrint]
Multidrug-resistant bacterial infections are being increasingly treated in clinics with polymyxins, a class of antibiotics associated with adverse effects in the kidney, nervous system, or airways of a significant proportion of human and animal patients. Although many of the resistant pathogens display enhanced virulence, a hazard of cytotoxic interactions between polymyxin antibiotics and bacterial virulence factors (VFs) has not been assessed, to date. We report here on testing paired combinations of four Pseudomonas aeruginosa VF phenazine toxins, pyocyanin (PYO), 1-hydroxyphenazine (1-HP), phenazine-1-carboxylic acid (PCA), phenazine-1-carboxamide (PCN), and two commonly prescribed polymyxin drugs, colistimethate (CMS)/colistin and polymyxin B, in three human airway cell lines, BEAS-2B, HBE-1, and CFT-1. Cytotoxicities of individual antibiotics, toxins, and their combinations were evaluated by simultaneous measurement of mitochondrial metabolic, total transcriptional/translational, and the Nrf2 stress response regulator activities in treated cells. Two phenazines, PYO and 1-HP, were cytotoxic at clinically relevant concentrations (100-150 μM) and prompted a significant increase in the oxidative stress-induced transcriptional activity in surviving cells. The polymyxin antibiotics arrested the cell proliferation at clinically achievable (< 1 mM) concentrations, as well, with CMS displaying a surprisingly high cytotoxicity (ED50 = 180 μM) in BEAS-2B. The dose-response curves were probed by the median-effect analysis which established a synergistically enhanced cytotoxicity of the PYO/CMS combination in all three airway cell lines; a particularly strong effect was observed in the BEAS-2B cells, with the combination index (CI) = 0.27 at ED50. PCA, PCN, and 1-HP potentiated CMS cytotoxicity to a smaller extent. The cytotoxicity of CMS could be reduced with 10 mM N-acetyl-cysteine. Iron chelators, while ineffective against the polymyxins, could rescue all three bronchial epithelial cell lines treated with lethal PYO or CMS/PYO doses. These findings suggest further evaluations of CMS safety are needed, along with a search for means to moderate the potentially cytotoxic interactions.
https://ift.tt/2x2xhUX
Pharmacokinetics of piperaquine and safety profile of dihydroartemisinin-piperaquine co-administered with antiretroviral therapy in malaria-uninfected HIV-positive Malawian adults. [PublishAheadOfPrint]
There are limited data on the pharmacokinetic and safety profiles of dihydroartemisinin-piperaquine (DHA-PQ) among human immunodeficiency virus infected (HIV+) individuals taking antiretroviral therapy (ART). In a two step (parallel-group) pharmacokinetic trial with intensive blood sampling, we compared area under the concentration-time curve (AUC0-28 days) and safety outcomes of piperaquine among malaria-uninfected HIV+ adults. In step 1, half the adult dose of DHA-PQ was administered for three days as an intitial safety check in four groups (n=6/group) of HIV+ adults (age≥18 years): (i) antiretroviral-naïve, (ii) on nevirapine-based ART, (iii) on efavirenz-based ART, and (iv) on ritonavir-boosted lopinavir-based ART. In step 2, a full adult treatment course of DHA-PQ was administered to a different cohort of participants in three groups: (i) antiretroviral naïve, (ii) on efavirenz-based ART and (iii) on nevirapine-based ART (n=10-15/group). Ritonavir-boosted lopinavir-based ART group was dropped in step 2 due to limited number of participants who were on this second line ART and were eligible for recruitment. Piperaquine's AUC0-28 days in both steps was 43% lower among participants on efavirenz-based ART compared to ART naïve participants. There were no significant differences in AUC0-28 days between the other ART groups and the ART naïve group in each of the two steps. Furthermore, no differences in treatment-emergent clinical and laboratory adverse events were observed across the groups in steps 1 and 2. Although well tolerated at half and full standard adult treatment courses, efavirenz based antiretroviral regimen was associated with reduced piperaquine exposure which may compromise dihydroartemisinin-piperaquine's effectiveness in programmatic settings.
https://ift.tt/2Lgu8Uy
Evaluation of Telavancin Alone and Combined with Ceftaroline or Rifampin against Methicillin-Resistant Staphylococcus aureus (MRSA) in an in vitro Biofilm Model [PublishAheadOfPrint]
Biofilm-producing methicillin-resistant Staphylococcus aureus (MRSA) infections are challenging due to increasing antibiotic resistance. Synergistic activity of lipopeptides and lipoglycopeptides with β-lactams has been demonstrated for MRSA, but little is known about biofilm-embedded organisms. Our objective was to evaluate two telavancin (TLV) dosage regimens (7.5 mg/kg and 10 mg/kg q 24h)alone and in combination with ceftaroline (CPT) (600 mg q 8 h) or rifampin (RIF) (450 mg q 12h) against two biofilm-producing MRSA (494 and N315). Pharmacokinetic/pharmacodynamic CDC biofilm reactor models with polyurethane coupons were used to evaluate the efficacy of the antibiotic combinations over 72h. Overall, there were no significant differences observed between the two TLV dosing regimens either alone or in combination with RIF or CPT against these strains. Both TLV dosing regimens or CPT alone demonstrated killing but did not reach bactericidal reduction at 72h. However, both TLV regimens in combination with RIF demonstrated enhanced activity against both strains with a rapid decrease in CFU/ml at 4h that was bactericidal and maintained over the 72h experiment (- 3.75 log10CFU/ml from baseline; P <0.0001). Of interest, no enhanced activity was observed for TLV combined with CPT. No development of resistance was observed in any of the combination models. However, resistance to RIF developed as early as 24h with MIC values exceeding 32 mg/L. Our results show that TLV plus RIF displayed therapeutic improvement against biofilm-producing MRSA. These results suggest that the TLV 7.5 and 10mg/kg q24h are equally effective in eradicating biofilm-associated MRSA in vitro.
https://ift.tt/2IEQNs6
In vitro and in vivo activity of contezolid (MRX-I) against Mycobacterium tuberculosis [PublishAheadOfPrint]
The in vitro activity of contezolid (MRX-I) against clinical isolates of M. tuberculosis was evaluated using a microtiter broth dilution assay. MRX-I was as effective in vitro as linezolid (LZD). MRX-I and LZD were subsequently studied in BALB/c mice infected intranasally with M. tuberculosis Erdman. MRX-I and LZD at 100mg/kg significantly reduced the bacterial load in lungs compared to the untreated early and late controls.
https://ift.tt/2IBqsiP
In vivo and in vitro effects of a ClpP activating antibiotic against vancomycin resistant enterococci [PublishAheadOfPrint]
Antibiotics with novel bactericidal mechanisms of action are urgently needed. The antibiotic acyldepsipeptide 4 (ADEP4) activates the ClpP protease and causes cells to self-digest. The effects of ADEP4 and ClpP activation have not been sufficiently characterized for the enterococci, which are important pathogens known for high levels of acquired and intrinsic antibiotic resistance. In the present study, ADEP4 was found to be potently active against both Enterococcus faecalis and Enterococcus faecium with an MIC90 of 0.016 μg/ml and 0.031 μg/ml, respectively. ClpP purified from E. faecium was found to bind ADEP4 using surface plasmon resonance analysis and ClpP activation by ADEP4 was demonstrated biochemically with a β -casein digestion assay. In addition, E. faecium ClpP was crystallized in the presence of ADEP4, revealing ADEP4 binding to ClpP in the activated state. These results confirm that the anti-enterococcal activity of ADEP4 occurs through ClpP activation. In kill curves, ADEP4 was found to be bactericidal against stationary phase vancomycin resistant E. faecalis (VRE) strain V583, and resistance development was prevented when ADEP4 was combined with multiple classes of approved antibiotics. ADEP4 also eradicated mature VRE biofilms in combination with partnering antibiotics within 72 h of treatment. Biofilm killing with ADEP4 antibiotic combinations was superior to the clinically used combinations of ampicillin and gentamicin or ampicillin and daptomycin. In a murine peritoneal septicemia model, ADEP4 alone was as effective as ampicillin. ADEP4 co-administered with ampicillin was significantly more effective than either drug alone. These data suggest ClpP activating antibiotics may be useful for treating enterococcal infections.
https://ift.tt/2x0dhlT
The Inoculum Effect in the Era of Multidrug Resistance: Minor Differences in Inoculum Have Dramatic Effect on Minimal Inhibitory Concentration Determination [PublishAheadOfPrint]
The observed MIC may depend on the number of bacteria initially inoculated into the assay. This phenomenon is termed the inoculum effect (IE) and is often most pronounced for β-lactams in strains expressing β-lactamase enzymes. The Clinical and Laboratory Standards Institute (CLSI) recommended inoculum is 5 x 105 CFU mL-1 with an acceptable range of 2-8 x 105 CFU mL-1. IE testing is typically performed using an inoculum 100-fold greater than the CLSI recommended inoculum. Therefore, it remains unknown whether the IE influences MICs during testing performed according to CLSI guidelines. Here, we utilized inkjet printing technology to test the IE on cefepime, meropenem, and ceftazidime-avibactam. First, we determined that inkjet dispense volume correlated well with the number of bacteria delivered to microwells in two-fold (R2 = 0.99) or 1.1-fold (R2 = 0.98) serial dilutions. We then quantified the IE by dispensing orthogonal titrations of bacterial cells and antibiotics. For cefepime resistant and susceptible dose-dependent strains, a 2-fold increase in inoculum resulted in a 1.6 Log2-fold increase in MIC. For carbapenemase-producing strains, each 2-fold reduction in inoculum resulted in a 1.26 Log2-fold reduction in meropenem MIC. At the lower end of the CLSI allowable inoculum range, minor error rates of 34.8% were observed for meropenem when testing a resistant strain set. Ceftazidime-avibactam was not subject to an appreciable IE. Our results suggest that IE is sufficiently pronounced for meropenem and cefepime in multidrug-resistant Gram-negative pathogens to affect categorical interpretations during standard laboratory testing.
https://ift.tt/2IzmmYp
Incidences of Pseudomonas associated Ventilator-associated pneumonia within studies of respiratory tract applications of polymyxin: testing the Stoutenbeek concurrency postulates. [PublishAheadOfPrint]
Regimens containing topical polymyxin appear highly effective at preventing Ventilator-associated pneumonia (VAP) overall and more-so, gram negative VAP. However, Soutenbeek's postulates, that VAP incidences within studies of topical antibiotics would depend on the context of whether the component (control and intervention) groups of each study were concurrent versus non-concurrent, remain untested.
The literature was searched for concurrent control (CC) versus non-concurrent control (NCC) designed studies of respiratory tract applications of topical polymyxin to mechanically ventilated (MV) patients that reported Pseudomonas associated Ventilator-associated pneumonia (PsVAP) incidences. Studies of various interventions other than topical polymyxin (non-polymyxin studies) served to provide additional points of reference. The PsVAP incidences within the component groups of all studies were benchmarked against groups from observational studies. This was undertaken by meta-regression using generalized estimating equation methods. Dot plots, caterpillar plots and funnel plots enable visual benchmarking.
The PsVAP benchmark (and 95 % confidence interval) derived from 102 observational groups is 4.6 % (4.0-5.3 %). By contrast, the mean PsVAP within NCC polymyxin intervention groups (1.6 %; 1.0 – 4.5 %) is lower than all other component group categories. The mean PsVAP within CC polymyxin control groups (9.9 %; 7.6 – 12.8 %) is higher than all other component group categories.
The PsVAP incidences of control and intervention groups of studies of respiratory tract applications of polymyxin is dependent on whether the groups were within a concurrent versus non-concurrent study. Soutenbeek's concurrency postulates are validated.
https://ift.tt/2x0d4z7
The metabolism of piperaquine to its antiplasmodial metabolites and their pharmacokinetic profiles in healthy volunteers [PublishAheadOfPrint]
As a partner antimalarial for artemisinin drug-based combination therapy (ACT), piperaquine (PQ) can be metabolized into two major metabolites, including piperaquine N-oxide (M1) and N,N-dioxide (M2). To better understand the antimalarial potency of PQ, the antimalarial activity of PQ metabolites (M1 and M2) was studied in vitro (Plasmodium strains Pf3D7 and PfDd2) and in vivo (murine Plasmodium yoelii) in this study. The recrudescence and survival time of infected mice were also recorded after drug treatment. The pharmacokinetic profiles of PQ and its two metabolites (M1 and M2) were investigated in healthy subjects after oral doses of two widely used ACT regimens, i.e., Duo-Cotecxin (dihydroartemisinin plus piperaquine phosphate) and Artequick (artemisinin plus piperaquine). Remarkable antiplasmodial activity was found for PQ (IC50 4.5 nM against Pf3D7 and IC50 6.9 nM against PfDd2 strain; ED90 of 1.3 mg/kg), M1 (IC50 25.5 nM against Pf3D7 and IC50 38.7 nM against PfDd2 strain; ED90 of 1.3 mg/kg) and M2 (IC50 31.2 nM against Pf3D7 and IC50 33.8 nM against PfDd2 strain; ED90 of 2.9 mg/kg). Compared with PQ, M1 showed comparable efficacy, in terms of recrudescence and survival time, and M2 had relatively weaker antimalarial potency. PQ and its two metabolites displayed a long elimination half-life (~11 days for PQ, ~9 days for M1 and ~4 days for M2), and they accumulated after repeated administrations. The contribution of two PQ metabolites to the efficacy of piperaquine as a partner drug of ACT for the treatment of malaria should be considered for PQ dose optimization.
https://ift.tt/2LlyA4r
Oxidative Stress and First-Line Antituberculosis Drug-Induced Hepatotoxicity [PublishAheadOfPrint]
Hepatotoxicity induced by antituberculosis drugs is a serious adverse reaction with significant morbidity and even rarely mortality. This form of toxicity potentially impacts the treatment outcome of tuberculosis in some patients. Confining to first-line antituberculosis drugs, this review addresses whether and how oxidative stress, and more broadly, disturbance in redox homeostasis alongside mitochondrial dysfunction, may contribute to the hepatotoxicity induced by them. Risk factors for such toxicity that have been identified, in addition to genetic factors, principally include old age, malnutrition, alcoholism, chronic hepatitis C and chronic hepatitis B infection, HIV infection and pre-existing liver disease. Importantly, these comorbid conditions are associated with oxidative stress and beyond, per se. Thus, the shared pathogenetic mechanism(s) for liver injury might be in operation, due to disease-drug interaction. Our current ability to predict, prevent, or treat hepatotoxicity (other than removing potentially hepatotoxic drugs) remains limited. More translational research to unravel the pathogenesis, inclusive of the underlying molecular bases, regarding antituberculosis drug-induced hepatotoxicity is needed, and so is clinical research pertaining to the advances in therapy, with antioxidants and beyond. The role of pharmacogenetics in the clinical management of drug-induced hepatotoxicity also likely merits further evaluation.
https://ift.tt/2x08gdc
High Dose and Delayed Treatment with Bile Acids Ineffective in RML Prion-Infected Mice [PublishAheadOfPrint]
Prion diseases are a group of neurodegenerative diseases associated with the misfolding of the cellular prion protein (PrPC) into the infectious form (PrPSc). There are currently no treatments for prion disease. Bile acids have the ability to protect hepatocytes from apoptosis and are neuroprotective in animal models of other protein folding neurodegenerative diseases including Huntington's, Parkinson's, and Alzheimer's disease. Importantly, bile acids are approved for clinical use in patients with cirrhosis, and have recently been shown to be safe and possibly effective in pilot trials of patients with amyotrophic lateral sclerosis (ALS). We previously reported that the bile acid, ursodeoxycholic acid (UDCA), given early in disease, prolonged incubation periods in male RML-infected mice. Here we expand on this result to include tauro-ursodeoxycholic acid (TUDCA) treatment trials and delayed UDCA treatment. We demonstrate that, despite a high dose of TUDCA given early in disease, there was no significant difference in incubation periods between treated and untreated cohorts, regardless of sex. In addition, delayed treatment with a high dose of UDCA resulted in a significant shortening of the average survival time for both male and female mice when compared to their sex-matched controls, with evidence of increased BiP, a marker of apoptosis, in treated female mice. Our findings suggest that treatment with high dose TUDCA provides no therapeutic benefit and that delayed treatment with high dose UDCA is ineffective and could potentially worsen outcomes.
https://ift.tt/2IzwS1z
EUCAST Determination of olorofim (F901318) susceptibility of mould species, method validation and MICs [PublishAheadOfPrint]
Olorofim is a novel antifungal agent with in vitro activity against Aspergillus and some other moulds. Here we addressed technical aspects for EUCAST olorofim testing and generated contemporary MIC data.
EUCAST E.Def 9.3.1 testing was performed comparing two plate preparation methods (serial-dilution in medium (serial-plates) versus pre-dilution in DMSO (ISO-plates)), two lots of olorofim, visual (visual-MIC) versus spectrophotometer (spec-MIC) reading and four polystyrene plates using 34-53 Aspergillus isolates from five genera. Subsequently, olorofim MICs were compared to itraconazole, voriconazole, posaconazole and amphotericin B MICs for 298 clinical mould isolates (2016-2017). Wild-type upper limits (WT-UL) were determined following EUCAST principles for ECOFF setting.
Olorofim median MICs comparing serial-plates and ISO-plates were identical (25/36, 69%) or one dilution apart (11/36, 31%). Inter-person agreement for visual-MICs was 92-94%/100% for ≤1/≤2 dilutions, respectively. Visual-MICs across tested microtitre plates and olorofim lots revealed only discrete differences (≤1 dilution lower for treated plates). No single spec-MIC criteria was applicable to all species.
Olorofim MICs were low against 275 Aspergillus spp. isolates (modal-MIC=0.06 mg/L, MIC range <0.004-0.25 mg/L) and three dermatophytes (MICs 0.03-0.06 mg/L). MICs against Fusarium were diverse with full inhibition of F. proliferatum (MIC=0.016), 50% growth inhibition of Fusarium solani at 1-2 mg/L and no inhibition of F. dimerum.
Olorofim displayed potent in vitro activity against most mould isolates and was associated with limited variation in EUCAST susceptibility testing.
https://ift.tt/2x087Xc
Review of educational interventions to increase traditional birth attendants’ neonatal resuscitation self-efficacy
Publication date: Available online 21 May 2018
Source:Women and Birth
Author(s): Marvesh M. Mendhi, Kathleen B. Cartmell, Susan D. Newman, Shahirose Premji, Charlene Pope
BackgroundAnnually, up to 2.7 million neonatal deaths occur worldwide, and 25% of these deaths are caused by birth asphyxia. Infants born in rural areas of low-and-middle-income countries are often delivered by traditional birth attendants and have a greater risk of birth asphyxia-related mortality.AimThis review will evaluate the effectiveness of neonatal resuscitation educational interventions in improving traditional birth attendants' knowledge, perceived self-efficacy, and infant mortality outcomes in low-and-middle-income countries.MethodsAn integrative review was conducted to identify studies pertaining to neonatal resuscitation training of traditional birth attendants and midwives for home-based births in low-and-middle-income countries. Ten studies met inclusion criteria.FindingsMost interventions were based on the American Association of Pediatrics Neonatal Resuscitation Program, World Health Organization Safe Motherhood Guidelines and American College of Nurse-Midwives Life Saving Skills protocols. Three studies exclusively for traditional birth attendants reported decreases in neonatal mortality rates ranging from 22% to 65%. These studies utilized pictorial and oral forms of teaching, consistent in addressing the social cognitive theory. Studies employing skill demonstration, role-play, and pictorial charts showed increased pre- to post-knowledge scores and high self-efficacy scores. In two studies, a team approach, where traditional birth attendants were assisted, was reported to decrease neonatal mortality rate from 49–43/1000 births to 10.5–3.7/1000 births.ConclusionCulturally appropriate methods, such as role-play, demonstration, and pictorial charts, can contribute to increased knowledge and self-efficacy related to neonatal resuscitation. A team approach to training traditional birth attendants, assisted by village health workers during home-based childbirths may reduce neonatal mortality rates.
https://ift.tt/2s1tkLp
Clinically Relevant Cytotoxic Immune Cell Signatures and Clonal Expansion of T Cell Receptors in High-risk MYCN-not-amplified Human Neuroblastoma
Purpose: High-risk neuroblastoma is an aggressive disease. DNA sequencing studies have revealed a paucity of actionable genomic alterations and a low mutation burden, posing challenges to develop effective novel therapies. We used RNA sequencing (RNA-seq) to investigate the biology of this disease including a focus on tumor-infiltrating lymphocytes (TILs). Experimental Design: We performed deep RNA-seq on pre-treatment diagnostic tumors from 129 high-risk and 21 low- or intermediate-risk patients with neuroblastomas. We used single-sample gene set enrichment analysis to detect gene expression signatures of TILs in tumors and examined their association with clinical and molecular parameters including patient outcome. The expression profiles of 190 additional pre-treatment diagnostic neuroblastomas, a neuroblastoma tissue microarray, and T-cell receptor (TCR) sequencing were used to validate our findings. Results: We found that MYCN-not-amplified (MYCN-NA) tumors had significant higher cytotoxic TIL signatures compared to MYCN-amplified (MYCN-A) tumors. A reported MYCN-activation-signature was significantly associated with poor outcome for high-risk patients with MYCN-NA tumors; however, a subgroup of these patients who had elevated activated NK cells, CD8+ T-cells, and cytolytic signatures showed improved outcome and expansion of infiltrating T-cell receptor (TCR) clones. Furthermore, we observed up-regulation of immune exhaustion marker genes, indicating an immune suppressive microenvironment in these neuroblastomas. Conclusions: This study provides evidence that RNA signatures of cytotoxic TIL are associated with the presence of activated NK-/T-cells and improved outcomes in high-risk neuroblastoma patients harboring MYCN-NA tumors. Our findings suggest that these high-risk patients with MYCN-NA neuroblastoma may benefit from additional immunotherapies incorporated into the current therapeutic strategies.
https://ift.tt/2IFz5sI
Radiation followed by OX40 stimulation drives local and abscopal antitumor effects in an anti-PD1-resistant lung tumor model
Purpose: Radiation is used extensively to treat localized cancer, but improved understanding of its effects on the immune system have increased interest in its potential systemic (abscopal) effects, particularly in combination with checkpoint inhibitors such as anti-PD1. The majority of patients either do not respond or develop resistance to monotherapy over time. Here, we investigated the efficacy of OX40 (CD134) stimulation as an alternative immunotherapeutic approach in combination with radiotherapy (XRT) in a murine model of anti-PD1-resistant lung tumors. Experimental Design: We established a bilateral tumor model in 129Sv/Ev mice using an anti-PD1 resistant lung tumor cell line. Primary tumors were treated with intratumoral injection of an OX40 agonist antibody, given as adjuvant therapy after XRT (36 Gy in three 12-Gy fractions), while secondary tumors were left untreated to investigate abscopal outcomes. Results: The combination of XRT followed by OX40 stimulation effectively inhibited local and systemic antitumor growth, limited lung metastases, and improved survival rates. This treatment regimen augmented CD4+ and CD8+ T cell expansion. XRT induced the expression of OX40 on T cells in tumors and spleens and increased the percentages of splenic CD103+ dendritic cells. Conclusion: Our data extends the benefits of radiation to systemic disease control, especially when combined with anti-OX40 agonist to promote immunologically mediated abscopal effects. Moreover, this study provides a rational treatment approach and sequence to overcome anti-PD1 resistant poorly immunogenic tumors.
https://ift.tt/2x0kmD5
Molecular subtype-specific immunocompetent models of high-grade urothelial carcinoma reveal differential neoantigen expression and response to immunotherapy
High-grade urothelial cancer contains intrinsic molecular subtypes that exhibit differences in underlying tumor biology and can be divided into luminal-like and basal-like subtypes. We describe here the first subtype-specific murine models of bladder cancer and show that Upk3a-CreERT2; Trp53L/L; PtenL/L; Rosa26LSL-Luc (UPPL: luminal-like) and BBN (basal-like) tumors are more faithful to human bladder cancer than the widely-used MB49 cells. Following engraftment into immunocompetent C57BL/6 mice, BBN tumors were more responsive to PD-1 inhibition than UPPL tumors. Responding tumors within the BBN model showed differences in immune microenvironment composition, including increased ratios of CD8+:CD4+ and memory:regulatory T cells. Finally, we predicted and confirmed immunogenicity of tumor neoantigens in each model. These UPPL and BBN models will be a valuable resource for future studies examining bladder cancer biology and immunotherapy.
https://ift.tt/2rZ9lNv
Patterns of Potential Misuse Help Assess Risk of Opioid Overdose
MONDAY, May 21, 2018 -- Patterns of potential opioid misuse are positively associated with subsequent opioid overdose, according to a study published online May 22 in the Annals of Internal Medicine. In an observational study, Colleen M. Carey,...
https://ift.tt/2GDCD8E
FDA OKs Doptelet for Liver Dz Patients Undergoing Procedures
MONDAY, May 21, 2018 -- Doptelet (avatrombopag) has been approved by the U.S. Food and Drug Administration to treat adults with chronic liver disease who are slated to have a medical or dental procedure. Doptelet was evaluated in a pair of clinical...
https://ift.tt/2IzS8o5
Bioengineering Feasible for Airway Reconstruction
MONDAY, May 21, 2018 -- Airway bioengineering appears feasible for tracheal and bronchial reconstruction, according to a study published online May 20 in the Journal of the American Medical Association to coincide with the American Thoracic...
https://ift.tt/2GC8xlX
Slower Decline in Lung Function With Anthocyanin Intake
MONDAY, May 21, 2018 -- Anthocyanin intake is associated with slower decline in lung function, according to a study presented at the American Thoracic Society's 2018 International Conference, held from May 18 to 23 in San Diego. Vanessa...
https://ift.tt/2kdegpF
Nurses' Overtime Can Negatively Impact Collaborative Practice
MONDAY, May 21, 2018 -- Working overtime may negatively influence nurses' collaboration with other health care providers in the acute care setting, according to a study published online May 4 in the Journal of Nursing Administration. Chenjuan Ma,...
https://ift.tt/2s0IO1u
SWATHHM-Based Metabolomics of Follicular Fluid in Patients Shows That Progesterone Adversely Affects Oocyte Quality
Objective. We reveal the relationship between progesterone level in follicular fluid and oocyte quality based on sequential window acquisition of all theoretical fragment-ion spectra (SWATH™), a powerful high-resolution mass spectrometric data independent acquisition technique. Method. Follicular fluid samples were collected from 22 subjects (the level of progesterone > 1.5 ng/mL) of progesterone group, as well as from 22 subjects (the level of progesterone
https://ift.tt/2KM2VID
The Biological Activities of Vitamin D and Its Receptor in Relation to Calcium and Bone Homeostasis, Cancer, Immune and Cardiovascular Systems, Skin Biology, and Oral Health
Vitamin D plays an important role in calcium homeostasis and bone metabolism, with the capacity to modulate innate and adaptive immune function, cardiovascular function, and proliferation and differentiation of both normal and malignant keratinocytes. 1,25(OH)2D, the biologically active form of vitamin D, exerts most of its functions through the almost universally distributed nuclear vitamin D receptor (VDR). Upon stimulation by 1,25(OH)2D, VDR forms a heterodimer with the retinoid X receptor (RXR). In turn, VDR/RXR binds to DNA sequences termed vitamin D response elements in target genes, regulating gene transcription. In order to exert its biological effects, VDR signalling interacts with other intracellular signalling pathways. In some cases 1,25(OH)2D exerts its biological effects without regulating either gene expression or protein synthesis. Although the regulatory role of vitamin D in many biological processes is well documented, there is not enough evidence to support the therapeutic use of vitamin D supplementation in the prevention or treatment of infectious, immunoinflammatory, or hyperproliferative disorders. In this review we highlight the effects of 1,25(OH)2D on bone and calcium homeostasis, on cancer, and refer to its effects on the cardiovascular and immune systems.
https://ift.tt/2rYSESb
Effect of Camphorquinone Concentration in Physical-Mechanical Properties of Experimental Flowable Resin Composites
The aim of this study was to evaluate the effect of camphorquinone concentration in physical-mechanical properties of experimental flowable composites in order to find the concentration that results in maximum conversion, balanced mechanical strength, and minimum shrinkage stress. Model composites based on BISGMA/TEGDMA with 70% wt filler loading were prepared containing different concentrations of camphorquinone (CQ) on resin matrix (0.25%, 0.50%, 1%, 1.50%, and 2% by weight). Degree of conversion was determined by FTIR. Surface hardness was assessed before and after 24 h ethanol storage and softening rate was determined. Depth of cure was determined by Knoop hardness evaluation at different depths. Color was assessed by reflectance spectrophotometer, employing the CIE-Lab system. Flexural strength and elastic modulus were determined by a three-point bending test. Shrinkage stress was determined in a Universal Testing Machine in a high compliance system. Data were submitted to ANOVA and Tukey's test (α = 0.05). The increase in CQ concentration caused a significant increase on flexural strength and luminosity of composites. Surface hardness was not affected by the concentration of CQ. Composite containing 0.25% wt CQ showed lower elastic modulus and shrinkage stress when compared to others. Depth of cure was 3 mm for composite containing 1% CQ and 2 mm for the other tested composites. Degree of conversion was inversely correlated with softening rate and directly correlated with elastic modulus and shrinkage stress. In conclusion, CQ concentration affects polymerization characteristics and mechanical strength of composites. The concentration of CQ in flowable composite for optimized polymerization and properties was 1% wt of the resin matrix, which allows adequate balance among degree of conversion, depth of cure, mechanical properties, and color characteristics of these materials.
https://ift.tt/2KM2OwH
Inflammatory bowel disease increases the risk of Parkinsons disease: a Danish nationwide cohort study 1977-2014
Objective
Intestinal inflammation has been suggested to play a role in development of Parkinson's disease (PD) and multiple system atrophy (MSA). To test the hypothesis that IBD is associated with risk of PD and MSA, we performed a nationwide population-based cohort study.
DesignThe cohort consisted of all individuals diagnosed with IBD in Denmark during 1977–2014 (n=76 477) and non-IBD individuals from the general population, who were comparable in terms of gender, age and vital status (n=7 548 259). All cohort members were followed from IBD diagnosis/index date to occurrence of PD and MSA (according to the Danish National Patient Register).
ResultsPatients with IBD had a 22% increased risk of PD as compared with non-IBD individuals (HR=1.22; 95% CI 1.09 to 1.35). The increased risk was present independently of age at IBD diagnosis, gender or length of follow-up. The overall incidence of MSA was low in our study, and the regression analysis suggested a tendency towards higher risk of developing MSA in patients with IBD as compared with non-IBD individuals (HR=1.41; 95% CI 0.82 to 2.44). Estimates were similar for women and men. The increased risk of parkinsonism was significantly higher among patients with UC (HR=1.35; 95% CI 1.20 to 1.52) and not significantly different among patients with Crohn's disease (HR=1.12; 95% CI 0.89 to 1.40).
ConclusionsThis nationwide, unselected, cohort study shows a significant association between IBD and later occurrence of PD, which is consistent with recent basic scientific findings of a potential role of GI inflammation in development of parkinsonian disorders.
https://ift.tt/2wZwLae
Childbirth after adolescent and young adult cancer: a population-based study
Abstract
Purpose
Annually, > 45,000 US women are diagnosed with cancer during adolescence and young adulthood (AYA). Since 2006, national guidelines have recommended fertility counseling for cancer patients. We examined childbirth after AYA cancer by calendar period, cancer diagnosis, and maternal characteristics.
Methods
We identified a cohort of women with an incident invasive AYA cancer diagnosis at ages 15–39 during 2000–2013 in North Carolina. Cancer records were linked with statewide birth certificates through 2014. Hazard ratios (HR) and 95% confidence intervals (CI) for first post-diagnosis live birth were calculated using Cox proportional hazards regression.
Results
Among 17,564 AYA cancer survivors, 1989 had ≥ 1 birth after diagnosis during 98,397 person-years. The 5- and 10-year cumulative incidence of live birth after cancer was 10 and 15%, respectively. AYA survivors with a post-diagnosis birth were younger at diagnosis, had lower stage disease, and had less often received chemotherapy than those without a birth. The 5-year cumulative incidence of post-diagnosis birth was 10.0% for women diagnosed during 2007–2012, compared to 9.4% during 2000–2005 (HR = 1.01; 0.91, 1.12), corresponding to periods before and after publication of American Society of Clinical Oncology fertility counseling guidelines in 2006.
Conclusions
Despite advances in fertility preservation options and recognition of fertility counseling as a part of high-quality cancer care, the incidence of post-diagnosis childbirth has remained stable over the last 15 years.
Implications for Cancer Survivors
Our study uses statewide data to provide recent, population-based estimates of how often AYA women have biological children after a cancer diagnosis.
https://ift.tt/2rXIj91
TOTALLY LAPAROSCOPIC, MULTI-STAGE, RESTORATIVE PROCTOCOLECTOMY FOR INFLAMMATORY BOWEL DISEASES. A PROSPECTIVE STUDY ON SAFETY, EFFICACY AND LONG-TERM RESULTS
Laparoscopic ileo-pouch-anal anastomosis (IPAA) has been reported as having low morbidity and several advantages.
https://ift.tt/2KHvmHo
Dialysis Without Borders
The study by Cervantes and colleagues in this issue is the first to provide empirical evidence about the effects of emergency-only hemodialysis (EOHD) on professionalism. The editorialist discusses the findings, draws parallels between providing standard dialysis to undocumented immigrants and providing universal health coverage to U.S. citizens, and proposes an approach to address the problem of EOHD.
https://ift.tt/2wZoYt0
https://ift.tt/2wZoYt0
Patterns of Potential Opioid Misuse and Subsequent Adverse Outcomes in Medicare, 2008 to 2012
Background:
Providers are increasingly being expected to examine their patients' opioid treatment histories before writing new opioid prescriptions. However, little evidence exists on how patterns of potential opioid misuse are associated with subsequent adverse outcomes nationally. Objective:
To estimate how a range of patterns of potential opioid misuse relate to adverse outcomes during the subsequent year. Design:
Observational study comparing outcomes for Medicare enrollees with potential opioid misuse patterns versus those for beneficiaries with no such patterns, adjusting for patient characteristics. Setting:
Medicare, 2008 to 2012. Patients:
A 5% sample of beneficiaries who had an opioid prescription without a cancer diagnosis. Measurements:
Several measures for opioid misuse were defined on the basis of drug quantity, overlapping prescriptions, use of multiple prescribers or pharmacies, and use of out-of-state prescribers or pharmacies. The primary outcome was a diagnosis of opioid overdose in the year after a 6-month index period. Secondary outcomes included subsequent opioid-related or overall mortality. Results:
Overall, 0.6% to 8.5% of beneficiaries fulfilled a misuse measure. Subsequent opioid overdose was positively associated with successively greater numbers of prescribers or pharmacies or higher opioid quantities during the index period. For example, patients who obtained opioids from 2, 3, or 4 prescribers were increasingly more likely to have an opioid overdose (adjusted absolute risk per 1000 beneficiary-years [aAR], 3.5 [95% CI, 3.3 to 3.7]; 4.8 [CI, 4.5 to 5.2]; or 6.4 [CI, 5.8 to 6.9], respectively) than those with a single prescriber (aAR, 1.9 [CI, 1.8 to 2.0]). Subsequent overdose risk increased meaningfully with any deviation in the single prescriber–single pharmacy opioid use pattern. All misuse measures examined had a positive association with subsequent opioid overdose and death. Limitation:
Risk estimates provide measures of association and may not generalize to non-Medicare populations. Conclusion:
To fully assess patients' opioid overdose risk, clinicians should examine a wide range of misuse patterns. Primary Funding Source:
National Institutes of Health.https://ift.tt/2kbM3zE
Amyloid-β (1-40) and Mortality in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome A Cohort Study
Background:
Amyloid-β (1-40) (Aβ40) is implicated in mechanisms related to plaque destabilization and correlates with adverse outcomes in stable coronary artery disease. Objective:
To determine the prognostic and reclassification value of baseline circulating levels of Aβ40 after adjustment for the Global Registry of Acute Coronary Events (GRACE) score, which is widely recommended for risk stratification in non–ST-segment elevation acute coronary syndrome (NSTE-ACS). Design:
Retrospective cohort study using data from 2 independent prospective cohorts, the Heidelberg study (n = 1145) and the validation multicenter international APACE (Advantageous Predictors of Acute Coronary Syndrome Evaluation) study (n = 734). Setting:
Academic hospitals in 7 European countries. Participants:
Patients with adjudicated NSTE-ACS followed for a median of 21.9 and 24.9 months in the Heidelberg and APACE studies, respectively. Measurements:
All-cause mortality was the primary end point. Results:
Amyloid-β (1-40) was associated with mortality after multivariate adjustment for age, sex, diabetes mellitus, high-sensitivity cardiac troponin T and C-reactive protein, revascularization, and ACS type (Heidelberg cohort hazard ratio [HR] for 80th vs. 20th percentiles, 1.66 [95% CI, 1.06 to 2.61; P = 0.026]; APACE cohort HR, 1.50 [CI, 1.15 to 1.96; P = 0.003]). It was also associated with mortality after adjustment for the GRACE score (Heidelberg cohort HR for 80th vs. 20th percentiles, 1.11 [CI, 1.04 to 1.18; P = 0.001]; APACE cohort HR, 1.39 [CI, 1.02 to 1.88; P = 0.036]). Amyloid-β (1-40) correctly reclassified risk for death over the GRACE score (net reclassification index, 33.4% and 47.1% for the Heidelberg and APACE cohorts, respectively) (P < 0.05). Limitation:
At low concentrations of Aβ40, dose–response associations with mortality differed between cohorts, possibly because of varying blood preparations used to measure Aβ40. Conclusion:
Circulating Aβ40 is a predictor of mortality and improves risk stratification of patients with NSTE-ACS over the GRACE score recommended by clinical guidelines. The clinical application of Aβ40 as a novel biomarker in NSTE-ACS should be further explored and validated. Primary Funding Source:
German Cardiac Society.https://ift.tt/2s0xQZS
Toward Better Stewardship: Gaining Control Over Controlled Substances
Carey and colleagues report a study examining the relationship between various opioid prescription patterns and opioid overdose and all-cause mortality. The editorialists discuss the findings and the need to improve prescription drug monitoring programs to better serve the needs of prescribers and, in turn, the patients to whom they provide care.
https://ift.tt/2IVLiIZ
https://ift.tt/2IVLiIZ
Guidelines Versus Guidelines: What's Best for the Patient?
This commentary by expert clinicians counters some of the recommendations regarding hemoglobin A1c targets for type 2 diabetes that were proposed in a recent American College of Physicians guideline.
https://ift.tt/2x74qie
https://ift.tt/2x74qie
Clinicians' Perspectives on Providing Emergency-Only Hemodialysis to Undocumented Immigrants A Qualitative Study
Background:
In the United States, nearly half of undocumented immigrants with end-stage kidney disease receive hemodialysis only when they are evaluated in an emergency department and are found to have life-threatening renal failure ("emergency-only hemodialysis" [EOHD]). These patients experience psychosocial distress and much higher mortality than patients receiving regularly scheduled hemodialysis, but little is known about how providing EOHD affects the clinicians involved. Objective:
To understand clinicians' experiences providing EOHD. Design:
Qualitative study using semistructured interviews. Setting:
A safety-net hospital in Denver, Colorado, and a safety-net system in Houston, Texas. Participants:
Fifty interdisciplinary clinicians experienced in providing EOHD. Measurements:
Interviews were analyzed using thematic analysis. Outcomes included themes and subthemes. Results:
Four themes and 13 subthemes (in parentheses) were identified: 1) drivers of professional burnout (emotional exhaustion from witnessing needless suffering and high mortality, jeopardizing patient trust, detaching from patients, perceived lack of control over EOHD criteria, and physical exhaustion from overextending to bridge care), 2) moral distress from propagating injustice (altered care based on nonmedical factors, focus on volume at the expense of quality, and need to game the system), 3) confusing and perverse financial incentives (wasting resources, confusing financial incentives, and concerns about sustainability), and 4) inspiration toward advocacy (deriving inspiration from patients and strengthened altruism). Limitation:
Whether the findings apply to other settings is unknown, and social desirability response bias might have reduced reporting of negative perceptions and experiences. Conclusion:
Clinicians in safety-net settings who provide EOHD to undocumented patients describe experiencing moral distress and being driven toward professional burnout. The burden of EOHD on clinicians should inform discussions of systemic approaches to support provision of adequate care based on medical need. Primary Funding Source:
Robert Wood Johnson Foundation and Doris Duke Charitable Foundation.https://ift.tt/2x0cem7
TOX expression decreases with progression of colorectal cancers and is associated with CD4 T-cell density and Fusobacterium nucleatum infection
Fusobacterium nucleatum (F. nucleatum) in the tumor microenvironment plays an important role in the development of colorectal cancer (CRC). The underlying mechanism of action, however, remains to be elucidated. We evaluated the relation of F. nucleatum amount to thymocyte selection-associated high-mobility group box (TOX) protein expression and CD4+ T cell density in 138 human colorectal tissues. TOX expression and CD4+ T cell density in F. nucleatum negative tissues were significantly higher compared to those in F.
https://ift.tt/2IZVoIS
Hydromorphone Conversion Dilemma: A Millennial Problem
We read with great interest the recent study by Reddy et al. (2017) which recommended a new opioid conversion ratio of 1 mg intravenous (IV) hydromorphone to 2.5 mg oral (PO) hydromorphone and 11.46 mg of oral morphine equivalent daily dose (MEDD).1 The authors have adapted this ratio at their institution and conclude that utilizing these new ratios may allow for more rapid opioid titrations, improved pain management, and may ultimately decrease hospital length of stay.1
https://ift.tt/2IBibY0
Immune checkpoint inhibitor toxicity review for the palliative care clinician
Immune checkpoint inhibitors (ICI) have opened an exciting chapter in the treatment of patients with advanced cancer. For the palliative care clinician, however, ICI present several new challenges, including new ways to define treatment success, as well as treatment-related toxicities which differ in nature and timing from traditional chemotherapy. In this article, we review the mechanism of action of immune checkpoint inhibitors, as well as selected published data supporting the efficacy of ICI in patients with advanced cancer.
https://ift.tt/2rZqDtQ
Caution, Vigilance, and Personalization: A Must for Any Opioid Conversion
It is with great enthusiasm that we read the letter written by Foxwell and Uritsky in response to our study "The Conversion Ratio from Intravenous Hydromorphone to Oral Opioids in Cancer Patients".1 Our study concluded after retrospectively reviewing the charts of 394 cancer patients that 1mg of intravenous (IV) hydromorphone is equivalent to 2.5 mg of oral hydromorphone and 11.46 mg of morphine equivalent daily dose (MEDD). A ratio of 1:2 from IV to oral hydromorphone was recommended in patients receiving high doses of IV hydromorphone.
https://ift.tt/2KHTzgH
Optimization and enhancement of textile reactive Remazol black B decolorization and detoxification by environmentally isolated pH tolerant Pseudomonas aeruginosa KY284155
Azo dyes are complex derivatives of diazene used in food and textile manufacture. They are highly recalcitrant compounds, and account for severe environmental and health problems. Different strains of Pseudomonas
https://ift.tt/2ICE6Oi
A study on the use of strain-specific and homologous promoters for heterologous expression in industrial Saccharomyces cerevisiae strains
Polymorphism is well known in Saccharomyces cerevisiae strains used for different industrial applications, however little is known about its effects on promoter efficiency. In order to test this, five different p...
https://ift.tt/2rX2Vyk
Rapid monitoring of the target protein expression with a fluorescent signal based on a dicistronic construct in Escherichia coli
Real-time quantification of recombinant proteins is important in studies on fermentation engineering, cell engineering, etc. Measurement of the expression level of heterologous proteins in bacterial fermentati...
https://ift.tt/2IGPw3X
Transition Home Plus Program Reduces Medicaid Spending and Health Care Use for High-Risk Infants Admitted to the Neonatal Intensive Care Unit for 5 or More Days
To evaluate the effects of a transition home intervention on total Medicaid spending, emergency department visits, and unplanned readmissions for preterm infants born at ≤366/7 weeks gestation and high-risk full-term infants.
https://ift.tt/2KJ6grK
A Pediatric Neurology Perspective on Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection and Pediatric Acute-Onset Neuropsychiatric Syndrome
The sudden onset of new neuropsychiatric symptoms in children is often a challenge for both parents and physicians. For the physician, there is a broad differential diagnosis to consider, and decisions must be made about the selection of diagnostic studies as well as the choice of therapy.1 In addition, there is often a belief that, even without a documented etiology, an immediate pharmacologic treatment targeted toward an undiagnosed biological etiology will prevent worsening symptoms or permanent sequelae.
https://ift.tt/2IBcpWb
Extreme Preterm Infant Rates of Overweight and Obesity at School Age in the SUPPORT Neuroimaging and Neurodevelopmental Outcomes Cohort
To identify rates of overweight (body mass index [BMI] ≥85th percentile) and obesity (BMI ≥95th percentile) at 6-7 years of age and associated risk factors among extremely preterm infants born at <28 weeks of gestation.
https://ift.tt/2rYabtI
Heart Rate, Responsiveness to Intravenous Immunoglobulin, and Coronary Artery Aneurysms in Kawasaki Disease
To evaluate whether heart rate (HR) was associated with intravenous immunoglobulin (IVIG) responsiveness or development of coronary artery lesions (CALs) in patients with Kawasaki disease.
https://ift.tt/2rYv3RN
Lower Distending Pressure Improves Respiratory Mechanics in Congenital Diaphragmatic Hernia Complicated by Persistent Pulmonary Hypertension
To investigate the effects of distending pressures on respiratory mechanics and pulmonary circulation in newborn infants with congenital diaphragmatic hernia (CDH) and persistent pulmonary hypertension (PPHN).
https://ift.tt/2rYhem6
Cell Count Analysis from Nonbronchoscopic Bronchoalveolar Lavage in Preterm Infants
To establish the reference values, diagnostic accuracy, and effect of various factors on cell count in intubated preterm neonates subjected to nonbronchoscopic bronchoalveolar lavage.
https://ift.tt/2KEGcOg
Investigating aquifer contamination and groundwater quality in eastern Terai region of Nepal
This study aims at assessing the groundwater quality of the three districts of Eastern Terai region of Nepal viz. Morang, Jhapa, Sunsari using physicochemical characteristics and statistical approach so that p...
https://ift.tt/2IAHAoH
Atrioventricular block after acute myocardial infarction and its association with other clinical parameters in Pakistani patients: an institutional perspective
Conduction defects complicating acute myocardial infarction are frequently associated with increased morbidity and mortality. As frequency of this complication has not been widely studied in our population, th...
https://ift.tt/2IGxePW
HLA class I alleles frequencies in the Syrian population
The HLA system is known to be the most polymorphic genetic loci in humans. Distribution and frequencies of HLA alleles are highly variable among different human ethnic groups. The HLA system has an important r...
https://ift.tt/2LhYYfK
Recommendations for application of Haemophilus influenzae PCR diagnostics to respiratory specimens for children living in northern Australia: a retrospective re-analysis
Haemophilus haemolyticus can be misidentified as nontypeable Haemophilus influenzae (NTHi) due to their phenotypic similarities in microbiological culture. This study aimed to determine the prevalence of misident...
https://ift.tt/2x2G3T2
Effects of ionizing radiation on the viability and proliferative behavior of the human glioblastoma T98G cell line
Radiotherapy is the traditional therapy for glioma patients. Glioma has poor response to ionizing radiation (IR). Studying radiation-induced cell death can help in understanding the cellular mechanisms underly...
https://ift.tt/2LjnlJZ
Addendum: Campos D, Peeters W, Nickel K, Burkel B, Bussink J, Kimple RJ, van der Kogel A, Eliceiri KW, KissickMW. “Radiation Promptly Alters Cancer Live Cell Metabolic Fluxes: An In Vitro Demonstration.” Radiat Res 2016; 185:496-504.
Radiation Research, Volume 189, Issue 6, Page 668-668, June 2018.
https://ift.tt/2x2FVmw
FDA Approves Aimovig to Prevent Migraines
MONDAY, May 21, 2018 -- Aimovig (erenumab-aooe) has been approved by the U.S. Food and Drug Administration to prevent migraine headaches in adults. Aimovig is the first FDA-approved preventive migraine treatment in a new class of drugs that work by...
https://ift.tt/2ISZH8G
AUA: Most Women Report Dysfunctional Toileting Behaviors
MONDAY, May 21, 2018 -- Many women report dysfunctional toileting behaviors, which are associated with lower urinary tract symptoms, according to a study presented at the annual meeting of the American Urological Association, held from May 18 to 21...
https://ift.tt/2s5U1xU
Risk of Dementia Up for Older Adults With Lowest Wealth
MONDAY, May 21, 2018 -- The risk of dementia is increased for adults in the lowest versus the highest wealth quintile, according to a study published online May 16 in JAMA Psychiatry. Dorina Cadar, Ph.D., from University College London, and...
https://ift.tt/2ISZEd0
Surgical Site Infection Rate Can Be Reduced in Hysterectomy
MONDAY, May 21, 2018 -- Implementation of a perioperative surgical site infection prevention bundle may reduce the rate of surgical site infection among patients undergoing hysterectomy, according to a study published online May 7 in Obstetrics...
https://ift.tt/2s1waPM
Robust Immune Responses for Herpes Zoster Subunit Vaccine
MONDAY, May 21, 2018 -- Recipients of the herpes zoster subunit vaccine (HZ/su), consisting of varicella-zoster virus glycoprotein E (gE) and AS01B Adjuvant System, develop robust immune responses, according to a study published in the June 1 issue...
https://ift.tt/2kg7Aam
Rivaroxaban Linked to Low VTE Recurrence in Active Cancer
MONDAY, May 21, 2018 -- For patients with active cancer and venous thromboembolism (VTE), rivaroxaban is associated with lower VTE recurrence compared with dalteparin, but with elevated clinically relevant non-major bleeding (CRNMB), according to a...
https://ift.tt/2x6pHce
Social, Communication Delays With False-Negative on M-CHAT
MONDAY, May 21, 2018 -- Children who pass the Modified Checklist for Autism in Toddlers (M-CHAT) screening at 18 months but later receive diagnoses of autism spectrum disorder (ASD) exhibit delays in social, communication, and motor skills,...
https://ift.tt/2kfcIvr
Semaglutide Found to Be Effective Against Type 2 Diabetes
MONDAY, May 21, 2018 -- Semaglutide is safe and effective for the treatment of type 2 diabetes, according to a review published online May 13 in Diabetes, Obesity and Metabolism. Panagiotis Andreadis, M.D., from the Aristotle University of...
https://ift.tt/2x2Pp0Y
Starting Exercise Even in Older Age Cuts Heart Failure Risk
MONDAY, May 21, 2018 -- Increasing patients' physical activity is an effective strategy to lower future risk of heart failure, according to a study published in the May issue of Circulation. Roberta Florido, M.D., from Johns Hopkins University in...
https://ift.tt/2khmNYx
Depression-Heart Rate Variability Link Is Bidirectional
MONDAY, May 21, 2018 -- There is a bidirectional association between depression and heart rate variability (HRV), according to a study published online May 16 in JAMA Psychiatry. Minxuan Huang, Sc.M., from the Emory University Rollins School of...
https://ift.tt/2s2OM1E
Bronchoalveolar Lavage Exosomes in Lipopolysaccharide-induced Septic Lung Injury
Mice exposed to intraperitoneal LPS secrete exosomes in Broncho-alveolar lavage (BAL) fluid that are packaged with miRNAs. Using a co-culture system, we show that exosomes released in the BAL fluid disrupt expression of tight junction proteins in bronchial epithelial cells and increase expression of pro-inflammatory cytokines that accentuate lung injury.
https://ift.tt/2KLbzqO
Biological Stimulus‐Driven Assembly/Disassembly of Functional Nanoparticles for Targeted Delivery, Controlled Activation, and Bioelimination
Advanced Healthcare Materials, EarlyView.
https://ift.tt/2Lm9eTY
Epidemiology of carbapenem-resistant Klebsiella pneumoniae bloodstream infections after renal transplantation from donation after cardiac death in a Chinese hospital: a case series analysis
Although the high mortality rates have been extensively reported worldwide, few studies have investigated the epidemiology of CRKP-BSIs in the early stage after kidney transplantation (KTx) from donation after...
https://ift.tt/2x9sVM7
Homeopathic Teething Drops, Nausea Drops, Intestinal Colic Drops, Stomach Calm, Expectorant Cough Syrup, Silver-Zinc Throat Spray, and Argentum Elixir by MBI Distributing: Recall - Due to a Lack of Adequate Controls
[Posted 05/21/2018] AUDIENCE: Consumer, Health Professional, Pharmacy ISSUE: MBI Distributing, Inc. is voluntarily recalling all lots of homeopathic Teething Drops, Nausea Drops, Intestinal Colic Drops, Stomach Calm, Expectorant Cough Syrup,...
https://ift.tt/2keA6t3
High-throughput Identification of Synergistic Drug Combinations by the Overlap2 Method
https://ift.tt/2rVONWc
Rapid and Specific Immunomagnetic Isolation of Mouse Primary Oligodendrocytes
https://ift.tt/2KL0juv
New observations in tumor cell plasticity: mutational profiling in a case of metastatic melanoma with biphasic sarcomatoid transdifferentiation
Abstract
We describe a highly unusual case of metastatic melanoma in a 61-year-old female that manifested as a single groin lymph node metastasis accompanied by two distinct, subcutaneous sarcomatoid tumors on the same leg, without evidence of a primary tumor. Characterization encompassed extensive immunohistochemical staining as well as next-generation sequencing (NGS). The lymph node metastasis showed obvious features of melanoma. The two subcutaneous lesions, however, were morphologically and immunohistochemically consistent with high-grade myxofibrosarcoma and soft tissue mixed tumor, respectively. All three lesions were BRAF wild-type and found to harbor an identical NRAS p.Q61R mutation. Metachronic intestinal metastases, showing intermingled conventional and sarcomatoid morphology, as well as an identical genetic phenotype, corroborated these findings. The concordant genetic profile provided evidence of biphasic sarcomatoid transdifferentiation of melanoma. Interestingly, the lack of genetic heterogeneity between the three morphologically distinct tumors suggests factors other than genetic mutations to be involved in melanoma transdifferentiation.
https://ift.tt/2IzhQJe
Homeopathic Teething Drops, Nausea Drops, Intestinal Colic Drops, Stomach Calm, Expectorant Cough Syrup, Silver-Zinc Throat Spray, and Argentum Elixir by MBI Distributing: Recall - Due to a Lack of Adequate Controls
[Posted 05/21/2018] AUDIENCE: Consumer, Health Professional, Pharmacy ISSUE: MBI Distributing, Inc. is voluntarily recalling all lots of homeopathic Teething Drops, Nausea Drops, Intestinal Colic Drops, Stomach Calm, Expectorant Cough Syrup,...
https://ift.tt/2keA6t3
Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma
https://ift.tt/2rWBHI6
Primary headaches in children and adolescents – experiences at a single headache center in Korea
Headache is a common complaint in children and adolescents. Recently, an increased prevalence of headache in children and adolescents has been reported.
https://ift.tt/2LjrXzR
Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma
New England Journal of Medicine, Ahead of Print.
https://ift.tt/2rWBHI6
Small Poisoned Humans
by Diane Calello A patient is brought back from triage. He is uncooperative with your exam and it is difficult to obtain vital signs. His speech is mostly incoherent, and he is drooling. You notice with disgust that he is chewing on the bedrails. He is incontinent of urine and feces, but […]
EMCrit Project by Tox & Hound.
https://ift.tt/2IDvATe
Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages
We describe the detection of NLRP3 inflammasome activation on cellular basis using fluorescence microscopy and staining for active caspase-1 and the adaptor, ASC. A lactate dehydrogenase release assay is presented to detect pyroptotic lysis on a population basis. These techniques can be adapted to study many aspects of inflammasome biology.
https://ift.tt/2GCg5p4
Custom Engineered Tissue Culture Molds from Laser-etched Masters
https://ift.tt/2LhHSP6
Prediction of mortality in severe dengue cases
Increasing incidence of dengue cases in Malaysia over the last few years has been paralleled by increased deaths. Mortality prediction models will therefore be useful in clinical management. The aim of this st...
https://ift.tt/2rTpZht
Enterococcus gallinarum meningitis: a case report and literature review
As an opportunistic pathogen, E. gallinarum mainly leads to nosocomial infections, and it's multi-drug resistance has gained more and more attention. Central nervous system infections caused by E. gallinarum are ...
https://ift.tt/2IG0lmv
Immunologic and virological response to ART among HIV infected individuals at a tertiary hospital in Ghana
The need to study the outcome of Antiretroviral Therapy (ART) among Human Immunodeficiency Virus (HIV) infected individuals in Ghana, a sub-Saharan African country crucial in the era of the "Treat All" policy....
https://ift.tt/2rWQG4W
Enrichment of Bacterial Lipoproteins and Preparation of N-terminal Lipopeptides for Structural Determination by Mass Spectrometry
The enrichment of bacterial lipoproteins using a non-ionic surfactant phase partitioning method is described for direct use in TLR assays or other applications. Further steps are detailed to prepare N-terminal tryptic lipopeptides for structural characterization by mass spectrometry.
https://ift.tt/2x624k2
FDA Approves Lucemyra (lofexidine hydrochloride) as a Non-Opioid Treatment for Opioid Withdrawal
THURSDAY, May 17, 2018 -- Lucemyra (lofexidine hydrochloride) has been approved by the U.S. Food and Drug Administration to treat symptoms of opioid withdrawal. Lucemyra, an oral selective alpha 2-adrenergic receptor agonist, limits the body's...
https://ift.tt/2kd1OGz
An interview with Divyanshu Dubey, 2018 Epilepsia Prize winner for clinical research
Epilepsia, EarlyView.
https://ift.tt/2IFUTQU
Impact of a VAP bundle in Belgian intensive care units
In order to decrease the incidence of ventilator-associated pneumonia (VAP) in Belgium, a national campaign for implementing a VAP bundle involving assessment of sedation, cuff pressure control, oral care with...
https://ift.tt/2rVBjK6
Influence of uvrA, recJ and recN gene mutations on nucleoid reorganization in UV-treated Escherichia coli cells
Abstract
Exposure to ultraviolet (UV) radiation blocks DNA replication and arrests cellular division in Escherichia coli. Restoration of chromosome replication involves nucleoid reorganization, which involves the participation of the recombination-catalyzing proteins RecA, RecO, RecR and RecN. In this work, we evaluated the influence of recN, uvrA and recJ gene mutations on post-irradiation nucleoid reorganization. We used isogenic E. coli strains that are defective for these genes to study post-irradiation kinetics of the nucleoid shape fractions using fluorescence microscopy. The results showed that in the wild-type strain, post-irradiation nucleoid reorganization occurs, which restores the nucleoid shape fractions in the cells to those observed prior to irradiation. First, the nucleoid condenses into the central area of the irradiated cell. Second, the nucleoid disperses along the cell. Third, the cell enters the chromosome replicative phase and cytokinesis. Escherichia coli cells with a recN mutation did not exhibit increased nucleoid condensation, but chromosome replication and cytokinesis occurred. In the uvrA and recJ strains, the condensation step was delayed compared to the wild-type strain, and chromosome replication and cytokinesis did not occur. The results are discussed with an emphasis on the functions of RecN, UvrA and RecJ in nucleoid reorganization in UV-irradiated E. coli cells.https://ift.tt/2s0Pi0i
Monitoring substrate enables real-time regulation of a protein localization pathway
Abstract
Protein localization machinery supports cell survival and physiology, suggesting the potential importance of its expression regulation. Here, we summarize a remarkable scheme of regulation, which allows real-time feedback regulation of the machinery expression. A class of regulatory nascent polypeptides, called monitoring substrates, undergoes force-sensitive translation arrest. The resulting ribosome stalling on the mRNA then affects mRNA folding to expose the ribosome-binding site of the downstream target gene and upregulate its translation. The target gene encodes a component of the localization machinery, whose physical action against the monitoring substrate leads to arrest cancellation. Thus, this scheme of feedback loop allows the cell to adjust the amount of the machinery to correlate inversely with the effectiveness of the process at a given moment. The system appears to have emerged late in evolution, in which a narrow range of organisms selected a distinct monitoring substrate-machinery combination. Currently, regulatory systems of SecM-SecA, VemP-SecDF2 and MifM-YidC2 are known to occur in different bacterial species.https://ift.tt/2kbvnYQ
CRISPR-Cas9 enabled targeted mutagenesis in the thermotolerant methylotrophic yeast Ogataea thermomethanolica
Abstract
Ogataea thermomethanolica TBRC656 is a thermotolerant methylotrophic yeast suitable for heterologous protein expression at various temperatures. However, the lack of efficient methods for targeted gene mutagenesis limits strain engineering in this yeast. In this study, we applied a CRISPR-Cas9-based tool for targeted gene mutagenesis in O. thermomethanolica. The putative unfolded protein response regulator OtHAC1, and the OtMAL1 (maltase) and OtMAL2 (maltose permease) genes involved with sucrose and maltose utilization were targeted for CRISPR-Cas9 mutagenesis. Plasmids were constructed for integrative and episomal expression of CRISPR-Cas9 elements in O. thermomethanolica in which Cas9 and gRNA are transcribed from the alcohol oxidase (AOX) promoter. The expression of these genome-editing elements is controlled by derepression with glycerol and gRNA are flanked by self-cleaving ribozymes. For integrative system, OtHAC1, OtMAL1 and OtMAL2 were disrupted at 63%, 97% and 93%, respectively. In addition, OtMAL1 was also disrupted with episomal system at 92%. These findings indicate that the CRISPR-Cas9 system described herein is thus applicable for studying gene function and strain engineering in yeast O. thermomethanolica.https://ift.tt/2rZ6G5F
A xenograft model for venous malformation
Abstract
Vascular malformations are defects caused by the abnormal growth of the vasculature. Among them, venous malformation (VM) is an anomaly characterized by slow-flow vascular lesions with abnormally shaped veins, typically in sponge-like configuration. VMs can expand over years causing disfigurement, obstruction of vital structures, thrombosis, bleeding, and pain. Treatments have been very limited and primarily based on supportive care, compression garments, sclerotherapy, and/or surgical resection. Sirolimus treatment has recently shown efficacy in some patients with complicated vascular anomalies, including VMs. Activating somatic TIE2 gene mutations have been identified in up to 60% of VMs and PIK3CA mutations have been found in another 25%. Here, we report a xenograft model of VM that reflects the patients' mutation heterogeneity. First, we established a protocol to isolate and expand in culture endothelial cells (VM–EC) from VM tissue or VM blood of nine patients. In these cells, we identified somatic mutations of TIE2, PIK3CA, or a combination of both. Both TIE2 and PIK3CA mutations induced constitutive AKT activation, while TIE2 mutations also showed high MAPK–ERK signaling. Finally, VM–EC implanted into immune-deficient mice generated lesions with ectatic blood-filled channels with scarce smooth muscle cell coverage, similar to patients' VM. This VM xenograft model could be instrumental to test the therapeutic efficacy of Sirolimus in the presence of the different TIE2 or PIK3CA mutations or to test for efficacy of additional compounds in targeting the specific mutated protein(s), thus enabling development of personalized treatment options for VM patients.
https://ift.tt/2KKkMzB
Novel non-invasive early detection of lung cancer using liquid immunobiopsy metabolic activity profiles
Abstract
Lung cancer is the leading cause of cancer death worldwide. Survival is largely dependent on the stage of diagnosis: the localized disease has a 5-year survival greater than 55%, whereas, for spread tumors, this rate is only 4%. Therefore, the early detection of lung cancer is key for improving prognosis. In this study, we present an innovative, non-invasive, cancer detection approach based on measurements of the metabolic activity profiles of immune system cells. For each Liquid ImmunoBiopsy test, a 384 multi-well plate is loaded with freshly separated PBMCs, and each well contains 1 of the 16 selected stimulants in several increasing concentrations. The extracellular acidity is measured in both air-open and hermetically-sealed states, using a commercial fluorescence plate reader, for approximately 1.5 h. Both states enable the measurement of real-time accumulation of 'soluble' versus 'volatile' metabolic products, thereby differentiating between oxidative phosphorylation and aerobic glycolysis. The metabolic activity profiles are analyzed for cancer diagnosis by machine-learning tools. We present a diagnostic accuracy study, using a multivariable prediction model to differentiate between lung cancer and control blood samples. The model was developed and tested using a cohort of 200 subjects (100 lung cancer and 100 control subjects), yielding 91% sensitivity and 80% specificity in a 20-fold cross-validation. Our results clearly indicate that the proposed clinical model is suitable for non-invasive early lung cancer diagnosis, and is indifferent to lung cancer stage and histological type.
https://ift.tt/2rX1qA1
Novel non-invasive early detection of lung cancer using liquid immunobiopsy metabolic activity profiles
Abstract
Lung cancer is the leading cause of cancer death worldwide. Survival is largely dependent on the stage of diagnosis: the localized disease has a 5-year survival greater than 55%, whereas, for spread tumors, this rate is only 4%. Therefore, the early detection of lung cancer is key for improving prognosis. In this study, we present an innovative, non-invasive, cancer detection approach based on measurements of the metabolic activity profiles of immune system cells. For each Liquid ImmunoBiopsy test, a 384 multi-well plate is loaded with freshly separated PBMCs, and each well contains 1 of the 16 selected stimulants in several increasing concentrations. The extracellular acidity is measured in both air-open and hermetically-sealed states, using a commercial fluorescence plate reader, for approximately 1.5 h. Both states enable the measurement of real-time accumulation of 'soluble' versus 'volatile' metabolic products, thereby differentiating between oxidative phosphorylation and aerobic glycolysis. The metabolic activity profiles are analyzed for cancer diagnosis by machine-learning tools. We present a diagnostic accuracy study, using a multivariable prediction model to differentiate between lung cancer and control blood samples. The model was developed and tested using a cohort of 200 subjects (100 lung cancer and 100 control subjects), yielding 91% sensitivity and 80% specificity in a 20-fold cross-validation. Our results clearly indicate that the proposed clinical model is suitable for non-invasive early lung cancer diagnosis, and is indifferent to lung cancer stage and histological type.
https://ift.tt/2rX1qA1
Empire State Building to light up for EMS Week
The Empire State Building will be illuminated in yellow, white and blue with a red and white halo at sunset
https://ift.tt/2LdGRYl
Celebrate EMS Week 2018 with EMS superlatives
You know who they are – recognize the Ferdinand Magellans, Yodas and Cliff Clavens of your agency during EMS Week
https://ift.tt/2IzDkG0
Sanguinarine triggers intrinsic apoptosis to suppress colorectal cancer growth through disassociation between STRAP and MELK
Abstract
Background
Previous studies showed sanguinarine induced apoptosis in CRC cells but did not define the underlying mechanisms. The purpose of this work was to determine the in vivo and in vitro effects of sanguinarine on CRC tumors and to elucidate the mechanism in regulating the intrinsic apoptosis.
Methods
Cell viability of CRC cell lines treated with sanguinarine was measured by MTT assay. Apoptotic cells stained with Annexin V and 7-AAD were detected by flow cytometry. Mitochondrial membrane potential and reactive oxygen species (ROS) were analyzed by JC-1 and DCFH-DA staining, respectively. The in vitro kinase activity of MELK was analyzed by using HTRF® KinEASE™-STK kit. The expression of proteins were determined using Western blotting and immunohistochemistry. Co-immunoprecipitation and immunofluorecence were used to study the interaction between STRAP and MELK. The anti-neoplastic effect of sanguinarine was observed in vivo in an orthotopic CRC model.
Results
Sanguinarine decreased the tumor size in a dose-dependent manner in orthotopical colorectal carcinomas through intrinsic apoptosis pathway in BALB/c-nu mice. It significantly increased cleavage of caspase 3 and PARP in implanted colorectal tissues. Sanguinarine increased mitochondrial ROS and triggered mitochondrial outer membrane permeabilization in multiple colorectal cancer (CRC) cell lines. NAC pretreatment lowered ROS level and downregulated apoptosis induced by sanguinarine. The intrinsic apoptosis induced by sanguinarine was Bax-dependent. The elevated expression and association between serine-threonine kinase receptor-associated protein (STRAP) and maternal embryonic leucine zipper kinase (MELK) were observed in Bax positive cells but not in Bax negative cells. Sanguinarine dephosphorylated STRAP and MELK and disrupted the association between them in HCT116 and SW480 cells. The expression and association between STRAP and MELK were also attenuated by sanguinarine in the tumor tissues. Importantly, we found that STRAP and MELK were overexpressed and highly phosphorylated in colorectal adenocarcinomas and their expression were significantly correlated with tumor stages. Furthermore, the expression of MELK, but not STRAP, was associated with lymph node metastasis.
Conclusions
Sanguinarine dephosphorelates STRAP and MELK and disassociates the interaction between them to trigger intrinsic apoptosis. Overexpression of STRAP and MELK may be markers of CRC and their disassociation may be a determinant of therapeutic efficacy.
https://ift.tt/2rZNaWx
The impact of pharmacokinetic gene profiles across human cancers
Abstract
Background
The right drug to the right patient at the right time is one of the ideals of Individualized Medicine (IM) and remains one of the most compelling promises of the post-genomic age. The addition of genomic information is expected to increase the precision of an individual patient's treatment, resulting in improved outcomes. While pilot studies have been encouraging, key aspects of interpreting tumor genomics information, such as somatic activation of drug transport or metabolism, have not been systematically evaluated.
Methods
In this work, we developed a simple rule-based approach to classify the therapies administered to each patient from The Cancer Genome Atlas PanCancer dataset (n = 2858) as effective or ineffective. Our Therapy Efficacy model used each patient's drug target and pharmacokinetic (PK) gene expression profile; the specific genes considered for each patient depended on the therapies they received. Patients who received predictably ineffective therapies were considered at high-risk of cancer-related mortality and those who did not receive ineffective therapies were considered at low-risk. The utility of our Therapy Efficacy model was assessed using per-cancer and pan-cancer differential survival.
Results
Our simple rule-based Therapy Efficacy model classified 143 (5%) patients as high-risk. High-risk patients had age ranges comparable to low-risk patients of the same cancer type and tended to be later stage and higher grade (odds ratios of 1.6 and 1.4, respectively). A significant pan-cancer association was identified between predictions of our Therapy Efficacy model and poorer overall survival (hazard ratio, HR = 1.47, p = 6.3 × 10− 3). Individually, drug export (HR = 1.49, p = 4.70 × 10− 3) and drug metabolism (HR = 1.73, p = 9.30 × 10− 5) genes demonstrated significant survival associations. Survival associations for target gene expression are mechanism-dependent. Similar results were observed for event-free survival.
Conclusions
While the resolution of clinical information within the dataset is not ideal, and modeling the relative contribution of each gene to the activity of each therapy remains a challenge, our approach demonstrates that somatic PK alterations should be integrated into the interpretation of somatic transcriptomic profiles as they likely have a significant impact on the survival of specific patients. We believe that this approach will aid the prospective design of personalized therapeutic strategies.
https://ift.tt/2ke4Ha9
Lynch syndrome-associated endometrial carcinoma with MLH1 germline mutation and MLH1 promoter hypermethylation: a case report and literature review
Abstract
Background
Lynch syndrome is an autosomal dominant inherited disease caused by germline mutations in mismatch repair genes. Analysis for microsatellite instability (MSI) and immunohistochemistry (IHC) of protein expressions of disease-associated genes is used to screen for Lynch syndrome in endometrial cancer patients. When losses of both MLH1 and PMS2 proteins are observed by IHC, MLH1 promoter methylation analysis is conducted to distinguish Lynch syndrome-associated endometrial cancer from sporadic cancer.
Case presentation
Here we report a woman who developed endometrial cancer at the age of 49 years. She had a family history of colorectal cancer (first-degree relative aged 52 years) and stomach cancer (second-degree relative with the age of onset unknown). No other family history was present, and she failed to meet the Amsterdam II criteria for the diagnosis of Lynch syndrome. Losses of MLH1 and PMS2, but not MSH2 and MSH6, proteins were observed by IHC in endometrial cancer tissues. Because MLH1 promoter hypermethylation was detected in endometrial cancer tissue samples, the epigenetic silencing of MLH1 was suspected as the cause of the protein loss. However, because of the early onset of endometrial cancer and the positive family history, a diagnosis of Lynch syndrome was also suspected. Therefore, we provided her with genetic counseling. After obtaining her consent, MLH1 promoter methylation testing and genetic testing of peripheral blood were performed. MLH1 promoter methylation was not observed in peripheral blood. However, genetic testing revealed a large deletion of exon 5 in MLH1; thus, we diagnosed the presence of Lynch syndrome.
Conclusions
Both MLH1 germline mutation and MLH1 promoter hypermethylation may be observed in endometrial cancer. Therefore, even if MLH1 promoter hypermethylation is detected, a diagnosis of Lynch syndrome cannot be excluded.
https://ift.tt/2ke3NKN
Exposing the Science in Citizen Science: Fitness to Purpose and Intentional Design
Abstract
Citizen science is a growing phenomenon. With millions of people involved and billions of in-kind dollars contributed annually, this broad extent, fine grain approach to data collection should be garnering enthusiastic support in the mainstream science and higher education communities. However, many academic researchers demonstrate distinct biases against the use of citizen science as a source of rigorous information. To engage the public in scientific research, and the research community in the practice of citizen science, a mutual understanding is needed of accepted quality standards in science, and the corresponding specifics of project design and implementation when working with a broad public base. We define a science-based typology focused on the degree to which projects deliver the type(s) and quality of data/work needed to produce valid scientific outcomes directly useful in science and natural resource management. Where project intent includes direct contribution to science and the public is actively involved either virtually or hands-on, we examine the measures of quality assurance (methods to increase data quality during the design and implementation phases of a project) and quality control (post hoc methods to increase the quality of scientific outcomes). We suggest that high quality science can be produced with massive, largely one-off, participation if data collection is simple and quality control includes algorithm voting, statistical pruning and/or computational modeling. Small to mid-scale projects engaging participants in repeated, often complex, sampling can advance quality through expert-led training and well-designed materials, and through independent verification. Both approaches – simplification at scale and complexity with care – generate more robust science outcomes.https://ift.tt/2KG76p4
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
