Polymorphisms in matricellular SPP1 and SPARC contribute to susceptibility to papillary thyroid cancer.
There is a compelling need to identify novel genetic variants for papillary thyroid cancer (PTC) susceptibility. The Cancer Genome Atlas (TCGA) data showed associations between SPP1 and SPARC mRNA overexpression and aggressive behaviors of PTC, which prompted us to assess potential associations between genetic variants in these genes and PTC risk. Three highly linked SPARC loci (rs1054204, rs3210714, and rs3549) contributed to reduced PTC risk under a codominant model (odds ratio [OR], 0.79-0.80). Variant CAG alleles at these loci significantly enhanced SPARC transcription activation upon cotransfection with miR-29b and miR-495 when compared to the common alleles GGC (all P < 0.05). The three SPARC polymorphisms interacted with SPP1 rs4754, with elevated joint ORs of 2.43, 2.52, and 2.52, respectively. Additionally, interaction between SPP1 rs2358744 and SPARC rs2304052 was observed. Our study revealed associations between SPP1 and SPARC polymorphisms that, individually or in combination, are involved in PTC susceptibility.


Substrate entasis and electronic coupling elements in electron transfer from Fe in a multicopper ferroxidase.
Outersphere electron transfer in multicopper oxidases occurs at the type 1, blue Cu(II). One class of MCO proteins exhibits a specificity in this reaction towards Fe(II). In work carried out in collaboration with the Solomon lab over the past 7 years, we have delineated the structural motifs that support this ferroxidase specificity and have quantified the contributions that each makes to this outersphere electron transfer reaction from Fe(II) to the type 1 Cu(II). Two features of this electron transfer catalysis stand out. First, the protein provides a binding site for Fe(II) that actually favors Fe(III); this coordination sphere places the bound Fe(II) in a state of "entasis" that can be relieved by loss of an electron. In short, the E(O) of the bound Fe(II) is lowered relative to that of aqueous ferrous iron making electron transfer thermodynamically favorable. Second, carboxylates within this coordination sphere provide an electronic coupling pathway for the electron transfer via their H-bond network with type 1 Cu histidine ligands thus making electron transfer kinetically efficient. This brief report breaks down these contributions to ferroxidase specificity in terms of the semi-classical Marcus equation describing outersphere electron transfer.


XPS and structural studies of Fe3O4-PTMS-NAS@Cu as a novel magnetic natural asphalt base network and recoverable nanocatalyst for the synthesis of biaryl compounds.
In this research, natural asphalt as a mineral carbonuous material was converted to sodium natural asphalt sulfonate (Na-NAS) and, then, was linked to Fe3O4 MNPs in order to synthesize the magnetic nanocatalyst. Afterwards, Cupper (I) and Cu (II) was grafted on Fe3O4-PTMS-NAS. Moreover, it is worth mentioning that the synthesized the novel magnetic nanocatalyst (Fe3O4-PTMS-NAS@Cu) was successfully used in Suzuki and Stille coupling reactions. The Fe3O4-PTMS-NAS@Cu MNPs were characterized by Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), thermogravimetric analysis (TGA), vibrating sample magnetometry (VSM), inductively coupled plasma (ICP), BET and X-ray photoelectron spectroscopy (XPS) analysis. Besides, sulfonation of natural asphalt, magnetization of catalyst, grafting of Cu (I) and Cu (II) to NAS and catalyst formation were investigated and proved carefully. This nanocatalyst can be comfortably separated from the reaction medium through an external magnetic field and can also be recovered and reused, while maintaining its catalytic activity.


Fluoroscopy guided transpedicular abscess infusion and drainage in thoracic-lumbar spondylitis with prevertebral abscess.
To evaluate the effectiveness of fluoroscopy guided transpedicular abscess infusion and drainage in thoracic-lumbar spondylitis with prevertebral abscess. We retrospectively reviewed 14 patients with infectious spondylitis with prevertebral abscesses from January 2019 to December 2022. All patients underwent fluoroscopy guided transpedicular abscess infusion and drainage. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), visual analog scale (VAS), Macnab criteria, and magnetic resonance imaging (MRI) were compared before and after the operation to evaluate clinical outcomes. Among the 14 patients with prevertebral abscesses, 64.29% (9/14) involved the lumbar spine and 35.71% (5/14) involved the thoracic spine. The ESR, CRP, and VAS scores decreased from 87.34 ± 9.21, 93.01 ± 11.17, and 8.38 ± 0.97 preoperatively to 12.35 ± 1.61, 8.52 ± 1.19, and 2.02 ± 0.64 at the final follow-up, respectively. MRI at the final follow-up showed the disappearance of the prevertebral abscess compared with that in the preoperative group (66.95 ± 12.63 mm in diameter). Ten patients achieved an "excellent" outcome, while the remaining four patients obtained a "good" outcome according to the Macnab criteria. Fluoroscopy guided transpedicular abscess infusion and drainage is a safe and minimally invasive procedure for the management of thoracic-lumbar spondylitis with a prevertebral abscess.


A complete prostaglandin pathway from synthesis to inactivation in the oral gland of the jawless vertebrate lamprey, Lethenteron camtschaticum.
Information on the prostaglandin pathway in lampreys is limited. Here, five genes related to the prostaglandin pathway from synthesis to inactivation, namely, phospholipase A2, cyclooxygenase-2, prostaglandin E synthase 3, prostaglandin D synthase, and 15-hydroxyprostaglandin dehydrogenase [NAD(+)], were screened and cloned from the lamprey, Lethenteron camtschaticum. Bioinformatic analysis showed that these lamprey genes are relatively conserved with teleost genes in domains, motifs, gene structure and 3D structure. Analysis of expression distribution of the genes in lamprey tissues revealed that a complete prostaglandin pathway from synthesis to inactivation exists in the oral gland of lamprey, especially the key gene of prostaglandin synthesis cyclooxygenase-2, which was highly expressed in the oral gland. Furthermore, cyclooxygenase-2 expression increased after LPS and Poly I:C stimulations. Using our established spatial metabolite database LampreyDB, six prostaglandin-related metabolites were screened from the oral gland of lamprey, four of which were highly expressed in the oral gland. This study provides new insights into prostaglandin synthesis and inactivation pathways in lamprey, thereby improving our understanding of the origin and evolution of the prostaglandin pathway and contributing to the recognition of lamprey regulatory mechanisms in development and immunity.


The study of water uptake in degradable polymers by thermally stimulated depolarization currents.
Poly(DTH succinate) is a new, degradable polymer with potential applications as a medical implant material. This polymer can be classified as an alternating copolymer of succinic acid and desaminotyrosyl-tyrosine hexyl ester (DTH), a diphenolic monomer derived from the natural amino acid L-tyrosine. In this study, the effects of water uptake (hydration) on the secondary relaxations of poly(DTH succinate) were investigated using the technique of thermally stimulated depolarization currents (TDSC). Four relaxation peaks were precisely characterized by means of Gaussian activation energy distributions. Drying and rehydration treatments show that only small amounts of water, at most 0.5% (w/w), are necessary to hydrate two of the four polar moieties in poly(DTH succinate): the pendent chain ester carbonyls and the amide carbonyls in the polymer backbone. Water appeared to be more tightly bound to the amide carbonyl group and more loosely bound to the ester carbonyl group in the pendent chain. Even at a high state of hydration (1.2% w/w), TDSC indicated that no water was associated with the phenyl ester bond in the polymer backbone. This finding may explain the unexpectedly high stability of this polymer toward hydrolysis under physiological conditions. Polymer packing was also affected by hydration. In an intermediate hydration state (water content: 0.5% w/w) polymer packing was less dense than in the wet state (water content: 1.2% w/w). This study represents the first application of the TDSC technique to the study of hydration in a degradable biomedical polymer. The results obtained indicate that the TDSC technique may be useful to assist in the understanding of the mechanisms of hydration and subsequent hydrolytic degradation in degradable biomaterials.


Morphobiometrical characteristics of indigenous chicken ecotype populations in Rwanda.
The rational of conservation and sustainable use of indigenous chicken (IC) resources requires their morphobiometrical characterisation. This study morphobiometrically characterised the IC ecotypes in Rwanda. The morphological features and zoometric measurement data were randomly collected on 1670 mature IC of both sexes from five ecotypes of Rwanda. The nonparametric Kruskal-Wallis and Mann-Whitney U test were used in evaluating the effect of ecotypes on the qualitative morphological variables. Zoometric measurements were analysed with the PROC GLM of SAS. The findings showed that the feather morphology and distribution were mainly normal (98.3 and 84.40%, respectively) while feather colour was dominated with multicoloured (38.10%). The majority of the birds had red earlobe (49.20%), yellow shanks (53.80%) and single comb-type (71.70%). These parameters were different (p < 0.05) between the ecotypes. Bodyweight and linear body measurements were highly different (P < 0.001) between ecotypes. Differences associated with sex (P < 0.001) were observed in body weight and linear body measurements. The interaction between ecotype and sex significantly (P < 0.001) influenced body weight, body length, shank length, comb length, comb height, wattle length, chest circumference, neck length and wingspan. The IC ecotypes in Rwanda were found to be diverse morphobiometrically both in quantitative and qualitative traits. These variations provide a foundation for classification of the chicken into breeds.


Check size and defocusing effects on equipotential maps of pattern-evoked electroretinograms.
The spatial distribution of the pattern-evoked potentials on the face was studied with a simultaneous 16-channel recording system. The potentials had the first positive component at a peak latency of approximately 55 msec, which was much earlier than the latency of the response picked up from the scalp. The maximal potential value in the maps was found at the region around the stimulated eye. This configuration of the equipotential map was not influenced by defocusing and check size of the pattern, but was altered by changing the contrast. Our results of equipotential maps constructed at around 55 msec after pattern reversal proved that the responses recorded in the facial region originated in the retina and were not a reflection of the scalp potentials.


Genetic effects of crocidolite asbestos in Chinese hamster lung cells.
Chinese hamster lung cells cultured in the presence of crocidolite asbestos displayed inhibition of cell growth. Cell death was directly associated with the phagocytosis of larger fibres as observed with the aid of trypan blue. Water soluble components of crocidolite did not appear to inhibit cell growth. Chromosomal aberrations were induced by the asbestos. The aberrations were confined mainly to structural aberrations--breaks and fragments. Electron-microscopic preparation indicated that asbestos was readily contained in phagosomes. Phagocytosed asbestos appeared to be a weak mutagen in its ability to induce gene mutation at the hypoxanthine-guanine phosphoribosyl transferase locus.


Purification and characterization of a rat liver cytosol neutral thiol peptidase that degrades glucagon, insulin, and isolated insulin A and B chains.
A thiol peptidase that catalyzes at near neutral pH the hydrolysis of insulin, the isolated A and B chains of insulin, and glucagon was purified from rat liver cytosol by fractionation on Sephadex G-200, Affi-Gel Blue, and Spherogel TSK-G 3000 SW. The purified enzyme showed a single component by chromatography on a Spherogel TSK column and by gel filtration on a Sephadex G-200 column. The native enzyme has a molecular weight of approximately 180,000 and consists of two subunits having pI's of 5.9 and 6.3. Studies on its substrate specificity showed that the purified enzyme degrades glucagon, insulin, insulin B chain, and insulin A chain, but it does not degrade proinsulin, ACTH, or denatured hemoglobin. Kinetic analyses were performed on three substrates. The Km values were: 34 nM for insulin, 276 nM for insulin B chain, and 3.5 microM for glucagon. The kcat and Vm/Km values were glucagon greater than B chain greater than insulin. Thus, the enzyme has the highest affinity/lowest efficiency for insulin, an intermediate affinity/intermediate efficiency for B chain of insulin and the lowest affinity/highest efficiency for glucagon. The effect of several potential activators and inhibitors on the enzyme's activity was investigated. The enzyme activity was markedly inhibited by N-ethylmaleimide, p-chloromercuribenzoic acid, iodoacetamide, and Np-tosyl-L-phenylalanine chloromethyl ketone (TPCK), and was partially inhibited by dithiothreitol, by the chelating agents EDTA and EGTA, and by phenylmethylsulfonyl fluoride (PMSF). Bacitracin inhibited the activity of the enzyme, but the protease inhibitors aprotinin, leupeptin, pepstatin, and phosphoramidon had little or no effect. Reduced glutathione, iodoacetate, and N alpha,p-tosyl-L-lysine chloromethyl ketone (TLCK) also had little or no effect on the enzyme activity.


Vasodilatation produced by apomorphine in the hindleg of the dog.
Apomorphine, injected into the dog femoral artery in doses of 0.6 microng or higher, produced a marked increase in femoral blood flow, without a change in blood pressure. No increase in flow was produced by comparable doses of dopamine or morphine. After sympathetic denervation or administration of phenoxybenzamine, the apomorphine vasodilatation was either abolished or greatly reduced. When the vascular tone in the denervated hindleg was restored by sympathetic nerve stimulation, the vasodilatory effect of apomorphine often re-established itself; this was not the cases when the vascular tone was restored by an infusion of noradrenaline. The apomorphine vasodilatation was not antagonized by propranolol or atropine. Mepyramine, in doses that antagonize histamine, often inhibited the apomorphine vasodilatation. Haloperidol, injected i.a., antagonized the apomorphine effect without changing the responses to isopropylnoradrenaline, acetylcholine, histamine and and nitroglycerin. Haloperidol blockade was overcome by increasing the dose of apomorphine. These results suggest that apomorphine dilates the femoral vasculature by an action on a "dopamine receptor." The possibility that the receptor is located on sympathetic nerve endings is discussed.


Field water relations of a wet-tropical forest tree species, Pentaclethra macroloba (Mimosaceae).
The water relations of Pentaclethra macroloba (Willd.) Kuntze, a dominant, shade-tolerant, tree species in the Atlantic lowlands of Costa Rica, were examined within the forest canopy. Pressure-volume curves and diurnal courses of stomatal conductance and leaf water potential were measured in order to assess differences in water relations between understory, mid-canopy and canopy leaves. Leaves in the canopy had the smallest pinnules but the largest stomatal frequencies and stomatal conductances of the three forest levels. Osmotic potentials at full turgidity decreased with height in the forest; in the canopy and midcanopy they were reduced relative to those in the understory just enough to balance the gravitational component of water potential. Consequently, maximum turgor pressures were similar for leaves from all three canopy levels. Bulk tissue elastic modulus increased with height in the canopy. Leaf water potentials were lowest in the canopy and highest in the understory, even when the gravitational component was added to mid-canopy and canopy values. As a result, minimum turgor pressures were also lowest in the canopy compared to those at lesser heights, and approached zero in full sunlight on clear days.Osmotic potentials at each canopy level were similar for both wet and dry season samples dates suggesting that seasonal osmotic adjustment does not occur. Despite lowered predawn water potentials during the dry season, turgor was maintained in the understory by reduced stomatal conductances.


Riboflavin-mediated delivery of a macromolecule into cultured human cells.
Cell surface receptors for the vitamins folic acid and biotin have been previously reported to mediate the endocytosis of vitamin-conjugated macromolecules into cultured cells. To evaluate whether a similar uptake pathway for riboflavin-conjugated macromolecules might exist, riboflavin was covalently linked to bovine serum albumin (BSA) via the vitamin's ribityl side chain, and uptake of the protein by cultured human cells was examined. Whereas unconjugated BSA was not internalized by KB, A549, SK-LU-1 or SK-OV cells, riboflavin-conjugated BSA was readily internalized (>106 molecules/cell). Analysis of the uptake pathway revealed that the riboflavin-BSA conjugate likely docks on cells at a carrier/transport protein that is distinct from the uptake pathway for free riboflavin and then enters via normal membrane cycling. Evidence for this contention is: (i) the internalized conjugate accumulates in endosomal compartments, (ii) uptake into cells is halted at temperatures near 0 degreesC where membrane trafficking is abrogated, (iii) cell association is inhibited by unlabeled riboflavin-BSA, but not by free riboflavin, and (iv) cellular uptake of [3H]riboflavin is only partially inhibited by riboflavin-BSA. Regardless of the pathway of internalization, these data demonstrate that riboflavin conjugation can facilitate protein entry into human cells in culture.


Detection of Circulating Tumor Cells in Patients with Small Choroidal Melanocytic Lesions.
To determine the presence of circulating tumor cells (CTCs) in patients with indeterminate small choroidal melanocytic lesions (SCMLs). Retrospective case series. Forty-seven patients with choroidal melanocytic lesions 2.5 mm or less in tumor thickness and ≤ 10 mm in largest basal diameter (LBD). Blood samples were analyzed for CTCs and the presence of monosomy-3 (M3) in CTCs. Tissue biopsy was performed in the patients who were CTC-positive (pCTC). Presence and M3 status of the CTCs with regard to the clinical characteristics and results from tissue biopsy. Median thickness of all (n = 47) lesions was 1.1 mm (range: 0.2-2.5 mm), and LBD was 5.6 mm (range: 2.0-10.0 mm). Circulating tumor cells were found in 25 patients (n = 25). This group was classified as pCTC and compared with the CTC-negative (nCTC) group consisting of 22 patients (n = 22). Median tumor dimensions in the pCTC versus the nCTC group were 1.6 mm (range: 0.6-2.5 mm) versus 0.5 mm (range: 0.2-2.5 mm) for thickness and 6.6 mm (range: 4.1-10.0 mm) versus 4.0 mm (range: 2.0-8.0 mm) for LBD, respectively. Both LBD and thickness were positively associated (P < 0.001) with the presence of CTC. Compared with the nCTC group, a higher percentage of the pCTC group exhibited LBD > 5 mm (36% vs. 88%), subretinal fluid (9.1% vs. 56%), orange pigment (4.5% vs. 60%), sonographic hollowness (9.1% vs. 60%), and the presence of multiple risk factors (0% vs. 68% for ≥3 factors) with P < 0.001 for all parameters. No significant difference was detected in the clinical parameters of the patients who had disomy-3 (D3) (n = 7) versus M3 (n = 17) in their CTC. The tissue biopsy confirmed the uveal melanoma (UM) in 22 of the 25 pCTC patients (88%), whereas no conclusive diagnosis could be determined in the remaining 3 cases because of insufficient or invalid material. We report compelling evidence for the potential of liquid biopsy as an additional tool to screen SCMLs for malignancy. These findings pave the way toward the implementation of liquid biopsy to detect small UM and monitor melanocytic lesions. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.


Injection laryngoplasty in children with cystic fibrosis and abnormal swallow.
Children with cystic fibrosis (CF) are uniquely vulnerable to the pulmonary complications of chronic aspiration. We present a case series of children with CF and evidence of chronic aspiration who underwent injection laryngoplasty to improve the safety and efficacy of their swallow. Retrospective chart review. Tertiary care children's hospital. A chart review was performed on three consecutive cases of children with CF and evidence of aspiration on modified barium swallow (MBS) evaluated at a tertiary care, academic children's medical center. Three patients with CF underwent injection laryngoplasty for evidence of aspiration or laryngeal penetration on MBS evaluation. Normal laryngeal anatomy was identified intraoperatively in each case. At the time of the procedure, patients were 22 months, 70 months, and 24 months old, and follow-up information was available for 7 months, 11 months, and 12 months post-procedure, respectively. Presenting symptoms included chronic cough, cough with oral liquids, and recurrent pneumonia. Each patient underwent successful injection into the interarytenoid space. Post-operatively, modified barium swallow demonstrated resolution of aspiration or penetration in all patients. No procedure-related complications were encountered. Patients with CF are highly susceptible to pulmonary infections, and aggressive treatment of chronic aspiration is often necessary. Injection laryngoplasty may be effective in normalizing swallowing in these children. Future study will elucidate the duration of effect and if this technique improves long-term pulmonary outcomes in CF patients.


New placement of recording electrodes on the thyroid cartilage in intra-operative neuromonitoring during thyroid surgery.
During thyroid surgery, extreme caution is needed not to harm the recurrent laryngeal nerve and to avoid vocal cord palsy. Intra-operative neuromonitoring became increasingly popular as an adjunct to the gold standard of visual identification of the recurrent laryngeal nerve (RLN). Electromyographic (EMG) responses are normally recorded by electrodes attached to the endotracheal tube. Alteration in position can lead to false loss of signal. We developed thyroid cartilage electrodes that can be fixed directly onto the thyroid cartilage. Prospective clinical cohort METHODS: Thyroid surgery with intra-operative neuromonitoring using both endotracheal tube-based electrodes and thyroid cartilage electrodes was performed in 25 patients undergoing thyroid surgery. EMG data were collected and reported as median and interquartile ranges (IQR), and the results were compared with the x Wilcoxon signed-rank test for paired measurements. After stimulating vagal nerve (VN), recurrent laryngeal nerve (RLN) and external branch of the superior laryngeal nerve (EBSLN), significantly higher EMG amplitudes were measured before and after thyroid resection for the thyroid cartilage (TC) electrodes, in all comparisons except for the right VN. At the level of the left EBSLN, median amplitude of 560 mV (IQR 190-1050) before and 785 mV (IQR 405-3670) after resection was noted. At the level of the right EBSLN, median amplitude of 425 μV (IQR 257-698) before and 668 mV (IQR 310-1425) after resection was noted. Median amplitudes of 760 mV (IQR 440-1180) and 830 mV (IQR 480-1490) were noted at the left RLN, median amplitudes of 695 mV (IQR 405-1592) and 1078 mV (IQR 434-1895) were noted at the right RLN. Thyroid cartilage electrodes appear to be a feasible and reliable alternative for endotracheal electrodes.


Age-related changes of the mossy fibre system in rat hippocampus: effect of long term acetyl-L-carnitine treatment.
Age-related changes of the hippocampal mossy fibre system were studied in rats of different ages (4, 12, and 24 months) using the Timm's histochemical technique for the detection of tissue stores of zinc and heavy transitional metals. Quantitative image analysis and microdensitometry techniques were applied for the evaluation of the changes themselves. The area occupied by mossy fibres and the intensity of Timm's staining in field CA3 of hippocampus were greater in adult rats than in young and old animals. These findings are consistent with previous behavioural data indicating that young and old rats exhibited a reduced passive avoidance learning with respect to adult animals. The above techniques were also used in a second session of this study designed to investigate the effect of a 6-months treatment with acetyl-L-carnitine (ALC) on the hippocampal mossy fibre system. ALC was found to increase significantly the area occupied by mossy fibres and the intensity of Timm's staining in the hippocampus of old rats. These findings are in agreement with and support from an anatomical point of view, the data indicating that long-term treatment with ALC improves passive avoidance performance.


Lung cancer cell invasion and expression of intercellular adhesion molecule-1 (ICAM-1) are attenuated by secretory phospholipase A₂ inhibition.
Invasive lung tumors are associated with intercellular adhesion molecule-1 (ICAM-1) expression. Secretory phospholipase A(2) (sPLA(2)) enzymes produce inflammatory mediators that stimulate ICAM-1 expression, and upregulation of PLA(2) activity can enhance metastasis. We hypothesize a link between sPLA(2) activity, ICAM-1 expression, and tumor cell invasion. We propose that inhibition of sPLA(2) modulates ICAM-1 expression in cancer cells and attenuates their invasiveness. Human lung adenocarcinoma cells (A549) were treated with an ICAM-1 blocking antibody and assayed for invasion. Lung cancer cells (A549 and H358) were then treated with an sPLA(2) inhibitor and evaluated by immunoblotting for ICAM-1 expression. Next cells (A549) treated with sPLA(2) inhibitor were assayed for invasion. Finally, sPLA(2) messenger RNA and protein expression were evaluated by quantitative reverse-transcriptase polymerase chain reaction and immunofluorescence microscopy, respectively. Statistical analysis was performed by the Student t test or analysis of variance, as appropriate. Antibody blockade of ICAM-1 decreased lung cancer cell invasion. sPLA(2) inhibition significantly reduced ICAM-1 expression and invasion. sPLA(2) inhibition also significantly decreased sPLA(2) mRNA expression and immunofluorescent staining of sPLA(2). sPLA(2) plays a significant role in mediating the inflammatory signals that induce ICAM-1 expression in lung cancer cells. Inhibition of the enzyme can significantly decrease ICAM-1 expression and subsequent cancer cell invasion. This lays the groundwork for further investigation into the cellular mechanisms of sPLA(2) and its role in lung cancer.


Epidemiological and clinical factors associated with post-exertional malaise severity in patients with myalgic encephalomyelitis/chronic fatigue syndrome.
Post-exertional malaise (PEM), the cardinal feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), occurs generally after exposure to a stressor. It is characterized by the worsening of ME/CFS symptoms and results in aggravating the course of the disease and the quality of life of patients. Due to its unpredictable onset, severity, and recovery time, identifying patients with higher risk for severe PEM would allow preventing or reducing its occurrence. We thus aimed at defining possible factors that could be associated with PEM severity. Adult patients fulfilling ME international consensus criteria who attended the internal medicine department of University hospital Angers-France between October 2011 and December 2019 were included retrospectively. All patients were systematically hospitalized for an etiological workup and overall assessment. We reviewed their medical records for data related to the assessment: epidemiological data, fatigue features, clinical manifestations, and ME/CFS precipitants. PEM severity was appreciated by the Center for Disease Control self-reported questionnaire. The study population was classified into quartiles according to PEM severity scores. Analyses were performed with ordinal logistic regression to compare quartile groups. 197 patients were included. PEM severity was found to be positively associated with age at disease onset ≥ 32 years (OR 1.8 [95% CI 1.1-3.0] (p = 0.03)), recurrent infections during the course of the disease (OR 2.1 [95% CI 1.2-3.7] (p = 0.009)), and when ME/CFS was elicited by a gastrointestinal infectious precipitant (OR 5.7 [1.7-19.3] (p = 0.006)). We identified some epidemiological and clinical features, which were positively associated with PEM severity in subsets of ME/CFS patients. This could help improving disease management and patients' quality of life.


Transcriptome analysis reveals pathogenesis-related gene 1 pathway against salicylic acid treatment in grapevine (Vitis vinifera L).
Salicylic acid (SA) is a well-studied phenolic plant hormone that plays an important role in plant defense against the hemi-biothrophic and biothrophic pathogens and depends on the living cells of host for the successful infection. In this study, a pathogenesis test was performed between Vitis davidii and V. vinifera cultivars against grape white rot disease (Coniella diplodiella). V. davidii was found to be resistant against this disease. SA contents were found to be higher in the resistant grape cultivar after different time points. RNA-seq analysis was conducted on susceptible grapevine cultivars after 12, 24, and 48 h of SA application with the hypothesis that SA may induce defense genes in susceptible cultivars. A total of 511 differentially expressed genes (DEGs) were identified from the RNA-seq data, including some important genes, VvWRKY1/2, VvNPR1, VvTGA2, and VvPR1, for the SA defense pathway. DEGs related to phytohormone signal transduction and flavonoid biosynthetic pathways were also upregulated. The quantitative real-time PCR (qRT-PCR) results of the significantly expressed transcripts were found to be consistent with the transcriptome data, with a high correlation between the two analyses. The pathogenesis-related gene 1 (VvPR1), which is an important marker gene for plant defense, was selected for further promoter analysis. The promoter sequence showed that it contains some important cis-elements (W-box, LS7, as-1, and TCA-element) to recruit the transcription factors VvWRKY, VvNPR1, and VvTGA2 to express the VvPR1 gene in response to SA treatment. Furthermore, the VvPR1 promoter was serially deleted into different fragments (-1,837, -1,443, -1,119, -864, -558, -436, and -192 ) bp and constructed vectors with the GUS reporter gene. Deletion analysis revealed that the VvPR1 promoter between -1837 bp to -558 bp induced significant GUS expression with respect to the control. On the basis of these results, the -558 bp region was assumed to be an important part of the VvPR1 promoter, and this region contained the important cis-elements related to SA, such as TCA-element (-1,472 bp), LS7 (-1,428 bp), and as-1 (-520 bp), that recruit the TFs and induce the expression of the VvPR1 gene. This study expanded the available information regarding SA-induced defense in susceptible grapes and recognized the molecular mechanisms through which this defense might be mediated.


Assessment of the effect of deviated nasal septum on the structure of nasal cavity.
The present study was aimed to investigate the effects of DNS on the structure of nasal cavity. The paranasal sinus coronal view CT of 108 patients with DNS and 129 hospitalized patients without DNS was retrospectively analyzed. The transverse diameter of nasal cavity (a), transverse diameter of nasal cavity and paranasal sinus (b), angle between maxillary and palatal bone, interalveolar distance, and maxillary rotation distance were measured. The ratio of a/b in experimental group was 0.367 ± 0.006 which was significantly (P = 0.0023) less than that in control group (0.391 ± 0.005). For the angle between maxillary and palatal bone, there was no significant difference found between DNS and control group for both right and left sides. The interalveolar distance was 40.75 mm in experimental group, and 38.8 mm in control (P = 0.0002). For the maxillary rotation distance, findings were considered as significant (P < 0.0001) in experimental group (11.25 mm) compared with control (10.1 mm). The present study demonstrates that long-term DNS affects the development of nasal cavity and paranasal sinus, as well as increases the interalveolar distance and maxillary rotation distance. These influences may be caused by the alteration of airflow inside the nasal cavities.


Tandem derivatization combined with salting-out assisted liquid-liquid microextraction for determination of biothiols in urine by gas chromatography-mass spectrometry.
Detection of polar organic compounds (POCs) using gas chromatography (GC) is not straightforward due to high polarity, hydrophilicity, and low volatility of POCs. In this study, we report a tandem microwave-assisted derivatization method combined with salting-out assisted liquid-liquid microextraction (SALLME) to modify successively the polar groups of POCs in protic and aprotic solvents. Biothiols (cysteine and homocysteine) served as a proof of concept for this method because they possess three polar groups (thiol, amine, and carboxyl); the derivatizing reagent was 3,4,5-trifluorobenzyl bromide (Br-TFB) for alkylation. The solubility of the POCs in the protic or aprotic reaction medium affected the number of TFB molecules attached. Using the tandem derivatization with Br-TFB, the thiol and amine groups of biothiols were alkylated in the protic system, and the carboxylic groups of biothiols were alkylated in the aprotic system. The developed method was then successfully applied to measure biothiols in human urine. Because of the complex urine matrix and the lack of urine samples without endogenous biothiols, the standard addition method was utilized to avoid the matrix effect, check the recovery, and calculate the initial biothiol content in the urine. Regarding the linearity of the standard addition curves, the coefficient of determination was >0.996, and the linear regression showed satisfactory reproducibility with a relative standard deviation <3.9% for the slope and <8.8% for the intercept. The levels of cysteine and homocysteine in healthy human urine ranged from 28.8 to 111μmolL-1 and from 1.28 to 3.73μmolL-1, respectively. The proposed method effectively increased the sensitivity of GC-MS assays of water-soluble compounds in human urine.


A self-assembled Pd2L4 cage that selectively encapsulates nitrate.
A M2L4 cage with D4 symmetry was self-assembled from four anthracene-bridged benzimidazole ligands and two Pd(II) ions. The cage features a concise hydrophobic pocket wrapped up by the anthracene walls with eight hydrogen-bond donors pointing inward, which provide a specific binding site for nitrate, with a binding affinity at least two orders of magnitude higher than all the other anions screened including halide anions, which have a very similar ionic radius and charge density.


Strategies for the microextraction of polar organic contaminants in water samples.
In this paper the most recent developments in the microextraction of polar analytes from aqueous environmental samples are critically reviewed. The particularities of different microextraction approaches, mainly solid-phase microextraction (SPME), stir-bar-sorptive extraction (SBSE), and liquid-phase microextraction (LPME), and their suitability for use in combination with chromatographic or electrically driven separation techniques for determination of polar species are discussed. The compatibility of microextraction techniques, especially SPME, with different derivatisation strategies enabling GC determination of polar analytes and improving their extractability is revised. In addition to the use of derivatisation reactions, the possibility of enhancing the yield of solid-phase microextraction methods for polar analytes by using new coatings and/or larger amounts of sorbent is also considered. Finally, attention is also focussed on describing the versatility of LPME in its different possible formats and its ability to improve selectivity in the extraction of polar analytes with acid-base properties by using separation membranes and buffer solutions, instead of organic solvents, as the acceptor solution.


Understanding administrative coding of emergency department visits for unspecified acute allergic reactions.
Emergency department (ED) visits for food-related acute allergic reactions enable estimation of temporal trends in food allergy prevalence. To use this approach in New Zealand requires an understanding of the proportion of ED visits coded as 'anaphylaxis, unspecified' or 'allergy, unspecified' that are food-related allergic reactions. We reviewed all ED presentations of children, coded as 'anaphylaxis, unspecified' or 'allergy, unspecified', from 1988-2011 to the Auckland City Hospital ED. Charts were reviewed independently by two investigators to determine agreement on categorisation of presentations as being food-related acute allergic reactions. We compared ED presentation rates in different time intervals using rate ratios (RR) and 95% confidence intervals (CI). Sixty-five (29%) of the 221 ED presentations given a discharge code of 'anaphylaxis, unspecified' or 'allergy, unspecified', were a food-related allergic reaction. Inter-observer agreement was very good (kappa >0.80). The ED presentation rate with food-related allergic reactions in 2004-2011 was 98% higher than in 1988-1995 (RR=1.98, 95%CI 1.10-3.72). By contrast, ED presentation rates for non-food-related allergic reactions did not change over these years. ED presentations for food-related allergic reactions are identifiable from within ED presentations coded as 'anaphylaxis, unspecified' or 'allergy, unspecified'. ED presentations for food-related allergic reactions have increased over time in Auckland.


Disruption of the adenosine deaminase (ADA) gene using a dicistronic promoterless construct: production of an ADA-deficient homozygote ES cell line.
In man, deficiency of ADA activity is associated with an autosomal recessive form of severe combined immunodeficiency (SCID), a disease with profound defects both cellular and humoral immunity. Current treatments of ADA deficient patients include bone marrow transplantation, enzyme replacement and somatic gene therapy. The mechanism of the selective immune cell pathogenesis in ADA-SCIDS is, however, still poorly understood. Thus, the generation of an ADA deficient mouse model will be of considerable benefit to understand better the pathophysiology of the disorder and to improve the gene therapy treatments. We have disrupted the adenosine deaminase (ADA) gene in embryonic stem cells using a new efficient promoter trap gene-targeting approach. To this end, a dicistronic targeting construct containing a promoterless IRES beta geo cassette was used. This cassette allows, via the internal ribosomal entry site (IRES), the direct cap-independent translation of the beta geo reporter gene which encodes a protein with both beta-galactosidase and neomycin activities. After indentification of targeted clones by Southern blot, successful inactivation of the ADA gene was first confirmed by producing, from our heterozygote clones, an homozygote cell line. This line shows no ADA activity as judged by zymogram analysis. Second, we have been able to detect in the targeted clones, a specific beta galactosidase activity using a sensitive fluorogenic assay. The targeted ES cell clones are currently being injected into blastocysts to create an ADA deficient mouse model.


Detection and treatment of depressive and anxiety disorders among cancer patients: feasibility and preliminary findings from a liaison service in an oncology division.
Our aim in this observational study was to evaluate the feasibility of a multiphasic screening project for the detection and treatment of mood and anxiety disorders among cancer patients in a natural setting. One hundred sixty-five patients with cancer, consecutively admitted to the Oncology Division of San Camillo-Forlanini Hospital, were recruited to the study. All patients had solid tumors; the majority of them were colon, breast, and lung cancers. All patients completed the Hospital Anxiety and Depression Scale (HADS). Patients screened as positive were administered the following instruments by a psychiatrist: the Structured Clinical Interview for DSM-IV (SCID-I), the Beck Depression Inventory (BDI), the Hamilton Anxiety Rating Scale (HARS), and a validated scale for the rapid dimensional assessment of psychopathology (SVARAD). The BDI, HARS, and SVARAD were administered again at 4 and 10 weeks to all treated patients. Out of 45 patients administered the SCID-I, 37 had a mood or anxiety disorder. Adjustment disorders were identified in 20 patients, depressive disorders in 14, and anxiety disorders in three patients. Most patients were prescribed psychotropic medications: mirtazapine was prescribed to 15 patients, citalopram to 13 patients, and escitalopram to four patients. A significant improvement in symptoms of depression and anxiety was observed on all measures (P<.001). Although the design of the study prevents any firm conclusions about effectiveness, this study suggests that including psychiatric expertise in an oncology division is feasible and may lead to improved detection and treatment of psychiatric disorders among cancer patients. Further randomized trials are needed to elaborate on our findings.


Risk factors for consecutive exotropia after vertical rectus transposition for esotropic Duane retraction syndrome.
To define risk factors for postoperative exotropia after vertical rectus transposition (VRT) for Duane syndrome. The records of patients with Duane syndrome who underwent augmented VRT were retrospectively reviewed; those with postoperative exotropia (study group) were compared with those with postoperative esotropia/orthotropia (controls). A total of 51 patients were included, of whom 14 were exotropic postoperatively. Of the 14, 6 became exotropic after augmented VRT, and 8 who were initially esotropic became exotropic after subsequent medial rectus muscle (MR) recession. Study subjects were significantly younger (2 ± 2 years vs 6 ± 10 years, P = 0.04) and demonstrated less restriction on intraoperative forced duction testing than control subjects. Subjects who became exotropic after MR muscle recession had significantly less esotropia at near (5.2(Δ) ± 6.5(Δ) vs 18.4 (Δ) ± 7.9(Δ) esotropia, respectively; P = 0.005) and in adduction (1(Δ) ± 2(Δ) exotropia vs 3(Δ) ± 4(Δ) esotropia, respectively; P = 0.02) than control patients who also underwent VRT and MR muscle recession. Forced duction testing was also significantly different among these groups (P = 0.03). Risk factors for exotropia after augmented VRT include younger age and less restriction on forced duction testing. Additional risk factors for exotropia after VRT and subsequent MR muscle recession include preoperative exotropia in adduction and smaller deviation at near. These factors may be useful in distinguishing patients at risk, allowing for consideration of less powerful procedures.


Dihydroartemisinin Attenuates Pulmonary Hypertension Through Inhibition of Pulmonary Vascular Remodeling in Rats.
Pulmonary arterial hypertension (PAH) is a malignant disease characterized by pulmonary arterial remodeling because of the abnormal proliferation and migration of pulmonary arterial smooth muscle cells. Dihydroartemisinin (DHA), an artemisinin derivative used to treat malaria, is able to inhibit fibrosis, neovascularization, and tumor proliferation. In this study, we hypothesized that DHA can be beneficial in treating PAH. To test this hypothesis, a rat model of pulmonary hypertension induced with monocrotaline (MCT) was used. Compared with MCT treatment alone, treatment with 50 or 100 mg/kg DHA significantly reduced the mean pulmonary arterial pressure (30.11 ± 2.48 mm Hg vs. 21.35 ± 3.04 mm Hg and 19.18 ± 1.98 mm Hg, respectively, both P < 0.01), right ventricular transverse diameter (4.36 ± 0.41 mm vs. 3.72 ± 0.24 mm and 3.67 ± 0.27 mm, respectively, both P < 0.01), pulmonary artery medial wall thickness (57.93 ± 11.14% vs. 34.45 ± 4.39% and 25.01 ± 6.66%, respectively, both P < 0.01), and increased tricuspid annular plane systolic excursion (1.34 ± 0.17 mm vs. 1.62 ± 0.3 mm and 1.62 ± 0.16 mm, respectively, both P < 0.05). We also found that DHA inhibited platelet-derived growth factor-BB-mediated pulmonary arterial smooth muscle cells proliferation and migration in a dose-dependent manner. Moreover, DHA downregulated β-catenin levels while upregulating the levels of axis inhibition protein 2 (Axin2) and glycogen synthase kinase 3β (GSK-3β). Our findings suggest that DHA, which may be a potential candidate for PAH therapy, attenuates experimental pulmonary hypertension possibly by inhibiting pulmonary vascular remodeling.


Juvenile Siberian hamsters display torpor and modified locomotor activity and body temperature rhythms in response to reduced food availability.
Siberian hamsters as young as 16 and 28 d displayed torpor in response to treatment with 2,500 mg/kg 2-deoxy-D-glucose and reduced food availability, respectively. In addition, most food-restricted hamsters displayed increased locomotor activity and elevated body temperatures in the 3 h immediately preceding daily food delivery. This anticipatory activity disappeared within a few days of reimposition of ad lib. feeding. Torpor first appeared spontaneously at approximately 13 wk of age in hamsters fed ad lib. and maintained in short day lengths. The onset of this "spontaneous" torpor was unaffected by the hamsters' history of food restriction before age 2 mo. Siberian hamsters born late in the breeding season can conserve energy by undergoing torpor immediately after weaning when they contend with food shortages and concurrent energetic challenges imposed by growth requirements and low ambient temperatures.


The response to inhaled nitric oxide in patients with pulmonary artery hypertension is not masked by baseline vasodilator use.
Assessment of pulmonary vasodilator responsiveness is important in determining the prognosis and management of patients with pulmonary hypertension. Many patients, however, are already on vasodilators at the time of testing. It is unclear if these agents should be temporarily discontinued to improve the sensitivity of testing. We examined the hemodynamic effects of nitric oxide (NO) inhalation in 60 patients with pulmonary arterial hypertension. Thirty-one of these patients were receiving medications with vasodilating properties. Vasodilator testing was performed with invasive measurement of pressure of the right side of the heart at baseline and during inhalation of 40 ppm NO. No significant demographic differences were seen between patients receiving and not receiving vasodilators. Similar reductions in mean pulmonary artery pressure (19 +/- 12% vs 20 +/- 12%, P = .734) and pulmonary vascular resistance (31 +/- 18 vs 32 +/- 16, P = .967) were seen in patients receiving and not receiving vasodilators. Using the definition of positive vasodilator response (> or = 20% drop in mean pulmonary artery pressure), 55% (17/31) of patients in the baseline vasodilator group had a positive response compared with 62% (18/29) of the patients not on vasodilators (P = .570). Concurrent use of oral vasodilators does not appear to mask a significant response to inhaled NO on the pulmonary vasculature. Therefore, routine discontinuation of pulmonary vasodilators is likely unnecessary before vasodilator testing in patients with pulmonary arterial hypertension.


Chemokine Receptor Signaling and the Hallmarks of Cancer.
The chemokines are a family of chemotactic cytokines that mediate their activity by acting on seven-transmembrane-spanning G protein-coupled receptors. Both the ability of the chemokines and their receptors to form homo- and heterodimers and the promiscuity of the chemokine-chemokine receptor interaction endow this protein family with enormous signaling plasticity and complexity that are not fully understood at present. Chemokines were initially identified as essential regulators of homeostatic and inflammatory trafficking of innate and adaptive leucocytes from lymphoid organs to tissues. Chemokines also mediate the host response to cancer. Nevertheless, chemokine function in this response is not limited to regulating leucocyte infiltration into the tumor microenvironment. It is now known that chemokines and their receptors influence most-if not all-hallmark processes of cancer; they act on both neoplastic and untransformed cells in the tumor microenvironment, including fibroblasts, endothelial cells (blood and lymphatic), bone marrow-derived stem cells, and, obviously, infiltrating leucocytes. This review begins with an overview of chemokine and chemokine receptor structure, to better define how chemokines affect the proliferation, survival, stemness, and metastatic potential of neoplastic cells. We also examine the main mechanisms by which chemokines regulate tumor angiogenesis and immune cell infiltration, emphasizing the pro- and antitumorigenic activity of this protein superfamily in these interrelated processes.


Serum sex hormone levels and renin-sodium profile in men with hypertension.
Both a high renin-sodium profile and abnormal levels of sex hormones have been linked to myocardial infarction (MI) in men. The present study was carried out in men with hypertension to determine whether renin-sodium profile and sex hormone levels are related to each other. Renin-sodium profile, estradiol, testosterone, sex-hormone binding globulin (SHBG), and risk factors for MI, ie, cholesterol, insulin, glucose, and blood pressure, were determined in 45 men with hypertension. The mean serum estradiol level of the 13 men with high renin profile (30.1 +/- 6.5 pg/mL) was significantly higher (P = .01) than that of the nine men with low renin profile (22.6 +/- 3.9), while the mean level of the 23 men with normal renin profile was intermediate (26.2 +/- 5.3). The levels of estradiol and plasma renin activity correlated in the 45 patients before (r = 0.48, P = .001) and after (r = 0.46, P = .002) controlling for age. The mean estradiol-to-testosterone ratio was also higher (P = .04) and the mean SHBG level lower (P < .02) in the high renin group, but the mean testosterone level was not significantly different between the high and low renin groups. Although none of the risk factors was significantly different between the high and low renin groups, all of the mean values in the high renin group were in the direction of increased MI risk. These findings suggest that in men with hypertension, renin profile may be related to estradiol level and possibly to risk factors for MI.


A review of the application of mesenchymal stem cells in the field of hematopoietic stem cell transplantation.
Hematopoietic stem cell transplantation (HSCT) is an effective treatment for many malignant hematological diseases. Mesenchymal stem cells (MSCs) are nonhematopoietic stem cells with strong self-renewal ability and multidirectional differentiation potential. They have the characteristics of hematopoietic support, immune regulation, tissue repair and regeneration, and homing. Recent studies have shown that HSCT combined with MSC infusion can promote the implantation of hematopoietic stem cells and enhance the reconstruction of hematopoietic function. Researchers have also found that MSCs have good preventive and therapeutic effects on acute and chronic graft-versus-host disease (GVHD), but there is still a lack of validation in large-sample randomized controlled trials. When using MSCs clinically, it is necessary to consider their dose, source, application time, application frequency and other relevant factors, but the specific impact of the above factors on the efficacy of MSCs still needs further clinical trial research. This review introduces the clinical roles of MSCs and summarizes the most recent progress concerning the use of MSCs in the field of HSCT, providing references for the later application of the combination of MSCs and HSCT in hematological diseases.


Toxic and essential elements in Nigerian rice and estimation of dietary intake through rice consumption.
In this study, levels and estimated daily intake (EDI) of two toxic elements, Cd and Pb, and eight essential elements: Ca, P, Zn, Mn, Co, Cu, Se and Mo, were determined in Nigerian rice samples. The mean levels of Cd, Pb and Co were 5.43±0.88, 38.66±5.42, 25.8±3.18 ng/g. The mean levels of Ca, P, Zn, Mn, Cu, Se and Mo were 71.5±7.31, 951±52.0, 10.2±0.63, 8.5±0.47, 3.07±0.18, 40.1±9.2 and 0.39±0.05 µg/g, respectively. The percentage contribution to the reference values for each element was 0.54, 7.71, 0.38, 9.51, 8.97, 31.3, 30.7, 5.1 and 60.7% for Cd, Pb, Ca, P, Zn, Mn, Cu, Se and Mo, respectively. The elemental nutrient levels in Nigerian rice samples are comparable to those obtained from other regions and their consumption does not pose any serious health risk to consumers.


Evolution of treatment of fistula in ano.
Fistula-in-ano is a common medical problem affecting thousands of patients annually. In the past, the options for treatment of fistula-in-ano were limited to fistulotomy and/or seton placement. Current treatment options also include muscle-sparing techniques such as a dermal island flap, endorectal advancement flap, fibrin sealent injection, anal fistula plug, and most recently ligation of the intersphincteric fistula tract (procedure). This study seeks to evaluate types and time trends for treatment of fistula-in-ano. A retrospective review from 1975 to 2009 was performed. Data were collected and sorted into 5-year increments for type and time trends of treatment. Fistulotomy and partial fistulotomy were grouped as cutting procedures. Seton placement, fibrin sealant, dermal flap, endorectal flap, and fistula plug were grouped as noncutting procedures. Statistical analysis was performed for each time period to determine trends. With institutional review board approval, the records of 2,267 fistula operations available for analysis were included. Most of the patients were men (74 vs. 26%). Cutting procedures comprised 66.6% (n = 1510) of all procedures. Noncutting procedures were utilized in 33.4% (n = 757), including Seton placement alone 370 (16.3%), fibrin sealant 168 (7.4%), dermal or endorectal flap 147 (6.5%), and fistula plug 72 (3.2%). The distribution of operations grouped in 5-year intervals is as follows: 1975-1979, 78 cutting and one noncutting; 1980-1984, 170 cutting and 10 noncutting; 1985-1989, 54 cutting and five noncutting; 1990-1994, 37 cutting and six noncutting; 1995-1999, 367 cutting and 167 noncutting; 2000-2004, 514 cutting and 283 noncutting; 2005-2009, 290 cutting and 285 noncutting. The percentage of cutting and noncutting procedures significantly differed over time, with cutting procedures decreasing and noncutting procedures increasing proportionally (χ(2) linear-by-linear association, p < 0.05). Fistula-in-ano remains a common complex disease process. Its treatment has evolved to include a variety of noncutting techniques in addition to traditional fistulotomy. With the advent of more sphincter-sparing techniques, the number of patients undergoing fistulotomy should continue to decrease over time. Surgeons should become familiar with various surgical techniques so the treatment can be tailored to the patient.


Soluble Megalin is Reduced in Cerebrospinal Fluid Samples of Alzheimer's Disease Patients.
Megalin or low-density lipoprotein receptor-related protein-2 is a member of the low-density lipoprotein receptor family, which has been linked to Alzheimer's disease (AD) by clearing brain amyloid β-peptide (Aβ) across the blood-cerebrospinal fluid barrier at the choroid plexus. Here, we found a soluble form of megalin secreted from choroid plexus epithelial cells. Soluble megalin levels were also localized in the human cerebrospinal fluid (CSF), being reduced in AD patients. We have also shown that soluble megalin binding to Aβ is decreased in the CSF of AD patients, suggesting that decreased sequestration of Aβ in the CSF could be associated with defective clearance of Aβ and an increase of brain Aβ levels. Thus, therapies, which increase megalin expression, at the choroid plexus and/or enhance circulating soluble megalin hold potential to control brain Aβ-related pathologies in AD.


Chemotherapeutic approaches to nematodes: current knowledge and outlook.
The situation in the chemotherapy of nematode infections. in both human and veterinary medicine, is currently satisfactory. There are different drugs available: the benzimidazoles, levamisole, pyrantel, and the different macrocyclic lactones (Tables 1. 2, 3, 4). In human medicine, mebendazole and albendazole are mainly used against the intestinal nematodes. while ivermectin and diethylcarbamazine are microfilaricidal drugs used in prophylaxis against onchocercosis and filarial infections. The situation in veterinary medicine is, however, governed by the great resistance problem in some animal hosts against all important anthelmintics. There are various reports of resistance against benzimidazoles, levamisole, pyrantel, and macrocyclic lactones in trichostrongylides in small ruminants (sheep, goats) and also Strongylides in horses. Resistance against ivermectin is now arising in cattle (Coles 2001; Sangster 2001). There are no reports of resistance problems in dogs and cats. Thus, there is always an urgent need in veterinary medicine for new anthelmintics with a new mode of action, which can easily break resistance against the existing anthelmintics. The situation in the chemotherapy of filarial infections in human medicine is not satisfactory. There is an urgent need for a new macrofilaricidal drug with only slight side-effects. Today, the only way is the prophylactic control of Onchocerca vovulus infections and treating lymphatic filariosis with ivermectin, diethylcarbamacine, ivermectin/diethylcarbamazine. or ivermectin/albendazole combinations.


Spectrophotometry of amniotic fluid: a simple and rapid method for distinguishing between gestational sacs in second-trimester amniocentesis of twin pregnancies.
To evaluate the use of an alternative and simple spectrophotometric method that could replace the intraamniotic injection of dye in the second-trimester amniocentesis of twins. Optical densities (OD) of amniotic fluid (AF) obtained at second-trimester genetic amniocentesis were measured at 360 nm. Comparison was made between 36 twin pregnancies and 60 singleton controls. The mean difference in OD between two samples taken from the same sac of singleton pregnancies was very small (mean 0.004, standard deviation [SD] 0.003). However, samples drawn from each of the twin pairs' amniotic sacs varied widely (raw mean 0.176, SD 0.223; median 0.096, range 0.011-0.943). The difference between the groups was highly significant statistically (P < .001). Our preliminary experience with spectrophotometry of AF in twin amniocentesis suggests that this simple test may be useful in ascertaining that the AF samples were obtained from each of the two gestational sacs.


Postnatal treatment with NAN-190 but not with 5-HT1A receptor agonists retards growth of the rat brain.
We investigated the influence of prolonged administration of the 5-HT1A receptor agonists (8-OH-DPAT or buspirone) or its antagonist, NAN-190 to rat pups on development of their cortical barrel field. Pups were injected daily with the drugs starting from the day of birth till either the 5th postnatal day or the 22-25th postnatal day and were perfused one day later. Square areas of their whisker barrel fields were measured on tangential sections of the cortex stained for cytochrome oxidase. Injections of 8-OH-DPAT or buspirone till the 5th postnatal day did not change any of the investigated parameters, while injections of NAN-190 resulted in 15% reduction of the pups' body and brain weight and proportional reduction of the square area of their barrel fields. Groups treated till the 22-25th postnatal day showed similar results. Some of these pups were injected with [C(14)]2-deoxyglucose to investigate the strength of responses of their cortical barrels to stimulation of corresponding vibrissae. The cortical area labeled with 2-deoxyglucose after stimulation of vibrissae of the row C was narrower in the NAN-190 injected rats. This functional deficit was more pronounced than the anatomical one, which resembled the effects of neonatal serotonin depletion (Neuroreport, 1997). Therefore, the results of injecting NAN-190 to the rat pups point to a deficit of trophic developmental influences of serotonin, adding new arguments for the hypothesis of a trophic role of 5-HT1A receptors in the brain development.


Maternal migration and child health: An analysis of disruption and adaptation processes in Benin.
Children of migrant mothers have lower vaccination rates compared to their peers with non-migrant mothers in low-income countries. Explanations for this finding are typically grounded in the disruption and adaptation perspectives of migration. Researchers argue that migration is a disruptive process that interferes with women's economic well-being and social networks, and ultimately their health-seeking behaviors. With time, however, migrant women adapt to their new settings, and their health behaviors improve. Despite prominence in the literature, no research tests the salience of these perspectives to the relationship between maternal migration and child vaccination. We innovatively leverage Demographic and Health Survey data to test the extent to which disruption and adaptation processes underlie the relationship between maternal migration and child vaccination in the context of Benin-a West African country where migration is common and child vaccination rates have declined in recent years. By disaggregating children of migrants according to whether they were born before or after their mother's migration, we confirm that migration does not lower children's vaccination rates in Benin. In fact, children born after migration enjoy a higher likelihood of vaccination, whereas their peers born in the community from which their mother eventually migrates are less likely to be vaccinated. Although we find no support for the disruption perspective of migration, we do find evidence of adaptation: children born after migration have an increased likelihood of vaccination the longer their mother resides in the destination community prior to their birth.


Irradiation as adjunctive treatment of diffuse pigmented villonodular synovitis of the foot and ankle prior to tumor surgical excision.
In this manuscript, the author undertakes a brief description of the diffuse form of pigmented villonodular synovitis and provides a recommendation of pre-surgical tumor irradiation as adjunctive treatment for reduction of recurrence and better preservation of function of the lower extremity.


Novel protein contact points among TP53 and minichromosome maintenance complex proteins 2, 3, and 5.
Identify protein contact points between TP53 and minichromosome maintenance (MCM) complex proteins 2, 3, and 5 with high resolution allowing for potential novel Cancer drug design. A next-generation sequencing-based protein-protein interaction method developed in our laboratory called AVA-Seq was applied to a gold-standard human protein interaction set. Proteins including TP53, MCM2, MCM3, MCM5, HSP90AA1, PCNA, NOD1, and others were sheared and ligated into the AVA-Seq system. Protein-protein interactions were then identified in both mild and stringent selective conditions. Known interactions among MCM2, MCM3, and MCM5 were identified with the AVA-Seq system. The interacting regions detected between these three proteins overlap with the structural data of the MCM complex, and novel domains were identified with high resolution determined by multiple overlapping fragments. Fragments of wild type TP53 were shown to interact with MCM2, MCM3, and MCM5, and details on the location of the interactions were provided. Finally, a mini-network of known and novel cancer protein interactions was provided, which could have implications for fundamental changes in multiple cancers. We provide a high-resolution mini-interactome that could direct novel drug targets and implicate possible effects of specific cancer mutations.


Effects of diabetes, vanadium, and insulin on glycogen synthase activation in Wistar rats.
In vivo effects of insulin and vanadium treatment on glycogen synthase (GS), glycogen synthase kinase-3 (GSK-3) and protein phosphatase-1 (PP1) activity were determined in Wistar rats with streptozotocin (STZ)-induced diabetes. The skeletal muscle was freeze-clamped before or following an insulin injection (5 U/kg i.v.). Diabetes, vanadium, and insulin in vivo treatment did not affect muscle GSK-3beta activity as compared to controls. Following insulin stimulation in 4-week STZ-diabetic rats muscle GS fractional activity (GSFA) was increased 3 fold (p < 0.05), while in 7-week diabetic rats it remained unchanged, suggesting development of insulin resistance in longer term diabetes. Muscle PP1 activity was increased in diabetic rats and returned to normal after vanadium treatment, while muscle GSFA remained unchanged. Therefore, it is possible that PP1 is involved in the regulation of some other cellular events of vanadium (other than regulation of glycogen synthesis). The lack of effect of vanadium treatment in stimulating glycogen synthesis in skeletal muscle suggests the involvement of other metabolic pathways in the observed glucoregulatory effect of vanadium.


Household clustering supports a novel chemoprophylaxis trial design for a mosquito-borne viral disease.
Infections because of chikungunya and other mosquito-borne viruses, such as dengue and Zika, represent an area of significant unmet medical need. There are currently no approved medicines for prophylaxis or treatment of these diseases, and the development and implementation of vaccines against these viruses have proved problematic. Although antiviral molecules with treatment and prophylactic potential against the chikungunya virus have been identified, no successful field trials have been reported. Chemoprophylaxis may be attractive for unvaccinated at-risk populations; however, performing a successful chemoprophylaxis trial during a chikungunya outbreak will require a clearly identifiable at-risk population. We propose the application of a household transmission model as used in testing drugs against respiratory viruses. Current evidence on household clustering of chikungunya and other Aedes mosquito-borne viral infections is supportive. We suggest that this model may improve prophylaxis trial feasibility and focus research and future treatment on a population likely to benefit.


Physician breastfeeding education leads to practice changes and improved clinical outcomes.
Lack of physician knowledge about breastfeeding is associated with decreased initiation and continuation of breastfeeding by patients. We evaluated the effects of a breastfeeding education program on physicians' breastfeeding knowledge, attitudes, and beliefs, measured changes in clinical practice, and examined breastfeeding rates of patients of participating physicians. Six breastfeeding sessions addressed breastfeeding problem-solving and counseling and specific clinical issues including mastitis, perceived insufficient milk, poor infant weight gain, and return to work. We measured physicians' breastfeeding knowledge, attitudes, and beliefs before and after curriculum implementation and also measured changes in practice. We analyzed breastfeeding rates of patients in the practice before, during, and after the intervention. We studied 24 residents and 15 faculty members at the intervention site; there were 12 residents and nine faculty in a similar control program. Attendance at education sessions improved breastfeeding knowledge (p<0.01) and attitudes/beliefs (p=0.03). Participants identified 15 unique practice changes with a strong commitment to make these changes (4.7 on a 5-point scale) and fulfillment of practice change of 3.6. Participation in education sessions improved patients' rates of any breastfeeding at 4 and 6 months and of full breastfeeding at 4 months. A breastfeeding education program at a semirural residency program improved physicians' breastfeeding knowledge. Implementation of practice changes was fair. Two years into the intervention, breastfeeding rates improved for patients of the physicians with high levels of participation in the program.


Explanations for 10 of the most puzzling aspects of multisystem inflammatory syndrome and other Kawasaki-like diseases.
An extensively documented multisystem inflammatory syndrome (MIS) has been observed in a small but significant percentage of COVID-19 patients, in some adults but primarily in paediatric patients, and for these patients it is sometimes called MIS-C. Kawasaki disease has also been observed over the last several decades in patients that tested positive for a variety of very virulent pathogens. Several differences and similarities between MIS-C and Kawasaki disease pathology have been observed. Several puzzling aspects of MIS-C, Kawasaki disease and other Kawasaki-like diseases have been discussed, but not yet explained. An explanatory hypothesis has been presented. Using the hypothesis that a transient or permanent inability to quickly phagocytize antigen-antibody immune complexes created by a novel virulent pathogen infection induces a Type III hypersensitivity immune response and the resulting proteinase exposure and expression of new autoantigens are the fundamental steps for MIS and other Kawasaki-like diseases, it is possible to provide straightforward explanations for at least 10 of the most puzzling aspects of these diseases. The validity of the hypothesis itself is also supported by its ability to provide consistent and straightforward explanations for a large number of these disease aspects. Furthermore, these straightforward explanations and the explanatory hypothesis on which they are based also suggest several potential new treatments, which could possibly be more effective than various treatments in current use.


IL-6-induced acetylation of E2F1 aggravates oxidative damage of retinal pigment epithelial cell line.
Oxidative damage in retinal pigment epithelial cells (RPE) is considered to be a crucial pathogenesis of age-related macular degeneration (AMD). Although dysregulation of the DNA repair system has been found in RPE cells of AMD patients, the detailed molecular mechanisms of this dysregulation and their relationship with the intraocular microenvironment of AMD patients remain unclear. Here, we established an RPE model of H2O2-induced oxidative stress and found that Sirtuin 1 (Sirt1)-mediated deacetylation of E2F transcription factor 1 (E2F1) was required for oxidation resistance in RPE cells. Moreover, E2F1 induced the expression of the chromatin-binding protein, high mobility group AT-Hook 1 (HMGA1), which promoted the transcription of glucose 6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway, to increase NADPH level for antioxidant defense. Interrupting the E2F1/HMGA1/G6PD regulatory axis increased reactive oxygen species (ROS) levels, DNA damage, and apoptosis in RPE cells under oxidative stress. Notably, interleukin 6 (IL-6), an inflammatory cytokine that is known to be upregulated in the intraocular fluid of AMD patients, induced phosphorylation (S47) of Sirt1 by activating PI3K/AKT/mTOR signaling, thereby inhibiting Sirt1 activity and increasing the acetylation of E2F1. Specific inhibitors of PI3K/AKT/mTOR signaling decreased DNA damage and ROS while increasing NADPH in RPE cells. Collectively, our findings demonstrate that IL-6-induced acetylation of E2F1 impairs the antioxidant capacity of RPE cells by disturbing the pentose phosphate pathway, which elucidates a relationship between the intraocular microenvironment and RPE oxidative damage in AMD and provides a possible therapeutic target for AMD.


Patient symptoms and experience following COVID-19: results from a UK-wide survey.
To investigate the experience of people who continue to be unwell after acute COVID-19, often referred to as 'long COVID', both in terms of their symptoms and their interactions with healthcare. We conducted a mixed-methods analysis of responses to a survey accessed through a UK online post-COVID-19 support and information hub, between April and December 2020, about people's experiences after having acute COVID-19. 3290 respondents, 78% female, 92.1% white ethnicity and median age range 45-54 years; 12.7% had been hospitalised. 494(16.5%) completed the survey between 4 and 8 weeks of the onset of their symptoms, 641(21.4%) between 8 and 12 weeks and 1865 (62.1%) >12 weeks after. The ongoing symptoms most frequently reported were: breathing problems (92.1%), fatigue (83.3%), muscle weakness or joint stiffness (50.6%), sleep disturbances (46.2%), problems with mental abilities (45.9%), changes in mood, including anxiety and depression (43.1%) and cough (42.3%). Symptoms did not appear to be related to the severity of the acute illness or to the presence of pre-existing medical conditions. Analysis of free-text responses revealed three main themes: (1) experience of living with COVID-19: physical and psychological symptoms that fluctuate unpredictably; (2) interactions with healthcare that were unsatisfactory; (3) implications for the future: their own condition, society and the healthcare system, and the need for research CONCLUSION: Consideration of patient perspectives and experiences will assist in the planning of services to address problems persisting in people who remain symptomatic after the acute phase of COVID-19.


Non-A, non-B hepatitis in hemophilic patients with inhibitor treated with activated prothrombin complex concentrates: lack of correlation with an antigen possibly related to non-A, non-B hepatitis.
A population of 30 severe hemophilia-A patients with antibodies to factor VIII, treated with Autoplex since 1980, experienced a 30% incidence of non-A, non-B (NANB) hepatitis. 8 of the 9 patients affected had clinical signs of hepatitis and 7 had ALT levels in excess of 200 IU/l; the mean incubation time was 13 days. Only 5 of the 26 lots of Autoplex used were possibly transmitting the infective agent. An ELISA test to detect an antigen (DS-Ag) possibly related to NANB hepatitis was used to screen hemophilia-A and B patients. Its incidence was lower in patients treated less than 5 times a year (7.9%) than in patients treated over 15 times a year (25-27%) with locally prepared blood derivatives. Following treatment with Autoplex, the incidence of DS-Ag in inhibitor patients increased significantly (50%). In this last population, DS-Ag was shown to be unrelated to the NANB hepatitis observed. Although no direct evidence could be given, Autoplex was likely to transmit both the agent responsible for short incubation NANB hepatitis and DS-Ag.


The stability of a predator-prey system with linear mass-action functional response perturbed by white noise.
The present paper deals with the problem of an ecoepidemiological model with linear mass-action functional response perturbed by white noise. The essential mathematical features are analyzed with the help of the stochastic stability, its long time behavior around the equilibrium of deterministic ecoepidemiological model, and the stochastic asymptotic stability by Lyapunov analysis methods. Numerical simulations for a hypothetical set of parameter values are presented to illustrate the analytical findings.


Pelvic floor disorders 4 years after first delivery: a comparative study of restrictive versus systematic episiotomy.
To compare two policies for episiotomy: restrictive and systematic. Quasi-randomised comparative study. Two French university hospitals with contrasting policies for episiotomy: one using episiotomy restrictively and the second routinely. Seven hundred and seventy-four nulliparous women delivered during 1996 of a singleton in cephalic presentation at a term of 37-41 weeks. A questionnaire was mailed 4 years after delivery. Sample size was calculated to allow us to show a 10% difference in the prevalence of urinary incontinence with 80% power. Urinary incontinence, anal incontinence, perineal pain, and pain during intercourse. We received 627 responses (81%), 320 from women delivered under the restrictive policy, 307 from women delivered under the routine policy. In the restrictive group, 186 (49%) deliveries included mediolateral episiotomies and in the routine group, 348 (88%). Four years after the first delivery, there was no difference in the prevalence of urinary incontinence (26 versus 32%), perineal pain (6 versus 8%), or pain during intercourse (18 versus 21%) between the two groups. Anal incontinence was less prevalent in the restrictive group (11 versus 16%). The difference was significant for flatus (8 versus 13%) but not for faecal incontinence (3% for both groups). Logistic regression confirmed that a policy of routine episiotomy was associated with a risk of anal incontinence nearly twice as high as the risk associated with a restrictive policy (OR = 1.84, 95% CI: 1.05-3.22). A policy of routine episiotomy does not protect against urinary or anal incontinence 4 years after first delivery.


Screening of new bioactive metabolites for diabetes therapy.
Microorganisms and plants produce bioactive metabolites that are potentially useful in the treatment of disease. We have designed and synthesized DHMEQ as a specific inhibitor of NF-κB based on the structure of epoxyquinomicin. It directly binds to NF-κB components to inhibit DNA-binding and was shown to be endowed with inhibiting activity in various inflammatory and cancer models in experimental animals. It was also effective to improve the success of islet transplantation especially when administered to donor mice. We have also isolated from the leaves of Ervatamia microphylla conophylline, a compound that induces differentiation of beta cells from the precursor cells and was recently found to suppress islet fibrosis in diabetes model rats.


Safety and Efficacy of Poly-L-Lactic Acid Filler (Gana V vs. Sculptra) Injection for Correction of the Nasolabial Fold: A Double-Blind, Non-Inferiority, Randomized, Split-Face Controlled Trial.
Poly-L-lactic acid (PLLA) fillers have shown excellent results as soft tissue fillers for progressive midface volume enhancement, with long-lasting results and high patient satisfaction. Herein, we investigated the safety and effectiveness of a new PLLA filler (Gana V) in comparison with those of the widely used Sculptra. This double-blind, non-inferiority, randomized, split-face controlled trial was performed in France to evaluate the safety and effectiveness of injectable Gana V compared with those of Sculptra for correction of nasolabial fold (NLF) depression. The primary outcome was improvement in NLFs, as determined using the Wrinkle Severity Rating Scale (WSRS). This trial is an interim report of the results at 6 months. The trial was registered at ClinicalTrials. gov, number NCT05215054. Fifty-five participants with moderate-to-severe NLFs (mean age 53.8 [standard deviation 8.7] years; 48 [87.3%]) female) were enrolled. After 6 months, Gana V showed improved WSRS score (mean difference - 0.25; 95% confidence interval [CI] - 0.49 to - 0.01) in intention-to-treat analysis, while Sculptra did not (mean difference - 0.20; 95% CI - 0.42 to 0.03). Furthermore, Gana V showed an acceptable 6-month effectiveness compared with Sculptra, within our defined non-inferiority margin (pnon-inferiority = 0.1787). The immediate results by the investigator after the initial injection showed higher satisfaction in the Gana V than in the Sculptra group. Gana V and Sculptra showed no difference in adverse reactions. Similar patterns were observed in per-protocol analyses. Gana V is non-inferior to Sculptra with respect to the correction of NLFs and has higher investigator satisfaction. Further research is required to ensure long-term safety. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Superantigen-induced CD4 memory T cell anergy. I. Staphylococcal enterotoxin B induces Fyn-mediated negative signaling.
Memory CD4 T cells must provide robust protection for an organism while still maintaining self-tolerance. Superantigens reveal a memory cell-specific regulatory pathway, by which signaling through the TCR can lead to clonal tolerance (anergy). Here we show that the src kinase Fyn is a critical regulator of anergy in murine memory CD4 T cells induced by the bacterial superantigen staphylococcal enterotoxin B (SEB). Exposure to SEB results in impaired TCR signaling due to failed CD3/ZAP-70 complex formation. Further, signal transduction through the TCR remains similarly blocked when anergic memory cells are subsequently exposed to agonist peptide antigen. Pharmacological inhibition or genetic elimination of Fyn kinase reverses memory cell anergy, resulting in SEB-induced cell proliferation. The mechanism underlying impaired TCR signaling and subsequent memory cell anergy must involve a Fyn signaling pathway given that the suppression of Fyn activity restores CD3/ZAP-70 complex formation and TCR proximal signaling.


[Varicella zoster virus infections in pregnancy].
Varicella in pregnancy are a rare event, but they may result in severe disease of child. During the first and second trimenon they may cause congenital defects, so-called congenital varicella syndrome. Primary infections with the varicella-zoster virus are also a risk shortly before or during delivery because of intrauterine transmission of the virus with subsequent connatal varicella. On the basis of own clinic-virological investigations there is reported on 27 women and their newborns affected with varicella during pregnancy. Measures for diagnosis, prophylaxis and therapy in the case of congenital varicella syndrome as well as connatal varicella are discussed.


Maternal leucocyte zinc deficiency at start of third trimester as a predictor of fetal growth retardation.
Leucocyte zinc concentrations were measured in 70 mothers at the beginning of the third trimester of pregnancy and compared with the weight centiles of their subsequently delivered babies. The median maternal leucocyte zinc concentrations rose progressively with weight centile. Thus the median leucocyte zinc concentration of the mothers delivering babies weighing below the 10th centile was 112 nmol/10(9) leucocytes and that of the mothers with babies weighing above the 90th centile was 229.5 nmol/10(9) leucocytes. A maternal leucocyte zinc concentration less than 120 nmol/10(9) leucocytes strongly predicted a baby weighing below the 10th centile (positive predictive value = 71.9%, negative predictive value = 91.5%, sensitivity = 64.3%, specificity = 81.8%). These findings suggest that maternal zinc concentration might have a role in antenatal screening, but larger studies are required.


Management of lower gastrointestinal tract bleeding.
Acute bleeding from the colon and rectum is less frequent and less dramatic than haemorrhage from the upper gastrointestinal tract. In most cases, bleeding from the colon and rectum is self-limiting and requires no specific therapy. Diverticula and angiectasias are the most frequent sources of bleeding. Malignancy, colitis (inflammatory bowel disease, non-steroidal anti-inflammatory drugs, and infectious colitis), ischaemia, anorectal disorders, postpolypectomy bleeding, and HIV-related problems are less frequent causes. The recurrence rate, especially in diverticular bleeding, is high. Resuscitation and haemodynamic stabilisation of the patient is the first step in the management of colonic bleeding. Urgent colonoscopy is the method of choice for diagnosis and therapy. By analogy with peptic ulcer bleeding, risk stratification using stigmata of haemorrhage is gaining more importance. Modern endoscopic techniques such as injection therapy, thermocoagulation and mechanical devices seem to be effective in achieving haemostasis and avoiding precarious surgery. Angiography and nuclear scintigraphy are reserved for those patients in whom colonoscopy is not possible or has repeatedly failed to localise the bleeding site.


Sulfadiazine plasma concentrations in women with pregnancy-acquired compared to ocular toxoplasmosis under pyrimethamine and sulfadiazine therapy: a case-control study.
Dosing recommendations for the treatment of pregnancy-acquired toxoplasmosis are empirical and widely based on experimental data. There are no pharmacological data on pregnant women with acute Toxoplasma gondii infection under treatment with pyrimethamine (PY) and sulfadiazine (SA) and our study intends to tighten this gap. In this retrospective case-control study, we included 89 pregnant women with primary Toxoplasma infection (PT) treated with PY (50 mg first dose, then 25 mg/day), SA (50 mg/kg of body weight/day), and folinic acid (10-15 mg per week). These were compared to a group of 17 women with acute ocular toxoplasmosis (OT) treated with an initial PY dose of 75 mg, thereafter 25 mg twice a day but on the same SA and folinic acid regimen. The exact interval between drug intake and blood sampling and co-medication had not been recorded. Plasma levels of PY and SA were determined 14 ± 4 days after treatment initiation using liquid chromatography-mass spectrometry and compared using the Mann-Whitney U test at a p < 0.05 level. In 23 PT patients (26%), SA levels were below 20 mg/l. Fifteen of these 23 patients (17% of all patients) in parallel presented with PY levels below 700 µg/l. Both drug concentrations differed remarkably between individuals and groups (PY: PT median 810 µg/l, 95% CI for the median [745; 917] vs. OT 1230 µg/l [780; 1890], p = 0.006; SA: PT 46.2 mg/l [39.9; 54.4] vs. OT 70.4 mg/l [52.4; 89], p = 0.015) despite an identical SA dosing scheme. SA plasma concentrations were found in the median 34% lower in pregnant women with PT compared to OT patients and fell below a lower reference value of 50 mg/l in a substantial portion of PT patients. The interindividual variability of plasma concentrations in combination with systematically lower drug levels and possibly a lower compliance in pregnant women may thus account for a still not yet supportable transmission risk. Systematic drug-level testing in PT under PY/SA treatment deserves to be considered.


The specificity of antibodies induced by infection with rhinovirus type 2.
Mouse monoclonal antibodies (MAbs) against three distinct antigenic sites on rhinovirus type 2 have been obtained and the sites identified. We describe how these MAbs were used in a blocking test to detect antibodies in human sera directed against the same three defined sites. Sera from twelve volunteers were studied. All had been exposed to rhinovirus type 2 by intranasal inoculation, four had been uninfected, eight were infected of whom four developed a cold while four did not. Blocking antibodies were high and did not increase in the resistant volunteers, and were lower and increased in the infected volunteers. The antibodies were almost as sensitive as other antibody assays for detecting infection. The responses to all three sites were similar. Correlations between the results of all tests were calculated and the results are summarised. Tests were also devised to measure the Ig subclass of antibodies against the whole virus particle. The A1, G1, and G4 classes showed most frequent rises in response to infection. Correlations between these results and other antibody assays were found and are presented.


Relationship between early maladaptive schemas and symptom dimensions in patients with obsessive-compulsive disorder.
The aims of this study were to evaluate early maladaptive schemas (EMSs) of patients with obsessive-compulsive disorder (OCD) and to clarify relationships between particular EMSs and the five factor-analyzed symptom dimensions and other clinical variables. Fifty-seven patients with OCD and 70 normal controls completed the Young Schema Questionnaire, the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the Y-BOCS symptom checklist, and the Beck Depression Inventory. Patients with OCD had significantly higher scores for schema related to defectiveness/shame, social isolation/alienation, and failure than did normal controls. Among the five OCD symptom dimensions, the sexual/religious dimension was only significantly correlated with two schemas of vulnerability to harm or illness and enmeshment/undeveloped self. These two schemas were significant predictors of the sexual/religious dimension, accounting for 33% of the total variance in this dimension. Any EMSs in patients with OCD were not related to clinical variables such as severity of OCD and duration of illness. These findings may constitute evidence to improve our understandings of OCD from a perspective of schema theory.


Overview of Community Collaborative Partnerships and Empirical Findings: The Foundation for Youth HIV Prevention.
This article presents a summary history and context of the CHAMP Family Program. Primarily, CHAMP was created and developed in response to rising levels of HIV and AIDS in inner-city communities of color. Concurrently, major changes in the field of psychology were underway during the late 1980s and early 1990s including new perceptions of the effect of culture and context on development; the birth of development psychopathology as a field; and increasing interest in-and recognition of-adolescent psychology. It is within the context of these transformations that this article places the design and implementation of CHAMP. The evolution of the CHAMP Family Program a relatively small, cyclical study in Chicago, to a major, multi-site project is discussed, with particular emphasis on the role of community collaboration in the transitions that CHAMP has experienced thus far.


Review of the Different Treatments and Management for Prostate Cancer and Fertility.
To compare the options available for prostate cancer management and their consequences on fertility for men, in order to best advise these men to choose their treatment, especially if they are young, with no child with their current partner. A literature review on prostate cancer and fertility over the last 26 years was carried out on PubMed database. The literature was based on evidence and practical considerations. Twenty-nine articles were selected according to their relevance. After prostatectomy, there is an obstructive infertility in 100% of the cases. In external radiotherapy, doses more than 15 cGy induced reduction in sperm count. Direct irradiation between 15 and 35 cGy caused oligozoospermia and doses between 35 and 50 cGy caused reversible azoospermia. The calculated projected doses on testicles were 196 cGy (± 145 cGy). The brachytherapy effects on fertility seems to be less harmful. The irradiation dose received by testicles is less important (less than 20 cGy) after brachytherapy than after external radiotherapy. Infertility induced by hormonal therapy alone should be reversible. Fertility and focal therapy have not been well evaluated yet. Active surveillance is the management of prostate cancer which allows to keep at best men's fertility. Urologists should consider approaching the topic of infertility when discussing the pros and cons of various prostate cancer management with their younger patients. If a patient with prostate cancer expresses interest in future fertility, a semen analysis should be performed. Cryopreservation represents the only preemptive accompanying possibility to preserve fertility in young cancer patients.


Percutaneous transhepatic biliary decompression. Results and complications in 30 patients.
The palliative management of malignant obstruction of the biliary tree continues to challenge clinicians. The technique of PTBD has become increasingly popular to decompress the obstructed biliary system. Our initial experience with 30 consecutive patients treated with PTBD has been retrospectively reviewed. Internal drainage and effective biliary decompression was achieved in 90 and 86 percent of patients, respectively. Complications developed in 7 of 11 patients with long-term PTBD. Two patients died from septic complications. Three of 10 patients had major complications associated with preoperative PTBD. The remaining seven patients had permanent PTBD but did not derive any clinical improvement. Postoperative mortality after palliative procedures for malignant biliary obstruction is most often associated with carcinomatosis and advanced disease. Palliative biliary bypass provides effective palliation until the patient's death. There are groups of patients with an expected survival of more than 3 months and technically bypassable biliary obstruction who are best palliated by biliary enteric anastomosis. Patients with advanced disease are not candidates for either form of treatment. In patients with lesions not suitable for surgical bypass, PTBD remains a useful alternative.


The control by atmospheric factors and water stress of midday stomatal closure in Arbutus unedo growing in a natural macchia.
Midday closure of stomata of well-watered (ψ between-10 and-25 bar) or moderately stressed (ψ between-25 and-35 bar) Arbutus unedo plants occurs when midday leaf temperatures increase above 30°C and vapor pressure difference between leaf air spaces and the external air increases above approximately 30 mbar/bar. Moderate water stress decreases maximum conductance and may result in greater sensitivity to high leaf temperature and vapor pressure dificit, which results in earlier closure and later reopening of stomata. Severe water stress (ψ of-50 bar) changes the form of the daily pattern observed for leaf conductance. A single morning peak in conductance occurs followed by decrease in conductance over the remainder of the day. Morning fog in Portugal during the dry season may facilitate stomatal opening and may allow improvement of carbon balances of the leaves for short periods, but contributes little to improvement of plant water balances over the longer term.


Acoustic microbubble propulsion, train-like assembly and cargo transport.
Achieving controlled mobility of microparticles in viscous fluids can become pivotal in biologics, biotechniques, and biomedical applications. The self-assembly, trapping, and transport of microparticles are being explored in active matter, micro and nanorobotics, and microfluidics; however, little work has been done in acoustics, particularly in active matter and robotics. This study reports the discovery and characterization of microbubble behaviors in a viscous gel that is confined to a slight opening between glass boundaries in an acoustic field. Where incident waves encounter a narrow slit, acoustic pressure is amplified, causing the microbubbles to nucleate and cavitate within it. Intermittent activation transforms microbubbles from spherical to ellipsoidal, allowing them to be trapped within the interstice. Continuous activation propels ellipsoidal microbubbles through shape and volume modes that is developed at their surfaces. Ensembles of microbubbles self-assemble into a train-like arrangement, which in turn capture, transport, and release microparticles.


Chronic ethanol consumption enhances inducible endothelium-dependent hyperpolarizing factor-mediated relaxation in the rat artery.
The inducible endothelium-dependent hyperpolarizing factor (iEDHF) pathway is activated as a compensatory response to adverse changes in the body. It causes vasorelaxation and maintains circulatory homeostasis in the organs. Small to moderate quantities of ethanol enhance vascular relaxation. However, its mechanism and the involvement of the iEDHF pathway in this process are unknown. Therefore, we studied iEDHF-mediated, acetylcholine-induced, endothelium-dependent relaxation in the superior mesenteric arteries (SMAs) of rats chronically fed ethanol. Rats were administered a standard diet (S-Control group), Lieber's control diet (L-Control group), or Lieber's ethanol diet (EtOH group). SMA relaxation was assessed by isometric tension measurements. Arachidonate 15-lipoxygenase (ALOX15) and soluble epoxide hydrolase (sEH) were determined by immunoblot. Acetylcholine-induced, endothelium-dependent relaxation was significantly greater in the EtOH than the control groups. These differences persisted after PGI2 and NO blockade. Thus, the increase in acetylcholine-induced relaxation was EDHF-mediated. In the EtOH group, however, it was prevented by iEDHF inhibitors. ALOX15 and sEH protein expression levels were higher in the EtOH than the L-Control group. The increase in acetylcholine-induced relaxation by chronic ethanol consumption was mediated by the iEDHF pathway. This mechanism may compensate for the blood pressure elevation induced by ethanol. This study suggests that iEDHF is induced during proper drinking and may help prevent the onset of cardiovascular conditions.