Spontaneous Regression of Ovarian Carcinoma After Septic Peritonitis; A Unique Case Report.
Despite advances in therapy, ovarian cancer remains the most lethal gynecological malignancy and prognosis has not substantially improved over the past 3 decades. Immunotherapy is a promising new treatment option. However, the immunosuppressive cancer microenvironment must be overcome for immunotherapy to be successful. Here, we present a unique case of spontaneous regression of ovarian carcinoma after septic peritonitis. A 79-year-old woman was diagnosed with stage IIIc ovarian cancer. The omental cake biopsy was complicated by sepsis. Although the patient recovered, her physical condition did not allow further treatment for her ovarian cancer. After 6 months, spontaneous regression of the tumor was observed during surgery. Analysis of the immune infiltrate in the tissues showed a shift from a pro-tumorigenic to an anti-tumorigenic immune response after sepsis. Strong activation of the immune system during sepsis overruled the immunosuppressive tumor microenvironment and allowed for a potent anti-tumor immune response. More understanding of immunological responses in cases with cancer and septic peritonitis might be crucial to identify potential new targets for immunotherapy.


CEBPA-bZip mutations are associated with favorable prognosis in de novo AML: a report from the Children's Oncology Group.
Biallelic CEBPA mutations are associated with favorable outcomes in acute myeloid leukemia (AML). We evaluated the clinical and biologic implications of CEBPA-basic leucine zipper (CEBPA-bZip) mutations in children and young adults with newly diagnosed AML. CEBPA-bZip mutation status was determined in 2958 patients with AML enrolled on Children's Oncology Group trials (NCT00003790, NCT0007174, NCT00372593, NCT01379181). Next-generation sequencing (NGS) was performed in 1863 patients (107 with CEBPA mutations) to characterize the co-occurring mutations. CEBPA mutational status was correlated with disease characteristics and clinical outcomes. CEBPA-bZip mutations were identified in 160 (5.4%) of 2958 patients, with 132 (82.5%) harboring a second CEBPA mutation (CEBPA-double-mutated [CEBPA-dm]) and 28 (17.5%) had a single CEBPA-bZip only mutation. The clinical and laboratory features of the 2 CEBPA cohorts were very similar. Patients with CEBPA-dm and CEBPA-bZip experienced identical event-free survival (EFS) of 64% and similar overall survival (OS) of 81% and 89%, respectively (P = .259); this compared favorably to EFS of 46% and OS of 61% in patients with CEBPA-wild-type (CEBPA-WT) (both P < .001). Transcriptome analysis demonstrated similar expression profiles for patients with CEBPA-bZip and CEBPA-dm. Comprehensive NGS of patients with CEBPA mutations identified co-occurring CSF3R mutations in 13.1% of patients and GATA2 mutations in 21.5% of patients. Patients with dual CEBPA and CSF3R mutations had an EFS of 17% vs 63% for patients with CEBPA-mutant or CSF3R-WT (P < .001) with a corresponding relapse rate (RR) of 83% vs 22%, respectively (P < .001); GATA2 co-occurrence did not have an impact on outcome. CEBPA-bZip domain mutations are associated with favorable clinical outcomes, regardless of monoallelic or biallelic status. Co-occurring CSF3R and CEBPA mutations are associated with a high RR that nullifies the favorable prognostic impact of CEBPA mutations.


Biological Mesh Repair of Paraesophageal Hernia: An Analysis of Our Outcomes.
Introduction: Symptomatic paraesophageal hernia (PEH) is an indication for surgical repair. Laparoscopic suture repair has high recurrence rates. Many surgeons prefer mesh repair to reduce PEH recurrence. Several types of mesh, synthetic and biological, are in use. Synthetic mesh has a risk of erosion and stricture, hence we preferred biological mesh repair. Our aim in this study is to assess medium-term outcomes of PEH repair with the use of biological mesh reinforcement over the cruroplasty. We also aimed to correlate clinical recurrences with radiological recurrences. Materials and Methods: This is a retrospective study of 154 consecutive patients from a single centre who underwent a standardized laparoscopic suture repair of the hiatus reinforced with an on-lay patch of Surgisis (porcine small intestine submucosa) and fundoplication. The mean age of the patients was 65 years. All patients were called for regular clinical follow-up and a barium study. Modified GERD-HRQL symptom severity instrument was used to assess postoperative symptoms and satisfaction. Results: The mean follow-up for barium swallow and clinical assessment were 28.42 ± 21.2 and 33.69 ± 23.46 months. The mean patient satisfaction score after surgery was 4.43 ± 1.09 (0-5). Follow-up barium swallow was performed in 122 (79.22%), 87 (56.49%) patients completed clinical follow-up questionnaire, and 77 (50%) had both. Symptomatic recurrence was noted in 25 (28.73%), recurrence on barium swallow 25(20.4%), and 10 (12.98%) had both. The reoperation rate was 3.25%. Mann-Whitney U test showed no statistical significance in reflux-related score between radiological recurrence group compared with no radiological recurrence (P = .06). Conclusions: Biological mesh repair of PEH is safe and well accepted by patients. There is significantly high PEH recurrence rate in long-term follow-up, even with mesh repair. Majority of these recurrences are small, asymptomatic, and the reoperation rate is very low.


Genetic Analysis of Toxocara Spp. in Stray Cats and Dogs in Van Province, Eastern Turkey.
Toxocara canis and Toxocara cati are roundworms of dogs and cats. The purpose of this study was to investigate the infection caused by these ascarids in cats and dogs, using microscopic and molecular analysis methods. Adult ascarids were gathered from the faeces of dogs and cats in Van province, in 2015-2016. Existing keys and PCR sequencing of the ITS-2 fragment were used to identify the morphological features of the parasite species. It was observed that out of 20 adult ascarids, 17 and 3 were found to be Toxocara canis and Toxocara cati, respectively. The ITS-2 gene region was amplified by PCR to perform molecular analysis. Genotyping indicated that the dogs and cats were infected with T. canis and T. cati, respectively, and none had Toxascaris leonina. To the best of our knowledge, this is the first report on the molecular characteristics of adult ascaridoid nematodes from cats and dogs in Turkey. The molecular approaches established in this study enable molecular identification and genetic structure studies of the ascaridoids.


[Effects of Low-magnitude Whole Body Vibration (WBV) on Knee Osteoarthritis in Rabbits].
To determine the effects of low-magnitude whole body vibration (WBV) on the structure and function of subchondral trabecular bones, cartilage degradation, bone/cartilage turnover, and osteoarthritis (OA) joint function. Knee osteoarthritis model was established in 96 rabbits through left anterior cruciate ligament transaction (ACLT). The rabbits were randomly divided into six groups: ACLT control group, WBV+ACLT group (five subgroups, each comprising 16 rabbits receiving 5 Hz, 10 Hz, 20 Hz, 30 Hz and 40 Hz WBV, respectively, with 2-4 mm amplitude for 40 min/d and 5 d/week over a period of 8 weeks). Joint function was tested via weight-bearing asymmetry. The microarchitecture of subchondral trabecular bones was examined using vivo micro-computed tomography (micro-CT). Cartilage samples from knee joints were taken for gross morphology and histology examinations. Serum samples were taken to detect cartilage oligomeric matrix protein (COMP), C-terminal telopeptide of type Ⅰ collagen (CTX)-Ⅰ and urine CTX-Ⅱ. Knee joint pain decreased with 10 Hz (P<0.05) and 20 Hz WBV treatment (P<0.05) , but increased with 40 Hz treatment (P<0.05). The micro-CT results showed that articular cartilage increased first, peaked at 20 Hz, and then decreased (P<0.05) . With increased frequency of WBV, the trabecular number, subchondral bone thickness and bone volume fraction increased, serum CTX-Ⅰ decreased, COMP and CTX-Ⅱ increased, especially at 20 Hz (P<0.05). Lower frequency (20 Hz) WBV can improve bone microstructure, increase bone turnover, delay cartilage degeneration and improve limb function of rabbits with OA.


Clostridium difficile colonization among patients with clinically significant diarrhea and no identifiable cause of diarrhea.
To determine the prevalence of Clostridium difficile colonization among patients who meet the 2017 IDSA/SHEA C. difficile infection (CDI) Clinical Guideline Update criteria for the preferred patient population for C. difficile testing. Retrospective cohort. Tertiary-care hospital in St. Louis, Missouri.PatientsPatients whose diarrheal stool samples were submitted to the hospital's clinical microbiology laboratory for C. difficile testing (toxin EIA) from August 2014 to September 2016.InterventionsElectronic and manual chart review were used to determine whether patients tested for C. difficile toxin had clinically significant diarrhea and/or any alternate cause for diarrhea. Toxigenic C. difficile culture was performed on all stool specimens from patients with clinically significant diarrhea and no known alternate cause for their diarrhea. A total of 8,931 patients with stool specimens submitted were evaluated: 570 stool specimens were EIA positive (+) and 8,361 stool specimens were EIA negative (-). Among the EIA+stool specimens, 107 (19% of total) were deemed eligible for culture. Among the EIA- stool specimens, 515 (6%) were eligible for culture. One EIA+stool specimen (1%) was toxigenic culture negative. Among the EIA- stool specimens that underwent culture, toxigenic C. difficile was isolated from 63 (12%). Most patients tested for C. difficile do not have clinically significant diarrhea and/or potential alternate causes for diarrhea. The prevalence of toxigenic C. difficile colonization among EIA- patients who met the IDSA/SHEA CDI guideline criteria for preferred patient population for C. difficile testing was 12%.


Primary lymphoma of the liver.
Nine adult white men ranging in age from 27 to 76 (mean, 55 years) were treated for primary hepatic lymphoma between 1972 and 1986 at the Memorial Sloan-Kettering Cancer Center. Six patients presented with right upper quadrant or epigastric pain or discomfort, and three patients complained of fatigue and lethargy. Fever and night sweats were evident in two, and two patients had lost weight. One patient was asymptomatic; the liver mass was detected during the work-up for cancer of the prostate. Seven patients on whom computerized tomography was performed all had solitary masses in the liver although in three of them tumor had extended into both lobes as noticed at surgery. One had additional porta hepatic lymph node metastasis. Eight patients underwent an exploratory laparotomy; four had hepatic resection, and four had wedge biopsies of unresectable liver tumor. One patient had a percutaneous needle biopsy of the liver. Eight patients received combination chemotherapy. Six patients are alive, five of whom are in initial complete remission. All three patients who died had persistent or recurrent disease in the liver. The results of therapy and surgery to date in these and in other cases in the literature are encouraging.


External monovalent cations that impede the closing of K channels.
We have examined the effects of a variety of monovalent cations on K channel gating in squid giant axons. The addition of the permeant cations K, Rb, or Cs to the external medium decreases the channel closing rate and causes a negative shift of the conductance-voltage relationship. Both of these effects are larger in Rb than in K. The opening kinetics of the K channel are, on the other hand, unaffected by these monovalent cations. Other permeant species, like NH4 and Tl, slightly increase the closing rate, whereas the relatively impermeant cations Na, Li, and Tris have little or no effect on K channel gating. The permeant cations have different effects on the reversal potential and the shape of the instantaneous current-voltage relationship. These effects give information about entry and binding of the cations in K channels. Rb, for example, enters the pore readily (large shift of the reversal potential), but binds tightly to the channel interior, inhibiting current flow. We find a correlation between the occupancy of the channel by a monovalent cation and the closing rate, and conclude that the presence of a monovalent cation in the pore inhibits channel closing, and thereby causes a leftward shift in the activation-voltage curve. In causing these effects, the cations appear to bind near the inner surface of the membrane.


Follicular mucinosis associated with nonlymphoid skin conditions.
Follicular mucinosis coexisting with lymphoproliferative disorders has been thoroughly debated. However, it has been rarely reported in association with inflammatory disorders. Thirteen cases have been retrieved, and those with cutaneous lymphoma or alopecia mucinosa were excluded. Follicular mucinosis was found in the setting of squamous cell carcinoma, seborrheic keratosis, simple prurigo, acne vulgaris, dextrometorphan-induced phototoxicity, polymorphous light eruption (2 cases), insect bite (2 cases), tick bite, discoid lupus erythematosus, drug-related vasculitis, and demodecidosis. Unexpectedly, our observations revealed a preponderating accumulation of mucin related to photo-exposed areas, sun-associated dermatoses, and histopathologic solar elastosis. The amount of mucin filling the follicles apparently correlated with the intensity of perifollicular inflammatory infiltrate, which was present in all cases. The concurrence of dermal interstitial mucin was found in 7 cases (54%). The concurrence of interstitial dermal mucinosis or the potential role of both ultraviolet radiation and the perifollicular inflammatory infiltrates in its pathogenesis deserves further investigations. Precise recognition and understanding of this distinctive, reactive histological pattern may prevent our patients from unnecessary diagnostic and therapeutic strategies.


Leading change: a three-dimensional model of nurse leaders' main tasks and roles during a change process.
This paper is a report of a qualitative study which explored how nurse leaders described and understood their main tasks and roles during a change process. During a database search for literature, no actual research that highlighted the main tasks and roles of nurse leaders during a change process was found. Earlier research has indicated the need for different leadership styles and the importance of strategies and values. In-depth interviews with 17 nurse leaders took place in 2004. A phenomenological-hermeneutical approach was used for data analysis. The findings resulted in a model of leading change in health care that focuses on good patient care and consists of three dimensions: leading relationships, leading processes and leading a culture. In addition to leading relationships and processes, nurse leaders, as role models, greatly impact caring culture and its inherent ethical behaviour, especially about the responsibility for achieving good patient care. Nurse leaders are also instrumental in leading ward culture. Nurse leaders need guidance and knowledge of what is expected of them during a structural change process. They play different roles by directing, guiding, motivating, supporting and communicating without losing their cultural ethos of caring and use various leadership styles to bring about actual change, which, in turn, requires learning so that the thought patterns, values and attitudes of personnel can be changed.


Modified test statistics by inter-voxel variance shrinkage with an application to f MRI.
Functional magnetic resonance imaging (f MRI) is a noninvasive technique which is commonly used to quantify changes in blood oxygenation and flow coupled to neuronal activation. One of the primary goals of f MRI studies is to identify localized brain regions where neuronal activation levels vary between groups. Single voxel t-tests have been commonly used to determine whether activation related to the protocol differs across groups. Due to the generally limited number of subjects within each study, accurate estimation of variance at each voxel is difficult. Thus, combining information across voxels is desirable in order to improve efficiency. Here, we construct a hierarchical model and apply an empirical Bayesian framework for the analysis of group f MRI data, employing techniques used in high-throughput genomic studies. The key idea is to shrink residual variances by combining information across voxels and subsequently to construct an improved test statistic. This hierarchical model results in a shrinkage of voxel-wise residual sample variances toward a common value. The shrunken estimator for voxel-specific variance components on the group analyses outperforms the classical residual error estimator in terms of mean-squared error. Moreover, the shrunken test statistic decreases false-positive rates when testing differences in brain contrast maps across a wide range of simulation studies. This methodology was also applied to experimental data regarding a cognitive activation task.


Early and delayed Tc-99m ECD brain SPECT in SLE patients with CNS involvement.
We compared early and delayed Tc-99m ECD SPECT scans in 32 SLE patients (Group 1, definite neuropsychiatric disorders; Group 2, minor neurologic symptoms or normal) with those of normal controls by visual inspection and semi-quantitative evaluation. With visual interpretation, 13 out of 14 patients in Group 1 (93%) and 7 out of 18 patients in Group 2 (39%) had diffuse uneven decrease in early scans. Seven patients in Group 2 (39%) who had normal early scans demonstrated focal decrease in the medial frontal lobe in delayed scans. With cerebral region to cerebellar ratios, in early scans, the medial frontal lobe in Group 1 and Group 2 was significantly lower than in normal controls, and lateral frontal lobe and occipital lobes in Group 1 were significantly lower than in normal controls. Nevertheless, in delayed scans, every cortical region except for the parietal lobe in Groups 1 and 2 was significantly lower than in normal controls. The retention rates in all regions in SLE patients were significantly lower than in normal controls. No case showed SPECT improvement on follow-up studies in either group in spite of clinical improvement. Delayed Tc-99m ECD brain SPECT of high sensitivity might be useful in detecting CNS involvement. Although the SPECT findings did not correlate with the neuropsychiatric symptoms, early and delayed Tc-99m ECD SPECT seems to provide useful objective diagnostic information in SLE patients.


Excess mortality during heat waves, Tehran Iran: an ecological time-series study.
In the past three decades, Tehran has experienced warmer summer so we need to determine heat-related mortality to establish appropriate public health activities during hot summers. The aim of the present study was to detect heat waves during the last decades and then determine excess mortality in immediate and lagged times. An ecological study based on time-series model was conducted in Tehran for recent decade using generalized linear lagged model (GLLM) with Poisson regression. Maximum daily temperature was heat exposure for death outcome on the same day (lag 0), 3 (lag01) and also 7 (lag02) day moving average. Relative risk with 95% confidence was reported to quantify for increasing of daily mortalities for 1°C risen exposure. Air pollutants considered as confounders in final model. Total excess mortality during 17 heat waves was 1069 (8.9 deaths/Heat wave days). All non-external cause of death increased significantly during heat waves (3-9%) and after adjusting for ozone and PM10, raised. Cause-specific deaths (especially circulatory disease) and death among elderly increased during heat waves (especially in the hottest wave). The largest positive lagged effect of hot temperature although seen during hottest waves for all mortalities. Three waves had the most harvest effect for all categories of mortalities. Study showed excess mortalities resulted from hot temperatures and exacerbated with air pollutants in Tehran in the context of climate change. Forward displacement mortality and lagged mortalities as well as were seen, but our results were not conclusive about the displacement pattern of mortalities.


Preliminary use of nematic liquid crystal adaptive optics with a 2.16-meter reflecting telescope.
A nematic liquid crystal adaptive optics system (NLC AOS) was assembled for a 2.16-m telescope to correct for atmospheric turbulence. LC AOS was designed and optimized with Zemax optical software. Second, an adaptive correction experiment was performed in the laboratory to test the performance of the NLC AOS. After the correction, the peak to valley (PV) and root mean square (RMS) of the wavefront were down to 0.2 lambda (lambda=633 nm) and 0.05 lambda, respectively. Finally, the star of Pollux (beta Gem) was tracked using the 2.16-m Reflecting Telescope, and real time correction of the atmospheric turbulence was performed with the NLC AOS. After the adaptive correction, the average PV and RMS of the wavefront were reduced from 11 lambda and 2.5 lambda to 2.3 lambda and 0.6 lambda, respectively. Although the intensity distribution of the beta Gem was converged and its peak was sharp, a halo still existed around the peak. These results indicated that the NLC AOS only partially corrected the vertical atmospheric turbulence. The limitations of our NLC AOS are discussed and some proposals are made.


Theoretical study of the photochemical initiation in nitroxide-mediated photopolymerization.
Nitroxide-mediated photopolymerization (NMP(2)) is a promising novel route to initiate radical polymerization. In NMP(2), alkoxyamines bounded to a monomer are attached to a chromophore. Upon light absorption, the excitation energy is transferred from the chromophore to the alkoxyamine moiety, inducing the cleavage of the oxygen-carbon bond and thus initiating the polymerization. The NMP(2) mechanism depends strongly on several factors like the type of chromophore, the monomer, the connectivity pattern, etc. This complexity makes it difficult to design new NMP(2) initiators with increased polymerization efficiency and selectivity. In the present article, we characterize by means of quantum mechanical calculations the main steps of the NMP(2) initiation for alkoxyamines attached to aromatic ketones. We show how the excitation energy can be transferred from the chromophore to the alkoxyamine moiety, and present two easily computed parameters which can account for the selectivity of the O-C bond photocleaveage. Finally, using results obtained for a series of isomers, we give some rules that may help the design of more efficient NMP(2) initiators.


Relationship Between Renal Function and Choroidal Thickness in Type 2 Diabetic Patients Detected by Swept-Source Optical Coherence Tomography.
To investigate the relationship between renal function and choroidal thickness (CT) in ocular treatment-naïve patients with diabetes mellitus using swept-source optical coherence tomography (SS-OCT). This cross-sectional study recruited type 2 diabetes mellitus (T2DM) patients with no history of ocular treatment from communities in Guangzhou, China. The estimated glomerular filtration rates (eGFR) were calculated by using the Xiangya formula. The impaired renal function was defined as eGFR < 60 mL/(min 1.73 m2). The choroid was imaged by using an SS-OCT, and the macular CT was quantified automatically in Early Treatment Diabetic Retinopathy Study maps, and only data from one eye was used. Univariate and multivariate linear regression analyses were performed to explore the influence of eGFR on CT. A total of 1395 patients with T2DM were included in the final analysis. The CT of all macular regions were significantly thinner in patients with renal impairment (all P < 0.001). A significantly positive correlation was observed between the average CT and eGFR (β = 0.4; 95% confidence interval, 0.041-0.8; P = 0.029) independent of age, sex, and other potential confounding factors. After adjusting for other factors, a higher eGFR was also associated with higher CT values in the central field (P = 0.019) and in the outer superior (P = 0.047), inner superior (P = 0.018), inner inferior (P = 0.025), and inner temporal (P = 0.038) regions. CT decreased in parallel with renal impairment in ocular treatment naïve diabetic patients, providing an accessible window for monitoring renal status. Knowledge of association between retinal microvasculature and renal microcirculation would allow applying in both clinical and research settings.


Efficient loading of nano Mn particles on calcined laterite soil (Lt-nMn) for higher removal of As(III) ions from groundwater: adsorption and eco-scale analysis.
Occurrence of arsenic in the groundwater has become a cause for concern in many countries. The presence of As(III) species in the groundwater had been one of the biggest challenges for the water workers especially in the southeast Asian countries. Nano based adsorption techniques are gaining attention among researchers for the removal of arsenic ions. However, synthesis of nano-adsorbents is a costly affair. Therefore, the present study utilized the cheap and readily available laterite soil as a base material for nano coating. Nano sized manganese (nMn) particles were synthesized by chemical reduction method and later coated on calcined laterite (Lt-nMn). Coating with 0.1 M nMn provided the best As(III) removal efficiency. The prepared material was characterised for its morphological and surface properties. Phase analysis using XRD (X-ray diffraction) showed the presence of zero valent manganese species, which assisted in adsorption. Adsorption studies were conceded by selecting the different affecting parameters such as contact time, concentration, dose, temperature, and pH. Very high removal in less time regime led to the investigation of the oxidation mechanism. Phosphate and sulphate anions insignificantly reduced the removal efficiency. Langmuir model for the sorption isotherms and pseudo-second order kinetic model for the sorption kinetics symbolized the experimental data. Sustainability studies in terms of eco-scaling and cost analysis were performed for the applied method of production of the nano materials. Adsorber design analysis was also conducted to estimate the required amount of Lt-nMn particles for achieving the desired equilibrium As(III) concentration.


Predictors of stigma toward alcohol misuse in Latino communities: a path model.
This study explores stigma-related beliefs within the Latino community concerning alcohol misuse. A community-based convenience sample of 251 self-identified Latino adults were recruited to participate in a research study using an experimental vignette methodology. Participants were randomly assigned one of four vignettes about alcohol misuse and asked to share their attitudes and stigma-related beliefs about the problem and the person in the vignette. Sociodemographic characteristics of participants differentially predicted alcohol-related stigma. These data may be used to inform health literacy and stigma reduction interventions within the Latino community.


Leukocyte colony-stimulating factor and inhibitor activity.
Native and density gradient separated rat peritoneal exudate cells were evaluated for both their capacity to stimulate granulocyte colony formation and their ability to inhibit colony growth in vitro. Granulocyte colony-stimulating factor (CSF) was primarily elaborated by monocytes and macrophages; neutrophils showed only minimal stimulatory activity. In contrast, freeze-thawed extracts of both monocyte-macrophage and granulocyte fractions were markedly inhibitory to colony growth using a standard L-cell-derived CSF. Characterization of the inhibitory material indicated it to be a low molecular weight, nonlipid, heat-stable substance. In addition to peritoneal leukocytes, other tissues including lymph node, thymic and splenic lymphocytes, liver, kidney, and skeletal muscle also contained inhibitory materials. These observations suggest that granulopoiesis, as assessed by in vitro culture techniques, is not influenced solely by a simple feedback loop; rather, leukocytic elements, as well as other tissues, appear to contain and release both stimulatory and inhibitory factors.


Pulmonary vein anatomy in patients undergoing catheter ablation of atrial fibrillation: lessons learned by use of magnetic resonance imaging.
This study sought to define the technique and results of magnetic resonance imaging (MRI) of pulmonary vein (PV) anatomy before and after catheter ablation of atrial fibrillation (AF). Twenty-eight patients with AF underwent ablation. Patients underwent gadolinium-enhanced MRI before and 6 weeks after their procedures. A control group of 27 patients also underwent MRI. Variant PV anatomy was observed in 38% of patients. AF patients had larger PV diameters than control subjects, but no difference was observed in the size of the PV ostia among AF patients. The PV ostia were oblong in shape with an anteroposterior dimension less than the superoinferior dimension. The left PVs had a longer "neck" than the right PVs. A detectable PV narrowing was observed in 24% of veins. The severity of stenosis was severe in 1 vein (1.4%), moderate in 1 vein (1.4%), and mild in 15 veins (21.1%). All patients were asymptomatic, and none required treatment. This study demonstrates that AF patient have larger PVs than control subjects and demonstrates the value of MRI in facilitating AF ablation. The benefits of preprocedural MRI of PVs include the ability to evaluate the number, size, and shape of the PVs. MRI also provides an assessment of the severity of PV stenosis.


Functioning and Disability Profile of Children with Microcephaly Associated with Congenital Zika Virus Infection.
The increase in the number of cases of microcephaly in Brazil and its association with the Zika virus (ZIKV) is a global public health problem. The International Classification of Functioning Disability and Health (ICF) model is a powerful tool and extremely relevant in managing disability. Describe the functioning profile of children with microcephaly associated with ZIKV in two states of northeastern Brazil. This is a descriptive cross-sectional study. The sociodemographic characteristics, head circumference, and other clinical data were collected from medical charts, physical examinations, measuring instruments, and interviews with the children and their parents. The Brazilian Portuguese version of the Brief Common ICF Core Set for cerebral palsy (CP) was used. Each ICF category was assigned a qualifier, which ranged from 0 to 4 (no problem, mild problem, moderate problem, severe problem, complete problem). For environmental factors, 0 represents no barrier and 4 represents complete barrier; +0, no facilitator and +4, complete facilitator. A total of 34 children with microcephaly caused by ZIKV were recruited (18 girls and 16 boys) at four rehabilitation facilities in Rio Grande do Norte and Paraíba states, Brazil. The average age of the participants was 21 months, monthly income was ≈USD 300.00, and head circumference z-scores ranged between 0.92 and -5.51. The functioning profile revealed complete disability in most of the body function categories (b). The activity and participation areas (d) were highly impacted, particularly in mobility-related categories. With respect to environmental factors (e), most of the sample reported a complete facilitator for the immediate family, friends, and health services, systems, and policies, as well as a complete barrier to societal attitudes. This is the first study that describes the functioning profile of children with microcephaly associated with ZIKV, using a tool based on the ICF in Brazil. Our findings reinforce the need to maximize health care and access to information, based on the ICF, for multiprofessional teams, administrators, family members, and children.


Perceptual dominance time distributions in multistable visual perception.
Perceptual multistability, alternative perceptions of an unchanging stimulus, gives important clues to neural dynamics. The present study examined 56 perceptual dominance time series for a Necker cube stimulus, for ambiguous motion, and for binocular rivalry. We made histograms of the perceptual dominance times, based on from 307 to 2478 responses per time series (median=612), and compared these histograms to gamma, lognormal and Weibull fitted distributions using the Kolmogorov-Smirnov goodness-of-fit test. In 40 of the 56 tested cases a lognormal distribution provided an acceptable fit to the histogram (in 24 cases it was the only fit). In 16 cases a gamma distribution, and in 11 cases a Weibull distribution, were acceptable but never as the only fit in either case. Any of the three distributions were acceptable in three cases and none provided acceptable fits in 12 cases. Considering only the 16 cases in which a lognormal distribution was rejected ( p<0.05) revealed that minor adjustments to the fourth-moment term of the lognormal characteristic function restored good fits. These findings suggest that random fractal theory might provide insight into the underlying mechanisms of multistable perceptions.


The effect of gestational weight gain by body mass index on maternal and neonatal outcomes.
To evaluate the effects of gestational weight gain on maternal and neonatal outcomes in different body mass index (BMI) classes. We compared maternal and neonatal outcomes based on gestational weight gain in underweight, normal weight, overweight, obese, and morbidly obese (BMI>or=40.00) women. The study group was a population-based cohort of women with singleton gestations who delivered between April 1, 2001, and March 31, 2007, drawn from the Newfoundland and Labrador Provincial Perinatal Program Database. Univariate analyses and multivariate logistic regression analyses (controlling for maternal age, parity, smoking status, partnered status, and gestational age) were performed and odds ratios (ORs) were calculated. Only 30.6% of women gained the recommended amount of weight during pregnancy; 52.3% of women gained more than recommended, and 17.1% gained less than recommended. In women with normal pre-pregnancy BMI, excess weight gain was associated with increased rates of gestational hypertension (OR 1.27; 95% CI 1.08-1.49), augmentation of labour (OR 1.09; 95% CI 1.01-1.18), and birth weight>or=4000 g (OR 1.21; 95% CI 1.10-1.34). In overweight women, excess weight gain was associated with increased rates of gestational hypertension (OR 1.31; 95% CI 1.10-1.55) and birth weight>or=4000 g (OR 1.30; 95% CI 1.15-1.47). In women who were obese or morbidly obese, excess weight gain was associated with increased rates of birth weight>or=4000 g (OR 1.20; 95% CI 1.07-1.34) and neonatal metabolic abnormality (OR 1.31; 95% CI 1.00-1.70). In morbidly obese women, poor weight gain was associated with less use of epidural analgesia (OR 0.34; 95% CI 0.12-0.95). In women who were of normal weight, overweight, or obese, the rate of adverse outcome (Caesarean section, gestational hypertension, birth weight<2500 g or birth weight>or=4000 g) was lower in women with recommended weight gain than in those with excess weight gain. Adverse outcomes were reduced in nulliparous morbidly obese women who had poor weight gain (OR 0.18; 95% CI 0.04-0.83). The effects of gestational weight gain on pregnancy outcome depend on the woman's pre-pregnancy BMI. Pregnancy weight gains of 6.7-11.2 kg (15-25 lb) in overweight and obese women, and less than 6.7 kg (15 lb) in morbidly obese women are associated with a reduction in the risk of adverse outcome.


Integrating Reproductive and Sexual Health Education and Services Into Opioid Use Disorder Treatment Programs: A Qualitative Study.
Women with opioid use disorder (OUD) in the USA are at risk for poor reproductive and sexual health (RSH) outcomes. The qualitative research presented here is part of a larger mixed methods study. The qualitative component used an implementation science framework to investigate provider and staff perspectives regarding the integration of RSH education and services for reproductive-age women in opioid treatment programs (OTPs) in North Carolina. Thirty-one semistructured interviews were conducted with providers and staff at 9 OTPs between November and December, 2017. The Consolidated Framework for Implementation Research (CFIR) was used to assess multilevel implementation contexts (eg, patient, provider, organizational) to identify barriers and facilitators that might influence effective intervention implementation. Interviews were audio-recorded, transcribed, coded, and analyzed to identify key themes. Deductive and inductive approaches were used. Barriers included transportation, childcare, and time constraints (patient-level), lack of communication between providers (provider-level), lack of political will, competing priorities, and shortages of available resources (organizational-level). Facilitators included a group education approach (patient-level), strong communication (provider-level), and a culture of collaboration (organizational-level). Assessing determinants of implementation is important to the development of RSH interventions. CFIR constructs were found to be important influences that could facilitate or hinder effective implementation. Integration of RSH education and services is a process, and, when addressed in stages, might be feasible. A broad range of RSH education and services has the potential to have a profound impact on the health of women with OUD and their children, their families, and their communities.


Prolonged kallikrein inhibition does not affect the basal growth and secretory capacity of rat adrenal cortex, but enhances mineralo- and glucocorticoid response to ACTH and handling stress.
The effects on the pituitary-adrenocortical functions of the prolonged (7-day) blockade of endogenous bradykinin (BK) synthesis, obtained by the administration of the kallikrein inhibitor (K-I) cyclohexylacetyl-Phe-Arg-Ser-Val-Gln amide, were investigated in the rat. K-I treatment did not cause significant changes in the (i) body and adrenal weights; (ii) basal plasma levels of ACTH, aldosterone and corticosterone; and (iii) average volume of adrenocortical cells and their basal secretory capacity. Conversely, K-I administration induced a significant magnification of the in vivo mineralo- and glucocorticoid responses to the intraperitoneal (i.p.) bolus injection of ACTH. Moreover, K-I-treated rats, but not control ones, displayed a moderate and short-term adrenal secretory response to the mild stress evoked by the placebo i.p. injection. Collectively, these findings rule out the possibility that endogenous BK plays a relevant role in the control of adrenocortical function under basal conditions. However, they suggest that endogenous BK may be involved in quenching exceedingly high adrenocortical responses to ACTH and stresses.


[Medical sociology: origin and field of action].
A review of the published literature on the origin of medical sociology and its field of action was made. For this, several publications were analyzed and the most relevant aspects were summarized. Although the concept of disease has always been linked to sociocultural aspects, only until the mid-twentieth century, Medicine recognized the importance of sociology to explain health-related issues, especially the social determinants of health. Currently, sociologists work in a multidisciplinary way with doctors to investigate and analyze issues concerning the health of people, to improve the welfare and quality of life of the population. In this sense, the contribution of Sociology has not only enriched the understanding of some diseases, but also different aspects of the work of Medicine.


Pollinator-mediated evolution of floral signals.
Because most plants rely on animals for pollination, insights from animal sensory ecology and behavior are essential for understanding the evolution of flowers. In this review, we compare and contrast three main types of pollinator responses to floral signals--receiver bias, 'adaptive' innate preferences, and associative learning--and discuss how they can shape selection on floral signals. We show that pollinator-mediated selection on floral signals can be strong and that the molecular bases of floral signal variation are often surprisingly simple. These new empirical and conceptual insights into pollinator-mediated evolution provide a framework for understanding patterns of both convergent (pollination syndromes) and advergent (floral mimicry) floral signal evolution.


Increased transgene expression by the mouse tyrosinase enhancer is restricted to neural crest-derived pigment cells.
In this study, we have addressed the impact of the mouse tyrosinase enhancer on regulated expression from the mouse tyrosinase promoter during embryonic development. Stable and transient transgenic experiments using the reporter gene lacZ reveal that (1) expression is detected in neural crest-derived melanoblasts from E11.5 onward, (2) the enhancer does not increase transgenic expression in optic cup-derived pigment cells of the retinal pigment epithelium (RPE), and (3) expression in the telencephalon is not any longer detected. The importance of the enhancer for expression in pigment cells of the eye was further investigated in adult mice using an attenuated diphtheria toxin A gene. This demonstrated that in presence of the enhancer the transgene expression is specifically targeted to neural crest-derived melanocytes of the choroid and not, or slightly, to the RPE. This suggests that tyrosinase is differentially regulated in the two pigment cell lineages, and that this promoter can be used to target expression preferentially to the neural crest-derived melanocyte lineage.


Transferability of Cardiopulmonary Parameters between Treadmill and Cycle Ergometer Testing in Male Triathletes-Prediction Formulae.
Cardiopulmonary exercise testing (CPET) on a treadmill (TE) or cycle ergometry (CE) is a common method in sports diagnostics to assess athletes' aerobic fitness and prescribe training. In a triathlon, the gold standard is performing both CE and TE CPET. The purpose of this research was to create models using CPET results from one modality to predict results for the other modality. A total of 152 male triathletes (age = 38.20 ± 9.53 year; BMI = 23.97 ± 2.10 kg·m-2) underwent CPET on TE and CE, preceded by body composition (BC) analysis. Speed, power, heart rate (HR), oxygen uptake (VO2), respiratory exchange ratio (RER), ventilation (VE), respiratory frequency (fR), blood lactate concentration (LA) (at the anaerobic threshold (AT)), respiratory compensation point (RCP), and maximum exertion were measured. Random forests (RF) were used to find the variables with the highest importance, which were selected for multiple linear regression (MLR) models. Based on R2 and RF variable selection, MLR equations in full, simplified, and the most simplified forms were created for VO2AT, HRAT, VO2RCP, HRRCP, VO2max, and HRmax for CE (R2 = 0.46-0.78) and TE (R2 = 0.59-0.80). By inputting only HR and power/speed into the RF, MLR models for practical HR calculation on TE and CE (both R2 = 0.41-0.75) were created. BC had a significant impact on the majority of CPET parameters. CPET parameters can be accurately predicted between CE and TE testing. Maximal parameters are more predictable than submaximal. Only HR and speed/power from one testing modality could be used to predict HR for another. Created equations, combined with BC analysis, could be used as a method of choice in comprehensive sports diagnostics.


Performance of conformal guided mode resonance filters.
Guided mode resonance (GMR) filters are highly functional micro-optics capable of narrowband spectral filtering. GMR devices have previously been demonstrated on flat substrates using a wide range of materials and configurations. In this Letter, we apply a soft lithographic technique followed by the deposition of dielectric layers to generate GMR filters on a concave lens surface. Resonances of the resulting conformal GMR filters are experimentally measured and characterized, and the results are compared to the performance of similar GMR filters fabricated on flat surfaces.


Linearly coded profilometry.
A new optical profilometry-linearly coded profilometry (LCP)-is presented. It uses a sawtoothlike linear light structure to code the surface to be measured and a phase-shifting technique to decode the profile. Two kinds of coding-light structure, one with right-angle triangle teeth and the other with isosceles triangle teeth, are proposed. For coding with light with right-angle triangle teeth, a general decoding method is given. In addition, an optimum sampling manner and the measurement error are discussed with respect to a special case. For coding with light with isosceles triangle teeth, a decoding method with three samples is given. In our laboratory, an experimental system was established, and experiments that verified the reliability of the proposed methods were performed. Experimental results typical of those obtained are given. We find that LCP is similar to the widely used phase-measuring profilometry but has a faster measuring speed.


Analysis of kinetic Langmuir model. Part I: Integrated kinetic Langmuir equation (IKL): a new complete analytical solution of the Langmuir rate equation.
In the article, a new integrated kinetic Langmuir equation (IKL) is derived. The IKL equation is a simple and easy to analyze but complete analytical solution of the kinetic Langmuir model. The IKL is compared with the nth-order, mixed 1,2-order, and multiexponential kinetic equations. The impact of both equilibrium coverage θ(eq) and relative equilibrium uptake u(eq) on kinetics is explained. A newly introduced Langmuir batch equilibrium factor f(eq) that is the product of both parameters θ(eq)u(eq) is used to determine the general kinetic behavior. The analysis of the IKL equation allows us to understand fully the Langmuir kinetics and explains its relation with respect to the empirical pseudo-first-order (PFO, i.e., Lagergren), pseudo-second-order (PSO), and mixed 1,2-order kinetic equations, and it shows the conditions of their possible application based on the Langmuir model. The dependence of the initial adsorption rate on the system properties is analyzed and compared to the earlier published approximate equations.


[1H-NMR study of immunoregulatory peptides].
Conformational and dynamic properties of the synthetic peptides, amino acid sequence of which correspond to biologically active fragments of the following human cytokines: alpha 2, gamma interferons and interleukins 1 beta, 2, were studied in aqueous solution and dimethylsulfoxide by one-dimensional and two-dimensional 1H-NMR spectroscopy (400 MHz). The analysis of nuclear Overhauser effect data, values of vicinal J3(NH-C alpha H) coupling constants of amide protons and their temperature coefficients of chemical shifts indicate an unordered flexible conformation of the peptides in aqueous solutions. The structural and dynamic features of the peptides investigated are discussed together with their biological activity.


Cavernous venous malformations in and around the central nervous system. Part 2: Intradural.
Cavernous venous malformations (CavVMs) account for a spectrum of lesions with a shared pathogenesis. Their anatomical location dictates their clinical features and surgical treatment. Extradural and dura-based CavVMs were discussed in Part 1 of this review. In this part, intradural CavVMs are discussed, encompassing malformations growing within the intradural space without direct dural involvement. In addition to classic intra-axial CavVMs, cranial nerve CavVMs, intraventricular CavVMs, and intradural extramedullary spinal CavVMs are discussed in this group, given the similar natural history and specific management challenges. Herein the authors focus on critical clinical aspects of and surgical management of these malformations based on their location and discuss optimal surgical approaches at each of these anatomical locations with illustrative cases. The commonalities of the natural history and surgical management that are dictated by anatomical considerations lend to a new location-based taxonomy for classification of CavVMs.


Photodynamic therapy and digital angiography of experimental iris neovascularization using liposomal benzoporphyrin derivative.
To study the efficacy of liposomal benzoporphyrin derivative (BPD) (Verteportin) for the angiographic visualization and photodynamic therapy (PDT) of experimental iris neovascularization. Experimental iris neovascularization was induced in eight cynomolgus monkey eyes by occluding all the branch retinal veins with a dye-yellow (577-nm) laser. Iris angiography was done with sodium fluorescein, indocyanine green (ICG), and liposomal BPD to compare the visualization of normal and neovascular vessels by these three dyes. PDT was performed using an intravenous infusion of liposomal BPD (0.375-0.75 mg/kg), followed by irradiation with 689-nm light from a diode laser/slit-lamp delivery system using 600 mW/cm2 irradiance and 150 J/cm2 fluence. The effect of treatment was followed by iris photography and angiography, and the findings were confirmed by histopathology using light and electron microscopy. Iris fluorescein angiography (FA) showed superficial tortuous and leaky new vessels. Liposomal BPD and ICG angiography of the same eye demonstrated deeper dilated and tortuous iris vessels, with minimal dye leakage. PDT of the iris with irradiation, performed within 20 minutes of the start of dye infusion (0.75 mg/kg), resulted in angiographic and histologic occlusion of iris vessels examined at 24 hours. Three to nine days after PDT, histopathologic examination showed regression of the iris neovascular membrane, with some open vessels. Liposomal BPD and ICG provided angiographic visualization of deeper normal and neovascular iris vessels. PDT using liposomal BPD leads to effective early closure to experimental iris neovascularization.


Caenorhabditis elegans HCF-1 functions in longevity maintenance as a DAF-16 regulator.
The transcription factor DAF-16/forkhead box O (FOXO) is a critical longevity determinant in diverse organisms, however the molecular basis of how its transcriptional activity is regulated remains largely unknown. We report that the Caenorhabditis elegans homolog of host cell factor 1 (HCF-1) represents a new longevity modulator and functions as a negative regulator of DAF-16. In C. elegans, hcf-1 inactivation caused a daf-16-dependent lifespan extension of up to 40% and heightened resistance to specific stress stimuli. HCF-1 showed ubiquitous nuclear localization and physically associated with DAF-16. Furthermore, loss of hcf-1 resulted in elevated DAF-16 recruitment to the promoters of its target genes and altered expression of a subset of DAF-16-regulated genes. We propose that HCF-1 modulates C. elegans longevity and stress response by forming a complex with DAF-16 and limiting a fraction of DAF-16 from accessing its target gene promoters, and thereby regulates DAF-16-mediated transcription of selective target genes. As HCF-1 is highly conserved, our findings have important implications for aging and FOXO regulation in mammals.


Skeleton-secreted PDGF-BB mediates arterial stiffening.
Evidence links osteoporosis and cardiovascular disease but the cellular and molecular mechanisms are unclear. Here we identify skeleton-secreted platelet-derived growth factor-BB (PDGF-BB) as a key mediator of arterial stiffening in response to aging and metabolic stress. Aged mice and those fed high-fat diet (HFD), relative to young mice and those fed normal chow food diet, respectively, had higher serum PDGF-BB and developed bone loss and arterial stiffening. Bone/bone marrow preosteoclasts in aged mice and HFD mice secrete an excessive amount of PDGF-BB, contributing to the elevated PDGF-BB in blood circulation. Conditioned medium prepared from preosteoclasts stimulated proliferation and migration of the vascular smooth muscle cells. Conditional transgenic mice, in which PDGF-BB is overexpressed in preosteoclasts, had 3-fold higher serum PDGF-BB concentration and developed simultaneous bone loss and arterial stiffening spontaneously at a young age. Conversely, in conditional knockout mice, in which PDGF-BB is deleted selectively in preosteoclasts, HFD did not affect serum PDGF-BB concentration; as a result, HFD-induced bone loss and arterial stiffening were attenuated. These studies confirm that preosteoclasts are a main source of excessive PDGF-BB in blood circulation during aging and metabolic stress and establish the role of skeleton-derived PDGF-BB as an important mediator of vascular stiffening.


Electrophysiological evidence of biphasic action of carnosine on long-term potentiation in urethane-anesthetized rats.
Carnosine is a dipeptide synthesized by the carnosine synthetase from β-alanine and l-histidine. The well-known effects of carnosine may be related with mechanisms producing long-term potentiation which is one of the electrophysiological signs of memory. In the present study we aimed to investigate the effect of four different doses of carnosine on long-term potentiation in urethane-anesthetized rat. A bipolar stimulating electrode was placed in the medial perforant path and a double-barrel glass micropipette was placed in the dentate gyrus as the recording electrode. Artificial cerebrospinal fluid (in the control group) or carnosine (0.1, 1, 10, and 100μg/μL) was infused into the dentate gyrus. Our results showed that the I/O curve of the excitatory postsynaptic potential slope or population spike amplitude was not significantly shifted by carnosine. We found that population spike amplitude increased to 244% and 287% at the dose of 100μg/μL in the post-tetanic and induction phases, respectively, but decreased to 163% and 186% at the dose of 0.1μg/μL and to 145% and 162% at the dose of 1μg/μL when compared with 203% and 232% of the control values. However, there were no significant differences for the slope of excitatory postsynaptic potential. Carnosine had no effect on the EPSP slope or PS amplitude recorded from the dentate gyrus in response to test stimuli when high-frequency stimulation was not delivered. In the present study, we speculated that the effects of carnosine in lower or higher doses could be explained by its effect on different processes, such as soluble guanylyl cyclase inhibition or the conversion of carnosine into histamine.


Iridium-catalyzed direct C-H amidation of anilines with sulfonyl azides: easy access to 1,2-diaminobenzenes.
An Ir(iii)-catalyzed regioselective C-H amidation of anilines with sulfonyl azides is described. The developed protocol has good compatibility with diverse functional groups, efficiently providing the monoamidated products with good to excellent yields under mild reaction conditions. Furthermore, the 2-pyrimidyl and sulfonyl moieties in the amidated products can readily be removed, offering the synthetically useful 1,2-diaminobenzene scaffold.


Association Between Physical Activity During Pregnancy and Perinatal Depressive Symptoms in Pregnant Individuals With Overweight and Obesity.
Current research on the association between physical activity and perinatal depression is inconclusive. This study examined the association between objectively measured physical activity during pregnancy and perinatal depressive symptoms among individuals with overweight and obesity. Data came from the Health in Pregnancy and Postpartum study (N = 205). Physical activity was measured using the SenseWear Armband at 16 weeks' or fewer and 32 weeks' gestation and categorized into 1) never meeting 2018 physical activity guidelines, 2) meeting the guidelines at one time point, or 3) meeting the guidelines at both time points. Antenatal depressive symptoms were assessed at 32 weeks' gestation, and postpartum depressive symptoms were assessed at 6 and 12 months postpartum using the Edinburgh Postnatal Depression Scale. A score of 10 or higher was defined as probable at least minor depression (hereafter, probable depression). Nearly one-half of the participants (45.4%) met physical activity guidelines both in early and late pregnancy. Pregnant individuals who met physical activity guidelines at one (adjusted odds ratio, 0.07; 95% [confidence interval], 0.01-0.76) or both time points (adjusted odds ratio, 0.08; 95% confidence interval, 0.01-0.69) during pregnancy had lower odds of probable depression at 6 months postpartum than individuals who never met physical activity guidelines during pregnancy. No significant associations were found between prenatal physical activity and probable antenatal or postpartum depression at 12 months. Antenatal physical activity was associated with lower odds of probable depression at 6 months after childbirth. Physicians should use evidence-based strategies to encourage pregnant people, especially those who are at risk for postpartum depression, to meet physical activity guidelines.


Comparative histomorphometrical study of genital tract in adult laying hen and duck.
This study was carried out to compare the histomorphological structures of oviductal regions of the apparently healthy adult laying hens (Gallus gallus dometicus) and ducks (Ansa ansa domesticus). For this purpose, 20 hens and 20 female ducks aged between 1-1.5 years were used. After euthanasia, the oviducts were dissected out and all of the gross morphometrical parameters including length, width and thickness as well as weight and length of them were recorded. For histological studies, after tissue preparation and staining with H&E, histological layers of isthmus, uterus and vagina were recognized and the size of them with micrometry method were determined. Our data analyses indicated that, the mean weight, length of oviduct as well as weight of isthmus, uterus in hen were significantly (P < 0.05) greater than that of duck, whereas the vaginal thickness and weight were greater in duck than the hen. In histological studies, epithelium and cilia were well developed in duck and lamina propria was filled with glands in the regions of the isthmus and uterus. The length of primary mucosal folds of isthmus and uterus in duck was more than hen. The longest mucosal fold has been seen in uterus. Most of the parameters in duck were greater than hen except the length of secondary fold of three parts of oviduct including isthmus, uterus, and vagina.


TRAIL-Sensitizing Effects of Flavonoids in Cancer.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a promising anticancer agent, as it selectively induces apoptosis in transformed cells without altering the cellular machinery of healthy cells. Unfortunately, the presence of TRAIL resistance mechanisms in a variety of cancer types represents a major hurdle, thus limiting the use of TRAIL as a single agent. Accumulating studies have shown that TRAIL-mediated apoptosis can be facilitated in resistant tumors by combined treatment with antitumor agents, ranging from synthetic molecules to natural products. Among the latter, flavonoids, the most prevalent polyphenols in plants, have shown remarkable competence in improving TRAIL-driven apoptosis in resistant cell lines as well as tumor-bearing mice with minimal side effects. Here, we summarize the molecular mechanisms, such as the upregulation of death receptor (DR)4 and DR5 and downregulation of key anti-apoptotic proteins [e.g., cellular FLICE-inhibitory protein (c-FLIP), X-linked inhibitor of apoptosis protein (XIAP), survivin], underlying the TRAIL-sensitizing properties of different classes of flavonoids (e.g., flavones, flavonols, isoflavones, chalcones, prenylflavonoids). Finally, we discuss limitations, mainly related to bioavailability issues, and future perspectives regarding the clinical use of flavonoids as adjuvant agents in TRAIL-based therapies.


Integrated Laser Sensor (ILS) for Remote Surface Analysis: Application for Detecting Explosives in Fingerprints.
Here, we describe an innovative Integrated Laser Sensor (ILS) that combines four spectroscopic techniques and two vision systems into a unique, transportable device. The instrument performs Raman and Laser-Induced Fluorescence (LIF) spectroscopy excited at 355 nm and Laser-Induced Breakdown Spectroscopy (LIBS) excited at 1064 nm, and it also detects Laser Scattering (LS) from the target under illumination at 650 nm. The combination of these techniques supplies information about: material change from one scanning point to another, the presence of surface contaminants, and the molecular and elemental composition of top target layers. Switching between the spectroscopic techniques and the laser wavelengths is fully automatic. The instrument is equipped with an autofocus, and it performs scanning with a chosen grid density over an interactively-selected target area. Alternative to the spectroscopic measurements, it is possible to switch the instrument to a high magnification target viewing. The working distances tested until now are between 8.5 and 30 m. The instrument is self-powered and remotely controlled via wireless communication. The ILS has been fully developed at ENEA for security applications, and it was successfully tested in two outdoor campaigns where an automatic recognition of areas containing explosives in traces had been implemented. The strategies for the identification of nitro-compounds placed on various substrates as fingerprints and the results obtained at a working distance of 10 m are discussed in the following.


Evidence for a neurotransmitter role for epinephrine derived from the adrenal medulla.
We examined the neurohumoral mechanisms underlying the hindlimb vasodilator response produced by electrical stimulation of the anteroventral region of the third ventricle (AV3V). Hindlimb blood flow velocity was recorded using a pulsed Doppler flow probe. The vasodilator response to AV3V stimulation was greater than that obtained after inhibition of neurogenic vasoconstrictor tone with sympathectomy and was, therefore, in part an active process. The hindlimb vasodilator response was not affected by cholinergic or histaminergic receptor blockade but was reduced by bilateral adrenalectomy (ADX) or adrenal demedullation (ADM) and was further reduced by beta-adrenergic receptor blockade with propranolol in ADX rats. In ADX or ADM rats the vasodilator response was attenuated by repeated AV3V stimulations and restored by epinephrine infusion. Moreover, restoration of the response after epinephrine infusion was completely blocked by the neuronal uptake blocker desmethylimipramine. As was observed with vasodilation, constrictor responses to AV3V stimulation in the renal and mesenteric vascular beds were also attenuated by adrenal demedullation and were restored by epinephrine infusion. These data suggest that circulating epinephrine, originating in the adrenal medulla, is taken up by sympathetic nerve terminals innervating blood vessels. The catecholamine is then released from these nerves and acts like a classical neurotransmitter, producing vasodilation in skeletal muscle and vasoconstriction in splanchnic and renal vascular beds.


Cis-limited action of the gene-A product of bacteriophage phiX174 and the essential bacterial site (E. coli-electron microscopy-cis-acting protein-specifically-nicked RF).
Parental replicative-form (RF(*)) DNA of bacteriophage varphiX174 in a replication-deficient host cell (rep(3) (-)) exhibits two characteristic features that correlate the function of viral gene A with the initiation of viral DNA replication: a specific discontinuity in the viral strand of a constant number of RF molecules and elongation of the viral strand to yield replicative-intermediate DNA forms with single-stranded tails. At high multiplicities of infection, these initiation events are limited to an average of four specifically nicked RFII molecules per cell. The limiting factor from the host cell may be related (or identical) to the essential bacterial sites known to limit the participation of parental genomes in RF replication. Double-infection experiments with wild-type phage and phage carrying an amber mutation in gene A show that the formation of gene A-specific RFII and RI is cis-limited to only the wild-type DNA. These results provide a basis at the DNA level for the known asymmetric complementation of gene A.


Further studies on the immunopathology of atopic keratoconjunctivitis using flow cytometry.
Atopic keratoconjunctivitis (AKC) is an ocular manifestation of systemic hypersensitivity. Although the pathogenesis of AKC is not fully understood, some previous data suggest that a decrease in numbers of suppressor T lymphocyte (Ts) and increase of Th, especially Th2 (the second subgroup of helper T lymphocyte), at the ocular surface may play an important role in the occurrence of the disease. In this study, the percentages of naive-Th (CD4/45RA+) and memory-Th (CD4/29+) cells, and the Th/Ts and memory-Th cells/naive-Th cells ratios were measured in the blood and tear samples of patients with AKC, atopic patients without ocular involvement and normal volunteers, using flow cytometry. Groups were compared using the Mann-Whitney U test. We found that patients with AKC had significantly higher memory-Th cell concentration, and Th/Ts and memory-Th cells/naive-Th cell ratios both in the tear and blood samples compared to normal subjects. While no significant difference existed between the tear samples of the atopic patients without ocular involvement and normal volunteers with respect to the above values, atopic patients had higher percentages of memory-Th cells and higher Th/Ts and memory-Th cells/naive-Th ratios in their blood than normal subjects. The percentages of memory-Th cells, and the Th/Ts and memory-Th cells/naive-Th cell ratios in the tear samples of AKC patients were also found to be higher than that of the atopic patients without ocular involvement, but no significant difference was present between the blood samples of these groups. The percentages of naive-Th cells did not show any significant difference between groups either in tear or blood samples. Since the mean memory-Th cells/naive-Th1 cells ratio in the tear samples of the patients with AKC was higher than in their blood samples, we propose that the localized accumulation of memory-Th2 cells, in addition to the increase of Th/Ts ratios in the external eye may cause AKC in atopic individuals.


Dutch women in midwife-led care at the onset of labour: which pain relief do they prefer and what do they use?
Pain experienced during labour is more extreme than many other types of physical pain. Many pregnant women are concerned about labour pain and about how they can deal with this pain effectively.The aim of this study was to examine the associations among low risk pregnant women's characteristics and their preferred use and actual use of pain medication during labour. Our study is part of the DELIVER study: a dynamic prospective multi-centre cohort study. The data for this study were collected between September 2009 and March 2011, from women at 20 midwifery practices throughout the Netherlands. Inclusion criteria for women were: singleton pregnancies, in midwife-led care at the onset of labour and speaking Dutch, English, Turkish or Arabic. Our study sample consisted of 1511 women in primary care who completed both questionnaire two (from 34 weeks of pregnancy up to birth) and questionnaire three (around six week post partum). These questionnaires were presented either online or on paper. Fifteen hundred and eleven women participated. Prenatally, 15.9% of women preferred some method of medicinal pain relief. During labour 15.2% of the total sample used medicinal pain relief and 25.3% of the women who indicated a preference to use medicinal pain relief during pregnancy, used pain medication. Non-Dutch ethnic background and planned hospital birth were associated with indicating a preference for medicinal pain relief during pregnancy. Primiparous and planned hospital birth were associated with actual use of the preferred method of medicinal pain relief during labour. Furthermore, we found that 85.5% of women who indicated a preference not to use pain medication prenatally, did not use any medication. Only a small minority of women had a preference for intrapartum pain medication prenatally. Most women did not receive medicinal pain relief during labour, even if they had indicated a preference for it.Care providers should discuss the unpredictability of the labour process and the fact that actual use of pain medication often does not match with women's preference prenatally.


Multilayer PZT 95/5 Antiferroelectric Film Energy Storage Devices with Giant Power Density.
A new type of energy storage devices utilizing multilayer Pb(Zr0.95 Ti0.05 )0.98 Nb0.02 O3 films is studied experimentally and numerically. To release the stored energy, the multilayer ferroelectric structures are subjected to adiabatic compression perpendicular to the polarization direction. Obtained results indicate that electrical interference between layers (10-120 layers) during stress wave transit through the structures has an effect on the generated current waveforms, but no impact on the released electric charge. The multilayer films undergo a pressure-induced phase transition to antiferroelectric phase at 1.7 GPa adiabatic compression and become completely depolarized, releasing surface screening charge with density equal to their remnant polarization. An energy density of 3 J cm-3 is successfully achieved with giant power density on the order of 2 MW cm-3 , which is four orders of magnitude higher than that of any other type of energy storage device. The outputs of multilayer structures can be precisely controlled by the parameters of the ferroelectric layer and the number of layers. Multilayer film modules with a volume of 0.7 cm3 are capable of producing 2.4 kA current, not achievable in electrochemical capacitors or batteries, which will greatly enhance the miniaturization and integration requirements for emerging high-power applications.


Renal toxicity due to reactive metabolites formed in situ in the kidney: investigations with 4-ipomeanol in the mouse.
The in vitro metabolism and covalent binding of the furan derivative, 4-ipomeanol, was mediated by oxygen-requiring, NADPH-dependent, CO-inhibitable microsomal enzymes present in the livers, lungs and kidneys of adult male mice. These activities were inhibitable by piperonyl butoxide and they were markedly enhanced in hepatic microsomes from C57/6J mice, but not DBA/2J mice, pretreated with 3-methylcholanthrene. The i.p. administration of 4-ipomeanol to adult male mice resulted in the covalent binding of large amounts of its metabolite(s) in the lungs and kidneys. The material bound in the kidneys was located predominantly in the proximal renal cortical tubules. The covalent binding and toxicity of 4-ipomeanol to the renal tubules could be prevented by pretreatment of the animals with piperonyl butoxide. The hepatic covalent binding and toxicity of 4-ipomeanol were enhanced and the pulmonary and renal covalent binding and toxicity were decreased in C57BL/6J mice pretreated with 3-methylcholanthrene; however, this pretreatment did not significantly alter the tissue covalent binding or toxicity of 4-ipomeanol in noninducible DBA/2J mice. These results support the view that renal damage by 4-ipomeanol in the mouse is caused by reactive 4-ipomeanol metabolite(s) formed in situ in the kidney.


A Novel Coronavirus and a Broad Range of Viruses in Kenyan Cave Bats.
To investigate virus diversity in hot zones of probable pathogen spillover, 54 oral-fecal swabs were processed from five bat species collected from three cave systems in Kenya, using metagenome sequencing. Viruses belonging to the Astroviridae, Circoviridae, Coronaviridae, Dicistroviridae, Herpesviridae and Retroviridae were detected, with unclassified viruses. Retroviral sequences were prevalent; 74.1% of all samples were positive, with distinct correlations between virus, site and host bat species. Detected retroviruses comprised Myotis myotis, Myotis ricketti, Myotis daubentonii and Galidia endogenous retroviruses, murine leukemia virus-related virus and Rhinolophus ferrumequinum retrovirus (RFRV). A near-complete genome of a local RFRV strain with identical genome organization and 2.8% nucleotide divergence from the prototype isolate was characterized. Bat coronavirus sequences were detected with a prevalence of 24.1%, where analyses on the ORF1ab region revealed a novel alphacoronavirus lineage. Astrovirus sequences were detected in 25.9%of all samples, with considerable diversity. In 9.2% of the samples, other viruses including Actinidia yellowing virus 2, bat betaherpesvirus, Bole tick virus 4, Cyclovirus and Rhopalosiphum padi virus were identified. Further monitoring of bats across Kenya is essential to facilitate early recognition of possibly emergent zoonotic viruses.


Coherent Charge Transport in Ballistic InSb Nanowire Josephson Junctions.
Hybrid InSb nanowire-superconductor devices are promising for investigating Majorana modes and topological quantum computation in solid-state devices. An experimental realisation of ballistic, phase-coherent superconductor-nanowire hybrid devices is a necessary step towards engineering topological superconducting electronics. Here, we report on a low-temperature transport study of Josephson junction devices fabricated from InSb nanowires grown by molecular-beam epitaxy and provide a clear evidence for phase-coherent, ballistic charge transport through the nanowires in the junctions. We demonstrate that our devices show gate-tunable proximity-induced supercurrent and clear signatures of multiple Andreev reflections in the differential conductance, indicating phase-coherent transport within the junctions. We also observe periodic modulations of the critical current that can be associated with the Fabry-Pérot interference in the nanowires in the ballistic transport regime. Our work shows that the InSb nanowires grown by molecular-beam epitaxy are of excellent material quality and hybrid superconducting devices made from these nanowires are highly desirable for investigation of the novel physics in topological states of matter and for applications in topological quantum electronics.


In-host adaptation and acquired triazole resistance in Aspergillus fumigatus: a dilemma for clinical management.
Aspergillus fumigatus causes a range of diseases in human beings, some of which are characterised by fungal persistence. A fumigatus can persist by adapting to the human lung environment through physiological and genomic changes. The physiological changes are based on the large biochemical versatility of the fungus, and the genomic changes are based on the capacity of the fungus to generate genetic diversity by spontaneous mutations or recombination and subsequent selection of the genotypes that are most adapted to the new environment. In this Review, we explore the adaptation strategies of A fumigatus in relation to azole resistance selection and the clinical implications thereof for management of diseases caused by Aspergillus spp. We hypothesise that the current diagnostic tools and treatment strategies do not take into account the biology of the fungus and might result in an increased likelihood of fungal persistence in patients. Stress factors, such as triazole exposure, cause mutations that render resistance. The process of reproduction-ie, sexual, parasexual, or asexual-is probably crucial for the adaptive potential of Aspergillus spp. As any change in the environment can provoke adaptation, switching between triazoles in patients with chronic pulmonary aspergillosis might result in a high-level pan-triazole-resistant phenotype through the accumulation of resistance mutations. Alternatively, when triazole therapy is stopped, an azole-free environment is created that could prompt selection for compensatory mutations that overcome any fitness costs that are expected to accompany resistance development. As a consequence, starting, switching, and stopping azole therapy has the risk of selecting for highly resistant strains with wildtype fitness. A similar adaptation is expected to occur in response to other stress factors, such as endogenous antimicrobial peptides; over time the fungus will become increasingly adapted to the lung environment, thereby limiting the probability of eradication. Our hypothesis challenges current management strategies, and future research should investigate the genomic dynamics during infection to understand the key factors facilitating adaptation of Aspergillus spp.


Gallium-67 myocardial imaging for the detection of bacterial endocarditis.
Eleven patients with a clinical diagnosis of bacterial endocarditis underwent scintillation scanning of the precordial region 2-7 days after the intravenous administration of 3 mCi of gallium-67 citrate. Seven had positive scans, 3 of which were confirmed by postmortem imaging at autopsy. Serial images revealed the scans to be frequently negative at 48 hours and positive from 3 to 8 days following injection. Uptake was not seen in the region of the myocardium 48 hours or longer after the injection of 15 patients without endocarditis used as controls.


Treatment of child and adolescent obesity: reports from pediatricians, pediatric nurse practitioners, and registered dietitians.
The primary aim of this study was to identify interventions used by pediatric health care providers in treatment of overweight children and adolescents to identify provider educational needs. A secondary aim was to examine the association of certain provider characteristics with recommended evaluation practices. A random sample of pediatricians, pediatric nurse practitioners, and registered dietitians (RDs) received questionnaires about their diet, activity, and medication recommendations for overweight patients and about referrals to specialists and programs. Results were examined for adherence to published recommendations and for associations with certain respondent characteristics. A total of 940 providers responded (response rate: 19%-33%). The majority recommended "changes in eating patterns" and "limitations of specific foods." Half or more used "low-fat diet" and "modest calorie restriction" in adolescents. Less than 15% used "very low-calorie diet." Fewer RDs recommended more restrictive diets. More than 60% of all groups followed recommended eating interventions for school-aged children and adolescents. More than 80% followed recommended physical activity interventions for all age groups. In each group, about 5% sometimes recommended prescription medication and herbal remedies for adolescents. None recommended surgery. Two thirds of pediatricians and pediatric nurse practitioners often referred to RDs. Approximately 20% referred to child/adolescent weight programs, but for 27% to 42%, these programs or pediatric obesity specialists were not available. No consistent associations between respondent characteristics and adherence to recommended interventions were identified. The providers generally promoted healthy eating and activity with minimal use of highly restrictive diets or medication to control weight.


Effects of interfacial adsorption configurations on dye-sensitized solar cell performance at the stoichiometric and defective TiO2 anatase (101) surfaces: a theoretical investigation.
Interfacial adsorption configuration plays a crucial role in influencing the photovoltaic performance of dye-sensitized solar cells (DSSCs), and thus, theoretical investigations are needed to further understand the impacts of different absorption configurations on stoichiometric and defective TiO2(101) surfaces on the short-circuit photocurrent density (JSC) and open-circuit voltage (VOC) of DSSCs. Herein, calculations of isolated dyes and dye/TiO2 systems were performed on the donor-π bridge-acceptor (D-π-A) type porphyrin sensitizers bearing different donor moieties and an α-cyanoacrylic acid anchoring group (T1-3), using DFT and TD-DFT methods. And, for the first time, comparative analysis of interfacial electron transfer (IET) and density of states (DOS) were carried out on dye/TiO2 systems with stoichiometric and defective surfaces to provide further insight into the electronic factors influencing the efficiency of DSSCs, which can well explain the experimental variation trends of JSC and VOC values. It turned out that attachment via the carboxyl and cynao groups in a tridentate binding mode can result in more efficient IET rates and an upshifted conduction band in comparison with those of the bidentate attachment. More interestingly, we found that the adsorption configuration on defective surfaces containing an O2c vacancy induced more upshifted CBM and relatively fast IET, especially for the bonding mode through two O atoms of the carboxyl group.


Detection of Superheated Steam during Sterilization Using Biological Indicators.
Saturated steam (SS) is used for sterilizing many medical devices. Exposure to SS for appropriate temperature/time combinations creates a microbicidal environment that renders product sterile. Superheated steam (SHS) has been heated beyond its saturation point and is less microbicidal, compromising process efficacy. Sterilization monitoring systems should detect SHS. One method is to use biological indicators (BIs; e.g., rapid-readout self-contained BIs [RRSCBIs]). The purpose of this study was to determine if RRSCBIs can detect SHS. Pressurizing the boiler to 4,700 mB, manifold to 4,000 mB, and chamber jacket to 3,600 mB and heating the viewing window to 150°C in a 10-L BI evaluation resistometer vessel allowed approximately 12°C and 4.5°C of superheat in a nominal 121.75 ± 0.25°C and 132.5 ± 0.25°C cycle, respectively, to be reproducibly achieved. Replicate tests using multiple RRSCBIs from different batches were exposed vertically (cap up), inverted (cap down), and horizontally to SS and SHS. RRSCBI viability was determined using a fluorescent readout method. RRSCBIs exposed to SS at 121.75 ± 0.25°C for 7 or 14 minutes were negative. A total of 135 type A RRSCBIs were exposed to SHS (12°C) at 121.75 ± 0.25°C for 14 minutes. Zero of 45 RRSCBIs mounted vertically showed a positive fluorescent result, 26 of 45 mounted inverted were positive, and 45 of 45 mounted horizontally were positive. A total of 135 type B RRSCBIs were exposed to SHS (12°C) at 121.75 ± 0.25°C for 7 minutes. Twenty-four of 45 mounted vertically were positive, 41 of 45 mounted inverted were positive, and 45 of 45 mounted horizontally were positive. RRSCBIs detected SHS, but this was orientation dependent. Further work is required to establish the application of these findings in healthcare facility settings.


Mendelian randomization for cardiovascular diseases: principles and applications.
Large-scale genome-wide association studies conducted over the last decade have uncovered numerous genetic variants associated with cardiometabolic traits and risk factors. These discoveries have enabled the Mendelian randomization (MR) design, which uses genetic variation as a natural experiment to improve causal inferences from observational data. By analogy with the random assignment of treatment in randomized controlled trials, the random segregation of genetic alleles when DNA is transmitted from parents to offspring at gamete formation is expected to reduce confounding in genetic associations. Mendelian randomization analyses make a set of assumptions that must hold for valid results. Provided that the assumptions are well justified for the genetic variants that are employed as instrumental variables, MR studies can inform on whether a putative risk factor likely has a causal effect on the disease or not. Mendelian randomization has been increasingly applied over recent years to predict the efficacy and safety of existing and novel drugs targeting cardiovascular risk factors and to explore the repurposing potential of available drugs. This review article describes the principles of the MR design and some applications in cardiovascular epidemiology.


Proceedings from an international conference on ablation therapy for Barrett's mucosa: Brittany, France, 31 August - 2 September 1997.
The increasing incidence of adenocarcinoma of the lower esophagus and cardia arising in Barrett's metaplastic epithelium continues to be of great concern because medical and surgical efforts to reverse the process have been disappointing. A potential answer to the problem is removal of the metaplastic epithelium. Modern technology has introduced physical and chemical modalities which facilitate ablation of the neo-epithelium endoscopically. These techniques have been used in several centers, and preliminary results are encouraging. This report summarizes the proceedings of an international symposium on ablative therapy held in Brittany, France in August 1997.Twenty-eight speakers contributed to the talks on the pathology, pathogenesis, current therapy experimental studies and clinical experience of ablation of Barrett's esophagus.


Machine learning to predict waitlist dropout among liver transplant candidates with hepatocellular carcinoma.
Accurate prediction of outcome among liver transplant candidates with hepatocellular carcinoma (HCC) remains challenging. We developed a prediction model for waitlist dropout among liver transplant candidates with HCC. The study included 18,920 adult liver transplant candidates in the United States listed with a diagnosis of HCC, with data provided by the Organ Procurement and Transplantation Network. The primary outcomes were 3-, 6-, and 12-month waitlist dropout, defined as removal from the liver transplant waitlist due to death or clinical deterioration. Using 1,181 unique variables, the random forest model and Spearman's correlation analyses converged on 12 predictive features involving 5 variables, including AFP (maximum and average), largest tumor size (minimum, average, and most recent), bilirubin (minimum and average), INR (minimum and average), and ascites (maximum, average, and most recent). The final Cox proportional hazards model had a concordance statistic of 0.74 in the validation set. An online calculator was created for clinical use and can be found at: http://hcclivercalc.cloudmedxhealth.com/. In summary, a simple, interpretable 5-variable model predicted 3-, 6-, and 12-month waitlist dropout among patients with HCC. This prediction can be used to appropriately prioritize patients with HCC and their imminent need for transplant.


Public behaviour in response to the COVID-19 pandemic: understanding the role of group processes.
In the absence of a vaccine, behaviour by the public is key to the response to the COVID-19 pandemic. Yet, as with other types of crises and emergencies, there have been doubts about the extent to which the public are able to engage effectively with the required behaviour. These doubts are based on outdated models of group psychology. We analyse the role of group processes in the COVID-19 pandemic in three domains: recognition of threat, adherence by the public to the required public health behaviours (and the factors that increase such adherence) and actions of the many community mutual aid groups that arose during lockdown. In each case, we draw upon the accumulated research on behaviour in emergencies and disasters, as well as the latest findings in relation to the COVID-19 pandemic, to show that explanations in terms of social identity processes make better sense of the patterns of evidence than alternative explanations. If behaviour in the pandemic is a function of mutable group processes rather than fixed tendencies, then behavioural change is possible. There was evidence of significant change in behaviour from the public, particularly in the early days of the pandemic. Understanding the role of group processes means we can help design more effective interventions to support collective resilience in the public in the face of the pandemic and other threats. We draw out from the evidence a set of recommendations on facilitating the public response to COVID-19 by harnessing group processes.


Single prolonged stress alters neural activation in the periacqueductal gray and midline thalamic nuclei during emotional learning and memory.
Clinical and preclinical studies that have examined the neurobiology of persistent fear memory in posttraumatic stress disorder (PTSD) have focused on the medial prefrontal cortex, hippocampus, and amygdala. Sensory systems, the periaqueductal gray (PAG), and midline thalamic nuclei have been implicated in fear and extinction memory, but whether neural activity in these substrates is sensitive to traumatic stress (at baseline or during emotional learning and memory) remains unexplored. To address this, we used the single prolonged stress (SPS) model of traumatic stress. SPS and control rats were either subjected to fear conditioning (CS-fear) or presented with CSs alone (CS-only) during fear conditioning. All rats were then subjected to extinction training and testing. A subset of rats were euthanized after each behavioral stage and c-Fos and c-Jun used to measure neural activation in all substrates. SPS lowered c-Jun levels in the dorsomedial and lateral PAG at baseline, but the elevated c-Jun expression in the PAG during emotional learning and memory. SPS also altered c-Fos expression during fear and extinction learning/memory in midline thalamic nuclei. These findings suggest changes in neural function in the PAG and midline thalamic nuclei could contribute to persistent fear memory induced by traumatic stress. Interestingly, SPS effects were also observed in animals that never learned fear or extinction (i.e., CS-only). This raises the possibility that traumatic stress could have broader effects on the psychological function that are dependent on the PAG and midline thalamic nuclei.


Heart failure as an endpoint in heart failure and non-heart failure cardiovascular clinical trials: the need for a consensus definition.
Specific criteria have been established to define the occurrence of myocardial infarction (MI) and stroke in cardiovascular clinical trials, but there is not a consistent definition for heart failure. Heart failure events appear to occur at a rate that is similar to stroke and MI in trials of hypertension, hyperlipidaemia, diabetes, and coronary heart disease, yet a consistent approach to defining heart failure events has not yet been realized. The wide range of definitions used in clinical trials makes it difficult to interpret new data in the context of existing literature. This inconsistency has led to challenges in determining the incidence of heart failure in cardiovascular studies and the effects of interventions on these endpoints. This paper examines issues related to defining heart failure events in cardiovascular clinical trials and presents a definition to formally address this issue.


[Reentrant ventricular tachycardia treated with RF ablation delivered through coronary sinus - a case report].
A case of a 58 year-old man with epicardially located reentrant ventricular tachycardia treated with RF ablation delivered through coronary sinus is presented. Based on multiple electrophysiological parameters (surface ECG, electroanatomical map collected from the endocardium, bipolar and unipolar endocardial recordings, and unsuccesful ablation attempts from the endocardial side) the tachycardia loop was found to be located epicardially. This allowed for successful ablation approach.


Shared synteny between human chromosome 10 and chromosome 1 of the marsupial tammar wallaby, Macropus eugenii.
Marsupial homologs of the human chromosome 10 loci IL2RA, HK1, and PLAU have been cloned and mapped by fluorescence in situ hybridization to chromosome 1q of the tammar wallaby, Macropus eugenii. Relative distance measurements of the hybridization signals on M. eugenii chromosome 1 show that marsupial homologs of human (HSA) 10p IL2RA and 10q HK1/PLAU flank the marsupial homologs of the human 5q gene IL5 and the human 15q imprinted genes SNRPN and ZNF127. The shared synteny, therefore, does not necessarily mean that HSA 10 represents an ancestral grouping; rather, it suggests that HSA 10p and HSA 10q represent two different ancestral mammalian units which fused directly in primates and were incorporated independently into two different regions of the same chromosome in marsupials.


Prediction of drug clearance by glucuronidation from in vitro data: use of combined cytochrome P450 and UDP-glucuronosyltransferase cofactors in alamethicin-activated human liver microsomes.
Glucuronidation via UDP-glucuronosyltransferase (UGT) is an increasingly important clearance pathway. In this study intrinsic clearance (CL(int)) values for buprenorphine, carvedilol, codeine, diclofenac, gemfibrozil, ketoprofen, midazolam, naloxone, raloxifene, and zidovudine were determined in pooled human liver microsomes using the substrate depletion approach. The in vitro clearance data indicated a varying contribution of glucuronidation to the clearance of the compounds studied, ranging from 6 to 79% for midazolam and gemfibrozil, respectively. The CL(int) was obtained using either individual or combined cofactors for cytochrome P450 (P450) and UGT enzymes with alamethicin activation and in the presence and absence of 2% bovine serum albumin (BSA). In the presence of combined P450 and UGT cofactors, CL(int) ranged from 2.8 to 688 microl/min/mg for zidovudine and buprenorphine, respectively; the clearance was approximately equal to the sum of the CL(int) values obtained in the presence of individual cofactors. The unbound intrinsic clearance (CL(int, u)) was scaled to provide an in vivo predicted CL(int); the data obtained in the presence of combined cofactors resulted in 5-fold underprediction on average. Addition of 2% BSA to the incubation with both P450 and UGT cofactors reduced the bias in the clearance prediction, with 8 of 10 compounds predicted within 2-fold of in vivo values with the exception of raloxifene and gemfibrozil. The current study indicates the applicability of combined cofactor conditions in the assessment of clearance for compounds with a differential contribution of P450 and UGT enzymes to their elimination. In addition, improved predictability of microsomal data is observed in the presence of BSA, in particular for UGT2B7 substrates.


Achieving Diagnostic Resolution in Young Children with Social Communication Concerns in a Predominantly Low-Income Population.
Children in low-income families are at risk for delayed diagnosis of autism spectrum disorder (ASD). The cascade-of-care model, which examines steps of care for quality and efficacy, can identify lesions in the process for evaluation and diagnosis for children at risk for ASD. Little is known about predictors that influence key steps in this process. We performed a retrospective chart review of 110 children under age five years from an academic medical center with social communication concerns. We assessed predictors of age of referral for ASD diagnostic evaluation, time to diagnosis, and likelihood of diagnostic completion. Children with continuity of primary care were referred at an earlier age than those receiving primary care at multiple centers. Compared with children with missed visits, children attending all well-child visits had a shorter median time to diagnosis. These findings illustrate a need for primary medical homes to facilitate early and timely ASD evaluations.


A Case of Phyllodes Tumor of the Breast with Mixed Liposarcoma: Case Report and Literature Review.
Phyllodes tumors (PTs) account for less than 1% of breast tumors, and malignant PTs account for even less. Here, we described an unusual case of malignant PT with mixed liposarcoma (myxoid liposarcoma [MLP] and pleomorphic liposarcoma [PLP]). A 52-year-old woman discovered a small lump in her left breast. Twenty years later, the lump suddenly grew within 1 month. Mammography showed space-occupying lesions of the left breast. Histologically, the tumor was characterized by hypercellular stroma covering the epithelium and protrusion of the myoepithelium into the cyst to form a lobulated structure; regions of loose mucus and hypercellular structures alternated. A region of peripheral benign fibroadenoma was also observed, and many stellate and spindle cells or signet ring-like cells were identified in loose areas. Some areas showed a characteristic thin branching vascular pattern. In the cell-rich area, adipocytes and odd megakaryocytes were observed. Atypical mitotic figures were observed in the cell-rich and mucus areas (16 mitoses/10 high-power fields [HPF] and 2 mitoses/10 HPF, respectively). In the immunohistochemical analysis, a small number of tumor cells were positive for AE1/3 and vimentin, whereas all cells were negative for cytokeratin 34βE12, E-cadherin, p63, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and S-100, ruling out the possibility of metaplastic carcinoma. Interestingly, cyclin-dependent kinase 4, mouse double minute 2 (MDM2), and p16 were strongly positive in both loose mucus and cell-rich areas. However, the fluorescence in situ hybridization test results showed that MDM2 was not amplified. Combined with morphological characteristics, these findings supported that the tumor was a mixed malignant PT with MLP and PLP. Our patient did not receive radiation therapy, and after 47 months of follow-up, no recurrence or metastasis occurred. This case report serves to expand the morphologic spectrum of mixed malignant PT with liposarcoma.