Miracle-dz/UniFAR-FTUs huggingface dataset:
Accumulation of Clonally Related B Lymphocytes in the Cerebrospinal Fluid of Multiple Sclerosis Patients1

The accumulation of B lymphocyte clones in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) and patients with other neurological disorders was investigated using PCR technologies. Oligoclonal B cell accumulations were detected in 10 of 10 MS patients, but only in 3 of 10 of the patients with other neurological disorders. Analyses of the Ig V(D)J sequences on the CSF from MS patients disclosed that VH3 and VH4 genes were extensively mutated compared with germline sequences. Moreover, a substantial proportion of the molecular clones analyzed shared the same third CDR of the H chain variable region gene (HCDR3) and the same VH genes, albeit with different numbers and locations of point mutations, thus indicating an ongoing process of intraclonal diversification. A larger number of clonally related VH sequences could be obtained by using a VH3 gene-specific PCR so that genealogical trees depicting the process of diversification could be drawn. Analyses of the Ig V(D)J from the CSF of a patient with viral meningitis and oligoclonal B cell accumulations revealed that VH3 genes were extensively mutated. However, no intraclonal diversification could be observed even using VH3 gene-specific PCR methodologies. Clone-specific PCR and sequencing was used to detect the V(D)J found in the CSF of one MS patient in the PBL of the same patient. Only 1/3 of the V(D)J sequences investigated could be demonstrated in the PBL, indicating that the V(D)J genes utilized by B cells in the CSF are much less represented in the PBL. Collectively, the data suggest that in MS there is a compartmentalized clonal expansion.
Neoadjuvant treatment in upper gastrointestinal adenocarcinomas: new paradigms from old concepts?

Purpose of review Despite a decline in the incidence of upper gastrointestinal adenocarcinomas in North America and western Europe during the past century, treatment remains a challenging problem for oncologists. The poor outcome associated with surgical resection with curative intent has generated intensive investigation of combined modality treatment approaches including systemic chemotherapy to prevent recurrences and improve overall mortality. This article reviews data on neoadjuvant and perioperative treatment modalities for upper gastrointestinal adenocarcinomas. Recent findings Postoperative chemoradiation is favored in the USA for good performance status patients with resected, high-risk gastric or gastroesophageal junction carcinoma (more stage IA). More recently, the UK Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) and Fédération Nationale des Centres de Lutte Contre le Cancer–Fédération Francophone de Cancérologie Digestive trials results, showing survival benefit with perioperative chemotherapy in operable gastric and lower esophageal cancers, have had an impact on the treatment practice in Europe. Summary Novel strategies, involving induction with chemotherapy followed by preoperative chemoradiation, addition of targeted therapies to perioperative chemotherapy or use of new cytotoxic regimens are under evaluation to improve current standards and try to tailor therapeutic strategies.
Amyloid-β42 Interacts Mainly with Insoluble Prion Protein in the Alzheimer Brain*

The prion protein (PrP) is best known for its association with prion diseases. However, a controversial new role for PrP in Alzheimer disease (AD) has recently emerged. In vitro studies and mouse models of AD suggest that PrP may be involved in AD pathogenesis through a highly specific interaction with amyloid-β (Aβ42) oligomers. Immobilized recombinant human PrP (huPrP) also exhibited high affinity and specificity for Aβ42 oligomers. Here we report the novel finding that aggregated forms of huPrP and Aβ42 are co-purified from AD brain extracts. Moreover, an anti-PrP antibody and an agent that specifically binds to insoluble PrP (iPrP) co-precipitate insoluble Aβ from human AD brain. Finally, using peptide membrane arrays of 99 13-mer peptides that span the entire sequence of mature huPrP, two distinct types of Aβ binding sites on huPrP are identified in vitro. One specifically binds to Aβ42 and the other binds to both Aβ42 and Aβ40. Notably, Aβ42-specific binding sites are localized predominantly in the octapeptide repeat region, whereas sites that bind both Aβ40 and Aβ42 are mainly in the extreme N-terminal or C-terminal domains of PrP. Our study suggests that iPrP is the major PrP species that interacts with insoluble Aβ42 in vivo. Although this work indicated the interaction of Aβ42 with huPrP in the AD brain, the pathophysiological relevance of the iPrP/Aβ42 interaction remains to be established.
Drug interactions: Proteins, pumps, and P-450s.

UNLABELLED The two major concerns in drug safety are adverse drug reactions and drug interactions. When multiple drug therapies are prescribed, drug interactions become an important consideration for patients and physicians. The life of a drug is reviewed with emphasis on absorption, distribution, metabolism, and excretion. Pharmacokinetic and pharmacodynamic mechanisms for drug interactions are reviewed. The contributions of P-glycoprotein, pharmacogenetic variation, and genetic polymorphisms to drug interactions are highlighted. Prediction of drug interactions is possible with knowledge of which agents are likely to cause alterations in drug metabolism. (J Am Acad Dermatol 2002;47:467-84.) LEARNING OBJECTIVE At the conclusion of this learning activity, participants should have an understanding of the life of a drug. This knowledge should help predict important potential drug interactions.
Temporary impairment of reticulocyte haemoglobin content in subjects with community‐acquired pneumonia

Introduction: In the case of inflammation, imbalance of iron homoeostasis is caused by increased retention of iron within cells of the reticuloendothelial system. Iron‐restricted erythropoiesis occurs because of decreased availability of iron for haemoglobin (Hb) synthesis in erythroid progenitor cells.
Conserving the evolutionary potential of California valley oak (Quercus lobata Née): a multivariate genetic approach to conservation planning

California valley oak (Quercus lobata Née) is a seriously threatened endemic oak species in California and a keystone species for foothill oak ecosystems. Urban and agricultural development affects a significant fraction of the species’ range and predicted climate change is likely to dislocate many current populations. Here, we explore spatial patterns of multivariate genotypes and genetic diversity throughout the range of valley oak to determine whether ongoing and future patterns of habitat loss could threaten the evolutionary potential of the species by eradicating populations of distinctive genetic composition. This manuscript will address three specific questions: (i) What is the spatial genetic structure of the chloroplast and nuclear genetic markers? (ii) What are the geographical trends in the distribution of chloroplast and nuclear genotypes? (iii) Is there any part of the species’ range where allelic diversity in either the chloroplast or nuclear genomes is particularly high? We analysed six chloroplast and seven nuclear microsatellite genetic markers of individuals widespread across the valley oak range. We then used a multivariate approach correlating genetic markers and geographical variables through a canonical trend surface analysis, followed by GIS mapping of the significant axes. We visualized population allelic richness spatially with GIS tools to identify regions of high diversity. Our findings, based on the distribution of multivariate genotypes and allelic richness, identify areas with distinctive histories and genetic composition that should be given priority in reserve network design, especially because these areas also overlap with landscape change and little degree of protection. Thus, without a careful preservation plan, valuable evolutionary information will be lost for valley oak.
Differential distribution of blood and lymphatic vessels in the murine cornea.

PURPOSE Because of its unique characteristics, the cornea has been widely used for blood and lymphatic vessel research. However, whether limbal or corneal vessels are evenly distributed under normal or inflamed conditions has never been studied. The purpose of this study was to investigate this question and to examine whether and how the distribution patterns change during corneal inflammatory lymphangiogenesis (LG) and hemangiogenesis (HG). METHODS Corneal inflammatory LG and HG were induced in two most commonly used mouse strains, BALB/c and C57BL/6 (6-8 weeks of age), by a standardized two-suture placement model. Oriented flat-mount corneas together with the limbal tissues were used for immunofluorescence microscope studies. Blood and lymphatic vessels under normal and inflamed conditions were analyzed and quantified to compare their distributions. RESULTS The data demonstrate, for the first time, greater distribution of both blood and lymphatic vessels in the nasal side in normal murine limbal areas. This nasal-dominant pattern was maintained during corneal inflammatory LG, whereas it was lost for HG. CONCLUSIONS Blood and lymphatic vessels are not evenly distributed in normal limbal areas. Furthermore, corneal LG and HG respond differently to inflammatory stimuli. These new findings will shed some light on corneal physiology and pathogenesis and on the development of experimental models and therapeutic strategies for corneal diseases.
Novel High Energy Intermediate Analogues with a Triazasterol Structure as Potential Ergosterol Biosynthesis Inhibitors IV: Antimicrobial Activity of Mono‐, Bi‐, and Tricyclic 8, 13, 15‐Triazasteroid Analogues Including the Synthesis of Novel 4‐Alkylamino‐ and 4‐Alkenylamino‐9‐hydroxypyrimidoisoquino

4‐Alkylamino‐and 4‐alkenylamino‐9‐hydroxy‐1, 6, 7, 11b‐tetrahydro‐2H‐pyrimido[4, 3‐a]isoquinolines were designed as inhibitory tricyclic triaza‐analogues of carbocationic high energy intermediates (HEI) of enzymes involved in fungal ergosterol biosynthesis. Various routes for effective synthesis of 9‐hydroxypyrimidoisoquinolines from 9‐methoxythiones were investigated. The ether cleavage of 9‐methoxy‐pyrimidoisoquinolines, a key step in the synthesis, was carried out using various protocols. The structures of the obtained 9‐hydroxy compounds were confirmed using homo‐ and hetero‐nuclear correlated 1D and 2D NMR experiments. In vitro antifungal susceptibility tests of the alkylaminohydroxypyrimidoisoquinolines revealed weak to good antimycotic effects. The maximum antifungal efficacy was found for 4‐[(3R)‐6‐isopropyl‐3‐methyl‐6‐heptenylamino]‐9‐hydroxypyrimidoisoquinoline. Furthermore, the in vitro activities of the newly synthezised 9‐hydroxypyrimidoisoquinolines and of a series of prepared 8, 13, 15‐triazasteroid analogues (N‐alkyl‐N′‐(phenethyl‐ and cyclohexenylethyl)guanidines, N2 ‐and N2, 4‐substituted imidazolin‐2‐amines, and N4‐alkylaminopyrimidoisoquinolines) against representatives of gram‐positive and gram‐negative bacteria were investigated. The compounds showed significant antibacterial effects against gram‐positive bacteria.
Investigation of lithium distribution in the rat brain ex vivo using lithium‐7 magnetic resonance spectroscopy and imaging at 17.2 T

Lithium is the first‐line mood stabilizer for the treatment of patients with bipolar disorder. However, its mechanisms of action and transport across the blood–brain barrier remain poorly understood. The contribution of lithium‐7 magnetic resonance imaging (7Li MRI) to investigate brain lithium distribution remains limited because of the modest sensitivity of the lithium nucleus and the expected low brain concentrations in humans and animal models. Therefore, we decided to image lithium distribution in the rat brain ex vivo using a turbo‐spin‐echo imaging sequence at 17.2 T. The estimation of lithium concentrations was performed using a phantom replacement approach accounting for B1 inhomogeneities and differential T1 and T2 weighting. Our MRI‐derived lithium concentrations were validated by comparison with inductively coupled plasma‐mass spectrometry (ICP‐MS) measurements ([Li]MRI = 1.18[Li]MS, R = 0.95). Overall, a sensitivity of 0.03 mmol/L was achieved for a spatial resolution of 16 μL. Lithium distribution was uneven throughout the brain (normalized lithium content ranged from 0.4 to 1.4) and was mostly symmetrical, with consistently lower concentrations in the metencephalon (cerebellum and brainstem) and higher concentrations in the cortex. Interestingly, low lithium concentrations were also observed close to the lateral ventricles. The average brain‐to‐plasma lithium ratio was 0.34 ± 0.04, ranging from 0.29 to 0.39. Brain lithium concentrations were reasonably correlated with plasma lithium concentrations, with Pearson correlation factors ranging from 0.63 to 0.90.
Intravenous self‐administration of amphetamine is increased in a rat model of depression

Affective disorders and substance abuse frequently coexist, yet few previous studies have examined drug self‐administration using animal models of depression. The olfactory‐bulbectomized rat is a well‐established model that exhibits a high degree of neurochemical similarity to depression. Olfactory bulbectomy (OBX) increases dopamine receptor densities in the ventral striatum, which may increase the reinforcing effects of drugs of abuse. Experiments were designed to test the hypotheses that acquisition and stable self‐administration of amphetamine would be increased in bulbectomized rats. In the first experiment, rats underwent bilateral OBX or sham surgery and intravenous jugular catheters were implanted 12–14 days later. Acquisition was examined using a standard operant paradigm involving a nose‐poke response for a very low dose of D‐amphetamine sulfate (12 μg/infusion, IV). A separate group of rats received coinfusions of sulpiride. In a second experiment designed to minimize differences in acquisition and examine stable self‐administration, lever pressing for a low (0.10 mg/kg, IV) or high (0.25 mg/kg, IV) dose of D‐amphetamine sulfate was measured in rats pretrained to lever press for food. Bulbectomized rats acquired the self‐administration of very low dose amphetamine faster than sham‐operated rats and this effect was reversed by sulpiride coinfusion. Stable self‐administration of the low dose of amphetamine was also markedly increased in bulbectomized rats. The findings reveal the utility of the OBX model for studying the neurobiological basis of depression and drug abuse comorbidity and support the hypothesis that neurochemical abnormalities associated with depression may enhance the addictive properties of some drugs of abuse. Synapse 46:4–10, 2002. © 2002 Wiley‐Liss, Inc.
Incentive Sensitivity as a Behavioral Marker of Clinical Remission From Major Depressive Episode.

BACKGROUND Reduction of goal-directed behaviors is frequently observed in depression and may be linked to dysfunction of incentive motivation process. OBJECTIVE To investigate whether incentive sensitivity could constitute a behavioral marker of clinical remission in major depression. METHODS A handgrip force measurement device was employed to assess the impact of incentive motivation and emotional manipulation on the effort produced by remitted patients (n = 20) compared to matched depressed patients (n = 22) and healthy controls (n = 26). Depressed and remitted patients fulfilled the major depressive disorder DSM-IV criteria for current episode and remission state, respectively. The study was performed between March and July 2013. RESULTS Relative to patients with acute depression, patients after remission retrieved a normal sensitivity to incentives (t1,40 = 4.18, P < 1.5 × 10-4), but relative to healthy controls, they kept an abnormally high susceptibility to emotional arousal (t1,44 = 2.4, P = .02). Normalization of incentive sensitivity exhibited in the behavioral test was associated with improvement of apathy measured on the clinical scale. CONCLUSIONS Using a simple behavioral paradigm at patients' bedside, we could identify the factors influencing effort production, so as to discriminate remitted patients from both depressed patients and healthy controls.
A PCS network with correlated arrival process and splitted-rating channels

The arrival of calls (i.e., new and handoff calls) in a personal communications services (PCS) network are modeled by a Markov arrival process (MAP) in which we allow correlation of the interarrival times among new calls, among handoff calls, as well as between these two kinds of calls. Each cell of the network consists of a finite number of channels and a buffer with finite size for handoff calls. There exist some channels among each cell which can be used by splitting the original rate into two channels with different rates if necessary when a handoff call arrives and finds all the channels busy. We obtain the stationary joint probability of number of calls in the cell and the phase of the arrival process, the blocking probability of a new call, the forced termination probability of a handoff call, and the mean dwell time of a handoff call in the buffer. Finally, we obtain the distribution and the mean of the cell's busy period, the distribution and the mean of the first time to split the cth channel, and some other interesting performance measures for the network. Some explicit results for special cases obtained by Lin et al. (see IEEE Trans. Vech. Technol., vol.45, no.1, p.122-30, 1996 and vol.43, no.3, p.704-12, 1994), Tekinary et al. (1992) and by Yoon et al. (1993) can also be directly obtained from the general conclusion. The results presented can provide guidelines for field data processing in PCS network design and performance evaluation.
Biomechanical Analysis of Thoracolumbar Interbody Constructs: How Important Is the Endplate?

Study Design A biomechanical study of human cadaveric thoracic vertebral bodies was conducted using several anterior fusion options subjected to axial loads. This study emphasized the contribution of the endplate to resistance of graft subsidence. Objectives To determine the importance of the vertebral endplate in resisting subsidence of various constructs into the vertebral body; the relative efficacy of potential alternative graft constructs such as iliac crest, ribs, humerus, and titanium mesh cage; and the importance of bone mineral content, vertebral level, and cross‐sectional graft area on construct subsidence. Summary of Background Data As the fixation length of anterior and posterior spinal constructs is reduced, load sharing of the anterior column has become more important to reduce failure of the shorter devices. Several alternative graft constructs and surgical techniques have been used for reconstruction of the anterior column. There exist little comparative data as to whether any of these constructs are superior and whether the vertebral endplate contributes significantly to the integrity of the construct. Methods Sixty‐three isolated human cadaveric vertebral bodies from T3 to T12 were used to test seven different constructs in direct axial load onto prepared endplates with an electrohydraulic testing device. These constructs were: 1) titanium mesh cage (17 × 22 mm) on intact endplate, 2) C‐shaped humerus on intact endplate, 3) tricorticated iliac graft in “tee configuration” on intact endplate, 4) tricorticated iliac graft in cancellous trough, 5) triple rib strut graft, 6) single rib on endplate, and 7) single rib on cancellous body. Dual X‐ray absorptiometry assessment of bone mineral content was performed. A uniaxial load was applied with force and displacement data collected to determine maximal load to “failure” of the vertebral body. Results Preservation of vertebral endplate did not significantly increase the resistance to graft subsidence. The titanium cage construct provided the greatest resistance to axial load. Conclusions Preservation of the vertebral endplate may not offer a significant biomechanical advantage in reconstructing the anterior column. Several alternative constructs are mechanically equivalent.
Decreased Implantation Number After In Utero Artificial Insemination Can Reflect an Impairment of Fertility in Adult Male Rats After Exogenous Leptin Exposure

Leptin is a protein secreted by the adipocytes, which serves as a link between fat and brain. Its main action is to decrease appetite and increase energy expenditure, but it is also involved in the control of different neuroendocrine systems, including gonadal axis. Although the effects of leptin deficiency on reproduction are well recognized, the effect of excess leptin on male reproductive function is not clear. The aim of this study was to evaluate fertility and sperm parameters of male rats exposed to exogenous leptin. A group of adult male rats received exogenous leptin intraperitoneally (30 μg/kg/day) for 42 days, and a control group received only the vehicle during the same period. After the treatment, animals were evaluated for sperm count, sperm motility, and fertility after intrauterine artificial insemination. There was no statistically significant difference between the groups related to sperm production, sperm concentration, and sperm motility. However, fertility evaluation after artificial insemination showed a quantitative decrease in the uterus plus fetuses weight, number of implantation sites, and number of live fetuses. The fertility potential showed a reduction of about 40%, whereas the preimplantation loss rate increased more than 2-fold in leptin-treated animals. In conclusion, leptin administration to nonobese male rats impairs ability of treated animals to generate offspring, since the occurrence of implantation was diminished. So leptin can impair sperm quality, affecting the reproductive capacity.
Mouse model to study human A β2M amyloidosis: generation of a transgenic mouse with excessive expression of human β2-microglobulin

Patients on long-term hemodialysis can develop dialysis-related amyloidosis (DRA) due to deposition of β2-microglobulin (β2m) into amyloid fibrils (Aβ2M). Despite intensive biochemical studies, the pathogenesis of amyloid deposition in DRA patients remains poorly understood. To elucidate the mechanisms that underlie Aβ2M fibril formation in DRA, we generated transgenic mice that overexpress human β2m protein in a mouse β2m gene knockout background (hB2MTg+/+ mB2m+/+). The hB2MTg+/+mB2m−/− mice express a high level of human β2m protein in many tissues as well as a high plasma β2m concentration (192.8 mg/L). This concentration is >100 times higher than that observed in healthy humans and >4 times higher than that detected in patients on dialysis. We examined spontaneous and amyloid fibril-induced amyloid deposition in these mice. Amyloid deposition of β2m protein was not observed in aged or amyloid fibril injected animals. However, mouse senile apolipoprotein A-II amyloidosis (AApoAII) was detected, particularly in the joints of mice that were injected with AApoAII amyloid fibrils. This study demonstrates that this mouse model could be valuable in studying the components and conditions that promote DRA, and indicates that high plasma concentrations of hβ2m as well as seeding with pre-existing amyloid fibrils may not be sufficient to induce Aβ2M.