Miracle-dz/UniFAR-FTUs huggingface dataset:
Interaction of Digibind with endogenous cardiotonic steroids from preeclamptic placentae

Background Preeclampsia is a major cause of maternal and fetal mortality, and its pathogenesis is not fully understood. Endogenous digitalis-like cardiotonic steroids (CTS) have been implicated in the pathophysiology of preeclampsia; this is illustrated by clinical observations that Digibind, a therapeutic digoxin antibody fragment which binds CTS, lowers blood pressure and reverses Na/K-ATPase inhibition in patients with preeclampsia. Recently we reported that plasma levels of marinobufagenin (MBG), a bufadienolide vasoconstrictor CTS, are increased four-fold in patients with severe preeclampsia. Methods In the present study, we compared levels of MBG in normal and preeclamptic placentae, as well as the interactions of Digibind and antibodies against MBG and ouabain with material purified from preeclamptic placentae using high-performance liquid chromatography (HPLC). Results Levels of endogenous MBG, but not that of endogenous ouabain, exhibited a four-fold elevation in preeclamptic placentae vs. normal placentae (13.6 ± 2.5 and 48.6 ± 7.0 nmoles/g tissue; P < 0.01). The elution time of endogenous placental MBG-like immunoreactive material from reverse-phase HPLC column was identical to that of authentic MBG. A competitive immunoassay based on Digibind exhibited reactivity to HPLC fractions having retention times similar to that seen with MBG and other bufadienolides, but not to ouabain-like immunoreactive material. Conclusions Our results suggest that elevated levels of endogenous bufadienolide CTS represent a potential target for immunoneutralization in patients with preeclampsia.
Left Atrial Structure in Relationship to Age, Sex, Ethnicity, and Cardiovascular Risk Factors: MESA (Multi-Ethnic Study of Atherosclerosis)

Background— Left atrial (LA) size is a marker of diastolic function and is associated with atrial fibrillation and cardiovascular outcomes. However, there are no large population studies measuring LA structure. The relationship of demographics and cardiovascular risk factors to LA size is largely unknown. This study aimed to determine associations of LA size with demographic factors, cardiac structure and function, and cardiovascular risk factors. Methods and Results— LA volume indexed to body surface area was measured by cardiovascular magnetic resonance steady-state free precession and fast gradient echo cine long- and short-axis images in 2576 asymptomatic participants of MESA ([Multi-Ethnic Study of Atherosclerosis] 68.7 years, 53.0% women, white 42.2%, Chinese American 12.0%, black 24.5%, and Hispanic 21.2%) using biplane and short-axis images. The mean LA volume index was 36.5±11.4 mL/m2 in the entire cohort and 35.5±10.1 mL/m2 in subjects free of cardiovascular risk factors (n=283). Multivariable analysis included adjustment for demographics, ethnicity, cardiovascular risk factors, serological studies, socioeconomic status, left ventricular structure, and medications. In the adjusted analysis, age (&bgr;=0.2 mL/m2 per year, P<0.0001), male sex (&bgr;=−4.2 mL/m2, P<0.0001), obesity (&bgr;=1.3 mL/m2, P<0.01), end-diastolic volume index (&bgr;=0.4 mL/m2, P<0.0001), Chinese American (&bgr;=−2.6 mL/m2, P<0.0001), and Hispanic (&bgr;=1.1 mL/m2, P<0.05) ethnicities were associated with LA volume index. Diabetes mellitus and smoking were not associated with LA volume index. LA volumes measured by steady-state free precession were 3% larger than by fast gradient echo cine cardiovascular magnetic resonance (P<0.001). Conclusions— Age, sex, ethnicity and left ventricular structural parameters were associated with LA size. Importantly, the study provides reference values of normal LA volume index.
Renal function up to the 5th decade of life after nephrectomy in childhood: A literature review

The aim of the present study was to find out if in children ablation of 50% of renal mass may be associated with a progressive renal damage (Brenner’s hypothesis). We collected 1035 adult or adolescent survivors who underwent nephrectomy for unilateral oncological or non‐oncological causes during childhood. Stratification of all survivors for age revealed that the number of subjects with blood hypertension and/or renal dysfunction (glomerular filtration rate < 90 mL/min per 1.73 m2) to be significantly higher in survivors ≥30 years old in comparison with younger patients. Available data on long‐term renal function after nephrectomy during childhood support the Brenner’s hypothesis.
Prevalence, awareness and risk factors of hypertension in a large cohort of Iranian adult population

Background: There is considerable variation in hypertension prevalence and awareness, and their correlates, across different geographic locations and ethnic groups. We performed this cross-sectional analysis on data from the Golestan Cohort Study (GCS). Methods: Enrollment in this study occurred in 2004–2008, and included 50 045 healthy individuals from Golestan Province in northeastern Iran. Hypertension was defined as a SBP at least 140 mmHg, a DBP at least 90 mmHg, a prior diagnosis of hypertension, or the use of antihypertensive drugs. Potential correlates of hypertension and its awareness were analyzed by logistic regression adjusted for sex, age, BMI, place of residence, literacy, ethnicity, physical activity, smoking, black and green tea consumption and wealth score. Results: Of the total cohort participants, 21 350 (42.7%) were hypertensive. Age-standardized prevalence of hypertension, using the 2001 WHO standard world population, was 41.8% (95% confidence interval: 38.3–45.2%). Hypertension was directly associated with female sex, increased BMI, Turkmen ethnicity, and lack of physical activity, and inversely associated with drinking black tea and wealth score. Among hypertensive patients, 46.2% were aware of their disease, 17.6% were receiving antihypertensive medication, and 32.1% of the treated patients had controlled hypertension. Hypertension awareness was greater among women, the elderly, overweight and obese patients, and those with a higher wealth score. Conclusion: Hypertension is highly prevalent in rural Iran, many of the affected individuals are unaware of their disease, and the rate of control by antihypertensive medications is low. Increasing hypertension awareness and access to health services, especially among less privileged residents are recommended.
Mortality from Cardiovascular Diseases in the Semipalatinsk Historical Cohort, 1960–1999, and its Relationship to Radiation Exposure

The data on risk of mortality from cardiovascular disease due to radiation exposure at low or medium doses are inconsistent. This paper reports an analysis of the Semipalatinsk historical cohort exposed to radioactive fallout from nuclear testing in the vicinity of the Semipalatinsk Nuclear Test Site, Kazakhstan. The cohort study, which includes 19,545 persons of exposed and comparison villages in the Semipalatinsk region, had been set up in the 1960s and comprises 582,656 person-years of follow-up between 1960 and 1999. A dosimetric approach developed by the U.S. National Cancer Institute (NCI) has been used. Radiation dose estimates in this cohort range from 0 to 630 mGy (whole-body external). Overall, the exposed population showed a high mortality from cardiovascular disease. Rates of mortality from cardiovascular disease in the exposed group substantially exceeded those of the comparison group. Dose–response analyses were conducted for both the entire cohort and the exposed group only. A dose–response relationship that was found when analyzing the entire cohort could be explained completely by differences between the baseline rates in exposed and unexposed groups. When taking this difference into account, no statistically significant dose–response relationship for all cardiovascular disease, for heart disease, or for stroke was found. Our results suggest that within this population and at the level of doses estimated, there is no detectable risk of radiation-related mortality from cardiovascular disease.
Intratumoral Immunotherapy of Established Solid Tumors With Chitosan/IL-12

IL-12 is a potent antitumor cytokine that exhibits significant clinical toxicities after systemic administration. We hypothesized that intratumoral (i.t.) administration of IL-12 coformulated with the biodegradable polysaccharide chitosan could enhance the antitumor activity of IL-12 while limiting its systemic toxicity. Noninvasive imaging studies monitored local retention of IL-12, with and without chitosan coformulation, after i.t. injection. Antitumor efficacy of IL-12 alone and IL-12 coformulated with chitosan (chitosan/IL-12) was assessed in mice bearing established colorectal (MC32a) and pancreatic (Panc02) tumors. Additional studies involving depletion of immune cell subsets, tumor rechallenge, and CTL activity were designed to elucidate mechanisms of regression and tumor-specific immunity. Coformulation with chitosan increased local IL-12 retention from 1 to 2 days to 5 to 6 days. Weekly i.t. injections of IL-12 alone eradicated ≤10% of established MC32a and Panc02 tumors, while i.t. chitosan/IL-12 immunotherapy caused complete tumor regression in 80% to 100% of mice. Depletion of CD4+ or Gr-1+ cells had no impact on chitosan/IL-12-mediated tumor regression. However, CD8+ or NK cell depletion completely abrogated antitumor activity. I.t. chitosan/IL-12 immunotherapy generated systemic tumor-specific immunity, as >80% of mice cured with i.t. chitosan/IL-12 immunotherapy were at least partially protected from tumor rechallenge. Furthermore, CTLs from spleens of cured mice lysed MC32a and gp70 peptide-loaded targets. Chitosan/IL-12 immunotherapy increased local retention of IL-12 in the tumor microenvironment, eradicated established, aggressive murine tumors, and generated systemic tumor-specific protective immunity. Chitosan/IL-12 is a well-tolerated, effective immunotherapy with considerable potential for clinical translation.
Novel protein therapeutic joint retention strategy based on collagen‐binding Avimers

Designing drugs to treat diseases associated with articular joints, particularly those targeting chondrocytes, is challenging due to unique local environmental constraints including the avascular nature of cartilage, the absence of a closed joint compartment, and a highly cross‐linked extracellular matrix. In an effort to address these challenges, we developed a novel strategy to prolong residence time of intra‐articularly administered protein therapeutics. Avimer domains are naturally found in membrane polypeptides and mediate diverse protein–protein interactions. Screening of a phage Avimer domain library led to identification of several low affinity type II collagen‐binding Avimers. Following several rounds of mutagenesis and reselection, these initial hits were transformed to high affinity, selective type II collagen‐binding Avimers. One such Avimer (M26) persisted in rat knees for at least 1 month following intra‐articular administration. Fusion of this Avimer to a candidate therapeutic payload, IL‐1Ra, yielded a protein construct which simultaneously bound to type II collagen and to IL‐1 receptor. In vitro, IL‐1Ra_M26 bound selectively to cartilage explants and remained associated even after extensive washing. Binding appeared to occur preferentially to pericellular regions surrounding chondrocytes. An acute intra‐articular IL‐1‐induced IL‐6 challenge rat model was employed to assess in vivo pharmacodynamics. Whereas both IL‐1Ra_M26 and native IL‐1Ra inhibited IL‐6 output when co‐administered with the IL‐1 challenge, only IL‐1Ra_M26 inhibited when administered 1 week prior to IL‐1 challenge. Collagen‐binding Avimers thus represent a promising strategy for enhancing cartilage residence time of protein therapeutics. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1238–1247, 2018.
Cortical Representation of Natural Complex Sounds: Effects of Acoustic Features and Auditory Object Category

How the brain processes complex sounds, like voices or musical instrument sounds, is currently not well understood. The features comprising the acoustic profiles of such sounds are thought to be represented by neurons responding to increasing degrees of complexity throughout auditory cortex, with complete auditory “objects” encoded by neurons (or small networks of neurons) in anterior superior temporal regions. Although specialized voice and speech–sound regions have been proposed, it is unclear how other types of complex natural sounds are processed within this object-processing pathway. Using functional magnetic resonance imaging, we sought to demonstrate spatially distinct patterns of category-selective activity in human auditory cortex, independent of semantic content and low-level acoustic features. Category-selective responses were identified in anterior superior temporal regions, consisting of clusters selective for musical instrument sounds and for human speech. An additional subregion was identified that was particularly selective for the acoustic–phonetic content of speech. In contrast, regions along the superior temporal plane closer to primary auditory cortex were not selective for stimulus category, responding instead to specific acoustic features embedded in natural sounds, such as spectral structure and temporal modulation. Our results support a hierarchical organization of the anteroventral auditory-processing stream, with the most anterior regions representing the complete acoustic signature of auditory objects.
Dysfunctional representation of expected value is associated with reinforcement-based decision-making deficits in adolescents with conduct problems.

BACKGROUND Previous work has shown that patients with conduct problems (CP) show impairments in reinforcement-based decision-making. However, studies with patients have not previously demonstrated any relationships between impairment in any of the neurocomputations underpinning reinforcement-based decision-making and specific symptom sets [e.g. level of CP and/or callous-unemotional (CU) traits]. METHODS Seventy-two youths [20 female, mean age = 13.81 (SD = 2.14), mean IQ = 102.34 (SD = 10.99)] from a residential treatment program and the community completed a passive avoidance task while undergoing functional MRI. RESULTS Greater levels of CP were associated with poorer task performance. Reduced representation of expected values (EV) when making avoidance responses within bilateral anterior insula cortex/inferior frontal gyrus (AIC/iFG) and striatum was associated with greater levels of CP but not CU traits. CONCLUSIONS The current data indicate that difficulties in the use of value information to motivate decisions to avoid suboptimal choices are associated with increased levels of CP (though not severity of CU traits). Moreover, they account for the behavioral deficits observed during reinforcement-based decision-making in youth with CP. In short, an individual's relative failure to utilize value information within AIC/iFG to avoid bad choices is associated with elevated levels of CP.
Population Pharmacokinetics of Micafungin and Its Metabolites M1 and M5 in Children and Adolescents

ABSTRACT The aim of this analysis was to identify therapeutic micafungin regimens for children that produce the same micafungin exposures known to be effective for the prevention and treatment of Candida infections in adults. Pediatric pharmacokinetic data from 229 patients between the ages of 4 months and <17 years were obtained from four phase I and two phase III clinical trials. Population pharmacokinetic models were used to simulate the proportion of children who had a steady-state area under the concentration-time curve at 24 hours (AUC24) of micafungin within the 10th to 90th percentile range observed in a population of adults receiving a dose of micafungin with established efficacy for invasive candidiasis (100 mg/day), i.e., 75 to 139 μg · h/ml. Simulated pediatric dosages of 0.5 to 5 mg/kg of body weight/day were explored. A two-compartment model was used that incorporated body weight as a predefined covariate for allometric scaling of the pharmacokinetic parameters. During construction of the model, aspartate aminotransferase and total bilirubin were also identified as covariates that had a significant effect on micafungin clearance. A dose of 2 mg/kg resulted in the highest proportion of children within the predefined micafungin AUC24 target range for invasive candidiasis. Cutoffs of 40 or 50 kg for weight-based dosing resulted in heavier children being appropriately dosed. Thus, dose regimens of 1, 2, and 3 mg/kg/day micafungin are appropriate for the prevention of invasive candidiasis, the treatment of invasive candidiasis, and the treatment of esophageal candidiasis, respectively, in children aged 4 months to <17 years.
E2F1 in neurons is cleaved by calpain in an NMDA receptor‐dependent manner in a model of HIV‐induced neurotoxicity

The transcription factor E2F1 activates gene targets required for G1‐S phase progression and for apoptosis, and exhibits increased expression levels in neurons in several CNS diseases including HIV encephalitis, Alzheimer disease, and Parkinson's Disease. While E2F1 is known to regulate cell viability through activation of caspases, here we present evidence supporting the involvement of E2F1 in N‐methyl‐d‐aspartate (NMDA) receptor‐dependent, HIV‐induced neuronal death mediated by calpains. Using an in vitro model of HIV‐induced neurotoxicity that is dependent on NMDA receptor and calpain activation, we have shown that cortical neurons lacking functional E2F1 are less susceptible to neuronal death. In addition, we report that neuronal E2F1 is cleaved by calpain to a stable 55‐kiloDalton fragment following NR2B‐dependent NMDA receptor stimulation. This cleavage of E2F1 is protein conformation‐dependent and involves at least two cleavage events, one at each terminus of the protein. Intriguingly, the stabilized E2F1 cleavage product is produced in post‐mitotic neurons of all ages, but fails to be stabilized in cycling cells. Finally, we show that a matching E2F1 cleavage product is produced in human fetal neurons, suggesting that calpain cleavage of E2F1 may be produced in human cortical tissue. These results suggest neuronal E2F1 is processed in a novel manner in response to NMDA receptor‐mediated toxicity, a mechanism implicated in HIV‐associated neurocognitive disorders pathogenesis as well as several other diseases of the CNS.
Mental health difficulties and academic attainment: Evidence for gender-specific developmental cascades in middle childhood

Abstract We present a developmental cascade model of the longitudinal relationships between internalizing symptoms, externalizing problems, and academic performance in middle childhood, utilizing a large sample (N = 1,771) from the United Kingdom in a 3-year, cross-lag design. Three hypotheses were tested: adjustment erosion, academic incompetence, and (cumulative) shared risk. In addition, we sought to examine whether developmental cascade pathways varied across gender, while also statistically exploring indirect, mediation pathways. Structural equation models that accounted for within-time covariance, data nesting, and temporal stability provided evidence of gender-specific effects as follows: externalizing-attainment adjustment erosion pathways were found only in boys, while attainment-internalizing/externalizing academic incompetence pathways were found only in girls. Analysis of mediation pathways provided further support for these gender-specific longitudinal profiles. Protective longitudinal internalizing-externalizing and externalizing-internalizing pathways were found for both boys and girls. Finally, while it improved model fit for both genders, the influence of cumulative shared risk on the aforementioned pathways was relatively meager, substantively affecting only one (externalizing-attainment adjustment erosion pathway in boys). The implications of these findings are discussed, and study limitations noted.
Prototypical Priors: From Improving Classification to Zero-Shot Learning

Recent works on zero-shot learning make use of side information such as visual attributes or natural language semantics to define the relations between output visual classes and then use these relationships to draw inference on new unseen classes at test time. In a novel extension to this idea, we propose the use of visual prototypical concepts as side information. For most real-world visual object categories, it may be difficult to establish a unique prototype. However, in cases such as traffic signs, brand logos, flags, and even natural language characters, these prototypical templates are available and can be leveraged for an improved recognition performance. The present work proposes a way to incorporate this prototypical information in a deep learning framework. Using prototypes as prior information, the deepnet pipeline learns the input image projections into the prototypical embedding space subject to minimization of the final classification loss. Based on our experiments with two different datasets of traffic signs and brand logos, prototypical embeddings incorporated in a conventional convolutional neural network improve the recognition performance. Recognition accuracy on the Belga logo dataset is especially noteworthy and establishes a new state-of-the-art. In zero-shot learning scenarios, the same system can be directly deployed to draw inference on unseen classes by simply adding the prototypical information for these new classes at test time. Thus, unlike earlier approaches, testing on seen and unseen classes is handled using the same pipeline, and the system can be tuned for a trade-off of seen and unseen class performance as per task requirement. Comparison with one of the latest works in the zero-shot learning domain yields top results on the two datasets mentioned above.
Temporal Deformity Objectively Measured Before and After Surgery for Metopic Synostosis: Retrusion Rather than Hollowing

Abstract The temporal contour deformity typical of metopic synostosis is often referred to as temporal hollowing, but has not been quantitatively defined. This deformity is present before surgery and remains to a varying extent at long-term follow-up. The present study aimed to objectively evaluate the degree of this contour deformity in metopic synostosis before and after surgical correction. All children surgically treated for metopic synostosis at Sahlgrenska University Hospital between 2002 and 2014 (n = 120) with appropriate computed tomography scans (n = 160) performed preoperatively and/or at follow-up at 3 years of age were included. Depending on age, 1 of 2 surgical techniques was used. Children presenting before the age of 6 months were treated with frontal remodeling in combination with a spring (S group), whereas children older than 6 months were treated with a bone transplant (BT group). The bony temporal deformity was measured with a semiautomatic MATLAB program and patients were compared to sex- and age-matched controls. The deformity was significantly reduced in both groups (P < 0.001). In the S group, it was reduced from a mean ± standard deviation of 3.6 ± 1.9% to 1.0 ± 1.2% and in the BT group, it was reduced from 3.3% ± 1.4% to 1.1% ± 0.8%. The contour deformity in metopic synostosis is present both before and after surgery and should therefore be termed temporal retrusion (TR). This assessment method enables objective comparison of TR before and after surgical correction and is a potential tool to evaluate TR in metopic synostosis.