In 2009, we have described the use of freestyle facial artery perforator flaps for one-stage nose reconstruction. Since then, several articles have reported the use of facial artery perforator flaps for nose reconstruction. The purpose of this article is to provide an update of the published technique after 10 years of experience. Since 2004, 21 patients have been treated with a freestyle facial artery perforator flap for one-stage reconstruction of the nasal ala. The flaps were 16 propellers, 4 V-V, and 1 island transposition. A single venous congestion leading to a minor flap tip necrosis and a wound dehiscence was observed. All other flaps healed uneventfully. The V-Y design and multiple subunit reconstruction gave suboptimal results. It was concluded that indications for freestyle facial artery perforator flaps are total nasal alar subunit reconstruction or reconstruction of lateral alar defects when perforator anatomy allows. In these cases, freestyle facial artery perforator flaps are the first choice technique at our institution because they allow excellent results in one-stage operation. One-stage nasal ala reconstruction with freestyle facial artery perforator flaps.
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Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Παρασκευή 1 Ιουλίου 2016
Reconstruction of nasal alar defects with freestyle facial artery perforator flaps
Multivariable Prediction of Return to Work at Six-Month Follow-up in Mild to Moderate Acute Stroke Patients
Publication date: Available online 1 July 2016
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Ryan Van Patten, Zachary C. Merz, Kyler Mulhauser, Robert Fucetola
ObjectiveTo investigate predictors of return to work (RTW) in a post-stroke sample. We hypothesized that acutely measured stroke severity, occupational status, and neurocognitive abilities would predict RTW six months later.DesignA retrospective investigation of archival data from an inception cohort. Acute care records and six-month follow up telephone interview data were obtained for analysis.SettingThe Brain Recovery Core (BRC), a collaborative interinstitutional endeavor among an academic medical center, an acute care hospital, and a rehabilitation center.ParticipantsData from 298 stroke patients from the BRC. Excluded cases with nontraditional and/or nonpaid job status, no National Institute of Health Stroke Scale (NIHSS) score, and an NIHSS score of > 16. Our final sample included 244 individuals, aged 25-87.InterventionsNot applicableMain Outcome MeasuresSociodemographic variables, stroke severity (NIHSS), physical and neurocognitive measures.ResultsAdding predictor variables to our logistic regression model increased accuracy by approximately 18%. Greater independence in the Functional Independence Measure Sit-to-Stand movement predicted improved RTW rates (OR = 1.80; 95% CI = 1.0 – 3.1), while non-Caucasian race (odds ratio [OR] = 2.52; 95% confidence interval [CI] = 1.16 – 5.47) and greater impairment on the NIHSS (OR = .88; 95% CI = .77 – .99) predicted attenuated RTW rates.ConclusionsValid measures of stroke severity and a clinician-rated sit-to-stand movement have utility in the acute prediction of later RTW in mild to moderate stroke patients. Given the complexity of the RTW construct and the acute measurement of these variables, we believe that our findings can be used to a) inform clinical decisions and to b) appropriately tailor rehabilitative strategies that improve quality of life for stroke survivors.
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Social support and actual versus expected length of stay in inpatient rehabilitation facilities
Publication date: Available online 1 July 2016
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Zakkoyya H. Lewis, Catherine Cooper Hay, James E. Graham, Yu-Li Lin, Amol M. Karmarkar, Kenneth J. Ottenbacher
ObjectivesDescribe impairment-specific patterns in shorter- and longer-than-expected lengths of stay in inpatient rehabilitation and examine the independent effects of social support on deviations from expected lengths of stay.DesignRetrospective cohort study.SettingInpatient rehabilitation facilities across the United States.ParticipantsMedicare fee-for-service beneficiaries (N=119,437) who were discharged from inpatient rehabilitation facilities in 2012 following stroke, lower extremity fracture, or lower extremity joint replacement.InterventionNot applicable.Main Outcome MeasureRelative length of stay (actual – expected). The Centers for Medicare and Medicaid Services posts annual expected lengths of stay based on patients' clinical profiles at admission. We created a 3-category outcome variable: short, expected, long. Our primary independent variable (social support) also included 3 categories: family/friends, paid/other, none.ResultsMean (SD) actual lengths of stay for joint replacement, fracture, and stroke were 9.8 (3.6), 13.8 (4.5), and 15.8 (7.3) days, respectively; relative lengths of stay were -1.2 (3.1), -1.6 (3.7), and -1.7 (5.2) days. Nearly half of patients (47-48%) were discharged more than 1 day earlier than expected in all 3 groups, whereas 14% of joint replacement, 15% of fracture, and 20% of stroke patients were discharged more than 1 day later than expected. In multinomial regression analysis, using family/friends as the reference group, paid/other support was associated (p<.05) with higher odds of long stays in joint replacement. No social support was associated with lower odds of short stays in all 3 impairment groups and higher odds of long stays in fracture and joint replacement.ConclusionInpatient rehabilitation experiences and outcomes can be substantially impacted by a patient's level of social support. More research is needed to better understand these relationships and possible unintended consequences in terms of patient access issues and provider-level quality measures.
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Two Different Types of High-frequency Physical Therapy Promote Improvements in the Balance and Mobility of Persons with Multiple Sclerosis
Publication date: Available online 1 July 2016
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Brenda L. Davies, David J. Arpin, Min Liu, Heidi Reelfs, Kathleen G. Volkman, Kathleen Healey, Rana Zabad, Max J. Kurz
ObjectiveTo evaluate the mobility and postural balance improvements that could be achieved in a cohort of persons with multiple sclerosis (MS) that participated in a motor adaptation protocol (MAC) and a cohort of persons with MS who participated in a therapeutic exercise protocol (TEC).DesignA cohort design, where subjects were evaluated before and after a six week intervention period.SettingClinical laboratory setting.ParticipantsForty-two individuals with relapsing-remitting or secondary progressive MS (EDSS = 3.0-6.5) were initially screened for eligibility for participation in the study, from which 32 persons fit the inclusion criteria and enrolled in the study. Subjects were pseudo-randomly assigned to a treatment group and matched based on EDSS scores. Fourteen individuals in the MAC (Mean age: 52.6±9 years; EDSS: 5.5±0.9) and 13 individuals in the TEC (Mean age: 54.0±9 years; EDSS: 5.3±0.9) completed the entire duration of their respective programs.InterventionsBoth cohorts completed their therapy twice-a-day, five days each week, for six weeks. Each MAC session consisted of balance and gait training that encouraging new ways to adapt to challenging task demands. The TEC program was similar to a traditional exercise program.Main Outcome MeasuresThe main outcome measures were the sensory organization test, 6-minute walk test, and gait spatiotemporal kinematics.ResultsCollectively, both treatment groups had improvements in postural balance (p=0.001), walking endurance (p=0.002), walking speed (p=0.004), and step length (p<0.001) after therapy. However, there were no statistical differences between the two treatment groups for any of the outcome variables (ps>0.01).ConclusionsOur exploratory results suggest that a high frequency of physical therapy rather than a specific activity focus might be an important parameter for persons with MS.
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The Difficulty in Identifying Factors Responsible for Pressure Ulcer Healing in Veterans with Spinal Cord Injury
Publication date: Available online 1 July 2016
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Marylou Guihan, Min-Woong Sohn, William A. Bauman, Ann M. Spungen, Gail M. Powell-Cope, Susan S. Thomason, Joseph F. Collins, Barbara M. Bates-Jensen
ObjectiveTo identify characteristics associated with pressure ulcer (PrU) healing for individuals with spinal cord injury (SCI)DesignSecondary analysis of a large clinical trial data for healing PrUs in individuals with SCI; Prospective Delphi process was conducted with SCI and/or PrU experts.SettingUS Department of Veterans Affairs Spinal Cord Injury CentersParticipants629 screening and 162 treatment participants; 185 SCI clinicians/national PrU/wound care experts participated in the Delphi process.InterventionsNoneMain Outcome Measure(s)50% and 100% PrU healing at Weeks 4 and 12ResultsScreening participants were 57±11 years, non-Hispanic white (61%), with complete motor paraplegia and more than a college education (55%). Baseline PrU size was 15.3 ± 19.0 cm2 and located on the ischium or perineum (48%).Poisson regression models using the top Delphi-recommended factors found that baseline ulcer size and ulcer severity (Stage IV) did not significantly predict 50% or 100% healing at Weeks 4 or 12. Ischial/perineal location was associated with 33% higher likelihood of 50% healing at Week 4. Patient non-compliance with treatment recommendations, the top-ranked Delphi factor, did not predict 50% or 100% healing at Week 12. At Week 4, baseline PrU size, PrU stage IV, multiple PrUs, PrU pain, and ASIA A significantly predicted 100% healing. At Week 12, only PrU stage (IV) significantly predicted 100% healing. Significant predictors of 50% healing at Week 12 included PrU duration and paraplegia. SCI center identifiers consistently showed two to five-fold variation in 50% PrU healing.ConclusionsDelphi panel-recommended factors such as patient compliance did not predict PrU healing. Reducing center-level variability in wound healing by learning from best practices should be a health system goal. PrU healing in SCI is still poorly understood and future studies should focus on as yet unidentified or under-appreciated factors.
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Reliability and Validity of Nonradiologic Measures of Forward Flexed Posture in Parkinson’s Disease
Publication date: Available online 1 July 2016
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Prajakta Nair, Richard W. Bohannon, Laurie Devaney, Catherine Maloney, Alexis Romano
ObjectiveTo examine the inter-tester reliability and validity of 5 nonradiologic measures of forward flexed posture in individuals with Parkinson's disease (PD).DesignCross-sectional observational study.SettingUniversity outpatient facility and community centers.ParticipantsIndividuals (n=28) with PD. Hoehn and Yahr scores: 1-4.InterventionsNot applicable.Main outcome measuresOcciput to wall (OTW) status, tragus to wall (TTW) distance, C7 to wall (C7W) distance, photographically derived trunk flexion angle (FA) and the inclinometric kyphosis measure (IKM)ResultsParticipants were older adults (mean [SD] = 69.7 [10.6] years) with a 14 month to 15 year (mean [SD] = 5.9 [3.5]) history of PD. Inter-tester reliability was excellent for all measures (kappa=0.89 and 1.0 for OTW; intraclass correlation coefficients = 0.779-0.897 for TTW, C7W, FA and IKM). Convergent validity was supported for all measures by significant correlations between the same measures obtained during relaxed and cued conditions (e.g., OTW-relaxed and OTW-cued) and for most measures by significant correlations between measures obtained under the same condition (e.g., OTW-cued and TTW-cued). Significant correlations between TTW, C7W, FA, and IKM and the Unified Parkinson's Disease Rating Scale 'Item 28- Posture' also supported convergent validity. Significant differences between TTW, C7W and IKM values under relaxed and cued conditions supported known condition validity. Known group validity was demonstrated by significant differences in TTW, C7W, and IKM measures obtained from individuals able and individuals unable to touch their OTW when cued to stand tall.ConclusionsTTW, C7W, and IKM are reliable and valid nonradiologic measures of FFP in PD.
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Plasma matrix metalloproteinases in stroke patients during intensive rehabilitation therapy
Publication date: Available online 1 July 2016
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Feifei Ma, Susana Rodriguez, Xavi Buxo, Anna Morancho, Iolanda Riba-Llena, Ana Carrera, Alejandro Bustamante, Dolors Giralt, Joan Montaner, Carmen Martinez, Immaculada Bori, Anna Rosell
ObjectiveTo study plasma levels of matrix metalloproteinases (MMPs) as potential markers of recovery during intensive rehabilitation therapy (IRT) after stroke.DesignProspective and descriptive 3-months follow-up study.SettingRehabilitation unit and research center.ParticipantsPatients with first-ever ischemic strokes (n=15) enrolled to IRT (≥3 hours per day/5 days per week) and healthy volunteers serving as non-ischemic controls (n=15).InterventionsNot ApplicableMain Outcome MeasuresThe primary outcome was to measure plasma MMP3, MMP12 and MMP13 levels and evaluate potential associations with motor/functional scales using a battery of tests (NIHSS, RANKIN, BI, FMA, FAC, MRC, CAHAI and the 10 meter walk) before IRT therapy and at one- and three-month follow-ups. The secondary outcome was to evaluate the use of these MMPs as biomarkers as predictors of patient's outcome.ResultsMMP levels remained stable during the study period and were similar to those in controls. However, baseline MMP12 and MMP13 levels were strongly associated with stroke severity and found elevated in those patients with the poorest outcomes. Interestingly, plasma MMP3 was independent of baseline stroke characteristics but was found to be increased in patients with better motor/functional recovery and in patients with larger improvements during rehabilitation.ConclusionsMMPS might act as biological markers of recovery during rehabilitation therapy related to their roles in both injury and tissue remodeling. Future confirmatory investigations in multicenter studies are warranted by our data.
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When Women’s Gains Equal Men’s Losses: Predicting a Zero-Sum Perspective of Gender Status
Abstract
Believing that reduced discrimination against women directly corresponds to increased discrimination against men, referred to as a zero-sum perspective (ZSP), may inhibit further attempts toward gender equality. Based on a sample of 313 men and women, we developed and tested both a general measure and a domain-specific measure of the ZSP of gender status then examined sociodemographics (age, education, political orientation, religious beliefs, and past experience with discrimination) and social dominance orientation as predictors of the ZSP of shifts in gender status. Hostile and modern sexism were examined as potential mediators of this relationship. Structural equation models were computed to examine predictive paths separately for men and women. Although some similarities were found, results showed important differences in predictive paths for women and men, and supported the expected mediating role of sexism in the relationships between sociodemographic predictors and the ZSP. Findings have implications for targeting intervention efforts to enhance a win-win or non-zero-sum perspective that may facilitate efforts toward reducing gender discrimination.
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Anticonvulsant properties of methanol leaf extract of Laggera Aurita Linn. F. (Asteraceae) in laboratory animals
Publication date: 15 September 2016
Source:Journal of Ethnopharmacology, Volume 191
Author(s): S. Malami, H. Kyari, N.M. Danjuma, J. Ya'u, I.M. Hussaini
Ethnopharmacological relevancePreparation of Laggera aurita Linn. (Asteraceae) is widely used in traditional medicine to treat various kinds of diseases such as epilepsy, malaria, fever, pain and asthma. Its efficacy is widely acclaimed among communities in Northern Nigeria.Aim of the studyThe present study is aimed at establishing the possible anticonvulsant effects of the methanol leaf extract of Laggera aurita using acute and chronic anticonvulsant models.Materials and methodMedian lethal dose (LD50) was determined in mice and rats via oral and intraperitoneal routes. Anticonvulsant screening of the extract was performed using maximal electroshock-induced seizure test in day-old chicks; pentylenetetrazole-, strychnine- and picrotoxin- induced seizure models in mice. Similarly; its effects on pentylenetetrazole-induce kindling in rats as well as when co-administered with fluphenamic and cyproheptadine in mice, were evaluated.ResultsMedian lethal dose (LD50) values were found to be >5000mg/kg, p.o. and 2154mg/kg, i.p., each for both rats and mice. The extract showed dose dependent protection against tonic hind limb extension (THLE) and significantly (p<0.05) decreased the mean recovery from seizure in the maximal electroshock-induced seizure. In the pentylenetetrazole-induced seizure model, the extract offered 50% protection at 600mg/kg and also increased the mean onset of seizure at all doses with significant (p<0.05) increase at the highest dose (600mg/kg). Similarly the extract produced significant (p<0.05) increase in the onset of seizures in both strychnine- and picrotoxin- induced seizure models, at all the doses except at 150mg/kg for the picrotoxin model. Co-administration of fluphenamic acid (FFA) (5mg/kg) and the extract (600mg/kg) showed an enhanced effect with percentage protection of 70% while co-administration of FFA (5mg/kg) and phenytoin (5mg/kg) as well phenytoin (5mg/kg) and the extract (600mg/kg) produced an additive effect. Administration of the extract (600mg/kg), phenytoin (20mg/kg) and cyproheptadine (4mg/kg) offered 40%, 100% and 0% protection against THLE, each respectively, while co-administration of cyproheptadine (4mg/kg) and the extract (600mg/kg) as well as co-administration of cyproheptadine (4mg/kg) and phenytoin (20mg/kg) offered reduced protection of 20% and 50% each respectively. The extract at all doses reduced the severity of seizure episodes induced by PTZ-induced kindling.ConclusionThe results suggest that the methanol leaf extract of Laggera aurita possesses anticonvulsant and antiepileptogenic properties.
Graphical abstract
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Antidepressant-like effect of the saponins part of ethanol extract from SHF
Publication date: 15 September 2016
Source:Journal of Ethnopharmacology, Volume 191
Author(s): Yan Liang, Xu Yang, Xiaojian Zhang, Hongquan Duan, Meina Jin, Yan Sun, Hengjie Yuan, Junqiang Li, Yuedong Qi, Wei Qiao
Ethnopharmacological relevanceSuanzaorenhehuan Formula (SHF) has been used for treating depression-like disorders for many years in China. The saponins part of the SHF (SSHF) extract was the antidepressant effective component.Aim of studyTo investigate the antidepressant-like effect of SSHF and its possible mechanisms.Materials and methodsExperimental approaches including the forced swim test (FST), the tail suspension test (TST) and unpredictable chronic mild stress (UCMS) were used to evaluate the effects of SSHF. The possible mechanisms were explored by measuring monoamine neurotransmitter in mice frontal cortex and hippocampus, testing monoamine oxidase enzyme (MAO) activities, antioxidant enzyme activities and free radicals levels in the brains of UCMS-exposed mice.ResultsThe results showed that SSHF (10, 20, 40mg/kg) significantly decreased the immobility period in FST and TST in mice after two-week treatment. Whereas, SSHF had no significant effect on locomotor activity in mice. It was also found that the serotonin (5-HT) and noradrenaline (NE) levels in the hippocampus and frontal cortex were significantly increased only in 40mg/kg SSHF treated mice. In addition, SSHF (10, 20, 40mg/kg) significantly inhibited monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B) after 21-day UCMS exposure. SSHF (10, 20, 40mg/kg) significantly decreased the nitrous oxide (NO) levels, and increased the activities of total antioxidant capability (T-AOC), glutathione peroxidase (GSH-PX), and catalase (CAT) in different degrees in the brains of UCMS-exposed mice.ConclusionsOur results suggested that SSHF may effectively produce an antidepressant-like effect, which appeared to involve the serotonergic, noradrenergic, monoamine oxidase enzyme and antioxidant systems.
Graphical abstract
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Effect of Choline on the Composition and Degradation Enzyme of Extracellular Matrix of Mice Chondrocytes Exposed to Fluoride
Abstract
Choline has been shown to mediate damage of the chondrocyte matrix and degradation enzymes of mice exposed to fluoride (F). To test the action of choline, pregnant mice were treated with differing amounts of F and choline. Newborn mice were weaned at 21 days after birth and treated with the same doses of F and choline as they mothers for 12 weeks. Using hematoxylin-eosin (HE) staining, real-time PCR (RT-PCR), and western blotting, changes in the structure of the cartilage, the expression of mRNA and protein related to proteoglycans (PG), and degradation enzymes were detected. The RT-PCR results show that the expression of the Aggrecan (Acan), transforming growth factor beta (TGF-β1), and Aggrecanases-1 gene were abnormal in the high fluoride (HiF) group, and treatments with choline reversed this phenomenon. The western blotting results show that the protein expression of Aggrecanases-1 was significantly increased in the HiF group (p < 0.01). These findings suggest that F can change the morphology of cartilage tissue, the gene expression of the Acan, TGF-β1, Aggrecanases-1, and the protein expression of the Acan, and that choline can attenuate the effect of F. This may provide the basis for the treatment and prevention of fluorosis.
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Intravarietal polymorphisms reveal possible common ancestor of native Schinus terebinthifolius Raddi populations in Brazil
Schinus terebinthifolius Raddi is a perennial native from Atlantic forest. It is of high ecological plasticity and is used in traditional medicine. Based on promising reports concerning its bioactivity, it was included as a species of great interest for distribution through the National Health System. A number of agronomic studies to guide its crop production are therefore underway. This study examined diversity and phylogenetic relationships among native S. terebinthifolius populations from different Brazilian ecosystems: Cerrado; sandbanks; dense rainforest; and deciduous forest. The intergenic regions rpl20-5'rps12, trnH-psbA, and trnS-trnG were sequenced from cpDNA and aligned using BLASTn. There were few fragments for comparison in GenBank and so only region trnS-trnG was informative. There were variations among and within populations with intravarietal polymorphisms and three distinct haplotypes (HpSM, HpDDO, HpNE), once populations from NE (sandbanks and rainforest) clustered together. Sequences from HpSM, HpNE, and HpDDO returned greater similarity to haplotypes A (AY928398.1), B (AY928399.1), and C (AY928400.1), respectively. A network, built by median-joining among native haplotypes and 10 available on GenBank, revealed HpSM as the origin of all other haplogroups. HpDDO showed the most mutations and was closely related to haplogroups from Argentina. While this could indicate hybridization, we believe that the polymorphisms resulted from adaptation to events such as deforestation, fire, rising temperature, and seasonal drought during the transition from Atlantic forest to Cerrado. While more detailed phylogeographical studies are needed, these results indicate eligible groups for distinct climates as an important step for prebreeding programs before field propagation.
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Phase I dose-finding study of monotherapy with atezolizumab, an engineered immunoglobulin monoclonal antibody targeting PD-L1, in Japanese patients with advanced solid tumors
Summary
Background Atezolizumab is an engineered immunoglobulin monoclonal antibody that targets the programmed death-1/programmed death-ligand 1 pathway. Methods In this phase I dose-finding study, we assessed the safety, feasibility, pharmacokinetics (PK), and exploratory anti-tumor activity of atezolizumab monotherapy up to 20 mg/kg in Japanese patients with advanced solid tumors who had failed standard therapy or for whom there is no standard therapy. Results Six patients were enrolled and received intravenous atezolizumab every 3 weeks (q3w) at doses of 10 or 20 mg/kg. Tumor types were non-small cell lung cancer (n = 3), melanoma (n = 1), pancreatic cancer (n = 1), and thymic cancer (n = 1). No dose-limiting toxicities were observed. All adverse events (AEs) were grade 1 or 2 in severity. No discontinuations or deaths due to AEs were observed. As of the data cutoff, no partial responses were observed; however, stable disease was observed in all six patients. The maximum mean serum atezolizumab concentration was 220 μg/mL (SD ± 21.9), with 10-mg/kg dosing and 536 μg/mL (SD ± 49.4) with 20-mg/kg dosing. Three patients were still on treatment, and three of the six had achieved a progression-free survival of >12 months. Conclusions Atezolizumab was well tolerated in Japanese patients at doses up to 20 mg/kg q3w. The safety profile and Cycle 1 serum atezolizumab concentrations were similar to those previously observed in non-Japanese patients. These data support the participation of Japanese patients in ongoing pivotal global studies of atezolizumab.
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Prediction of Posttransplantation Recurrence of Hepatocellular Carcinoma Using Metabolic and Volumetric Indices of 18F-FDG PET/CT
18F-FDG PET is an effective method of predicting recurrence of hepatocellular carcinoma (HCC) after liver transplantation. We compared recently introduced metabolic and volumetric 18F-FDG PET/CT indices with the current clinicopathologic predictors for ability to predict recurrence. Methods: In total, 110 HCC patients who underwent 18F-FDG PET and liver transplantation were enrolled. On PET, SUVs and tumor-to-background ratios (TBRs) were measured as metabolic activity indices. Various metabolic tumor volumes and uptake-volume products (UVP) were also measured as volumetric indices. The ability of these indices and other clinicopathologic factors to predict recurrence was compared. Results: All metabolic and volumetric indices were significant for recurrence prediction on receiver-operating-characteristic curve analyses (P < 0.001). On univariate survival analyses, all PET indices—as well as tumor size, tumor number, the Milan criteria, tumor grade, vascular invasion, and T-stage—were significant factors. However, on multivariate analyses, tumor size, tumor grade, maximum TBR, and UVP calculated by inferior vena cava activity were significant factors (P = 0.004, 0.014, 0.009, and 0.021, respectively). When the Milan criteria and PET factors were included in the multivariate analysis, the Milan criteria (P = 0.029), maximum TBR (P < 0.001), and UVP (P = 0.016) were significant. Conclusion: Volumetric and metabolic activity indices of 18F-FDG PET are effective predictors of posttransplantation HCC recurrence. In addition to clinicopathologic factors, these indices need to be considered in the selection of candidates for liver transplantation.
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Relationship Between 18F-FDG PET/CT Findings and HER2 Expression in Gastric Cancer
18F-FDG PET has been widely used in the management of malignant tumors. In gastric cancer, the status of human epidermal growth factor receptor 2 (HER2) predicts the response to anti-HER2 antibody therapy, and testing of HER2 expression is now routine in the management of gastric cancer patients. However, to date, the relationship between 18F-FDG uptake and HER2 expression has not, to our knowledge, been investigated. In this study, we aimed to investigate whether HER2 expression is associated with 18F-FDG uptake and whether 18F-FDG PET/CT can be used to predict the HER2 status of gastric cancer. Methods: A retrospective analysis was performed on 64 gastric cancer patients who had undergone 18F-FDG PET/CT before surgical resection. Tumor SUVmax was calculated from the level of 18F-FDG uptake. Results: No significant correlation was found between SUVmax and HER2 expression in gastric cancer. However, when signet-ring cell carcinoma was excluded, SUVmax was significantly higher in the HER2-negative group than in the HER2-positive group (8.619 ± 5.878 vs. 3.789 ± 2.613, respectively; P = 0.021). Multivariate analysis indicated that SUVmax and tumor differentiation remained significantly associated with HER2 expression (P = 0.048 and P = 0.028, respectively). HER2 expression was predicted with an accuracy of 64.4% when an SUVmax cutoff of 6.2 was used. Conclusion: 18F-FDG uptake by gastric cancer is associated with HER2 expression. 18F-FDG PET/CT may be useful for predicting the HER2 status of gastric cancer and for determining the therapeutic strategy.
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Standardization of Administered Activities in Pediatric Nuclear Medicine: A Report of the First Nuclear Medicine Global Initiative Project, Part 2--Current Standards and the Path Toward Global Standardization
The Nuclear Medicine Global Initiative (NMGI) was formed in 2012 and consists of 13 international organizations with direct involvement in nuclear medicine. The underlying objectives of the NMGI are to promote human health by advancing the field of nuclear medicine and molecular imaging, encourage global collaboration in education, and harmonize procedure guidelines and other policies that ultimately lead to improvements in quality and safety in the field throughout the world. For its first project, the NMGI decided to consider the issues involved in the standardization of administered activities in pediatric nuclear medicine. It was decided to divide the final report of this project into 2 parts. Part 1 was published in this journal in the spring of 2015. This article presents part 2 of the final report. It discusses current standards for administered activities in children and adolescents that have been developed by various professional organizations. It also presents an evaluation of the current practice of pediatric nuclear medicine specifically with regard to administered activities as determined by an international survey of 313 nuclear medicine clinics and centers from 29 countries. Lastly, it provides recommendations for a path toward global standardization of the administration of radiopharmaceuticals in children.
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PET Mapping for Brain-Computer Interface Stimulation of the Ventroposterior Medial Nucleus of the Thalamus in Rats with Implanted Electrodes
Brain–computer interface (BCI) technology has great potential for improving the quality of life for neurologic patients. This study aimed to use PET mapping for BCI-based stimulation in a rat model with electrodes implanted in the ventroposterior medial (VPM) nucleus of the thalamus. Methods: PET imaging studies were conducted before and after stimulation of the right VPM. Results: Stimulation induced significant orienting performance. 18F-FDG uptake increased significantly in the paraventricular thalamic nucleus, septohippocampal nucleus, olfactory bulb, left crus II of the ansiform lobule of the cerebellum, and bilaterally in the lateral septum, amygdala, piriform cortex, endopiriform nucleus, and insular cortex, but it decreased in the right secondary visual cortex, right simple lobule of the cerebellum, and bilaterally in the somatosensory cortex. Conclusion: This study demonstrated that PET mapping after VPM stimulation can identify specific brain regions associated with orienting performance. PET molecular imaging may be an important approach for BCI-based research and its clinical applications.
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Single-Cell Characterization of 18F-FLT Uptake with Radioluminescence Microscopy
The radiotracer 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) is commonly used to measure cell proliferation in vivo. As a marker of cell proliferation, 18F-FLT is expected to be differentially taken up by arrested and actively dividing cells, but PET measures only aggregate uptake by tumor cells and therefore the single-cell distribution of 18F-FLT is unknown. We used a novel in vitro radioluminescence microscopy technique to measure the differential distribution of 18F-FLT radiotracer with single-cell precision. Methods: Using radioluminescence microscopy, we imaged the absolute uptake of 18F-FLT in live MDA-MB-231 cells grown under different serum conditions. We then compared 18F-FLT uptake with a standard measure of cell proliferation, using fluorescence microscopy of 5-ethynyl-2'-deoxyuridine incorporation in fixed cells. Results: According to 5-ethynyl-2'-deoxyuridine staining, few cells (1%) actively cycled under serum deprivation whereas most of them (71%) did under 20% serum. The distribution of 18F-FLT reflected this dynamic. At 0% serum, uptake of 18F-FLT was heterogeneous but relatively low. At 20% serum, a subpopulation of 18F-FLT–avid cells, representing 61% of the total population, emerged. Uptake of 18F-FLT in this population was 5-fold higher than in the remainder of the cells. Such a dichotomous distribution is not typically observed with other radiotracers, such as 18F-FDG. Conclusion: These results suggest that increased 18F-FLT uptake by proliferating cells is due to a greater fraction of 18F-FLT–avid cells rather than a change in 18F-FLT uptake by individual cells. This finding is consistent with the fact that 18F-FLT uptake is mediated by thymidine kinase 1 expression, which is higher in actively dividing cells. Overall, these findings suggest that, within the same patient, changes in 18F-FLT uptake reflect changes in the number of actively dividing cells, provided other parameters remain the same.
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A Prototype High-Resolution Small-Animal PET Scanner Dedicated to Mouse Brain Imaging
We developed a prototype small-animal PET scanner based on depth-encoding detectors using dual-ended readout of small scintillator elements to produce high and uniform spatial resolution suitable for imaging the mouse brain. Methods: The scanner consists of 16 tapered dual-ended-readout detectors arranged in a 61-mm-diameter ring. The axial field of view (FOV) is 7 mm, and the transaxial FOV is 30 mm. The scintillator arrays consist of 14 x 14 lutetium oxyorthosilicate elements, with a crystal size of 0.43 x 0.43 mm at the front end and 0.80 x 0.43 mm at the back end, and the crystal elements are 13 mm long. The arrays are read out by 8 x 8 mm and 13 x 8 mm position-sensitive avalanche photodiodes (PSAPDs) placed at opposite ends of the array. Standard nuclear-instrumentation-module electronics and a custom-designed multiplexer are used for signal processing. Results: The detector performance was measured, and all but the crystals at the very edge could be clearly resolved. The average intrinsic spatial resolution in the axial direction was 0.61 mm. A depth-of-interaction resolution of 1.7 mm was achieved. The sensitivity of the scanner at the center of the FOV was 1.02% for a lower energy threshold of 150 keV and 0.68% for a lower energy threshold of 250 keV. The spatial resolution within a FOV that can accommodate the entire mouse brain was approximately 0.6 mm using a 3-dimensional maximum-likelihood expectation maximization reconstruction. Images of a hot-rod microphantom showed that rods with a diameter of as low as 0.5 mm could be resolved. The first in vivo studies were performed using 18F-fluoride and confirmed that a 0.6-mm resolution can be achieved in the mouse head in vivo. Brain imaging studies with 18F-FDG were also performed. Conclusion: We developed a prototype PET scanner that can achieve a spatial resolution approaching the physical limits of a small-bore PET scanner set by positron range and detector interaction. We plan to add more detector rings to extend the axial FOV of the scanner and increase sensitivity.
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Insights into the Dose-Response Relationship of Radioembolization with Resin 90Y-Microspheres: A Prospective Cohort Study in Patients with Colorectal Cancer Liver Metastases
Randomized controlled trials are investigating the benefit of hepatic radioembolization added to systemic therapy in the first- and second-line treatment of patients with colorectal liver metastases (CRLM). Remarkably, administered activity may still be suboptimal, because a dose–response relationship has not been defined. The purpose of this study was to characterize the relationship between tumor-absorbed dose and response after 90Y radioembolization treatment for CRLM. Methods: Thirty patients with unresectable chemorefractory CRLM were treated with resin 90Y-microspheres in a prospective phase II clinical trial. Tumor-absorbed dose was quantified on 90Y PET. Metabolic tumor activity, defined as tumor lesion glycolysis (TLG*) on 18F-FDG PET, was measured at baseline and 1 mo after treatment. The relationship between tumor-absorbed dose and posttreatment metabolic activity was assessed per metastasis with a linear mixed-effects regression model. Results: Treated metastases (n = 133) were identified. The mean tumor-absorbed dose was 51 ± 28 Gy (range, 7–174 Gy). A 50% reduction in TLG* was achieved in 46% of metastases and in 11 of 30 (37%) patients for the sum of metastases. The latter was associated with a prolonged median overall survival (11.6 vs. 6.6 mo, P = 0.02). A strong and statistically significant dose–response relationship was found (P < 0.001). The dose effect depended on baseline TLG* (P < 0.01). The effective tumor-absorbed dose was conservatively estimated at a minimum of 40–60 Gy. Conclusion: A strong dose–response relationship exists for the treatment of CRLM with resin microsphere 90Y radioembolization. Treatment efficacy is, however, still limited, because the currently used pretreatment activity calculation methods curb potentially achievable tumor-absorbed dose values. A more personalized approach to radioembolization is required before concluding on its clinical potential.
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Comparative Evaluation of the Biodistribution Profiles of a Series of Nonpeptidic Neurotensin Receptor-1 Antagonists Reveals a Promising Candidate for Theranostic Applications
Neurotensin receptor-1 (NTR1) is a promising target for diagnostic imaging and targeted radionuclide therapy. The aim of this study was to evaluate the biodistribution profiles of a series of newly developed diarylpyrazole-based NTR1 antagonists regarding their suitability as diagnostic and potentially radiotherapeutic agents. Methods: 3BP-227, 3BP-228, and 3BP-483 were labeled with 111In and injected intravenously into NTR1-positive HT29 xenograft–bearing nude mice. At 3, 6, 12, and 24 h after administration, SPECT/CT images were acquired or mice were sacrificed for ex vivo determination of tissue-associated radioactivity. Results: High-contrast tumor visualization in SPECT/CT images was achieved using the 3 compounds of this study. Ex vivo biodistribution studies confirmed a high and persistent tumor uptake, peaking at 6 h after injection for 111In-3BP-227 (8.4 ± 3.1 percentage injected dose per gram [%ID/g]) and at 3 h after injection for 111In-3BP-228 (10.2 ± 5.3 %ID/g) and 111In-3BP-483 (1.9 ± 0.8 %ID/g). Tumor–to–normal-tissue ratios obtained with 111In-3BP-227 and 111In-3BP-228 were consistently greater than 1. Conclusion: On the basis of the superior biodistribution profile compared with previously reported radiolabeled NTR1 ligands, 111In-3BP-227 is an ideal candidate for further development as a theranostic tracer.
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Dose-Response Relationship in Differentiated Thyroid Cancer Patients Undergoing Radioiodine Treatment Assessed by Means of 124I PET/CT
The dose–response relationship in a fixed-activity approach generally applied in the treatment of differentiated thyroid cancer was assessed using 124I PET/CT. Methods: Pretherapeutic 124I PET/CT images of 47 patients scheduled for radioiodine therapy were retrospectively analyzed. 124I PET/CT images were acquired 24 and 96 h after oral administration of approximately 28 MBq of 124I-sodium iodide. Lesions were identified as thyroid remnants or metastases (lymph node, lung, bone). After a neoteric segmentation technique allowing accurate volume estimation down to the 124I PET spatial resolution of 0.15 mL was applied, lesions were divided into a known-volume group and a small-volume group. For the known-volume group, average lesion-absorbed dose (AD) values were calculated, whereas for the small-volume group a minimum lesion AD was estimated. Lesion response was determined on the basis of 124I PET/CT and 131I SPECT/CT follow-up images. A lesion not detectable on any of the follow-up images was considered a completely responding lesion. Differences in lesion AD estimations between completely and incompletely responding lesions were evaluated by Mann–Whitney U test. Moreover, receiver-operating-characteristic curves were used to test the performance of pretherapeutic 124I PET/CT lesion AD for prediction of complete lesion response. Results: In the approach of fixed radioiodine activity (3.0 ± 1.0 GBq), 89% of thyroid remnants and 69% of metastases responded completely. Except for the small-volume groups, the lesion AD of completely responding lesions was significantly higher than that of incompletely responding lesions. Using receiver-operating-characteristic curve analysis, it was shown that for the known-volume group, pretherapeutic 124I PET/CT lesion dosimetry can be used as a prognostic tool to predict lesion-based 131I therapy response with an area under the curve of 0.76 for remnants and 0.97 for metastases. The corresponding lesion AD threshold value maximizing correct complete response prediction was 90 Gy for remnants and 40 Gy for metastases. Conclusion: In a fixed-activity approach, a statistically significant dose–response relationship for both thyroid remnants and metastases using pretherapeutic 124I PET/CT lesion dosimetry was found. The findings may be useful in patient management.
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177Lu-Labeled Prostate-Specific Membrane Antigen Radioligand Therapy of Metastatic Castration-Resistant Prostate Cancer: Safety and Efficacy
The objective of this study was to analyze the safety and efficacy of the 177Lu-labeled DOTAGA-based prostate-specific membrane antigen (PSMA) ligand 177Lu-DOTAGA-(I-y)fk(Sub-KuE) (177Lu-PSMA) in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: Fifty-six mCRPC patients underwent PSMA radioligand therapy (RLT) with 177Lu-PSMA. 68Ga-PSMA-(N,N'-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid) (68Ga-PSMA) PET/CT was used for patient selection and follow-up after PSMA RLT. Hematologic status, renal function, and serum prostate-specific antigen levels were documented before and after therapy. Dosimetry was performed in 30 patients. Results: 177Lu-PSMA demonstrated high absorbed tumor doses (median, 3.3 mGy/MBq) compared with the levels in normal organs. Parotid glands received higher doses (1.3 mGy/MBq) than kidneys (0.8 mGy/MBq). All patients tolerated the therapy without any acute adverse effects. Except for mild reversible xerostomia in 2 patients, no long-term side effects were observed. There was a small but statistically significant reduction in erythrocyte and leukocyte counts; only the reduction in erythrocyte counts decreased slightly below the reference range. No thrombocytopenia occurred. The severity of pain was significantly reduced in 2 of 6 patients (33.3%). A decrease in prostate-specific antigen levels was noted in 45 of 56 patients (80.4%). Of 25 patients monitored for at least 6 mo after 2 or more PSMA RLT cycles, a molecular response evaluation (68Ga-PSMA PET/CT) revealed partial remission in 14, stable disease in 2, and progressive disease in 9 patients. Contrast-enhanced CT revealed partial remission in 5, stable disease in 13, and progressive disease in 7 patients. The median progression-free survival was 13.7 mo, and the median overall survival was not reached during follow-up for 28 mo. Conclusion: PSMA RLT with 177Lu-PSMA is feasible, safe, and effective in end-stage progressive mCRPC with appropriate selection and follow-up of patients by 68Ga-PSMA PET/CT through application of the concept of theranostics.
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A Microdosimetric Analysis of Absorbed Dose to Tumor as a Function of Number of Microspheres per Unit Volume in 90Y Radioembolization
Differences in maximum tolerable absorbed dose to normal liver between 90Y radioembolization and external-beam radiation therapy have been explained by citing differences in absorbed-dose heterogeneity at the microscopic level. We investigated microscopic absorbed-dose heterogeneity in radioembolization as a function of the number of microspheres per unit volume in tumor. The goal was to determine what effect the number of microspheres may have, if any, on tumor control in 90Y radioembolization. Methods: 90Y PET/CT data were combined with microscopic probability-density functions describing microsphere clustering to provide realistic simulation using Monte Carlo modeling on both a macroscopic and a microscopic level. A complete microdosimetric analysis using 100-μm voxels was performed on the basis of 90Y PET/CT data from 19 tumors treated using radioembolization. Simulations were performed with average tumor microsphere-number densities from 200 to 70,000 spheres/mL. Monte Carlo simulations of each tumor and number density were repeated 20 times to establish SE. A 2-way balanced ANOVA was used to determine whether differences in microsphere-number density affected common tumor-dose metrics. Results: Decreasing the microsphere-number density resulted in a decrease in D70, the minimum dose to 70% of the tumor. The slope of the dose–volume histogram also decreased with decreasing microsphere-number density in all tumors. Compared with a density of 50,000 spheres/mL, decreases in D70 were statistically significant below 20,000 spheres/mL. However, these differences are unlikely to have clinical significance until the density decreases to below 5,000 spheres/mL. Although D70 was decreased at a low microsphere-number density, one can compensate for decreases by an increase in the average tumor-absorbed dose, that is, by increasing the radioembolization treatment dose. Conclusion: Differences in microsphere-number density may have an effect on microscopic tumor absorbed-dose inhomogeneity. These results begin to explain differences in treatment planning strategies between glass and resin radioembolization devices.
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Comparison of Tumor Uptake Heterogeneity Characterization Between Static and Parametric 18F-FDG PET Images in Non-Small Cell Lung Cancer
18F-FDG PET is well established in the field of oncology for diagnosis and staging purposes and is increasingly being used to assess therapeutic response and prognosis. Many quantitative indices can be used to characterize tumors on 18F-FDG PET images, such as SUVmax, metabolically active tumor volume (MATV), total lesion glycolysis, and, more recently, the proposed intratumor uptake heterogeneity features. Although most PET data considered within this context concern the analysis of activity distribution using images obtained from a single static acquisition, parametric images generated from dynamic acquisitions and reflecting radiotracer kinetics may provide additional information. The purpose of this study was to quantify differences between volumetry, uptake, and heterogeneity features extracted from static and parametric PET images of non–small cell lung carcinoma (NSCLC) in order to provide insight on the potential added value of parametric images. Methods: Dynamic 18F-FDG PET/CT was performed on 20 therapy-naive NSCLC patients for whom primary surgical resection was planned. Both static and parametric PET images were analyzed, with quantitative parameters (MATV, SUVmax, SUVmean, heterogeneity) being extracted from the segmented tumors. Differences were investigated using Spearman rank correlation and Bland–Altman analysis. Results: MATV was slightly smaller on static images (–2% ± 7%), but the difference was not significant (P = 0.14). All derived parameters, including those characterizing tumor functional heterogeneity, correlated strongly between static and parametric images (r = 0.70–0.98, P ≤ 0.0006), exhibiting differences of less than ±25%. Conclusion: In NSCLC primary tumors, parametric and static baseline 18F-FDG PET images provided strongly correlated quantitative features for both standard (MATV, SUVmax, SUVmean) and heterogeneity quantification. Consequently, heterogeneity quantification on parametric images does not seem to provide significant complementary information compared with static SUV images.
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PET/CT Imaging of Chemokine Receptors in Inflammatory Atherosclerosis Using Targeted Nanoparticles
Atherosclerosis is inherently an inflammatory process that is strongly affected by the chemokine–chemokine receptor axes regulating the trafficking of inflammatory cells at all stages of the disease. Of the chemokine receptor family, some specifically upregulated on macrophages play a critical role in plaque development and may have the potential to track plaque progression. However, the diagnostic potential of these chemokine receptors has not been fully realized. On the basis of our previous work using a broad-spectrum peptide antagonist imaging 8 chemokine receptors together, the purpose of this study was to develop a targeted nanoparticle for sensitive and specific detection of these chemokine receptors in both a mouse vascular injury model and a spontaneously developed mouse atherosclerosis model. Methods: The viral macrophage inflammatory protein-II (vMIP-II) was conjugated to a biocompatible poly(methyl methacrylate)-core/polyethylene glycol-shell amphiphilic comblike nanoparticle through controlled conjugation and polymerization before radiolabeling with 64Cu for PET imaging in an apolipoprotein E–deficient (ApoE–/–) mouse vascular injury model and a spontaneous ApoE–/– mouse atherosclerosis model. Histology, immunohistochemistry, and real-time reverse transcription polymerase chain reaction were performed to assess the plaque progression and upregulation of chemokine receptors. Results: The chemokine receptor–targeted 64Cu-vMIP-II-comb showed extended blood retention and improved biodistribution. PET imaging showed specific tracer accumulation at plaques in ApoE–/– mice, confirmed by competitive receptor blocking studies and assessment in wild-type mice. Histopathologic characterization showed the progression of plaque including size and macrophage population, corresponding to the elevated concentration of chemokine receptors and more importantly increased PET signals. Conclusion: This work provides a useful nanoplatform for sensitive and specific detection of chemokine receptors to assess plaque progression in mouse atherosclerosis models.
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Prediction of PSA Progression in Castration-Resistant Prostate Cancer Based on Treatment-Associated Change in Tumor Burden Quantified by 18F-Fluorocholine PET/CT
Measurements of metabolically active tumor volume (MATV) can be applied to 18F-fluorocholine PET/CT to quantify whole-body tumor burden. This study evaluated the serial application of these measurements as systemic treatment response markers and predictors of disease progression in patients with castration-resistant prostate cancer (CRPC). Methods: Forty-two patients completed sequential 18F-fluorocholine PET/CT scans before and 1–3 mo after starting treatment for CRPC. Whole-body tumor segmentation was applied to determine net MATV from each scan. Changes in net MATV were evaluated as predictors of time to prostate-specific antigen (PSA) progression by Kaplan–Meier and proportional hazards regression analysis. Results: Treatments consisted of chemotherapy in 16 patients, antiandrogens in 19 patients, 223Ra-dichloride in 5 patients, and sipuleucel-T in 2 patients. A significant MATV response (defined as a ≥30% decrease in net MATV) was observed in 20 patients on the basis of in-treatment PET/CT performed an average of 51 d (median, 49 d) into treatment. Significantly longer times to PSA progression were observed in patients who exhibited an MATV response (418 d vs. 116 d, P = 0.0067). MATV response was associated with a hazard ratio of 0.246 (P = 0.0113) for PSA progression, which remained significant when adjusted for treatment type. Conclusion: Significant changes in whole-body tumor burden can be measured on 18F-fluorocholine PET/CT over the course of contemporary treatments for CRPC. In this study, these changes were found to be predictive of PSA progression as a potential surrogate marker of treatment outcome. Because 18F-fluorocholine PET/CT can also be used for localizing resistant tumors, this modality can potentially complement other measures of response in the precision management of advanced prostate cancer.
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Neisseriae internalization by epithelial cells is enhanced by TLR2 stimulation
Source:Microbes and Infection
Author(s): Deana N. Toussi, Lee M. Wetzler, Xiuping Liu, Paola Massari
N. meningitidis (NM) is an opportunistic gram-negative human pathogen that colonizes the human nasopharyngeal epithelium. Asymptomatic carriage is common, but some meningococcal strains can invade nasopharyngeal epithelial cells and proceed to cause severe and often fatal infections. Invasion is predominantly driven by expression of bacterial virulence factors and host cell cognate receptors for bacterial recognition. Porins are among the Neisserial components involved in host cell activation and bacterial internalization processes. Similar to other virulence factors, porins present antigenic and structure variability among strains. Such sequence variability in the surface-exposed loop regions has been correlated to bacterial invasiveness and to variability in host cell responses via Toll-like receptor 2 (TLR2). Here, we examined whether TLR2 signaling by porins influences recovery of intracellular Neisseriae from epithelial cells in vitro. Our results show that TLR2 stimulation, either by the organism or exogenously, generally enhances Neisseriae internalization by epithelial cells. TLR2-driven intracellular signaling via ERK1/2, JNK and particularly NF-κB plays a role in this process. Based on these results, it is possible that expression of porin sequence variants that strongly induce TLR2 activation may be a mechanism to enhance the invasive features of pathogenic Neisseriae strains.
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Effects of TP53 and PIK3CA mutations in early breast cancer: a matter of co-mutation and tumor-infiltrating lymphocytes
Abstract
The purpose of this study is to investigate whether the outcome of breast cancer (BC) patients treated with adjuvant chemotherapy is affected by co-mutated TP53 and PIK3CA according to stromal tumor-infiltrating lymphocytes (TILs). Paraffin tumors of all clinical subtypes from 1661 patients with operable breast cancer who were treated within 4 adjuvant trials with anthracycline–taxanes chemotherapy were informative for TP53 and PIK3CA mutation status (semiconductor sequencing genotyping) and for stromal TILs density. Disease-free survival (DFS) was examined. TP53 mutations were associated with higher (p < 0.001) and PIK3CA with lower (p = 0.004) TILs in an ER /PgR-specific manner (p < 0.001). Mutations did not affect the favorable DFS of patients with lymphocyte-predominant (LP) BC. Within non-LPBC, PIK3CA-only mutations conferred best, while TP53–PIK3CA co-mutations (6 % of all tumors) conferred worst DFS (HR 0.59; 95 % CI 0.44–0.79; p = 0.001 for PIK3CA-only). TP53-only mutations were unfavorable in patients with lower TILs, while patients with lower TILs performed worse if their tumors carried TP53-only mutations (interaction p = 0.046). Multivariate analysis revealed favorable PIK3CA-only mutations in non-LPBC (HR 0.64; 95 % CI 0.47–0.88; p = 0.007), and unfavorable TP53 mutations in ER/PgRpos/HER2neg (HR 1.55; 95 % CI 1.07–2.24; p = 0.021). Mutations did not interact with TILs in non-LP triple-negative and HER2-positive patients. TP53 and PIK3CA mutations appear to have diverse effects on the outcome of early BC patients, according to whether these genes are co-mutated or not, and for TP53 according to TILs density and ER/PgR-status. These findings need to be considered when evaluating the effect of these two most frequently mutated genes in the context of large clinical trials.
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Fifty top-cited fracture articles from China: a systematic review and bibliometric analysis
Background: With more than 50,000 orthopaedic surgeons, China is having an increasing impact on fracture surgery research. However, the most influential Chinese articles on fracture surgery have not been determined. This study aimed to characterise the most-cited articles on fracture surgery by Chinese authors to provide insight into the fracture research in China. Methods: The Web of Science was used to search for citations of fracture surgery articles that originated in China. The 50 most-cited articles were identified. The title, number of citations, year of publication, journal, article type, level of evidence, city, institution, and authors were recorded and evaluated. Results: The 50 top-cited papers were published between 1984 and 2012. The most prolific decade began in the year 2000. These articles received 28 to 209 citations (mean 52), were written in English, and published in 12 journals. Injury was the most popular journal, with the largest number of articles (11) on the top 50 list. The region with the largest number of published articles was Hong Kong (20), followed by Kaohsiung (8), Shanghai (8), and Taipei (7). Most were clinical studies (39), while the remaining studies were basic science articles (11). The hip was the most common topic in the clinical studies. The most popular level of evidence was IV. Conclusions: This list of the top 50 publications identifies the most influential Chinese fracture surgery articles for the global community. This study presents insight into the historical contributions of Chinese researchers and the fracture surgery trends in China.
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The emergence of hepatitis E virus in Europe
Hepatitis E virus (HEV) infections appear to be an emerging problem in Europe. Infections are mainly caused by viruses of genotype 3. Pigs and wild boar are the main reservoirs of HEV in Europe and most autochthonous infections are probably caused by the consumption of uncooked or undercooked infected meat. Nevertheless, transfusion-associated transmission has been described in different European countries but the efficiency of this route of transmission need to be further investigated. Most acute infections are asymptomatic or the induced symptoms are rather nonspecific. Although people that are otherwise completely healthy can spontaneously clear an HEV infection, people with underlying liver disease and/or suffering from immune deficiencies may require treatment to avoid chronicity and exacerbation of liver disease. In this review, we give an epidemiological overview of HEV in Europe and the potential complications.
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Recurrent mutations in the basic domain of TWIST2 cause ablepharon macrostomia and Barber-Say syndromes
Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TW1ST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-1'WIST2 in HeLa cells. Comparison of wild-type and mutant TW1ST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TW1ST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding.
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Polyphenols inhibit hepatitis C virus entry by a new mechanism of action
Despite the validation of direct-acting antivirals for hepatitis C treatment, the discovery of new compounds with different modes of action may still be of importance for the treatment of special patient populations. We recently identified a natural molecule, epigallocatechin-3-gallate (EGCG), as an inhibitor of hepatitis C virus (HCV) targeting the viral particle. The aim of this work was to discover new natural compounds with higher anti-HCV activity than that of EGCG and determine their mode of action. Eight natural molecules with structure similarity to EGCG were selected. HCV JFH1 in cell culture and HCV pseudoparticle systems were used to determine the antiviral activity and mechanism of action of the compounds. We identified delphinidin, a polyphenol belonging to the anthocyanidin family, as a new inhibitor of HCV entry. Delphinidin inhibits HCV entry in a pangenotypic manner by acting directly on the viral particle and impairing its attachment to the cell surface. Importantly, it is also active against HCV in primary human hepatocytes, with no apparent cytotoxicity and in combination with interferon and boceprevir in cell culture. Different approaches showed that neither aggregation nor destruction of the particle occurred. Cryo-transmission electron microscopy observations of HCV pseudoparticles treated with delphinidin or EGCG showed a bulge on particles that was not observed under control conditions. In conclusion, EGCG and delphinidin inhibit HCV entry by a new mechanism, i.e., alteration of the viral particle structure that impairs its attachment to the cell surface. IMPORTANCE In this article, we identify a new inhibitor of hepatitis C virus (HCV) infection, delphinidin, that prevents HCV entry. This natural compound, a plant pigment responsible for the blue-purple color of flowers and berries, belongs to the flavonoid family, like the catechin EGCG, the major component present in green tea extract, which is also an inhibitor of HCV entry. We studied the mode of action of these two compounds against HCV and demonstrated that they both act directly on the virus, inducing a bulging of the viral envelope. This deformation might be responsible for the observed inhibition of virus attachment to the cell surface. The discovery of such HCV inhibitors with an unusual mode of action is important to better characterize the mechanism of HCV entry into hepatocytes and to help develop a new class of HCV entry inhibitors.
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Animal models for the study of HCV
The development and evaluation of effective therapies and vaccines for the hepatitis C virus (HCV) and the study of its interactions with the mammalian host have been hindered for a long time by the absence of suitable small animal models. Immune compromised mouse models that recapitulate the complete HCV life cycle have been useful to investigate many aspects of the HCV life cycle including antiviral interventions. However, HCV has a high propensity to establish persistence and associated histopathological manifestations such as steatosis, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Better understanding of these processes requires the development of a permissive and fully immunocompetent small animal model. In this review we summarize the in vivo models that are available for the study of HCV.
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The Development of Simple Methods for the Maintenance and Quantification of Polymyxa graminis
Abstract
Polymyxa graminis, a root endoparasite of several cereal species, is considered to be non-pathogenic but serves as a vector of various plant viruses belonging to the genera Bymovirus, Furovirus, and Pecluvirus. Specifically, it reduces barley productivity by transmitting the Barley Yellow Mosaic Virus (BaYMV). To date, due to its obligate biotrophic property, no artificial culturing of P. graminis was reported and its quantification was also technically challenging. Here, we developed a novel and simple method to infect P. graminis within sterile barley roots in contamination free by preparing nearly pure zoospore inoculum. Such artificial maintenance of P. graminis was verified based on the presence of various developmental stages in infected barley roots under microscope. In addition, the population of resting spores in host tissue was determined by establishing standard curve between manually counted number of spores and Ct values of 18S rDNA amplification using quantitative real-time PCR. Furthermore, it was validated that standard curve generated was also applicable to estimate the abundance of P. graminis in soil environments. In conclusion, the present study would help to generate a system to investigate the etiological causes as well as management of plant diseases caused by P. graminis and BaYMV in tissue and soil.
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Is your ambulance partner safe at home?
EMT Ashley Scott, allegedly shot to death by her husband — also an EMT, is my most recent reminder of Kelly Wing-Schmidt.
Throughout a 12-hour shift with paramedic student Kelly, I asked her all sorts of questions.
- What is the pediatric dose of diphenhydramine for anaphylaxis"
- When will you want to recheck this patient's vital signs"
- Are you worried about this woman's blood pressure" Why not"
- Should we assist this patient off the floor or do we need to lift her"
- Why do you want to be a paramedic"
- Do you want to get a job here"
I always enjoyed having students on the ambulance and really embraced the role of instructor and mentor. Kelly answered my questions and asked me just as many questions. She was eager to learn and I was thrilled to help.
The question I never asked Kelly that day: "Are you safe at home""
A few weeks later her estranged husband, Scott Schmidt, a full-time firefighter, fatally shot Kelly and injured his mother-in-law. Kelly was only 39 and was remembered as caring, genuine and full of life.
I made a vow to honor Kelly
I think of Kelly, her five kids and family and her potential as a caregiver — a life cut short by an abusive and violent man — each time I read news about a woman killed by a boyfriend or spouse.
I don't recall a hint, a gut feeling or notion that Kelly may have been in danger during the half-day I spent with her. But after she was murdered I made a vow that if I ever believed a friend, a relative or a co-worker was in danger from domestic abuse or intimate partner violence that I would start the conversation with this question: "Are you safe at home""
Intuition is the powerful hardwiring that drives us to fight or flee. It also enables us to suspect and recognize internal bleeding, sepsis, stroke or heart attack before we have collected any vital signs or connected patient electrodes. EMS providers make at-the-door first impressions on every patient contact. Is the patient sick or not sick"
I received an article from a woman dating a paramedic. She wrote about his struggles with PTSD. As I read the article, alarm bells were ringing — sleepless nights, alcohol abuse and unpredictable behaviors. I reached out to her immediately, "Are you safe at home""
She quickly replied, "Totally safe at home. I didn't realize it read like that."
Almost no one ever asks the question, "are you safe"" when they suspect domestic violence. So, for Kelly, I became the guy who always asks. I was thrilled and relieved the writer's answer was "safe."
Too often bad situations go on too long because no one was the first to reach out. Kelly Grayson so eloquently wrote, "peer support is the lifeline that never fails."
I don't want to be the one that could have said something and didn't out of fear for an awkward conversation.
Honor the dead by helping the living
My heartaches for the friends and family of Kelly Wing-Schmidt and Ashley Scott. I am sure they are worried sick about signs of abuse they either saw or might have missed. Forgive yourself, talk about it and ask for help. One of the best decisions I ever made was seeking out help from my agency's employee assistance program after Kelly's murder.
This isn't the first time EMS1 has covered an EMS provider who was known to be or might have been the victim of domestic abuse. Texas paramedic Melissa Morden was allegedly killed by her boyfriend. Ohio firefighter-paramedic Tonya Johnson was hit and killed by a car after an argument with her husband. Her family challenged the medical examiner's ruling that her death was a suicide. Connecticut EMT Lisa Infante was shot and killed by her husband.
EMS providers are constantly assessing safety in dynamic and potentially life-threatening situations. Our concern for safety is personal and partner focused. Our intuition skills don't shut down between calls or during off-duty interactions. If your alarm bells ring about the threat or actual danger of violence be willing to ask, "Are you safe at home""
Or make your own script. Art Hsieh, EMS1 editorial advisor, recommends this approach, "I am concerned for your safety. There are people and programs that can provide you with assistance. You do not need to be treated this way."
Yes, these scripts can be used for patients, partners, friends or relatives. Trust your instincts and ask a simple question which might save a life.
If you or someone you love is the victim of domestic violence, you are not alone and there is help available. Search http://ift.tt/1qmgnVB or call the National Domestic Violence Hotline at 1-800-799-7233 (SAFE).
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Strenuous physical exercise accelerates the lipid peroxide clearing transport by HDL
Abstract
Purpose
Physical exercise has cardioprotective functions, which have been partly linked to high-density lipoprotein (HDL), and its functions. We studied the effects of endogenous oxidative stress, induced by acute exhaustive physical exercise, on concentration of oxidized HDL lipids.
Methods
Twenty-four male national top-level endurance runners, 12 middle-distance runners and 12 marathon runners performed a maximal run on a treadmill until exhaustion. We analyzed concentrations of oxidized HDL (oxHDLlipids) and LDL lipids (oxLDLlipids), serum antioxidant potential (TRAP), paraoxonase activity and malondialdehyde. Venous blood samples were taken before, immediately, 15 and 90 min after exercise.
Results
Immediately after the treadmill run the concentration of oxHDLlipids was increased by 24 % (p < 0.01). Simultaneously, the ratio of oxHDLlipids to oxLDLlipids increased by 55 % and the oxLDLlipids levels decreased by 19 % (p < 0.001), while serum malondialdehyde and TRAP increased by 54 % (p < 0.001) and 29 % (p < 0.01), respectively. After the 90 min recovery the concentration of oxHDLlipids was decreased towards the pre-exercise level, but that of oxLDLlipids remained decreased below pre-exercise values (p < 0.001). The change in oxLDLlipids after the run correlated positively with VO2max (r = 0.67, p < 0.001) and negatively with the change in paraoxonase activity (r = −0.47, p < 0.05).
Conclusions
We conclude that acute exhaustive physical exercise increased the concentration of oxHDLlipids and decreased that of oxLDLlipids and the ratio of oxLDLlipids to oxHDLlipids, which suggests that during physical exercise HDL has an active role in the removal of lipid peroxides.
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Noninvasively detecting Isocitrate dehydrogenase 1 gene status in astrocytoma by dynamic susceptibility contrast MRI
Purpose
To investigate the value of dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) in the noninvasive evaluation of isocitrate dehydrogenase (IDH) 1 gene status in astrocytoma.
Materials and Methods
The preoperative DSC MRI data of 91 lesions with pathologically confirmed astrocytoma were retrospectively analyzed. MR examination was performed on a 3T MRI scanner. The normalized maximum ratios of relative cerebral blood volume (rCBV ratio) of tumor parenchyma were measured. The enrolled astrocytoma patients were divided into six groups according to the World Health Organization (WHO) classification method and IDH1 gene status. The differences in the rCBV ratio of tumor parenchyma between the IDH1 gene mutant and wildtype groups of WHO grade II, III, and IV were compared and plotted receiver operating characteristic (ROC) curves were drawn.
Results
The IDH1 gene mutant and wildtype groups of WHO grade II, III, and IV astrocytoma showed differences in the rCBV ratio (P = 0.005, 0.045, and 0.005, respectively). In WHO grade II, III, and IV astrocytoma, the area under the ROC curve was respectively 0.83, 0.86, and 0.94. The cutoff value of the rCBV ratio was respectively 2.20, 3.14, and 5.63.
Conclusion
The rCBV ratio value provided by DSC MRI provides a new potential imaging method for the noninvasive evaluation of the IDH1 status in astrocytoma. J. Magn. Reson. Imaging 2016.
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Assessment of histological differentiation in gastric cancers using whole-volume histogram analysis of apparent diffusion coefficient maps
Purpose
To investigate the efficacy of histogram analysis of the entire tumor volume in apparent diffusion coefficient (ADC) maps for differentiating between histological grades in gastric cancer.
Materials and Methods
Seventy-eight patients with gastric cancer were enrolled in a retrospective 3.0T magnetic resonance imaging (MRI) study. ADC maps were obtained at two different b values (0 and 1000 sec/mm2) for each patient. Tumors were delineated on each slice of the ADC maps, and a histogram for the entire tumor volume was subsequently generated. A series of histogram parameters (eg, skew and kurtosis) were calculated and correlated with the histological grade of the surgical specimen. The diagnostic performance of each parameter for distinguishing poorly from moderately well-differentiated gastric cancers was assessed by using the area under the receiver operating characteristic curve (AUC).
Results
There were significant differences in the 5th, 10th, 25th, and 50th percentiles, skew, and kurtosis between poorly and well-differentiated gastric cancers (P < 0.05). There were correlations between the degrees of differentiation and histogram parameters, including the 10th percentile, skew, kurtosis, and max frequency; the correlation coefficients were 0.273, –0.361, –0.339, and –0.370, respectively. Among all the histogram parameters, the max frequency had the largest AUC value, which was 0.675.
Conclusion
Histogram analysis of the ADC maps on the basis of the entire tumor volume can be useful in differentiating between histological grades for gastric cancer. J. Magn. Reson. Imaging 2016.
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Acute kidney damage induced by low- and iso-osmolar contrast media in rats: Comparison study with physiologic MRI and histologic-gene examination
Purpose
To investigate the physiopathological effects of low- and iso-osmolar contrast media (CM) on renal function with physiologic MRI and histologic-gene examination.
Materials and Methods
Forty-eight rats underwent time-course DWI and DCE-MRI at 3.0 Tesla (T) before and 5–15 min after exposure of CM or saline (Iop.370: 370 mgI/mL iopromide; Iod.320: 320 mgI/mL iodixanol; Iod.270: 270 mgI/mL iodixanol; 4 gI/kg body weight). Intrarenal viscosity was reflected by apparent diffusion coefficient (ADC). Renal physiologies were evaluated by DCE-derived glomerular filtration rate (GFR), renal blood flow (RBF), and renal blood volume (RBV). Potential acute kidney injury (AKI) was determined by histology and the expression of kidney injury molecule 1 (Kim-1).
Results
Iop.370 mainly increased ADC in inner-medulla (△ADCIM: 12.3 ± 11.1%; P < 0.001). Iod.320 and Iod.270 mainly decreased ADC in outer-medulla (△ADCIM; Iod.320: 16.8 ± 7.5%; Iod.270: 18.1 ± 9.5%; P < 0.001) and inner-medulla (△ADCIM; Iod.320: 28.4 ± 9.3%; Iod.270: 30.3 ± 6.3%; P < 0.001). GFR, RBF and RBV were significantly decreased by Iod.320 (△GFR: 45.5 ± 24.1%; △RBF: 44.6 ± 19.0%; △RBV: 35.2 ± 10.1%; P < 0.001) and Iod.270 (33.2 ± 19.0%; 38.1 ± 15.6%; 30.1 ± 10.1%; P < 0.001), while rarely changed by Iop.370 and saline. Formation of vacuoles and increase in Kim-1 expression was prominently detected in group of Iod.320, while rarely in Iod.270 and Iop.370.
Conclusion
Iso-osmolar iodixanol, given at high-dose, produced prominent AKI in nonhydrated rats. This renal dysfunction could be assessed noninvasively by physiologic MRI. J. Magn. Reson. Imaging 2016.
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Semiquantitative dynamic contrast-enhanced MRI for accurate classification of complex adnexal masses
Purpose
To identify the best dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) descriptive parameters in predicting malignancy of complex ovarian masses, and develop an optimal decision tree for accurate classification of benign and malignant complex ovarian masses.
Materials and Methods
Preoperative DCE-MR images of 55 sonographically indeterminate ovarian masses (27 benign and 28 malignant) were analyzed prospectively. Four descriptive parameters of the dynamic curve, namely, time-to-peak (TTP), wash-in-rate (WIR), relative signal intensity (SIrel), and the initial area under the curve (IAUC60) were calculated on the normalized curves of specified regions-of-interest (ROIs). A two-tailed Student's t-test and two automated classifiers, linear discriminant analysis (LDA) and support vector machines (SVMs), were used to compare the performance of the mentioned parameters individually and in combination with each other.
Results
TTP (P = 6.15E-8) and WIR (P = 5.65E-5) parameters induced the highest sensitivity (89% for LDA, and 97% for SVM) and specificity (93% for LDA, and 100% for SVM), respectively. Regarding the high sensitivity of TTP and high specificity of WIR and through their combination, an accurate and simple decision-tree classifier was designed using the line equation obtained by LDA classification model. The proposed classifier achieved an accuracy of 89% and area under the ROC curve of 93%.
Conclusion
In this study an accurate decision-tree classifier based on a combination of TTP and WIR parameters was proposed, which provides a clinically flexible framework to aid radiologists/clinicians to reach a conclusive preoperative diagnosis and patient-specific therapy plan for distinguishing malignant from benign complex ovarian masses. J. Magn. Reson. Imaging 2016.
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