Miracle-dz/UniFAR-FTUs huggingface dataset:
Developmental patterning and evolution of the mammalian viscerocranium: Genetic insights into comparative morphology

The vertebrate cranium is generally classified into the neurocranium and the viscerocranium. The latter is derived from the neural crest and so is the prechordal portion of the neurocranium. A view we favor considers the prechordal neurocranium as the premandibular component of the viscerocranium, and the vertebrate skull to consist of the neural crest‐derived viscerocranium and the mesodermal neurocranium. Of these developmental units, only the viscerocranium appears to have completely segmented metamerical organization. The Hox code which is known to function in specification of the viscerocranium does not extend rostrally into the mandibular and premandibular segments. By genetic manipulation of rostrally expressed non‐Hox homeobox genes, the patterning mechanism of the head is now demonstrated to be more complicated than isomorphic registration of the Hox code to pharyngeal arches. The phenotype by haplo‐insufficiency of Otx2 gene, in particular, implies the premandibular cranium shares a common specification mechanism with the mandibular arch. Our interpretation of the metamerical plan of the viscerocranium offers a new scheme of molecular codes associated with the vertebrate head evolution. Dev. Dyn. 209:139–155, 1997. © 1997 Wiley‐Liss Inc.
Vascular endothelial growth factor stimulates rat cholangiocyte proliferation via an autocrine mechanism.

BACKGROUND & AIMS Vascular endothelial growth factor (VEGF) is secreted by several epithelia and modulates cellular functions by autocrine and paracrine mechanisms. The role of VEGF in cholangiocyte pathophysiology is unknown. We evaluated the role of VEGF in the regulation of cholangiocyte proliferation in rats that underwent bile duct ligation. METHODS The expression of VEGF-A and VEGF-C and their receptors in cholangiocytes from normal and BDL rats was evaluated. Normal or BDL rats were treated with recombinant-VEGF-A or recombinant-VEGF-C or anti-VEGF antibodies, and proliferation of cholangiocytes was evaluated in situ by morphometry and in vitro by proliferating cell nuclear antigen immunoblots and MTS assay. In vitro, normal rat cholangiocyte cultures were stimulated with r-VEGF-A or r-VEGF-C and proliferation and signal transduction were evaluated. RESULTS We found that (1) cholangiocytes express messenger RNA and protein for VEGF-A, VEGF-C, VEGF receptor 2 (VEGFR-2), and VEGF receptor 3 (VEGFR-3) and secrete VEGF; (2) secretion of VEGF and expression of VEGFR-2 and VEGFR-3 increases in BDL cholangiocytes; (3) blocking VEGF in vivo by anti-VEGF-A or anti-VEGF-C antibodies decreases cholangiocyte proliferation; (4) the in vivo administration of r-VEGF-A or r-VEGF-C induces cholangiocyte proliferation in normal rats; and (5) in vitro, VEGF-A increases normal rat cholangiocyte culture proliferation by activation of inositol 1,4,5-triphosphate/Ca2+/protein kinase C alpha and phosphorylation of Src/ERK1/2. CONCLUSIONS Cholangiocytes secrete VEGF and express VEGFR-2 and VEGFR-3, all of which are amplified in BDL cholangiocytes. VEGF induces cholangiocyte proliferation by activation of inositol 1,4,5-triphosphate/[Ca2+]i/protein kinase C alpha and phosphorylation of Src/ERK1/2. VEGF mediates the adaptive proliferative response of cholangiocytes to cholestasis.
Biological Approaches to Treating Intervertebral Disk Degeneration: Devising Stem Cell Therapies

Intervertebral disk (IVD) degeneration is a common, chronic, and complex degeneration process that frequently leads to back pain and disability, resulting in a major public health issue. In this review we describe biological therapies under preclinical or clinical development with an emphasis on stem cell-based multimodal approaches that target prevention and treatment of IVD degeneration. Systematical review of the basic science and clinical literature was performed to summarize the current status of devising biological approaches to treating IVD degeneration. Since the exact mechanisms underlying IVD degeneration have not yet been fully elucidated and conservative managements appear to be mostly ineffective, current surgical treatment focuses on removal of the pathological disk tissues combined with spinal fusion. The treatment options, however, often produce insufficient efficacy and even serious complications. Therefore, there have been growing demands and endeavors for developing novel regenerative biology-guided strategies for repairing the IVD via delivery of exogenous growth factors, introduction of therapeutic genes, and transplantation of stem cells, or combinatorial therapies. Overall, the data suggest that when applied under a recovery neurobiology principle, multimodal regimens comprising ex vivo engineered stem cell-based disks hold a high potential promise for efficacious clinical translations.
Levosimendan and Nesiritide as a Combination Therapy in Patients With Acute Heart Failure

Background:Individually, levosimendan and nesiritide have been associated with substantial clinical benefits for the treatment of acute decompensated heart failure (ADHF). The aim of this study was to evaluate the efficacy of the combination of levosimendan and nesiritide for the treatment of ADHF. Methods:One hundred and twenty patients were randomly assigned to control, levosimendan, nesiritide or combination groups. The patients received 2 drugs: 1 was levosimendan or placebo A and the other was nesiritide or placebo B. The primary end points were rates of clinical effectiveness at 1, 3, 5 and 9 days after the start of therapy. Results:Nine days after the initiation of drug infusion, the clinical effectiveness rate in the combination group was better than that in the control group (odds ratio: 1.43, 95% confidence interval: 0.46–2.41, P = 0.004). The combination treatment also resulted in higher rates of clinical effectiveness than individually provided levosimendan or nesiritide at 1 day (both P = 0.04) or placebo at 1, 3 or 5 days (P = 0.002, 0.006 and 0.009, respectively). The combination method was associated with fewer deaths and readmissions, as compared with the rate observed in the placebo group during the 3-month follow-up (hazard ratio: 0.43, 95% confidence interval: 0.19–0.96, P = 0.038). Conclusions:Among patients with ADHF, intravenous infusion of levosimendan and nesiritide was superior to placebo and single-drug therapies in terms of improvements in clinical conditions during the early stages of therapy.
Identification of the Protein C/Activated Protein C Binding Sites on the Endothelial Cell Protein C Receptor

The endothelial cell protein C receptor (EPCR) is an endothelial cell-specific transmembrane protein that binds both protein C and activated protein C (APC). EPCR regulates the protein C anticoagulant pathway by binding protein C and augmenting protein C activation by the thrombin-thrombomodulin complex. EPCR is homologous to the MHC class 1/CD1 family, members of which contain two α-helices that sit upon an 8-stranded β-sheet platform. In this study, we identified 10 residues that, when mutated to alanine, result in the loss of protein C/APC binding (Arg-81, Leu-82, Val-83, Glu-86, Arg-87, Phe-146, Tyr-154, Thr-157, Arg-158, and Glu-160). Glutamine substitutions at the four N-linked carbohydrate attachment sites of EPCR have little affect on APC binding, suggesting that the carbohydrate moieties of EPCR are not critical for ligand recognition. We then mapped the epitopes for four anti-human EPCR monoclonal antibodies (mAbs), two of which block EPCR/Fl-APC (APC labeled at the active site with fluorescein) interactions, whereas two do not. These epitopes were localized by generating human-mouse EPCR chimeric proteins, since the mAbs under investigation do not recognize mouse EPCR. We found that 5 of the 10 candidate residues for protein C/APC binding (Arg-81, Leu-82, Val-83, Glu-86, Arg-87) colocalize with the epitope for one of the blocking mAbs. Three-dimensional molecular modeling of EPCR indicates that the 10 protein C/APC binding candidate residues are clustered at the distal end of the two α-helical segments. Protein C activation studies on 293 cells that coexpress EPCR variants and thrombomodulin demonstrate that protein C binding to EPCR is necessary for the EPCR-dependent enhancement in protein activation by the thrombin-thrombomodulin complex. These studies indicate that EPCR has exploited the MHC class 1 fold for an alternative and possibly novel mode of ligand recognition. These studies are also the first to identify the protein C/APC binding region of EPCR and may provide useful information about molecular defects in EPCR that could contribute to cardiovascular disease susceptibility.
Elevated CA 125 in Breast Cancer – A Sign of Advanced Disease

The serum tumor markers CA 125, MUC1 and CEA were measured in 221 breast cancer patients over a period of 2 years. Patients examined on at least three occasions were included in the study. Thirty-three patients had increasing or continuously high concentrations of CA 125. Thirty (91%) of these had involvement of the pleura, either as pleural metastasis or metastasis in surrounding tissue i.e. bone structures in the thorax cavity or lung parenchyma. MUC1 and CEA were elevated in 27 (82%) and 24 (73%) of the 33 patients, respectively. Increased concentrations of these two markers did not relate to the site of metastasis. However, the three tumor markers complemented each other in detecting early metastases. Increased CA 125 was associated with metastasis in or near the pleura, and in stage IV breast cancer it was related to poor prognosis.
Offender Characteristics in Lethal Violence With Special Reference to Antisocial and Autistic Personality Traits

The objective of the study is to assess the relationships between personality traits, lifetime psychosocial functioning, and crime scene behavior. Thirty-five male offenders referred for forensic psychiatric assessment in Sweden (1996-2001) and assigned a main diagnosis of either antisocial personality disorder (APD) or autism spectrum disorder (AUT) were retrospectively studied. APD were subcategorized into impulsive (APDi) and controlled (APDc). Those in the AUT group were less intoxicated at the time of the crime and did not often use knives or guns compared to the APD group. Males in the APDi group were older and had a higher proportion of abuse of alcohol and drugs in biological parents, physical abuse during childhood, psychiatric contacts, and suicide attempts compared to the APDc group. In the APDi group, knives were used in the homicide compared to the use of guns in the APDc group. The results suggest differences in psychosocial functioning and crime scene characteristics related to personality traits.
A real-time smart charging station for EVs designed for V2G scenario and its coordination with renewable energy sources

In this paper, a real-time smart charging station (CS) for charging and discharging of electric vehicles (EVs) has been presented. The proposed CS is coupled with renewable energy sources to support and stabilize grid operations at all times. The main focus of this paper is to illustrate the interaction between various entities such as-CS, EVs, and renewable energy sources. EVs act as controllable loads which can be efficiently utilized to store the excess energy generated from the renewable energy sources during off-peak hours. During peak hours, EVs manage voltage fluctuations by discharging their stored energy back to grid. This bi-directional flow of power is utilized to cater the intermittency issues caused by renewable energy sources. In addition to it, a fuzzy logic controller (FLC) has been designed to regulate the flow of power between the grid and EV's batteries. Also, EVs' batteries are made to charge and discharge based on various constraints such as-minimum state of charge (SoC) and charging rate (Crate). In short, regulated coordination between EVs and CSs plays a potential role in regulating voltage fluctuations at grid level besides handling the intermittency issues of renewable energy sources. The proposed scheme has been modeled and tested on a distribution grid of a city where its performance is found satisfactory with respect to various metrics.
Inverting VARK what are the possibilities?

Systems Analysis and Design, a second year subject offered as two modules is offered as part of the Information Technology course at the North-West University's Vaal Triangle Campus. Being sensitive to the learning preferences of the learners, varied opportunities for learners to learn have been developed over a period of time. These include visual, auditory, reading-and-writing, learn-by-doing (VARK), or a combination of these. Although teaching during the second module uses inverted instruction, the first module uses conventional teaching methods. Learners still struggling with particular concepts after a class, have a repertoire of material to choose from to facilitate understanding. Since 2015, the first half of the offering was split into two classes to accommodate new enrollments and repeating learners separately. The offering for repeaters requires learners to prepare for weekly interactive classes. In doing so, they may attend the conventional class. They also have access to a wide variety of material and tools to support their learning, done in their own time. To support the inverted VARK notion, the repeating learners are intentionally made aware of their learning preference. Towards the end of the module offering, these learners have an opportunity to reflect on the new experience compared to their original experience as new enrollments during a previous year, their learning preference, and their learning. At the end of the year they reminisce on the experience by answering a questionnaire.
Risk of Recurrence of Resected Stage I Non-small Cell Lung Cancer in Elderly Patients as Compared with Younger Patients

Purpose: Half of all patients with non-small cell lung cancer (NSCLC) are 70 years or older at the time of diagnosis. Surgery is an option for fit elderly patients with early stage disease, but rates of disease recurrence after surgical resection are not well described. We report the outcomes in elderly patients (70 years or older) with stage I NSCLC after surgical resection. Patients and Methods: We conducted a retrospective study of patients diagnosed with stage I NSCLC after surgical resection at Washington University School of Medicine-Alvin J. Siteman Cancer Center from 1990 to 2000. Demographic, pathologic, treatment, and follow-up data were collected. Recurrence rates and overall survival were calculated by the Kaplan-Meier method. Multivariate Cox proportional hazards models were used to detect associations between potential prognostic factors and survival and recurrence. Results: Of the 715 patients with stage I NSCLC, 286 were 70 years or older at diagnosis. In this elderly cohort, the median age was 74 years (range, 70–89 years) and 140 of them were women (49%). Lobectomy was performed in 237 patients (83%) whereas 43 patients (15%) had a wedge or segmental resection, and six patients (2%) underwent pneumonectomy. Clinical and pathologic characteristics were not statistically different between the elderly and younger cohorts, with the exception that older patients were more likely to be white (90% versus 80%, p = 0.0003) and less likely to be smokers (88% versus 95%, p = 0.019) compared with the younger cohort. With a median follow-up of 4.6 years, the overall 5-year survival rate was 52% with a 5-year recurrence rate of 24%. In comparison, the patients younger than 70 years had a 5-year survival rate of 67% (p < 0.001) and a 5-year recurrence rate of 24%. Conclusions: Although overall survival was worse in elderly patients, estimated disease recurrence rates after resection were identical.
Pharmacokinetics of intraventricular and intravenous N,N',N''-triethylenethiophosphoramide (thiotepa) in rhesus monkeys and humans.

The cerebrospinal fluid (CSF) and plasma pharmacokinetics of N,N',N"-triethylenethiophosphoramide (thiotepa), an alkylating agent used for treatment of carcinomatous meningitis, were determined in rhesus monkeys in order to assess the relative advantage of intraventricular versus systemic administration of the drug. Following an i.v. thiotepa dose of 0.9 mg/kg (11 mg/sq m), peak plasma levels of parent drug reached approximately 1 microgram/ml. Thiotepa was rapidly equilibrated with lumbar and ventricular CSF. Systemic, lumbar, and ventricular exposure to the drug, measured as area under the curve (AUC), were similar in all cases. After a 1-mg intraventricular dose of thiotepa, peak ventricular levels were greater than 100 micrograms/ml. However, peak levels in the lumbar CSF at 1 h after intraventricular administration were less than 10 micrograms/ml. The AUC for ventricular CSF was nearly 100-fold greater for the intraventricular route than for the i.v. route; however, the AUC for lumbar CSF following intraventricular delivery was only 5% of the AUC for ventricular CSF. N,N',N''-Triethylenephosphoramide, an active metabolite of thiotepa observed in all fluids, appeared to have a much slower total body clearance than thiotepa. Comparison of the data obtained from monkey experiments with data from a patient with meningeal disease supports the use of the monkey as a model for intraventricular pharmacokinetics. The data presented indicate that there is no relative advantage to intraventricular administration of thiotepa at the doses currently used in clinical trials.
Pathogenicity of IgA and/or IgM antibodies to heparin–PF4 complexes in patients with heparin‐induced thrombocytopenia

Antibodies to heparin–PF4 (H‐PF4) complexes have been tested and isotyped in 38 patients who developed severe heparin‐induced thrombocytopenia (type II HIT). All the patients had a platelet count < 120 × 109/l or a reduction of >30% of the initial value, occurring at least 5 d after the onset of heparin. Thrombocytopenia, which rapidly reversed following the withdrawal of heparin, was associated with thrombosis in nine patients. Although IgG isotypes were found in most cases (n = 26), the presence of only IgM and/or IgA was observed in 12 patients, including three cases showing a thrombotic complication. Our results indicate that type II HIT may be induced by IgA and/or IgM anti‐H‐PF4 antibodies even in the absence of IgG isotypes. This finding demonstrates that platelet Fc receptors (FcγRII) are not necessarily involved in the pathogenicity of heparin‐dependent antibodies and emphasizes the major role of platelet PF4 receptors. The increased expression of the latter following a slight activation by thrombin, and the subsequent binding of IgM and IgA antibodies to H‐PF4 on the platelet surface, may directly trigger platelet activation, aggregation and thrombosis. Alternatively, thrombocytopenia could be indirectly induced through the mediation of neutrophils, monocytes and lymphocytes which expose receptors for IgA (FcαR) or IgM (FcμR). IgM–platelet complexes may also bind and activate complement, leading to platelet activation or destruction. Moreover, the reactivity of the antibodies with glycosaminoglycans–PF4 complexes present on the endothelial surface could also induce endothelial lesions and promote procoagulant activity and predisposition to thrombosis.
The rate and extent of improvement with therapy from the different types of aphasia in the first year after stroke

Objective: To examine the rate and extent of improvement from the different types of aphasia in the first year after stroke. Design: A prospective longitudinal study. Setting: A specialist stroke unit. Participants: Seventy-five aphasic patients with first-ever stroke. Intervention: The type of aphasia was classified according to the criteria of the Western Aphasia Battery. The Western Aphasia Battery aphasia quotient was used to measure the initial severity and the rate and extent of improvement from aphasia. Assessments were made at baseline and 4, 8, 12 and 24 weeks later. Results: The median percentage increase in the Western Aphasia Battery aphasia quotient was statistically higher in patients with Broca's aphasia than in the other groups at all weeks. Patients with Wernicke's aphasia had a significantly greater median percentage increase in their aphasia quotient than those with conduction and anomic aphasia at weeks 12 and 24, but less than patients with global aphasia at week 24. Conclusions: Patients with Broca's aphasia appear to have the best prognosis for improvement of language function in the first year of stroke. The extent of improvement in patients with global aphasia is better than that of patients with Wernicke's aphasia.
Pellet Formation and Fragmentation in Submerged Cultures of Penicillium chrysogenum and Its Relation to Penicillin Production

The spores of Penicillium chrysogenum are of the noncoagulating type, and after spore germination a culture of disperse mycelia is obtained. In this study, it is shown that when the hyphal elements increase in size, they may agglomerate, and depending on the operating conditions, these agglomerates may develop into pellets with a dense core. The influence of initial spore concentration and agitation rate on agglomeration, leading to pellet formation, was studied. For a low concentration of spores in the inoculum, only a few hyphal elements agglomerate and pellets with a small diameter are obtained. At higher spore concentrations, many hyphal elements agglomerate and develop into large diameter pellets. Finally, at a very high spore concentration in the inoculum, the final hyphal element size is small and agglomerates therefore are not formed. With a high agitation rate, the agglomeration of hyphal elements is reduced. In a repeated fed‐batch cultivation, where there was a shift from pellet morphology to disperse mycelia, it was found that there is no relation between macroscopic morphology and penicillin production by P. chrysogenum. The morphology was quantified throughout the repeated fed‐batch cultivation, and both the pellet diameter and the concentration of pellets were affected by the agitation rate.
Adenosquamous carcinoma of the pancreas: a light and electron microscopic study.

The light microscopic diagnosis of the tissue removed from the head of the pancreas of an 82-year-old woman was undifferentiated carcinoma. Ultrastructur-ally, the tumor was composed of poorly differentiated glandular and squamous epithelial elements. This is the first detailed electron microscopic study of an adenosquamous carcinoma of the pancreas.
Developmental Defects of Enamel - Historical and Present-Day Perspectives of Their Pathogenesis

Developmental defects of enamel are visible deviations from the normal translucent appearance of tooth enamel resulting from enamel organ dysfunction. In the past, information about the activities of the ameloblasts has determined the terminology used to describe the lesions. Advances in our understanding of the complicated secretory and maturation phases of amelogenesis have required a re-appraisal of the concepts of defect formation. The phase of ameloblast activity, the duration of the disturbance, and its severity leading to temporary or permanent inactivity of the cells determine the appearance of the three common types of lesions—hypoplasia, and diffuse and demarcated opacities.