Miracle-dz/UniFAR-FTUs huggingface dataset:
Combination of Drug Level Measurement and Parasite Genotyping Data for Improved Assessment of Amodiaquine and Sulfadoxine-Pyrimethamine Efficacies in Treating Plasmodium falciparum Malaria in Gabonese Children

ABSTRACT Many African countries currently use a sulfadoxine-pyrimethamine combination (SP) or amodiaquine (AQ) to treat uncomplicated Plasmodium falciparum malaria. Both drugs represent the last inexpensive alternatives to chloroquine. However, resistant P. falciparum populations are largely reported in Africa, and it is compulsory to know the present situation of resistance. The in vivo World Health Organization standard 28-day test was used to assess the efficacy of AQ and SP to treat uncomplicated falciparum malaria in Gabonese children under 10 years of age. To document treatment failures, molecular genotyping to distinguish therapeutic failures from reinfections and drug dosages were undertaken. A total of 118 and 114 children were given AQ or SP, respectively, and were monitored. SP was more effective than AQ, with 14.0 and 34.7% of therapeutic failures, respectively. Three days after initiation of treatment, the mean level of monodesethylamodiaquine (MdAQ) in plasma was 149 ng/ml in children treated with amodiaquine. In those treated with SP, mean levels of sulfadoxine and pyrimethamine in plasma were 100 μg/ml and 212 ng/ml, respectively. Levels of the three drugs were higher in patients successfully treated with AQ (MdAQ plasma levels) or SP (sulfadoxine and pyrimethamine plasma levels). Blood concentration higher than breakpoints of 135 ng/ml for MdAQ, 100 μg/ml for sulfadoxine, and 175 ng/ml for pyrimethamine were associated with treatment success (odds ratio: 4.5, 9.8, and 11.8, respectively; all P values were <0.009). Genotyping of merozoite surface proteins 1 and 2 demonstrated a mean of 4.0 genotypes per person before treatment. At reappearance of parasitemia, both recrudescent parasites (represented by common bands in both samples) and newly inoculated parasites (represented by bands that were absent before treatment) were present in the blood of most (51.1%) children. Only 3 (6.4%) therapeutic failures were the result not of treatment inefficacy but of new infection. In areas where levels of drug resistance and complexity of infections are high, drug dosage and parasite genotyping may be of limited interest in improving the precision of drug efficacy measurement. Their use should be weighted according to logistical constraints.
Excitation and sensitization of fine articular afferents from cat's knee joint by prostaglandin E2.

1. In cats anaesthetized with alpha‐chloralose extracellular recordings were made from fine afferent units belonging to the medial articular nerve of the knee joint. The excitatory and sensitizing effects on articular afferents of prostaglandin E2 (PGE2) applied intra‐arterially close to the joint were examined. 2. Bolus injections of PGE2 doses of 0.03‐30 micrograms excited about 60% of both the group III (conduction velocity 2.5‐20 m/s) and the group IV units (conduction velocity less than 2.5 m/s). The duration and size of the responses were dose dependent consisting in most cases of low‐frequency discharges which lasted up to several minutes. Excitation was found among afferents with low and high mechanosensitivity. 3. Among the group III units PGE2 sensitized 64% for their responses to movements and 50% for their responses to bradykinin (applied intra‐arterially close to the joint). Sensitization did not depend on the mechanical threshold previous to chemical stimulation. Among the group IV units PGE2 sensitized only 25% for their responses to movements but 75% for their reactions to bradykinin. In group IV fibres a low mechanical threshold predisposed for sensitization to movements and a higher threshold for sensitization to bradykinin. 4. Some units were sensitized and excited, others were either sensitized or excited and some units were not affected by PGE2. We conclude that PGE2 induces in a large proportion of fine articular afferents of normal joints discharges which are similar to those induced by an experimental inflammation. Thus PGE2 may be an inflammatory mediator which has a major role in the generation of the afferent activity developing in the course of an arthritis.
Pigment epithelial cells isolated from human peripheral iridectomies have limited properties of retinal stem cells

Purpose: The identification of cells with properties of retinal progenitor cells (RPCs) in the adult human ciliary margin (CM) prompted a number of studies of their proliferative and differentiation potential. One of the remaining challenges is to find a feasible method of isolating RPCs from the patient’s eye. In the human CM, only the iris pigment epithelium (IPE) is easily obtained by a minimally invasive procedure. In the light of recent studies questioning the existence of RPCs in the adult mammalian CM, we wanted to assess the potential of the adult human IPE as source of RPCs.
Exercise Augments the Absorption of Isophane (NPH) Insulin

In order to determine the effect of exercise on the rate of absorption of an isophane (NPH) insulin, 7 normal men were studied on two separate occasions using the euglycaemic clamp technique. On one day subjects undertook 60 min of exercise on a treadmill (5 km h−1, 5 ° slope) 180 min after injection of human isophane (NPH) insulin (0.25 U kg−1), while on the control day they remained at rest throughout the 420 min study. Serum insulin concentrations rose in parallel after injection achieving similar values at 180 min on exercise and control days (13.7 ± 1.2 (± SE) vs 12.0 ± 1.5 mU) I−1; NS), respectively. After the onset of exercise, insulin concentrations rose markedly to a peak of 29.8 ± 2.2 mU I−1 after 50 min of exercise (p < 0.001), compared with a slight fall on the control day to 10.4 ± 1.7 mU I−1 (NS). At the end of the exercise period, serum insulin concentrations returned rapidly to control day values. Glucose infusion requirements rose significantly during the exercise period from 2.8 ± 0.5 mg kg−1 min−1 to a peak at 235 min of 11.1 ± 1.2 mg kg−1 min−1 (p < 0.001), compared with an increase on the control day from 2.0 ± 0.6 to 2.5 ± 0.6 mg kg−1 min−1 (NS) over the same period. These results demonstrate an enhanced rate of absorption of an isophane (NPH) insulin during exercise in normal subjects.
Prevalence and Patterns of Scoliosis in Children With Multiple Pterygium Syndrome

Background: Although scoliosis is a predominant feature of multiple pterygium syndrome (MPS), the pattern of deformity and the progression of the curvature have not been well described. The purpose of this study was to assess the prevalence of scoliosis among patients with MPS, and to characterize the abnormalities of the vertebrae and to assess the progression of the scoliosis. Methods: From 1969 to 2008, we identified 19 patients with MPS but only 16 patients (8 boys and 8 girls) had complete data. Medical records and radiographs of these 16 patients were reviewed. Magnetic resonance imaging was performed in 8 patients to evaluate intraspinal anomalies. Functional mobility score was used to assess the ambulatory ability. Results: Of 16 patients, 13 patients (81.3%) had scoliosis. The mean age when the scoliosis was first noticed was 3.3±2.6 years (range, 1 mo to 8.2 y). The mean Cobb angle at first visit was 37.4±18.1 degrees (range, 14.0 to 75.0 degrees). With a mean follow-up of 4.0±4.9 years, the Cobb angle at the last visit was 43.3±19.1 degrees (range, 20.0 to 72.0 degrees). Congenital scoliosis was observed in 7 patients (3 unilateral unsegmented bar, 3 fusion of the cervical spine, 1 block vertebrae), whereas neuromuscular scoliosis was observed in 1 patient. A common radiographic finding was narrowing of the intervertebral disc space with decreased height of vertebrae in the thoracic area. Intraspinal anomalies were seen in 4 patients (3 tethered spinal cords, 1 syrinx). At the last follow-up, 5 of 13 patients who had scoliosis were able to walk at school without assistance (Functional mobility scale-500 ≥5). Conclusions: Scoliosis is common among children with MPS. It is frequently accompanied by fusion of the cervical area. Intraspinal anomalies such as tethered cord syndrome and syringomyelia are common associated anomalies. Therefore, it is important to look for intraspinal anomalies. Closed monitoring of the patient’s ambulatory ability and bowel and bladder continence is also needed. Level of Evidence: Level IV, Diagnostic Study.
Prevalence and prognosis of heart failure with preserved ejection fraction and elevated N‐terminal pro brain natriuretic peptide: a 10‐year analysis from the Copenhagen Hospital Heart Failure Study

The aim of this study was to assess the epidemiological features and prognosis of heart failure with preserved ejection fraction (HFPEF) and to compare these findings with those from patients with reduced ejection fraction. Furthermore the effects of N‐terminal pro brain natriuretic peptide (NT‐proBNP) requirement in the heart failure diagnosis were assessed by repeating the analyses in the subgroup of patients with elevated NT‐proBNP.
Modified dipeptide-based nanoparticles: vehicles for targeted tumor drug delivery.

AIM Different nanoparticles have been investigated to deliver chemotherapeutic agents, but complex synthesis procedures and biocompatibility issues raise concerns in developing them for safe human usage. The aim of this work is to develop α,β-dehydrophenylalanine-containing, self-assembled, amphipathic dipeptide nanoparticles for tumor-targeted drug delivery and therapy. MATERIAL & METHODS Solution-phase peptide synthesis was used to synthesize dipeptides. Nanoparticles were prepared by molecular self-assembly. A tumor distribution study was carried out using a radiolabeling method. Tumor regression studies were carried out in murine ascitic tumors in BALB/c mice and breast tumor xenografts in in nonobese diabetic/severe combined immunodeficiency mice. RESULTS Arg-α,β-dehydrophenylalanine formed self-assembled nanoparticles that could be easily derivatized with folic acid. Folic acid-derivatized nanoparticles showed enhanced cellular uptake and, when loaded with doxorubicin, showed enhanced tumor regression compared with underivatized nanoparticles or native drug, without any adverse side effects, both in vitro and in vivo.
Evaluations of Shorter Exposures of Contact Lens Cleaning Solutions against Fusarium oxysporum Species Complex and Fusarium solani Species Complex To Simulate Inappropriate Usage

ABSTRACT An outbreak of Fusarium keratitis in contact lens users resulted in withdrawal of ReNu with MoistureLoc solution, although the exact cause of the outbreak remains enigmatic. We evaluated current and discontinued multipurpose cleaning solutions (MPSs; MoistureLoc, Equate, MultiPlus, and OptiFree Express) against plankton- and biofilm-derived cells of Fusarium oxysporum species complex (FOSC) and F. solani species complex (FSSC). The methods included a traditional assay based on CFU counts and a novel flow cytometry (FC) assay based on percent cell subpopulation (PCS) stained with two fluorochromes (Sytox Red and 5-chloromethylfluorescein diacetate). The tests were done with the respective manufacturers' recommended cleaning regimens (240 to 360 min) and under shorter exposures (15 to 60 min) to simulate inappropriate usage by the customers. FC assay measured PCS, which was available rapidly, in 5 to 7 h, whereas 24 to 48 h was needed for CFU counts, and there was good correlation between the two methods (r2 = 0.97). FC assays allowed identification of injured fungal cells, which are likely to be missed with growth assays. In general, a time- and inoculum-dependent survival pattern was seen for both FOSC and FSSC cells, and biofilm-derived cells were more resistant than plankton-derived cells. MultiPlus and Equate produced 100% sterilization of fungi even under shorter exposures. However, biofilm FOSC and FSSC cells survived for up to 4 h in MoistureLoc solution and up to 6 h in OptiFree Express solution under shorter exposure times. This finding was enigmatic, as OptiFree Express is not associated with any outbreak of Fusarium keratitis. This study provides additional support for possible roles that improper lens cleaning regimens and fungal biofilms could play as predisposing factors for Fusarium keratitis.
Neurokinin-1 Receptor Agonists Are Involved in Mediating Neutrophil Accumulation in the Inflamed, But Not Normal, Cutaneous Microvasculature: An In Vivo Study Using Neurokinin-1 Receptor Knockout Mice1

We have used tachykinin neurokinin-1 receptor (NK1 receptor) knockout mice to learn of the link between NK1 receptors and neutrophil accumulation in normal naive skin, as compared with inflamed skin. Intradermal substance P (300 pmol) induced edema formation in wild-type mice, but not in NK1 knockout mice, as expected. However, in contrast to IL-1β (0.3 pmol), substance P did not induce neutrophil accumulation in wild-type mice. IL-1β-induced neutrophil accumulation was similar in wild-type and knockout mice, but a significant (p < 0.05) contributory effect of added NK1 agonists, which by themselves have no effect on neutrophil accumulation in normal skin, was observed. The results support the concept that NK1 agonists such as substance P cannot act on their own to mediate neutrophil accumulation in naive skin and provide direct evidence that in inflamed skin, under certain circumstances, the NK1 receptor can play a pivotal role in modulating neutrophil accumulation during the ongoing inflammatory process. We investigated responses to two inflammatory stimuli (carrageenin and zymosan). Neutrophil accumulation was significantly attenuated (p < 0.001) in carrageenin- but not zymosan-induced inflammation in NK1 knockout mice. The carrageenin (500 μg)-induced response was inhibited (p < 0.05) by a NK1 receptor antagonist, SR140333 (480 nmol/kg i.v. at −5 min), in the wild-type group. The bradykinin B1 and B2 receptor antagonists (desArg9[Leu8]bradykinin and HOE 140) each reduced neutrophil accumulation to carrageenin in wild-type animals (p < 0.05), but did not cause further reduction of the suppressed response of knockout mice. The results provide evidence that kinin receptors participate in NK1 receptor-dependent neutrophil accumulation in inflamed mouse skin.
The predictive role of psychosocial stress on symptom severity in premenstrual syndrome.

&NA; Twenty‐five women with well defined, severe premenstrual syndrome (PMS) were studied prospectively during three consecutive menstrual cycles to examine the association between concurrent psychosocial stress and symptom severity. Stress, mood, physical symptoms, and urinary ovarian steroid metabolites were measured daily. Stress accounted for only 6% and 10% of the unique variance in physical symptom and mood scores, respectively, across the menstrual cycle. In individual woman, there was no association between the severity of symptoms and the cumulative daily stress reported during each cycle. We conclude that in this carefully screened population of women without coexisting psychiatric disorder, PMS symptom severity could not be determined by the amount of psychosocial stress.
Development and Application of Hepatitis C Reporter Viruses with Genotype 1 to 7 Core-Nonstructural Protein 2 (NS2) Expressing Fluorescent Proteins or Luciferase in Modified JFH1 NS5A

ABSTRACT To facilitate genotype-specific high-throughput studies of hepatitis C virus (HCV), we have developed reporter viruses using JFH1-based recombinants expressing core-nonstructural protein 2 (NS2) of genotype 1 to 7 prototype isolates. We introduced enhanced green fluorescent protein (EGFP) into NS5A domain III of the genotype 2a virus J6/JFH1 [2a(J6)]. During Huh7.5 cell culture adaptation, 2a(J6)-EGFP acquired a 40-amino-acid (aa) (Δ40) or 25-aa (Δ25) deletion in NS5A domain II, rescuing the impairment of viral assembly caused by the EGFP insertion. Δ40 conferred efficient growth characteristics to 2a(J6) tagged with EGFP, DsRed-Express2, mCherry, or Renilla luciferase (RLuc), yielding peak supernatant infectivity titers of 4 to 5 log10 focus-forming units (FFU)/ml. 2a(J6) with Δ40 or Δ25 was fully viable in Huh7.5 cells. In human liver chimeric mice, 2a(J6)-EGFPΔ40 acquired various deletions in EGFP, while 2a(J6)Δ40 did not show an impaired viability. We further developed panels of JFH1-based genotype 1 to 7 core-NS2 recombinants expressing EGFP- or RLuc-NS5AΔ40 fusion proteins. In cell culture, the different EGFP recombinants showed growth characteristics comparable to those of the nontagged recombinants, with peak infectivity titers of 4 to 5 log10 FFU/ml. RLuc recombinants showed slightly less efficient growth characteristics, with peak infectivity titers up to 10-fold lower. Overall, the EGFP and RLuc recombinants were genetically stable after one viral passage. The usefulness of these reporter viruses for high-throughput fluorescence- and luminescence-based studies of HCV-receptor interactions and serum-neutralizing antibodies was demonstrated. Finally, using RLuc viruses, we showed that the genotype-specific core-NS2 sequence did not influence the response to alfa-2b interferon (IFN-alfa-2b) and that genotype 1 to 7 viruses all responded to treatment with p7 ion channel inhibitors.
Results of isoproterenol tilt table testing in monozygotic twins discordant for chronic fatigue syndrome.

BACKGROUND The pathogenesis of chronic fatigue syndrome (CFS) is unknown. Neurally mediated hypotension (NMH) has been suggested as a common comorbid condition or a potential underlying cause. METHODS We conducted a cotwin control study of 21 monozygotic twins who were discordant for CFS. One twin met the 1994 Centers for Disease Control and Prevention criteria for CFS, and the other twin was healthy and denied chronic fatigue. The twins were selected from a volunteer twin registry in which at least 1 member reported persistent fatigue. As part of a 7-day clinical evaluation, all 21 twin pairs were evaluated with a 3-stage tilt table test with isoproterenol hydrochloride for the assessment of NMH. The presence of NMH was defined as syncope or presyncope associated with a decrease of 25 mm Hg in blood pressure and no associated increase in heart rate. RESULTS A positive tilt table test result was observed in 4 twins with CFS (19%) and in 4 healthy twins (19%). This difference was not statistically significant (matched pair odds ratio, 1.0; 95% confidence interval, 0.2-5.4; P>.90). Compared with the healthy twins, the twins with CFS reported more severe symptoms of CFS and NMH both in the week before and during the tilt table test. CONCLUSIONS These results do not support a major role for NMH in CFS. They highlight the importance of selecting well-matched control subjects, as well as the unique value of the monozygotic cotwin control design in the study of this illness. Arch Intern Med. 2000;160:3461-3468.
Global informatics and physical property selection in protein sequences

Significance Many bioinformatic investigations of protein sequence–structure relationships are based on preselected sets of amino acid physical properties. We investigate the extent to which such preselection is justified on information–theoretical grounds. It is shown that neither sequence-dependent nor -averaged properties can be identified as informatically negligible and that no physical properties can be identified that carry sufficient information about other variables to act as surrogates. This result implies that knowledge-based studies of proteins must be based on complete, nonredundant physical property sets. The degree of informatic independence between the physical properties of amino acids as encoded in actual protein sequences is calculated. It is shown that no physical property can be identified that carries significantly less information than others and that the information overlap between different properties and different length scales along the sequence is essentially zero. These observations suggest that bioinformatic models based on arbitrarily selected sets of physical properties are inherently deficient.
Dimethylated H3K27 Is a Repressive Epigenetic Histone Mark in the Protist Entamoeba histolytica and Is Significantly Enriched in Genes Silenced via the RNAi Pathway*

Background: Entamoeba histolytica has an RNAi-mediated TGS pathway but the epigenetic marks are not known. Results: H3K27Me2 is an inducible repressive histone modification enriched in loci silenced by small RNAs. Conclusion: Transcriptional gene silencing and chromatin modification are coupled to maintain prolonged gene silencing. Significance: This work identifies the first repressive histone mark in Entamoeba and links it to RNAi. RNA interference (RNAi) is a fundamental biological process that plays a crucial role in regulation of gene expression in many organisms. Transcriptional gene silencing (TGS) is one of the important nuclear roles of RNAi. Our previous data show that Entamoeba histolytica has a robust RNAi pathway that links to TGS via Argonaute 2-2 (Ago2-2) associated 27-nucleotide small RNAs with 5′-polyphosphate termini. Here, we report the first repressive histone mark to be identified in E. histolytica, dimethylation of H3K27 (H3K27Me2), and demonstrate that it is enriched at genes that are silenced by RNAi-mediated TGS. An RNAi-silencing trigger can induce H3K27Me2 deposits at both episomal and chromosomal loci, mediating gene silencing. Our data support two phases of RNAi-mediated TGS: an active silencing phase where the RNAi trigger is present and both H3K27Me2 and Ago2-2 concurrently enrich at chromosomal loci; and an established silencing phase in which the RNAi trigger is removed, but gene silencing with H3K27Me2 enrichment persist independently of Ago2-2 deposition. Importantly, some genes display resistance to chromosomal silencing despite induction of functional small RNAs. In those situations, the RNAi-triggering plasmid that is maintained episomally gets partially silenced and has H3K27Me2 enrichment, but the chromosomal copy displays no repressive histone enrichment. Our data are consistent with a model in which H3K27Me2 is a repressive histone modification, which is strongly associated with transcriptional repression. This is the first example of an epigenetic histone modification that functions to mediate RNAi-mediated TGS in the deep-branching eukaryote E. histolytica.
Fact and Artefact in Confocal Microscopy

High-resolution confocal microscopic images may be made of either the surface of a sample or beneath the surface. These images can be likened to optical tomograms, giving thin (> 0.35 μm) slices up to 200 μm below the surface of a transparent tissue: With microscopes running under normal conditions, the optical section thickness will be >1 μm and the effective penetration into enamel and dentin a maximum of 100 μm. For maximum resolution, high-quality, high-numerical-aperture objectives should be used. Refractive index matching of the lens immersion media and the substrate will avoid distortions of images in the optical axis. Such errors could occur when imaging a considerable distance (> 40 μm) into a cell containing water, with an oil immersion objective above the cover slip. Care should be taken in the interpretation of computerized z axis reconstructions made from serial optical sections: Their validity should be checked with equivalent views made with the sample oriented in the same direction as the reconstruction. The use of fluorescent dyes in microscopy is a very powerful investigative technique. It is important that the dyes used not be labile and that they be well-fixed to the materials being examined, or the images may indicate the dye distribution rather than the material to which it is "attached". Multiple labeling experiments must have crossover control experiments to verify the distribution of the individual dyes. Valuable information can often be gained by combining information from both reflection and fluorescence images. Two-photon laser excitation of dyes gives the potential for greater depth penetration and improved resolution.