The Testis Is a Primary Factor That Contributes to Epigenetic Modifications in the Ovaries of the Protandrous Black Porgy, Acanthopagrus schlegelii.
In most hermaphroditic fish, the sexual phase of the gonad responds to external stimuli so that only one sex remains functional while the other sex becomes dormant. However, protandrous black porgy are male during their first two reproductive cycles. Estradiol (E2)-induced female growth results in a transient and immature female, and the sexual phase reverts from female to male after E2 is withdrawn. Conversely, excising the testis results in a precocious female when performed during the second reproductive cycle. We used these characteristics to study epigenetic modifications of cyp19a1a promoter in black porgy. Our results showed that higher levels of gonadotropins receptors were observed in testis than in ovary during the alteration of sexual phase from induced femaleness to maleness, and hCG treatment did not stimulate ovarian gene expression in male (1-yr-old maleness) and female phase (testis excision-induced femaleness) fish. The cyp19a1a promoter exhibited tissue- and lineage-specific methylation patterns. The follicle cells in the ovary had a hypomethylated (0%-20%) cyp19a1a promoter region. In the ovary, the first sign of female phase decision was decreased methylation levels and increased numbers of hypomethylated clones of cyp19a1a promoter during the natural sex change process. Similar methylation patterns were observed in the testis-removed ovary 1 mo after surgery, with no histological difference between the sham and the testis-removed fish. Conversely, there was no increase in methylation levels of cyp19a1a promoter in E2-fed fish. These results suggest that in the digonic gonad of black porgy, the testis is the primary tissue that affects epigenetics of the ovary.


Comparison of Clinical Outcomes and Computed Tomography Analysis for Tunnel Diameter After Arthroscopic Bankart Repair With the All-Suture Anchor and the Biodegradable Suture Anchor.
To compare the clinical outcomes and radiological findings at the anchor site after arthroscopic Bankart repair with all-suture anchors and biodegradable suture anchors in patients with recurrent anterior shoulder dislocation. The patients who underwent arthroscopic Bankart repair were divided into 2 groups depending on the type of the suture anchor used in different periods. Power analysis was designed based on the postoperative Rowe score. Clinical outcomes, including the Rowe score, American Shoulder and Elbow Surgeons score, subjective instability, and redislocation rates were evaluated. In all patients enrolled, the tunnel diameter of the anchor was assessed with computed tomography arthrogram at 1 year postoperatively. The Institutional Review Board of Ewha Womans University approved this study (no. EUMC 2017-05-058). A total of 67 patients were enrolled: 33 underwent surgery with a 1.3-mm (single-loaded) or 1.8-mm (double-loaded) all-suture anchor (group A), and 34 underwent surgery with a 3.0-mm biodegradable anchor (10.8 mm in length, 30% 1,2,3-trichloropropane/70% poly-lactide-co-glycolic acid) (group B). There were no significant differences in clinical outcomes between groups A and B in the American Shoulder and Elbow Surgeons score (preoperatively, 51.2 ± 13.7 vs 47.7 ± 12.2; 2 years postoperatively, 88.5 ± 12.3 vs 89.7 ± 10.9; P = .667) and Rowe score (preoperatively, 41.4 ± 10.5 vs 41.3 ± 9.4; 2 years postoperatively, 87.9 ± 14.9 vs 88.5 ± 14.6; P = .857). Postoperative redislocation (6.1% vs 5.9%, P = .682) and subjective instability rate (12.2% vs 17.7%, P = .386) of both groups showed no significant difference. Average tunnel diameter increment was significantly greater with the 1.8-mm all-suture anchor (2.8 ± 0.9 mm) than the 1.3-mm all-suture anchor (1.2 ± 0.8 mm) and 3.0-mm biodegradable anchor (0.8 ± 1.2 mm) (P < .001). Arthroscopic Bankart repair with the all-suture anchor showed comparable clinical outcomes and postoperative stability as the conventional biodegradable suture anchor at 2 years after surgery. Tunnel diameter increment of the all-suture anchor was significantly greater than that of the biodegradable suture anchor at the 1-year computed tomography analysis. Although tunnel diameter increment was greater with the all-suture anchor, it did not influence the clinical outcomes. Level III, retrospective comparative study.


Measuring corneal thickness with a rotary scanning system.
Recently the authors presented a technique that allows measurement of the corneal thickness along a vertical meridian from optical sections obtained using a slit-lamp microscope. We present a new system that allows rotary scanning of the cornea and consequent measurement of the corneal thickness along any meridian. The corneal thickness along two perpendicular meridians was measured from optical sections obtained with a new rotary scanning system. To obtain the optical sections, the cornea is illuminated with a light beam that is previously expanded in a fan by a small cylindrical lens rotated on a plane-containing axis to explore the cornea. The light diffused by both corneal surfaces is collected by two video cameras placed at an angle with the light beam. The axes of the two cameras define, with the visual axis, two planes normal to each other. After image acquisition, a processing algorithm is applied in order to compute the corneal thickness along the two meridians. Some preliminary results for the vertical and the horizontal meridians of one eye are shown, as well as all the intermediate computations. With this system, we expect to be able to measure corneal topography and thickness along an arbitrary meridian. The rotary scanning of the cornea is mechanically simple and will eventually allow automated scanning.


Posterior cruciate ligament biomechanics and options for surgical treatment.
Treatment algorithms for posterior cruciate ligament (PCL) injury have evolved over the past two decades as the natural history of these injuries has become clearer. Whether they are isolated injuries or occur with other ligament trauma, PCL ruptures substantially alter knee kinematics. Because of the effects of PCL injury and the less than optimal results after nonsurgical treatment, new surgical techniques have been developed. Several surgical techniques currently are available for reconstruction of the PCL. Most recent reports suggest that the tibial inlay technique is the best choice for restoring posterior tibial stability. Tibial inlay PCL reconstructions can be performed through both open and arthroscopic approaches. Crucial to the outcome of these procedures is detecting all injuries to the secondary restraints, especially the posterolateral corner. Failure to recognize and treat these deficits can compromise the results of PCL reconstruction, emphasizing the need for a detailed, meticulous physical examination when PCL injuries are suspected.


Determination of free and total phenolic acids in plant-derived foods by HPLC with diode-array detection.
A high-performance liquid chromatographic (HPLC) method with diode-array detection (DAD) was used to identify and quantify free and total phenolic acids (m-hydroxybenzoic acid, p-hydroxybenzoic acid, protocatechuic acid, gallic acid, vanillic acid, syringic acid, o-coumaric acid, m-coumaric acid, p-coumaric acid, caffeic acid, ferulic acid, sinapic acid, chlorogenic acid, and ellagic acid) in plant foods. Free phenolic acids were extracted with a mixture of methanol and 10% acetic acid. Bound phenolic acids were liberated using first alkaline and then acid hydrolysis followed by extraction with diethyl ether/ethyl acetate (1:1). All fractions were quantified separately by HPLC. After HPLC quantification, results of alkali and acid hydrolysates were calculated to represent total phenolic acids. Ellagic acid was quantified separately after long (20 h) acid hydrolysis. The methods developed were effective for the determination of phenolic acids in plant foods. DAD response was linear for all phenolic acids within the ranges evaluated, with correlation coefficients exceeding 0.999. Coefficients of variation for 4-8 sample replicates were consistently below 10%. Recovery tests of phenolic acids were performed for every hydrolysis condition using several samples. Recoveries were generally good (mean >90%) with the exceptions of gallic acid and, in some cases, caffeic acid samples.


A Rare Case of Chondroblastoma with Revision After Graft RejectionA Case Report.
We present a rare case of calcaneal chondroblastoma with subsequent surgical revision after graft rejection in a 13-year-old boy. Complications were encountered after the injectable bone graft filler was placed in the calcaneus after curettage. With noted subsequent sinus tract formation, revision surgery was performed that involved dissection of the sinus tract, removal of bone void filler, and application of demineralized bone matrix sponge human allograft soaked in vancomycin-impregnated saline. Sixteen weeks after the revision surgical intervention, the patient resumed normal athletic activities without pain or restrictions. One and a half years after the initial surgery, the patient had complete resolution of the calcaneal cyst and was discharged.


[Phosphatonins: novel insights and clinical perspectives].
Phosphate plays a vital role in several biological processes including energy and nucleic acid metabolism, cell signaling and bone mineralization. Several endocrine factors coordinately act on the intestine, kidney and bone to maintain their physiological homeostasis. A number of peptides, collectively known as phosphatonins, have recently been identified as regulators of phosphate metabolism in physiological and pathological conditions. These factors--fibroblast growth factors (FGF) 23 and 7, secreted frizzled related protein 4 (sFRP-4), and matrix extracellular phosphoglycoprotein (MEPE)--primarily regulate tubular phosphate reabsorption by acting on the transmembrane expression of SLC34 sodium-phosphate cotransporters. FGF- 23, FGF-7 and sFRP-4 also inhibit the biosynthesis of 1,25(OH)2D3, leading to decreased intestinal phosphate absorption. In this review, we discuss the biological properties of these peptides, their physiological roles, and the alterations in their concentrations in various hypophosphatemic and hyperphosphatemic clinical disorders.


Contrasting evolutionary patterns of the Rp1 resistance gene family in different species of Poaceae.
Disease-resistance genes (R-genes) in plants show complex evolutionary patterns. We investigated the evolution of the Rp1 R-gene family in Poaceae, and 409 Rp1 fragments were sequenced from 21 species. Our data showed that the common ancestor of Poaceae had two Rp1 loci, but the number of Rp1 locus in extant species varies from one to five. Some wheat and Zea genotypes have dozens of Rp1 homologues in striking contrast to one or two copies in Brachypodium distachyon. The large number of diverse Rp1 homologues in Zea was the result of duplications followed by extensive sequence exchanges among paralogues, and all genes in maize have evolved in a pattern of Type I R-genes. The high frequency of sequence exchanges did not cause concerted evolution in Zea species, but concerted evolution was obvious between Rp1 homologues from genera Zea and Sorghum. Differentiation of Type I and Type II Rp1 homologues was observed in Oryza species, likely occurred in their common ancestor. One member (Type II R-gene) in the Oryza Rp1 cluster did not change sequences with its paralogues, whereas the other paralogues (Type I R-genes) had frequent sequence exchanges. The functional Pi37 resistance gene in rice was generated through an unequal crossover between two neighboring paralogues followed by four point mutations. The Rp1 homologues in wheat and barley were most divergent, probably due to lack of sequence exchanges among them. Our results shed more light on R-gene evolution, particularly on the differentiation of Type I and Type II R-genes.


Free anterolateral thigh flap for extremity reconstruction: clinical experience and functional assessment of donor site.
From August of 1995 through July of 1998, 38 free anterolateral thigh flaps were transferred to reconstruct soft-tissue defects. The overall success rate was 97 percent. Among 38 anterolateral thigh flaps, four were elevated as cutaneous flaps based on the septocutaneous perforators. The other 34 were harvested as myocutaneous flaps including a cuff of vastus lateralis muscle (15 to 40 cm3), either because of bulk requirements (33 cases) or because of the absence of a septocutaneous perforator (one case). However, vastus lateralis muscle is the largest compartment of the quadriceps, which is the prime extensor of the knee. Losing a portion of the vastus lateralis muscle may affect knee stability. Objective functional assessments of the donor sites were performed at least 6 months postoperatively in 20 patients who had a cuff of vastus lateralis muscle incorporated as part of the myocutaneous flap; assessments were made using a kinetic communicator machine. The isometric power test of the ratios of quadriceps muscle at 30 and 60 degrees of flexion between donor and normal thighs revealed no significant difference (p > 0.05). The isokinetic peak torque ratio of the quadriceps and hamstring muscles, including concentric and eccentric contraction tests, showed no significant difference (p > 0.05), except the concentric contraction test of the quadriceps muscle, which revealed mild weakness of the donor thigh (p < 0.05). In summary, the functional impairment of the donor thighs was minimal after free anterolateral thigh myocutaneous flap transfer.


Hearing decrease after loss of cerebrospinal fluid. A new hydrops model?
In a prospective study of 12 patients undergoing operation for acoustic neuromas the hearing on the contralateral ear was tested before and systematically day by day after operation. In 11 cases a perceptive loss of at least 20 dB was found at one or more frequencies during the first 2 postoperative weeks. A maximal average threshold decrease of 16.5 dB was found in the treble (2.4, 8 kHz average), while a tendency of a more pronounced decrease of 19.6 dB was seen in the low frequencies (125, 250, 500 Hz average). After 3 months the hearing had normalized in all cases. The explanation for the transitional loss supports the present theory: The loss of cerebro-spinal fluid during operation diminishes the CSF pressure. This decrease is transmitted to the perilymph via the cochlear aqueduct producing a transitory perilymphatic hypotonia, which in turn hydromechanically results in a relative endolymphatic hypertension mimicking an endolymphatic hydrops thus representing a human hydrops model.


A quantum chemical survey of metalloporphyrin-nitrosyl linkage isomers: insights into the observation of multiple FeNO conformations in a recent crystallographic determination of nitrophorin 4.
Using density functional theory-based geometry optimizations, we have searched for eta(1)-NO, eta(1)-ON (isonitrosyl), and eta(2)-NO (side-on bound NO) linkage isomers of a number of metalloporphyrin-NO complexes, M(Por)(NO)(L), where Por = porphinato dianion, M = Mn(II), Fe(II), Fe(III), Ru(II), Ru(III), Co(II), and Rh(II), and L = no ligand, SMe, Ph, and imidazole. The eta(1)-NO isomer had the lowest energy in all cases, and the isonitrosyl isomer was also located as a higher energy potential energy minimum in a number of cases. The eta(2)-NO isomer was only located as a minimum for Mn(II) (L = no ligand), Fe(III) (L = no ligand), and Ru(III) (L = Ph, imidazole, pyrdine), suggesting that an [MNO](6) electron count is important for stabilization of the eta(2) mode of ligation. However, in the presence of axial ligands L, the side-on isomers of [FeNO](6) complexes were not stable and opened up to an unusual geometry where the FeN(O) and NO vectors were tilted in opposite directions relative to the heme normal. Exactly such a geometry, as well as a "normal" upright geometry, has been observed in a recent crystallographic determination of nitrophorin 4 (Nature Struct. Biol. 2000, 7, 551), a salivary protein from the blood-sucking insect Rhodnius prolixus. Together, the calculated and experimental result illustrate the extreme softness of the FeNO potential energy surface toward various forms of tilting and bending deformations.


Differences in the misreporting of chronic conditions, by level of education: the effect on inequalities in prevalence rates.
Many studies of socio-economic inequalities in the prevalence of chronic conditions rely on self-reports. For chronic nonspecific lung disease, heart disease, and diabetes mellitus, we studied the effects of misreporting on variations in prevalence rates by respondents' level of education. In 1991, a health interview survey was conducted in the southeastern Netherlands with 2867 respondents. Respondents' answers were compared with validated diagnostic questionnaires in the same survey and the diagnoses given by the respondents' general practitioners. Misreporting of chronic lung disease, heart disease, and diabetes may be extensive. Depending on the condition and the reference data used, the confirmation fractions ranged between .61 and .96 and the detection fractions between .13 and .93. Misreporting varied by level of education, and although various patterns were observed, the dominant pattern was that of more underreporting among less educated persons. The effects on prevalence rates were to underestimate differences by level of education to a sometimes considerable degree. Misreporting of chronic conditions differs by respondents' level of education. Health interview survey data underestimate socioeconomic inequalities in the prevalence of chronic conditions.


A new totally flat N(sp(2))C(sp(2))N(sp(2)) pincer palladacycle: synthesis and photoluminescent properties.
The Sonogashira coupling of 2-bromopyridine with 8-quinolinyl-acetylene affords 2-pyridinyl-8-quinolinyl-acetylene (1) in high yields. The chloropalladation of 1 with Li(2)PdCl(4) in methanol at room temperature affords the pincer palladacycle (C(5)H(4)N-2-C=C(Cl)-8-C(9)H(6)kappaN,kappaC,kappaN)PdCl (2) in 63% yield. The X-ray molecular structure of (2) shows that it is totally flat and that it is associated in pairs though pi-stacking between alternate pyridine-quinoline moieties (3.448 A). The pairs are also connected by pi-stacking with an interpair distance of 3.452 A between quinoline-quinoline moieties. A very low fluorescence emission was also revealed by the pincer palladacycle 2 in both solution and the solid state, which has been ascribed to an excimeric emission due to the particular structure (rigid and totally flat) of 2 in the solid state.


Early Prediction of Clinical Response to Etanercept Treatment in Juvenile Idiopathic Arthritis Using Machine Learning.
At present, there is a lack of simple and reliable model for early prediction of the efficacy of etanercept in the treatment of juvenile idiopathic arthritis (JIA). This study aimed to generate and validate prediction models of etanercept efficacy in patients with JIA before administration using machine learning algorithms based on electronic medical record (EMR). EMR data of 87 JIA patients treated with etanercept between January 2011 and December 2018 were collected retrospectively. The response of etanercept was evaluated by using DAS44/ESR-3 simplified standard. The stepwise forward and backward method based on information gain was applied to select features. Five machine learning algorithms, including Extreme Gradient Boosting (XGBoost), Random Forest (RF), Gradient Boosting Decision Tree (GBDT), Extremely Random Trees (ET) and Logistic Regression (LR) were used for model generation and validation with fifty-fold stratified cross-validation. EMR data of additional 14 patients were collected for external validation of the model. Tender joint count (TJC), Time interval, Lymphocyte percentage (LYM), and Weight were screened out and included in the final model. The model generated by the XGBoost algorithm based on the above 4 features had the best predictive performance: sensitivity 75%, specificity 66.67%, accuracy 72.22%, AUC 79.17%, respectively. A pre-administration model with good prediction performance for etanercept response in JIA was developed using advanced machine learning algorithms. Clinicians and pharmacists can use this simple and accurate model to predict etanercept response of JIA early and avoid treatment failure or adverse effects.


Inflammasome activation mediates inflammation and outcome in humans and mice with pneumococcal meningitis.
Inflammasomes are multi-protein intracellular signaling complexes that have recently been hypothesized to play a role in the regulation of the inflammation response. We studied associations between inflammasome-associated cytokines IL-1β and IL-18 in cerebrospinal fluid (CSF) of patients with bacterial meningitis and clinical outcome, and pneumococcal serotype. In a murine model of pneumococcal meningitis we examined the pathophysiological roles of two inflammasome proteins, NLRP3 (Nod-like receptor protein-3) and adaptor protein ASC (apoptosis-associated speck-like protein). In a nationwide prospective cohort study, CSF cytokine levels were measured and related to clinical outcome and pneumococcal serotype. In a murine model of pneumococcal meningitis using Streptococcus pneumoniae serotype 3, we examined bacterial titers, cytokine profiles and brain histology at 6 and 30 hours after inoculation in wild-type (WT), Asc and Nlrp3 deficient mice. In patients with bacterial meningitis, CSF levels of inflammasome associated cytokines IL-1β and IL-18 were related to complications, and unfavorable disease outcome. CSF levels of IL-1β were associated with pneumococcal serotype (p<0.001). In our animal model, Asc and Nlrp3 deficient mice had decreased systemic inflammatory responses and bacterial outgrowth as compared to WT mice. Differences between Asc⁻/⁻ and WT mice appeared sooner after bacterial inoculation and were more widespread (lower pro-inflammatory cytokine levels in both blood and brain homogenate) than in Nlrp3⁻/⁻ mice. Nlrp3 deficiency was associated with an increase of cerebral neutrophil infiltration and cerebral hemorrhages when compared to WT controls. Our results implicate an important role for inflammasome proteins NLRP3 and ASC in the regulation of the systemic inflammatory response and the development of cerebral damage during pneumococcal meningitis, which may dependent on the pneumococcal serotype.


Direct observation of charge order in an epitaxial NdNiO3 film.
The first direct observation of charge order of Ni(3+delta(')) and Ni(3-delta) by resonant x-ray scattering experiments in an epitaxial film of NdNiO3 is reported. A quantitative value of delta+delta(') = (0.45 +/- 0.04)e was obtained. The temperature dependence of the charge order deviates significantly from those of the magnetic moment and crystallographic structure. This might be an indication of a difference in their fluctuation time scales. These observations are discussed in terms of the temperature-driven metal-insulator transition in the RNiO3 family.


Time-resolved grazing-incidence diffraction studies of thin films using an imaging-plate camera and focusing monochromator.
A multiple imaging-plate (IP) detector system and focusing monochromator have been developed and successfully applied to the time-resolved study of phase transitions in Langmuir-Blodgett (LB) films by grazing-incidence X-ray diffraction (GIXD). The first reported application of imaging plates to a GIXD study was carried out by our group and proved to be very successful in the determination of thin-film structure [Foran, Peng, Steitz, Barnes & Gentle (1996). Langmuir, 12, 774-777]. To extend the capabilities of this system, an IP camera was designed and built which can accommodate up to 13 IPs (40 x 20 cm) inside the vacuum chamber of the main diffractometer at the Australian Beamline at the Photon Factory. The camera allows the enclosed IPs to be successively exposed and stored inside the diffractometer for later scanning. The focusing monochromator employed in this technique combines fixed exit-beam height with sagittal focusing of the second crystal and delivers a gain in flux of >/=20 times when measured through a 0.1 x 0.1 mm aperture. The utility of the system incorporating the IP camera and the focusing monochromator has been demonstrated through the study of temperature-dependent phase transitions in LB films of metal fatty acids.


Bioavailability of decabromodiphenyl ether to the marine polychaete Nereis virens.
The flame retardant decabromodiphenyl ether (BDE 209) accumulates in humans and terrestrial food webs, but few studies have reported the accumulation of BDE 209 in aquatic biota. To investigate the mechanisms controlling the bioavailability of BDE 209, a 28-d bioaccumulation experiment was conducted in which the marine polychaete worm Nereis virens was exposed to a decabromodiphenyl ether (deca-BDE) commercial mixture (>85% BDE 209) in spiked sediments, in spiked food, or in field sediments. Bioaccumulation from spiked substrate with maximum bioavailability demonstrated that BDE 209 accumulates in this species. Bioavailability depends on the exposure conditions, however, because BDE 209 in field sediments did not accumulate (<0.3 ng/g wet weight; 28-d biota-sediment accumulation factors [BSAFs] <0.001). When exposed to deca-BDE in spiked sediments also containing lower brominated congeners (a penta-BDE mixture), bioaccumulation of BDE 209 was 30 times lower than when exposed to deca-BDE alone. Selective accumulation of the lower brominated congeners supports their prevalence in higher trophic level species. The mechanisms responsible for limited accumulation of BDE 209 may involve characteristics of the sediment matrix and low transfer efficiency in the digestive fluid.


Whisking in air: encoding of kinematics by VPM neurons in awake rats.
Rodent whisking behavior generates two types of neural signals: one produced by whisker contact with objects; the other by movements in air. While kinematic signals generated by contact reliably activate neurons at all levels of the trigeminal neuraxis, the extent to which the kinematics of whisking in air are reliably encoded at each level remains unclear. Previously, we showed that the responses of trigeminal ganglion (TG) neurons in awake, head-fixed rats are correlated with whisking kinematic parameters, but that individual neurons may differ substantially in the reliability of their kinematic encoding. Here, we extend that analysis to neurons in the ventral posterior medial (VPM) nucleus. Three possible coding strategies were examined: (1) firing rate across an entire movement; (2) the probability of individual spikes as a function of the instantaneous movement trajectory; and (3) the coherence between spikes and whisking. While VPM neurons were clearly responsive to variations in whisker kinematics during whisking in air, the encoding of whisker kinematics by VPM neurons was less consistent than that of TG neurons. Furthermore, we found that, in VPM as in TG, movement direction is an important determinant of unit responsiveness during whisking in air.


Sumoylation in Physiology, Pathology and Therapy.
Sumoylation is an essential post-translational modification that has evolved to regulate intricate networks within emerging complexities of eukaryotic cells. Thousands of target substrates are modified by SUMO peptides, leading to changes in protein function, stability or localization, often by modulating interactions. At the cellular level, sumoylation functions as a key regulator of transcription, nuclear integrity, proliferation, senescence, lineage commitment and stemness. A growing number of prokaryotic and viral proteins are also emerging as prime sumoylation targets, highlighting the role of this modification during infection and in immune processes. Sumoylation also oversees epigenetic processes. Accordingly, at the physiological level, it acts as a crucial regulator of development. Yet, perhaps the most prominent function of sumoylation, from mammals to plants, is its role in orchestrating organismal responses to environmental stresses ranging from hypoxia to nutrient stress. Consequently, a growing list of pathological conditions, including cancer and neurodegeneration, have now been unambiguously associated with either aberrant sumoylation of specific proteins and/or dysregulated global cellular sumoylation. Therapeutic enforcement of sumoylation can also accomplish remarkable clinical responses in various diseases, notably acute promyelocytic leukemia (APL). In this review, we will discuss how this modification is emerging as a novel drug target, highlighting from the perspective of translational medicine, its potential and limitations.


NR2B-subunit dependent facilitation of long-term potentiation in primary visual cortex following visual discrimination training of adult rats.
Long-term potentiation (LTP) is an important mechanism thought to mediate changes in synaptic connectivity following various types of experience. We examined the effects of visual discrimination training on LTP in the mature, rodent thalamocortical visual system. Adult rats underwent visual discrimination training in a modified Morris Water Maze containing a Y-maze insert, requiring rats to associate visual cues with the location of a hidden escape platform placed in one of the two goal arms of the Y-maze insert. On the day following successful task acquisition (average of nine training days), rats were anesthetized (urethane), and LTP in the thalamocortical system was characterized. In task-naïve rats, theta-burst stimulation of the lateral geniculate nucleus resulted in modest (∼40%) potentiation of field postsynaptic potentials recorded in the primary visual cortex (V1). Rats trained on the visual discrimination task showed significantly greater levels of LTP (∼60%), an effect that was not seen in rats trained to swim in the maze without a predictive association between visual cues and platform location. An antagonist of the N-methyl-d-aspartate (NMDA) receptor NR2B subunit ([R-(R *,S *)]-α-(4-hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidinepropanol hydrochloride (Ro 25-6981); 2 mm, applied locally at the recording site in V1) reversed the training-induced LTP enhancement without affecting LTP in task-naïve rats. An antagonist of metabotropic glutamate receptors [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY 341495); 2 mm] was ineffective in reversing the training-induced LTP facilitation. These data suggest that behavioral (visual) training can result in changes in plasticity exhibited by the mature, thalamocortical visual system that require activation of NMDA receptors containing the NR2B subunit.


Streptococcus pneumoniae in Saudi Arabia: antibiotic resistance and serotypes of recent clinical isolates.
During 2000, 154 clinical Streptococcus pneumoniae isolates were collected from or through three major hospitals serving the Western, Central, and Eastern regions of the Kingdom of Saudi Arabia. Ninety-one (59.1%) of the 154 isolates were resistant to penicillin with 23 strains (14.9%) highly resistant. Resistance was more prevalent among isolates obtained from patients <10 years of age and from isolates cultured from blood and cerebral spinal fluid. Decreased sensitivity to ceftriaxone, erythromycin, trimethoprim-sulphamethoxazole, and levofloxacin was found in 14.9, 15.6, 9.7, and 1.3% of isolates, respectively. There were no significant differences in the resistance pattern between isolates obtained from patients in the three different geographical areas. Serotypes of 116 isolates revealed the most prevalent types to be (descending order) 4, 3, 19F, 9V, 6A, 19A, 14 and 23F, comprising 75% of all strains typed; 9.5% of isolates were nontypable. S. pneumoniae isolates from Saudi Arabia have become more resistant to penicillin and other antimicrobials over the past 20 years.


Immunohistochemical detection of p53 in Wilms' tumors correlates with unfavorable outcome.
The role of p53 in the pathogenesis and progression of Wilms' tumors is only partly understood. Although p53 mutations were initially reported only in anaplastic Wilms' tumors, we had reported that, of two of twenty-one cases that had a p53 mutation, one tumor showed no evidence of anaplasia. To determine the significance of p53 expression in all clinical stages of Wilms' tumor, twenty-eight cases were analyzed for p53 immunoreactivity. Paraffin sections were immunolabeled with two different monoclonal antibodies, recognizing both mutant and wild-type p53. Fifteen of sixteen tumors in the recurrent/metastatic group and three of twelve tumors in the nonmetastatic/nonrecurrent group showed p53 immunopositivity. Only one of three positive tumors in the latter group showed moderate to strong positivity, whereas twelve of sixteen metastatic/recurrent tumors revealed a similar degree of p53 positivity. The positivity was stronger in the metastasis/recurrences as compared with the corresponding primary tumor. Western blot analysis revealed p53 expression in all of the Wilms' tumors tested, suggesting its involvement in the development of Wilms' tumors. Single-strand conformation polymorphism analysis performed on twenty-three of these tumors revealed p53 mutations in four of fourteen recurrent/metastatic tumors and none in the nonmetastatic/nonrecurrent group. Our results show that, whereas 60% of cases were immunopositive for p53 protein, mutations were detected in only 16% of tumors, indicating that wild-type p53 protein is retained in the other tumors. We conclude that p53 immunopositivity strongly correlates with recurrence/metastasis in Wilms' tumors. Furthermore, the accumulation of p53 in these tumors is not only due to mutations but may also involve stabilization of normal p53 with other proteins.


Complications of femtosecond-assisted laser in-situ keratomileusis flaps.
Femtosecond-assisted laser in-situ keratomileusis flaps have revolutionized refractive surgery since their introduction. Although these lasers are exceedingly safe, complications still do occur. This review focuses specifically on examining the literature and evidence for flap complications during femtosecond-assisted laser in-situ keratomileusis as well as their management.


Risk stratification for 1-year mortality in acute heart failure: classification and regression tree analysis.
Simple tools for risk stratification of patients with acute heart failure (AHF) are an unmet clinical need, particularly regarding long-term mortality. We prospectively enrolled 610 consecutive patients presenting to the emergency department with AHF. The diagnosis of AHF was adjudicated by two independent cardiologists. The classification and regression tree (CART) analysis was used to develop a simple risk algorithm. This was internally validated by cross-validation. One-year follow-up was complete in all patients (100%). A total of 201 patients (33%) died within 360 days. The CART analysis identified blood urea nitrogen (BUN) and age as the best single predictors of 1-year mortality and patients were categorised to three risk groups: high risk group (BUN >27.5 mg/dl and age >86 years), intermediate risk group (BUN >27.5 mg/dl and age ≤ 86 years) and low risk group (BUN ≤ 27.5 mg/dl). The Kaplan-Meier curves showed a significant increase in mortality in the high risk group compared with the lower risk groups (log-rank test p <0.001). The hazard ratio regarding 1-year mortality between patients identified as low and high risk was 2.0 (95% confidence interval, 1.7-2.4), with statistically significant differences between all risk groups (p <0.001). The likelihood-based 95%-confidence set for the age- and the urea-threshold is contained in the rectangular set defined by 25 mg/dl ≤ urea threshold ≤30.6 mg/dl and 76 years ≤ age threshold ≤96 years. These results suggest that AHF patients at low, intermediate and high risk for death within 360 days can be easily identified using patient's demographics and laboratory data obtained at presentation. Application of this simple risk stratification algorithm may help to improve the management of these patients.


Two models of suicide.
Objective: The aim of this paper is to present two models of separate but related aspects of suicide, developed with a view to improving understanding and management of this behaviour. Conclusions: First, the predicament model of suicide posits that all suicide represents an escape from a predicament and associated distress. Predicaments are composed of either external (environmental) or internal (mental disorders) factors, or both. Suicide occurs when a threshold is exceeded on a suicide risk ladder, and the degree of movement toward the threshold in response to a particular stressor depends on a range of factors. Second, the suicide pathways model integrates medical and sociological concepts, with distress as the central component, and three run-offs: mental disorder, medicalized and a non-mental disorder (egoistic/anomic; reaction) suicide.


Stability of core language skill across the first decade of life in children at biological and social risk.
Command of language is a fundamental skill, a cornerstone of multiple cognitive and socioemotional aspects of development, and a necessary ingredient of successful adjustment and functioning in society. Little is known about the developmental stability of language in at-risk youth or which biological and social risk factors moderate stability. This four-wave 10-year prospective longitudinal study evaluated stability of core language skill in 1,780 children in varying categories of biological and social risk in a multiage, multidomain, multimeasure, and multireporter framework. Structural equation modeling supported loadings of diverse age-appropriate measures of child language on single latent variables of core language skill at 15 and 25 months and 5 and 11 years, respectively. Core language skill was stable over the first decade of life; significant and comparable stability coefficients were obtained for children with diverse biological and social risks, including poor health, welfare status, teen motherhood, ethnicity, gender, birth order, and families that changed in income and maternal education over the study period; stability in language was strong even accounting for child nonverbal intelligence and social competence, maternal education and language, and the family home environment. Core language skill varies in stability with age but is robustly stable in children regardless of multiple biological and social risk factors.


A photoactivatable green-fluorescent protein from the phylum Ctenophora.
Genes for the family of green-fluorescent proteins (GFPs) have been found in more than 100 species of animals, with some species containing six or more copies producing a variety of colours. Thus far, however, these species have all been within three phyla: Cnidaria, Arthropoda and Chordata. We have discovered GFP-type fluorescent proteins in the phylum Ctenophora, the comb jellies. The ctenophore proteins share the xYG chromophore motif of all other characterized GFP-type proteins. These proteins exhibit the uncommon property of reversible photoactivation, in which fluorescent emission becomes brighter upon exposure to light, then gradually decays to a non-fluorescent state. In addition to providing potentially useful optical probes with novel properties, finding a fluorescent protein in one of the earliest diverging metazoans adds further support to the possibility that these genes are likely to occur throughout animals.


Changes in headache prevalence between pre-school and pre-pubertal ages.
The prevalence rates of headache in first-born children were determined at the ages of 6 and 12 years in over 1000 families. A headache questionnaire was mailed to 1132 families when the children were 6 years old, and to 1126 families when the children were 12 years old. Seven hundred and ninety-eight families responded to both questionnaires. The prevalence of headache before the 6 months preceding the questionnaire ('previous headache') was 19% when the children were 6 years of age and 31% when the children were 12 years of age. The corresponding prevalences of headache during the 6 months immediately proceeding the questionnaire ('present headache') were 16% and 19%. Variation in occurrence of headache was high during follow-up years. Maternal frequent headache (> or = 1/month) was significantly associated with the increase in prevalence of present headache in boys between the ages of 6 and 12 years. Frequent headache in mothers, fathers and siblings, and the occurrence of chronic illness, were also significantly associated with headache in the 12-year-old children.


[Hepatocarcinoma invasion of the portal vein: detection using lipiodol computed tomography. Apropos of 2 cases].
Portal vein involvement is a major complication of hepatocellular carcinoma and has an important impact on management and prognosis. Iodized-oil computed tomography is a well-established imaging technique for the pretherapeutic assessment of hepatocellular carcinoma because it allows detection of the primary tumor site and any daughter nodules. We report two cases of hepatocellular carcinoma extending to the portal vein which was documented by iodized-oil computed tomography. In both cases, tumor thrombus demonstrated marked retention of the iodized-oil on computed tomography. Our two cases demonstrate that iodized-oil computed tomography can depict portal vein extension of hepatocellular carcinoma. In addition, these two cases suggest that iodized-oil retention within the portal vein is a clue to the diagnosis of hepatocellular carcinoma.


Correlation between mandibular central incisor proclination and gingival recession during fixed appliance therapy.
The purpose of this study was to determine whether proclination of mandibular central incisors during fixed appliance therapy results in gingival recession. Complete records of 67 patients (39 female and 28 male patients; mean age, 16.4 years; age range, 10-45 years) were used in this retrospective case-control study. Using pretreatment and posttreatment lateral cephalograms, the change in mandibular central incisor inclination was measured to divide the patients into an experimental group (proclination) and a control group (no proclination). Changes in clinical crown length were determined from pretreatment and posttreatment study models, and changes in gingival recession were determined from intraoral slides. Eight of the 67 patients exhibited a measurable increase in gingival recession of at least 0.5 mm, and 27 patients had an increase in clinical crown length of at least 0.5 mm. Statistical analyses showed no correlation between mandibular central incisor proclination and gingival recession or clinical crown length. A t-test analysis showed no statistically significant difference in gingival recession or change in clinical crown length between patients whose mandibular central incisors were proclined and those whose incisors were not proclined. Multiple regression analysis demonstrated that age, sex, race, treatment duration, extraction, treatment type, Angle classification, and proclination were not related to gingival recession or change in clinical crown length of mandibular central incisors. We conclude that the degree of proclination of mandibular central incisors during fixed appliance therapy was not correlated to gingival recession in this sample.


Stem cell-derived biofactors fight against coronavirus infection.
Despite various treatment protocols and newly recognized therapeutics, there are no effective treatment approaches against coronavirus disease. New therapeutic strategies including the use of stem cells-derived secretome as a cell-free therapy have been recommended for patients with critical illness. The pro-regenerative, pro-angiogenic, anti-inflammatory, anti-apoptotic, immunomodulatory, and trophic properties of stem cells-derived secretome, extracellular vesicles (EVs), and bioactive factors have made them suitable candidates for respiratory tract regeneration in coronavirus disease 2019 (COVID-19) patients. EVs including microvesicles and exosomes can be applied for communication at the intercellular level due to their abilities in the long-distance transfer of biological messages such as mRNAs, growth factors, transcription factors, microRNAs, and cytokines, and therefore, simulate the specifications of the parent cell, influencing target cells upon internalization and/or binding. EVs exhibit both anti-inflammatory and tolerogenic immune responses by regulation of proliferation, polarization, activation, and migration of different immune cells. Due to effective immunomodulatory and high safety including a minimum risk of immunogenicity and tumorigenicity, mesenchymal stem cell (MSC)-EVs are more preferable to MSC-based therapies. Thus, as an endogenous repair and inflammation-reducing agent, MSC-EVs could be used against COVID-19 induced morbidity and mortality after further mechanistic and preclinical/clinical investigations. This review is focused on the therapeutic perspective of the secretome of stem cells in alleviating the cytokine storm and organ injury in COVID-19 patients.


Evidence for the efficacy of enzalutamide in postchemotherapy metastatic castrate-resistant prostate cancer.
The treatment of metastatic castrate-resistant prostate cancer (mCRPC) has evolved rapidly with the recent approval of a number of treatments and agents, including docetaxel, sipuleucel T, abiraterone, cabazitaxel, and enzalutamide. Enzalutamide (previously MDV-3100) is a novel oral androgen receptor inhibitor that targets multiple steps in the androgen receptor signaling pathway. The randomized phase III AFFIRM study demonstrated significant improvements in a number of efficacy endpoints, including the primary endpoint of overall survival and secondary endpoints of progression-free survival, and time to prostate-specific antigen progression in patients with progressive mCRPC who had received prior treatment with docetaxel. Enzalutamide was well tolerated and there were comparable incidences of grade 3 or greater adverse events reported for the enzalutamide and placebo control arms in AFFIRM. Unlike some other treatments for mCRPC, enzalutamide does not require administration with steroids. The ongoing randomized phase III PREVAIL trial will investigate the efficacy and safety of enzalutamide in chemotherapy-naïve patients with mCRPC. Additional trials are investigating the use of enzalutamide in a number of disease settings.


Tomography of anthropogenic nitrate contribution along a mesoscale river.
Elevated nitrate concentrations are a thread for water supply and ecological integrity in surface water. Nitrate fluxes obtained by standard monitoring protocols at the catchment outlet strongly integrate spatially and temporally variable processes such as mobilization and turnover. Consequently, inference of dominant nitrate sources is often problematic and challenging in terms of effective river management and prioritization of measures. Here, we combine a spatially highly resolved assessment of nitrate concentration and fluxes along a mesoscale catchment with four years of monitoring data at two representative sites. The catchment is characterized by a strong land use gradient from pristine headwaters to lowland sub-catchments with intense agricultural land use and wastewater sources. We use nitrate concentrations in combination with hydrograph separation and isotopic fingerprinting methods to characterize and quantify nitrate source contribution. The hydrological analysis revealed a clear dominance of base flow during both campaigns. However, the absolute amounts of discharge differed considerably from one another (outlet: 1.42m3s-1 in 2014, 0.43m3s-1 in 2015). Nitrate concentrations are generally low in the pristine headwaters (<3mgL-1) and increase downstream (15 to 16mgL-1) due to the contribution of agricultural and wastewater sources. While the agricultural contribution did not vary in terms of nitrate concentration and isotopic signature between the years, the wastewater contribution strongly increased with decreasing discharge. Wastewater-borne nitrate load in the entire catchment ranged between 19% (2014) and 39% (2015). Long-term monitoring of nitrate concentration and isotopic composition in two sub-catchment exhibits a good agreement with findings from spatially monitoring. In both datasets, isotopic composition indicates that denitrification plays only a minor role. The spatially highly resolved monitoring approach helped to pinpoint hot spots of nitrate inputs into the stream while the long-term information allowed to place results into the context of intra-annual variability.


Design of protein struts for self-assembling nanoconstructs.
Bacteriophage T4 tail fibers have a quaternary structure of bent rigid rods, 3 x 160 nm in size. The four proteins which make up these organelles are able to self-assemble in an essentially irreversible manner. To use the self-assembly domains of these proteins as elements in construction of mesoscale structures, we must be able to rearrange these domains without affecting the self-assembly properties and add internal binding sites for other functional elements. Here we present results on several alterations of the P37 component of the T4 tail fiber that change its length and add novel protein sequences into the protein. One of these sequences is an antibody binding site that is used to inactivate phage carrying the modified gene.


A geographic information systems (GIS) and spatial modeling approach to assessing indoor radon potential at local level.
This study integrates residential radon data from previous studies in Southern California (USA), into a geographic information system (GIS) linked with statistical techniques. A difference (p<0.05) is found in the indoor radon in residences grouped by radon-potential zones. Using a novel Monte Carlo approach, we found that the mean distance from elevated-radon residences (concentration>74 Bq m(-3)) to epicenters of large (> 4 Richter) earthquakes was smaller (p<0.0001) than the average residence-to-epicenter distance, suggesting an association between the elevated indoor-radon and seismic activities.


Carbon-tetrachloride-induced urinary excretion of formaldehyde, malondialdehyde, acetaldehyde and acetone in rats.
Previous studies have demonstrated that the hepatotoxin carbon tetrachloride rapidly promotes lipid peroxidation and inhibits microsomal calcium sequestration, microsomal glucose-6-phosphatase activity and cytochrome P-450. Due to its profound effects on lipid peroxidation, we have examined the oral administration of 2.5 ml/kg carbon tetrachloride on the urinary excretion of the lipid metabolites formaldehyde, malondialdehyde, acetaldehyde and acetone. Urine samples were collected up to 48 h after treatment. The urinary metabolites were identified and quantitated by gas chromatography-mass spectrometry and high-pressure liquid chromatography. Time-dependent increases in the urinary excretion of the four metabolites were observed after carbon tetrachloride administration. At 48 h after treatment, the increases in the excretion of malondialdehyde, formaldehyde, acetaldehyde and acetone were approximately 55, 78, 57 and 268%, respectively, relative to control values. The data were expressed in nanomoles per kilogram body weight per 4.5 h. The results clearly demonstrate that carbon tetrachloride increases the urinary excretion of four lipid metabolites which may serve as noninvasive biomarkers of xenobiotic-induced lipid peroxidation.


Downregulation of Blimp1 inhibits the maturation of bone marrow-derived dendritic cells.
Modulation of differentiation of dendritic cells (DCs), which are derived from bone marrow cells, may influence their maturation and consequently regulate their ability to present antigens to alloreactive T lymphocytes. B lymphocyte‑induced maturation protein‑1 (Blimp1) is a master regulator of immunocyte differentiation, which has been investigated for its effect on DCs. In the present study, a lentivirus was used as a vector to transduce Blimp1‑short hairpin (sh)RNA into primary bone marrow cells during their differentiation to DCs. Lentiviral‑mediated Blimp1‑shRNA (lenti‑shRNA‑Blimp1) had a transduction efficiency of >60% in DC precursors. Lenti‑shRNA‑Blimp1 significantly downregulated the expression levels of Blimp1 and modulated the expression of its target proteins, including class II major histocompatibility complex (MHC) transactivator, c‑myc and interleukin‑6. Although lenti‑shRNA‑Blimp1 did not interfere with the differentiation of bone marrow cells to DCs, it inhibited DC maturation by decreasing the expression of surface MHC‑II molecules, but not the expression of MHC‑I molecules and co‑stimulatory molecules [cluster of differentiation (CD)80/CD86]. Subsequently, alloreactive T cell proliferation was alleviated and regulatory T cells were expanded in response to lenti‑shRNA‑Blimp1. A toxicity assay indicated that the morphology and proliferation of cultured DCs were mildly influenced by the lentiviral vector, indicating that the use of alternative vectors with minimal or no toxicity could be investigated in future studies. In conclusion, transduction with lenti‑shRNA‑Blimp1 modulated the maturation of DCs via MHC‑II molecule suppression and inhibited alloreactive T cell activation. The present findings supported the application of Blimp1‑based intervention as a novel approach to induce immature DCs for further immunological research.


An integrated approach to Chlamydia trachomatis infection: the ICTI Consortium, an update.
The desire for an integrated approach to the study of Chlamydia trachomatis infection of the female genital tract resulted in the creation of the "ICTI Consortium" (Integrated approach to the study of Chlamydia Trachomatis Infection) in 2005. The ICTI consortium is based on tight interaction and collaboration between basic scientists, clinicians, epidemiologists and health-care policy makers. This translational approach will help to further the valuable insight into the immunopathogenesis of this sexually transmitted infection in order to develop new intervention strategies, including the vaccines and screening programs necessary to effectively diagnose, treat and prevent C. trachomatis infection. This article provides an update of ICTI Consortium activities carried out until September 2009.


Arabidopsis putative MAP kinase kinase kinases Raf10 and Raf11 are positive regulators of seed dormancy and ABA response.
We isolated an Arabidopsis ABA-insensitive mutant, ais143, by activation tagging screen. T-DNA was found to be located in the coding region of a putative mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) gene, Raf10, thereby abolishing its expression in the mutant. ais143 exhibited reduced seed dormancy as well as reduced ABA sensitivity. The phenotypes were complemented by the wild-type Raf10 gene, and the overexpression (OX) of Raf10 resulted in delayed seed germination and enhanced ABA sensitivity. Raf10 has high sequence identity to another MAP3K, Raf11. Parallel analysis of Raf11 knockout (KO) and OX lines showed that their phenotypes were similar to those of Raf10 KO and OX lines. An ais143 raf11 double mutant exhibited stronger phenotypes than single mutants, indicating the functional redundancy between Raf10 and Raf11. Transcript analysis revealed that the expression of many ABA-associated genes, including the key regulatory genes ABI3 and ABI5, was altered in the Raf10 and Raf11 OX lines. Recombinant Raf10 and Raf11 proteins exhibited kinase activity, which was inhibited by the MAP3K inhibitor BAY 43-9006 but not by the MAP2K inhibitor U0126. Collectively, our data indicate that Raf10 and Raf11 kinases are important regulators of seed dormancy and ABA response and that they affect the expression of ABI3, ABI5 and other ABA-regulated genes.


Changing patterns of presentations of patients with HIV-related disease at a tertiary referral centre and its implications for physician training.
Highly active antiretroviral therapy (HAART) has been shown to be highly effective in controlling HIV-related disease progression. Our objective was to determine whether HAART had altered the spectrum of HIV-related disease presentations at a tertiary medical referral centre and if a change in the clinical presentations of HIV-infected individuals to the hospital had impacted on physicians' training. A retrospective study which examined all admissions of HIV-infected patients identified between 1 October 1996 to 30 September 1998 using a hospital-designed computer database was undertaken at the Beth Israel Deaconess Medical Center (BIDMC) tertiary medical referral centre. All medical residents were surveyed in order to assess their knowledge of HIV-associated admissions and their confidence treating HIV-infected patients. There were significant changes in the admitting diagnosis for HIV-related illness between 1996 and 1998. Admissions for opportunistic infections (OIs) declined whereas admissions with bacterial infections increased significantly. Use of HAART remained stable between the 2 years of the study. Physicians' overestimated the use of HAART and only 8% of residents felt very comfortable taking care of an HIV-infected patient. In conclusion, the spectrum of presentations with HIV-related disease to a tertiary referral centre continues to change in the HAART era and impacts on physicians' experience of the management of HIV disease.


Early diagnosis crucial in ankylosing spondylitis.
Ankylosing spondylitis (AS) is an inflammatory autoimmune disorder that predominantly affects the spine. If untreated it may cause significant morbidity. Early diagnosis is particularly important as newer therapies are able to contain this condition and even induce remission. AS affects about 0.2-0.5% of the population. It is at least twice as common in men and most often manifests in the third to fifth decades. It is estimated that up to 5% of patients with chronic lower back pain in primary care have inflammatory disease. Although only 1% of patients with HLA-B27 develop AS, 90-95% of patients with AS are positive for HLA-B27. Immune dysfunction is the hallmark of this condition and it may be triggered by infection. The primary site of inflammation in AS is the entheses, the sites of insertion of tendons and ligaments into bone. If the inflammation remains untreated, there is resultant fibrosis and ultimately ossification at the entheseal sites. AS should be suspected in patients who report back pain and stiffness with rest, especially in the morning, which improves with exercise. Although the condition affects both the sacroiliac joints, a proportion of patients report pain radiating into the buttocks which may be unilateral or alternate, particularly in the early stages. In addition to the spine, large joint synovitis may develop as well as features of entheseal involvement. New classification criteria take into account early sacroiliitis evident on MRI scan and allow a diagnosis to be made far earlier than was previously possible. A proportion of patients respond well to NSAIDs coupled with a structured physiotherapy and exercise programme. However, about half these patients need escalation to biologic therapy. Patients with a suspected diagnosis should be referred to secondary care in order to confirm the diagnosis and commence treatment.


Opa expression correlates with elevated transformation rates in Neisseria gonorrhoeae.
Neisseria gonorrhoeae is naturally competent for DNA transformation. Under most conditions encountered in vivo, gonococci express one or more opacity (Opa) proteins on their surfaces. Recently, it was shown that DNA preferentially binds to the surfaces of Opa-expressing organisms compared to those of isogenic Opa-negative strains, presumably due to the numerous cationic residues in the predicted surface-exposed loops of the Opa protein. This study examined whether Opa-DNA interactions actually influence DNA transformation of the gonococcus. The data show that Opa-expressing gonococci are more efficient recipients of DNA for transformation and are more susceptible to exogenous DNase I treatment at early stages during the DNA transformation process than non-Opa expressors. Furthermore, inhibition of the transformation process was demonstrable for Opa(+) populations when either nonspecific DNA or the polyanion heparin was used. Overall, the data suggest that Opa expression, with its presumptive positive surface charge contribution, promotes DNA transformation by causing a more prolonged sequestration of donor DNA at the cell surface, which translates into more efficient transformation over time.


MULTIDISCIPLINARY APPROACH TO MANAGEMENT OF PEDIATRIC PATIENTS WITH SKIN SYMPTOMS OF FOOD ALLERGY.
The aim: To determine the significance of multidisciplinary approach to management of pediatric patients with skin symptoms of food allergy. Materials and methods: The study included of 36 patients aged 4 to 6 years with skin manifestations of food allergy, of which 18 were randomly included in the study group and had a multidisciplinary approach to treatment and the other 18 patients constituted a comparison group and used a standard therapy regimen. Observation of children was carried out for 3 months. Results: Assessment of the severity of the cutaneous form of food allergy by SCORAD score showed the average degree of disease activity in the groups of the study at the beginning of treatment and significantly better dynamics in patients of the study group (p=0.0055). In 88.9% (n=16) of patients in the study group and 61.1% (n=11) of the control group, the process became mild. Conclusions: The application of a multidisciplinary approach allows the integrated implementation of medical, nutritional, and psychological aspects, which significantly increases the effectiveness of treatment and improves the quality of life of patients and their parents.


Racial Differences in Associations of Perceived Health and Social and Physical Activities With Advance Care Planning, End-of-Life Concerns, and Hospice Knowledge.
Associations of perceived health and social and physical activities with end-of-life (EOL) issues have been rarely studied, not to mention racial disparities in such associations. To address this gap, this study examined racial differences in the associations of perceived health and levels of social and physical activities with advance care planning, EOL concerns, and knowledge of hospice care among community-dwelling older adults in Alabama. Data from a statewide survey of 1044 community-dwelling older adults on their long-term care needs were analyzed using descriptive statistics and logistic and linear regressions. Results showed that black older adults were less likely to know about or document advance care planning and to have accurate knowledge of hospice care; however, despite their poorer perceived health, black older adults reported fewer EOL concerns. Higher levels of perceived health and social and physical activities were associated with knowledge about advance care planning among white older adults but not among black older adults. Both black and white older adults with poorer perceived health and lower levels of social and physical activities tended to have more EOL concerns and less knowledge of hospice care. These findings suggest that interventions to address suboptimal levels of perceived health and social and physical activities among black older adults may increase knowledge of advance care planning. Also, supportive services to address EOL concerns should be targeted at older adults with poorer perceived health and limited participation in social and physical activities.


Electrospinning/Electrospray of Ferrocene Containing Copolymers to Fabricate ROS-Responsive Particles and Fibers.
We demonstrate an electrospray/electrospinning process to fabricate stimuli-responsive nanofibers or particles that can be utilized as stimuli-responsive drug-loaded materials. A series of random copolymers consisting of hydrophobic ferrocene monomers and hydrophilic carboxyl groups, namely poly(ferrocenylmethyl methacrylate-r-methacrylic acid) [poly(FMMA-r-MA)] with varied composition, was synthesized with free radical copolymerization. The morphologies of the resulting objects created by electrospray/electrospinning of the poly(FMMA-r-MA) solutions were effectively varied from particulate to fibrous structures by control of the composition, suggesting that the morphology of electrosprayed/electrospun copolymer objects was governed by its composition and hence, interaction with the solvent, highlighting the significance of the balance of hydrophilicity/hydrophobicity of the copolymer chain to the assembled structure. Resulting particles and nanofibers exhibited largely preserved responsiveness to reactive oxygen species (ROS) during the deposition process, opening up the potential to fabricate ROS-sensitive material with various desirable structures toward different applications.


A new species of Fageapseudes (Crustacea: Peracarida: Tanaidacea) from California, with comments on the systematics of the family Apseudidae.
Examination of material housed at the Los Angeles County Museum of Natural History revealed a new species of Fageapseudes from 4100 m depth off California, the first record of the genus in the eastern North Pacific. Fageapseudes pluma n. sp. is very similar to the Japanese species Fageapseudes brachyomos Bamber, but can be distinguished by differences in setation and by having fewer articles in the antennal flagellum and uropodal exopodite. It is unique for the genus and subfamily in having the inner caudodistal seta of the maxillipedal endite "feather-like" instead of "leaf-like" or simply setulose. Problems with the current classification of the Apseudidae are briefly discussed, and new diagnoses are established for the subfamily Leviapseudinae and the genus Fageapseudes.


Short-term changes in erythrocyte alpha-tocopherol content of vitamin E-deficient patients with cystic fibrosis.
Polyunsaturated fatty acids of biomembranes are a major target of lipid peroxidation. In vitamin E deficiency an efficient delivery of a high oral loading dose of all-rac-alpha-tocopheryl acetate to erythrocyte membranes could provide an early onset antioxidative effect. We investigated short-term changes in erythrocyte alpha-tocopherol after a single oral dose of 100 mg all-rac-alpha-tocopheryl acetate/kg in 10 vitamin E-deficient cystic fibrosis (CF) patients. Over 24 h, erythrocyte alpha-tocopherol increased 68% to 420% of preloading concentrations. With two exceptions, peak values were achieved 12 or 24 h after administration, which was 3-18 h later than peak plasma concentrations. Separate median-based curve estimates for the changes in erythrocyte alpha-tocopherol for five patients with and five without associated cholestatic liver disease were obtained. Cross-sectional test results revealed significantly lower erythrocyte alpha-tocopherol for the 9- and 24-h observations for patients with cholestatic liver disease compared with those without. Oral all-rac-alpha-tocopheryl acetate can be rapidly incorporated into erythrocyte membranes in vitamin E-deficient CF patients.


DISENGAGE Registry.
During fractional flow reserve (FFR) measurement, the simple presence of the guiding catheter (GC) within the coronary ostium might create artificial ostial stenosis, affecting the hyperemic flow. We aimed to investigate whether selective GC engagement of the coronary ostium might impede hyperemic flow, and therefore impact FFR measurements and related clinical decision-making. In the DISENGAGE (Determination of Fractional Flow Reserve in Intermediate Coronary Stenosis With Guiding Catheter Disengagement) registry, FFR was prospectively measured twice (with GC engaged [FFReng] and disengaged [FFRdis]) in 202 intermediate stenoses of 173 patients. We assessed (1) whether ΔFFReng-FFRdis was significantly different from the intrinsic variability of repeated FFR measurements (test-retest repeatability); (2) whether the extent of ΔFFReng-FFRdis could be clinically significant and therefore able to impact clinical decision-making; and (3) whether ΔFFReng-FFRdis related to the stenosis location, that is, proximal and middle versus distal coronary segments. Overall, FFR significantly changed after GC disengagement: FFReng 0.84±0.08 versus FFRdis 0.80±0.09, P<0.001. Particularly, in 38 stenoses (19%) with FFR values in the 0.81 to 0.85 range, GC disengagement was associated with a shift from above to below the 0.80 clinical cutoff, resulting into a change of the treatment strategy from medical therapy to percutaneous coronary intervention. The impact of GC disengagement was significantly more pronounced with stenoses located in proximal and middle as compared with distal coronary segments (ΔFFReng-FFRdis, proximal and middle 0.04±0.03 versus distal segments 0.03±0.03; P=0.042). GC disengagement results in a shift of FFR values from above to below the clinical cutoff FFR value of 0.80 in 1 out of 5 measurements. This occurs mostly when the stenosis is located in proximal and middle coronary segments and the FFR value is close to the cutoff value.


Amino acids control ammonia pulses in yeast colonies.
Individual yeast colonies produce pulses of volatile ammonia separated by phases of medium acidification. Colonies of Saccharomyces cerevisiae mutant defective in the general amino acid permease, Gap1p, exhibit decreased ammonia production. Mutations in the S. cerevisiae amino acid sensor SPS completely abolish the colony ammonia pulses. In contrast, the ammonia pulse production is independent of external concentrations of ammonium and of its uptake by the ammonium permeases Mep1p, Mep2p, and Mep3p. It is concluded that in S. cerevisiae colonies, the extracellular amino acids, but not the extracellular ammonium, serve as a source for volatile ammonia production. These phenomena are not restricted to S. cerevisiae, since we observe that extracellular levels of 8 out of the 20 tested amino acids are necessary for ammonia pulses produced by Candida mogii colonies.


pH-Sensitive, N-ethoxybenzylimidazole (NEBI) bifunctional crosslinkers enable triggered release of therapeutics from drug delivery carriers.
This paper presents a pH-sensitive bifunctional crosslinker that enables facile conjugation of small molecule therapeutics to macromolecular carriers for use in drug delivery systems. This N-ethoxybenzylimidazole (NEBI) bifunctional crosslinker was designed to exploit mildly acidic, subcellular environments to trigger the release of therapeutics upon internalization in cells. We demonstrate that an analog of doxorubicin (a representative example of an anticancer therapeutic) conjugated to human serum albumin (HSA, a representative example of a macromolecular carrier) via this NEBI crosslinker can internalize and localize into acidic lysosomes of ovarian cancer cells. Fluorescence imaging and cell viability studies demonstrate that the HSA-NEBI-doxorubicin conjugate exhibited improved uptake and cytotoxic activity compared to the unconjugated doxorubicin analog. The pH-sensitive NEBI group was also shown to be relatively stable to biologically-relevant metal Lewis acids and to serum proteins, supporting that these bifunctional crosslinkers may be useful for constructing drug delivery systems that will be stable in biological fluids such as blood.


Association between serum zinc level and lipid profiles in children with spinal muscular atrophy.
Children with spinal muscular atrophy (SMA) have a high rate of dyslipidaemia, which is a risk factor of vital importance for cardiovascular diseases in adulthood. Studies have demonstrated that the serum zinc level is associated with lipid profiles in the general population as well as in individuals diagnosed with obesity or diabetes. The purpose of this study was to evaluate the relationship between serum zinc level and lipid profiles in children with SMA. This cross-sectional study was launched in a tertiary children's medical center in China and involved pediatric patients with SMA under the management of a multidisciplinary team of outpatient services from July 2019 to July 2021. Anthropometric information, general clinical data, serum zinc level, lipid profiles, and body composition data were collected. Multivariate analysis was used for a thorough inquiry on the association between the serum zinc level and lipid profiles. Among the 112 patients with SMA [median (IQR) age 5.54 years (2.75-8.29), 58.04% female], who fulfilled the inclusion criteria of the study, dyslipidaemia was detected in 60 patients (53.57%). Based on multivariable linear regression, serum zinc level was positively associated with high-density lipoprotein cholesterol (HDL-C; β = 1.63, 95% CI = 0.44-3.22) and apolipoprotein A1 (APO A1; β = 2.94, 95% CI = 0.03-5.85) levels, independently of age, sex, type, activity, percentage of body fat, and body mass index. As the serum zinc level increased by 10 μmol/L, the risk of low APO A1 levels decreased by 35% (OR = 0.65, 95% CI = 0.44-0.97) according to multivariable logistic regression analyses. Serum zinc concentration was positively correlated with HDL-C and APO A1 levels among children with SMA. We suggest measures to correct the lower level of serum zinc to improve HDL-C and APO A1 levels.


Screening for attention-deficit/hyperactivity disorder in adult inpatients with psychiatric disorders.
The purpose was to assess the effectiveness of the adult ADHD Module from the MINI International Neuropsychiatric Interview (MINI) and the Conners' Adult ADHD Rating Scales: Screening Version DSM-IV ADHD Symptoms Total Scale (CAARS-S:SV) in screening for attention-deficit/hyperactivity (ADHD) disorder in patients hospitalized for other psychiatric disorders. Assessment measures were administered to 55 (50%) female and 55 (50%) male adult (>18 yr. old) inpatients. Only six (5%) of the 110 inpatients had been diagnosed with comorbid ADHD according to medical charts. In contrast, 55 (50%) patients met criteria for ADHD according to the MINI, and 39 (36%) patients met criteria on the CAARS-S:SV. The higher rates of prevalence for the MINI and the CAARS-S:SV were attributable to symptom criteria for ADHD being similar to those shared with comorbid disorders.


L/T-type calcium channel blocker reduces non-Gaussianity of heart rate variability in chronic kidney disease patients under preceding treatment with ARB.
Increased sympathetic nerve activity has been suggested in patients with chronic kidney disease (CKD). Pathologic sympathetic activity can alter heart rate variability (HRV), and the altered HRV has prognostic importance, so that reducing sympathetic activity may be an important strategy. Novel nonlinear HRVs, including deceleration capacity (DC), have greater predictive power for mortality. We have recently proposed an increase in a non-Gaussianity index of HRV, λ(25s), which indicates the probability of volcanic heart rate deviations of departure from each standard deviation level, as a marker of sympathetic cardiac overdrive. L/T-type calcium channel blocker (L/T-CCB), azelnidipine, decreases sympathetic nerve activity in experimental and clinical studies. In 43 hypertensive patients with CKD under treatment with an angiotensin receptor blocker (ARB), we investigated whether 8-week add-on L/T-CCB treatment could restore HRV. Means of all normal-to-normal intervals over 24 h (p<0.0001) and DC (p=0.002) increased, and λ(25s) (p=0.001) decreased regardless of gender, age, renal function or blood pressure, while no significant changes were observed in the other HRVs. Reduction of λ(25s) is useful to assess the effect of sympathoinhibitory treatment. Further studies are needed to investigate if the restoration of HRV is directly associated with the improvement of prognosis in patients with CKD.


Development of pattern visual evoked potentials: longitudinal measurements in human infants.
This experiment used longitudinal testing to trace the emergence of the major components of pattern visual evoked potentials (VEPs) in infants, using two paradigms: large-checkerboard pattern reversal and low spatial frequency pattern onset. Testing with both pattern-reversal and pattern-onset stimuli was performed on the same infants. Testing was conducted at weekly intervals during the first three postnatal months, and at intervals of 2 weeks to 1 month thereafter. The pattern-reversal and early pattern-onset responses recorded within individual subjects showed remarkably systematic developmental sequences. The broad, positive component seen at 200 to 250 ms in infants could be traced readily through the developmental sequence, to become the more sharply tuned positive component seen at about 100 ms in adults. Responses to low spatial frequency pattern onsets in infants were larger and more reliable than those in adults. The late components of the pattern-onset response, generally attributed to pattern offset, emerged later and with more complex changes. In all cases, response amplitude was much more variable than response latency, both within and between subjects. Frequent VEP recording in a longitudinal design can reveal systematic and detailed transitions of wave-form during development.


Additive combination studies of captopril and ditekiren, a renin inhibitor, in nonhuman primates.
Additive combination studies of an angiotensin converting enzyme (ACE) inhibitor, captopril, and a renin inhibitor, ditekiren (U-71038), were carried out in conscious sodium-depleted and sodium replete cynomolgus monkeys. The agents elicited dose-additive hypotensive responses regardless of the order of drug administration in sodium-depleted monkeys. A dose-additive blood pressure response was also observed when the administration of captopril was preceded by ditekiren in conscious sodium replete monkeys. None of the animals in these groups exhibited significant alterations of heart rate. An apparent over-additive hypotensive response, accompanied by tachycardia, occurred in sodium replete monkeys when ditekiren was administered after captopril. It was proposed that the captopril-induced hyperreninemia may have allowed the blood pressure to become partially renin-dependent and therefore susceptible to the inhibitory action of ditekiren. The results of these studies suggested that both ditekiren and captopril elicited cardiovascular effects in conscious cynomolgus monkeys via a decreased formation of angiotensin II.


Introduction of a Chimeric Chalcone Synthase Gene into Petunia Results in Reversible Co-Suppression of Homologous Genes in trans.
We attempted to overexpress chalcone synthase (CHS) in pigmented petunia petals by introducing a chimeric petunia CHS gene. Unexpectedly, the introduced gene created a block in anthocyanin biosynthesis. Forty-two percent of plants with the introduced CHS gene produced totally white flowers and/or patterned flowers with white or pale nonclonal sectors on a wild-type pigmented background; none of hundreds of transgenic control plants exhibited such phenotypes. Progeny testing of one plant demonstrated that the novel color phenotype co-segregated with the introduced CHS gene; progeny without this gene were phenotypically wild type. The somatic and germinal stability of the novel color patterns was variable. RNase protection analysis of petal RNAs isolated from white flowers showed that, although the developmental timing of mRNA expression of the endogenous CHS gene was not altered, the level of the mRNA produced by this gene was reduced 50-fold from wild-type levels. Somatic reversion of plants with white flowers to phenotypically parental violet flowers was associated with a coordinate rise in the steady-state levels of the mRNAs produced by both the endogenous and the introduced CHS genes. Thus, in the altered white flowers, the expression of both genes was coordinately suppressed, indicating that expression of the introduced CHS gene was not alone sufficient for suppression of endogenous CHS transcript levels. The mechanism responsible for the reversible co-suppression of homologous genes in trans is unclear, but the erratic and reversible nature of this phenomenon suggests the possible involvement of methylation.


[A multidisciplinary approach in diabetic foot disease is mandatory].
The history of two patients (66- and 53-year-old males) with diabetes and peripheral neuropathy illustrates the variety of clinical presentations and pitfalls in treatment of diabetic foot ulcers. Peripheral arterial disease and mechanical stress as a consequence of peripheral neuropathy are important risk factors for developing an ulcer and eventually loss of a limb. Revascularisation of the limb should be considered in the presence of critical limb ischaemia or in the presence of mild to severe ischaemia in combination with a deep infection. Infection is a major threat to the affected limb and requires treatment directly after taking samples for culture. After healing, education, adequate offloading and frequent foot examinations are important for secondary prevention. Presentation of these patients to a special multidisciplinary team, including a vascular surgeon, endocrinologist, rehabilitation specialist, cast technician, shoe technician and a podiatrist is mandatory, according to the Dutch guidelines on the diabetic foot.


[An experimental study on the cograft of auto-microskin and allo-dermal matrix].
To explore the promoting effects of cograft of auto-microskin and allo-dermal matrix on burn wound healing. Forty-six patches of full skin loss wounds were made in the backs of 6 small white swines. Auto-microskin and meshed acellular allo-dermal matrix were simultaneously prepared. The 46 wounds were averagely divided into test (T) and control (C) groups. The wounds in T group were covered with auto-microskin and allo-dermal matrix (1:4) and split-thick allo-porcine skin. While the wounds in C group were grafted with autoskin and allo-dermal matrix. The skin survival rate exhibited no difference between C and T groups (P > 0.05). There was similar histological exhibition in the two groups after skin grafting. The structure of collagen fibres appeared integrated, clear with regular arrangement and steady diameter at 8 - 20 post-operative weeks. Simultaneously, it was revealed by histological examination that normal vascular structure could be identified in the grafted skin and that inflammatory reaction ameliorated gradually and that epithelium combined well with dermis. It was also found that the epidermal papillar across the basement membrane fixed well to allo-dermis. The skin appeared smooth, elastic and functioned well at 5 months after skin grafting. The grafted skin survived well after the cograft of auto-microskin and allo-dermal matrix, which might be ideal covering material for the major deep burn wound healing.


Structures, energies, and bonding in the water heptamer.
In this paper we report the geometries and properties of 38 distinct geometrical motifs located on the B3LYP/6-31+G(d), MP2/6-311++G(d, p) potential energy surfaces of the water heptamer. Binding energies of up to 45 kcal/mol are calculated. All motifs fall within 10 kcal/mol of the most stable conformation, with at least 13 structural patterns located no more than 3 kcal/mol above, leading to a very complex potential energy surface, populated by a multitude of motifs each one allowing large numbers of conformations. Cluster stability does not seem to be correlated with the number of hydrogen bonds. Compact structures are energetically favored by electronic energies with zero-point energy corrections, while more open structures are preferred when temperature and entropy are accounted for. The molecular interactions holding the clusters as discrete units lead to large binding energies but are not strong enough to cause significant changes in the geometries of the interacting monomers. Our results indicate that bonding in the water heptamers can be considered as largely non-shared interactions with contributions from intermediate character of increasing covalency.


Remobilization of acorn nitrogen for seedling growth in holm oak (Quercus ilex), cultivated with contrasting nutrient availability.
The relative contribution of nitrogen (N) reserves from seeds or uptake by the roots to the growth and N content of young seedlings has received little attention. In this study, we investigated the contribution of N from the acorn or uptake by the roots to the N content of holm oak (Quercus ilex L.) seedlings and determined if remobilization of acorn N was affected by nutrient availability in the growing media. Q. ilex seedlings were cultivated for 3 months, until the end of the second shoot flush of growth, with three N fertilization rates: 8.6 mM N, 1.4 mM N or no fertilization. Fertilizer N was enriched in (15)N. Between 62 and 75% of the N contained in high and low fertilized seedlings, respectively, at the end of the second flush of growth was derived from the acorn. However, the dependence on acorn N was greater during the early root growth and first shoot flush of growth and decreased during the second shoot flush of growth, with root uptake contributing 32-54% of plant new N in this latter developmental stage in high and low fertilized plants, respectively. Fertilization rate did not affect the amount of N taken up during the earliest developmental stages, but it increased it during the second shoot flush of growth. Fertilization increased the mass of the shoot segment formed during the second shoot flush of growth and reduced the root mass, with no effect on whole plant growth. Remobilization of acorn N was faster in unfertilized plants than in fertilized plants. It is concluded that the holm oak seedlings depend greatly upon acorn N until the end of the second shoot flush of growth, that significant root N uptake starts at the beginning of the second shoot flush of growth and that acorn N remobilization is a plastic process that is accelerated under extremely low substratum nutrient content.


Tissue-specific differences between heart and liver cytochrome c oxidase.
Bovine liver cytochrome c oxidase has been isolated and the subunit structure of this preparation compared with that of the bovine heart enzyme. Of the 10 nuclear-coded subunits, 3 were different in the 2 tissue forms, having different migrations in sodium dodecyl sulfate-polyacrylamide gel electrophoresis, different antigenicities to antibodies made against the heart subunits, and different N-terminal amino acid sequences. Subunit ASA of heart begins with the N-terminal sequence of SSG in liver and is different in 17 of the first 33 residues including a deletion of 2 residues in the liver isoform of this subunit. Subunit CVII of liver differs from its heart counterpart in 6 of the first 37 residues while subunit CIX from liver differs from the heart isoform in 15 of the first 25 residues. No differences between tissue types were observed in partial sequencing of the remaining nuclear-coded subunits. Recently, the major portion of the sequence of subunit CIX from rat liver has been obtained by cloning and sequencing of the cDNA for this polypeptide [Suske, G., Mengel, T., Cordingley, M., & Kadenbach, B. (1987) Eur. J. Biochem. 168, 233-237]. There is a greater sequence homology of the rat and bovine liver forms of CIX than there is between the bovine heart and liver isoforms.


Stability of Coulomb crystals in a linear Paul trap with storage-ring-like confinement.
We report experiments on the stability of ion Coulomb crystals in a linear Paul trap with storage-ring-like confinement. The transverse dynamics of charged particles in a trap of this type is analogous to that of a fast beam traveling through a channel with periodic, magnetic alternating gradient confinement. The experimentally observed stability conditions for stationary crystals comply remarkably well with current theory of crystalline plasmas and beams.


The inhibitory effects of different curcuminoids on β-amyloid protein, β-amyloid precursor protein and β-site amyloid precursor protein cleaving enzyme 1 in swAPP HEK293 cells.
The hallmark of Alzheimer's disease (AD) is the accumulation of β-amyloid protein (Aβ). Aβ is generated from the β-amyloid precursor protein (APP) through the proteolysis of β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Aβ(42) isoform is more easily aggregate and more toxic to neurons than any other Aβ isoforms, thus being regarded as the primary toxic specie in AD. Curcumin mix has potent anti-amyloidogenic effect and shows great promise for AD treatment and prevention. The present study was conducted to examine the effects of curcumin mix and its different curcuminoids including curcumin (Cur), demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) on Aβ(42), APP and BACE1. We found that Cur was the most active curcuminoid fraction in suppressing Aβ(42) production and the order of inhibitory potency of other curcuminoids was DMC>curcumin mix>BDMC. Cur, but not other curcuminoids, could reduce APP protein expression and none of curcuminoids affected APP mRNA level. BDMC could reduce BACE1 mRNA and protein levels, while DMC only affected BACE1 mRNA expression. Our data indicate that the anti-amyloidogenic effect of Cur may be mediated through the modulation of APP, while the anti-amyloidogenic effect of BDMC may be mediated through the modulation of BACE1.


Nanocarriers-Assisted Needle-Free Vaccine Delivery Through Oral and Intranasal Transmucosal Routes: A Novel Therapeutic Conduit.
Drug delivery using oral route is the most popular, convenient, safest and least expensive approach. It includes oral transmucosal delivery of bioactive compounds as the mucosal cavity offers an intriguing approach for systemic drug distribution. Owing to the dense vascular architecture and high blood flow, oral mucosal layers are easily permeable and can be an ideal site for drug administration. Recently, the transmucosal route is being investigated for other therapeutic candidates such as vaccines for their efficient delivery. Vaccines have the potential to trigger immune reactions and can act as both prophylactic and therapeutic conduit to a variety of diseases. Administration of vaccines using transmucosal route offers multiple advantages, the most important one being the needle-free (non-invasive) delivery. Development of needle-free devices are the most recent and pioneering breakthrough in the delivery of drugs and vaccines, enabling patients to avoid needles, reducing anxiety, pain and fear as well as improving compliance. Oral, nasal and aerosol vaccination is a novel immunization approach that utilizes a nanocarrier to administer the vaccine. Nanocarriers improve the bioavailability and serve as adjuvants to elicit a stronger immune response, resulting in increased effectiveness of vaccination. Drugs and vaccines with lower penetration abilities can also be delivered transmucosally while maintaining their biological function. The development of micro/nanocarriers for transmucosal delivery of macromolecules, vaccines and other substances is currently drawing much attention and a number of studies were performed recently. This comprehensive review is aimed to summarize the most recent investigations on needle-free and non-invasive approaches for the delivery of vaccines using oral transmucosal route, their strengths and associated challenges. The oral transmucosal vaccine delivery by nanocarriers is the most upcoming advancement in efficient vaccine delivery and this review would help further research and trials in this field.


Assessment of cauda equina syndrome progression pattern to improve diagnosis.
Meta-analysis of individual patient data. To date, the progression pattern of cauda equina syndrome (CES) has not been summarized. This study assessed individual patient data from CES cases, investigated the CES progression pattern to help clinicians provide timely diagnoses. Because there were few randomized controlled trials about CES, our research was based on case reports of CES with detailed medical history. We searched English literature regarding CES in the PubMed database. We included a total of 198 publications involving 264 cases that met the inclusion criteria. The occurrence order of symptoms was determined by reviewing patients' medical histories, and the progression pattern of CES was analyzed using sequential pattern mining. Finally, we summarized and reassessed the current timing of CES diagnosis. Result of sequential pattern mining demonstrated that the progression process of CES could be divided into 3 stages: early stage of CES (CESE), with bilateral peripheral nerve dysfunction characterized by progressive sensory-motor defects from unilateral to bilateral in lower extremities; incomplete CES, with reduction of sphincter functions; and CES in retention, with sphincter dysfunction. Among all the cases, 81.08% (180 cases) were diagnosed at the stage of incomplete CES or CES in retention, in which 99.4% (179 cases) had experienced CESE without being diagnosed. The characteristic progressive sensory-motor CESE defects in lower extremities marked CES onset. Instead of waiting for the onset of sphincter function abnormalities, CES should be diagnosed when the CESE symptoms manifest.


Numerical study of aeolian vibration characteristics and fatigue life estimation of transmission conductors.
The 2D computational fluid dynamics (CFD) model of transmission conductor is set up to simulate the aerodynamic forces varying with time on the conductor. Taking into account the geometrical nonlinearity of conductor lines, the finite element (FE) models of single span and two-span transmission lines discretized with beam elements are established. By means of the FE models, the aeolian vibrations of the conductor lines excited by the aerodynamic forces under different wind velocities are numerically simulated. The nonlinear resonant characteristics, the amplitude-frequency relations of the conductor lines during aeolian vibration are investigated, and the influences of the span length as well as the initial tension in conductors on the aeolian vibration characteristics are analyzed. Furthermore, a 3D FE model of a conductor segment and the suspension clamp is created to study the stress distributions of the 3D model corresponding to different lines during aeolian vibrations. Finally, based on the stress analysis of the 3D model, the fatigue lives of the transmission conductors during aeolian vibration under different wind velocities are estimated. The jump phenomenon induced by the nonlinear vibration is reflected by the numerical simulation considering the geometric nonlinearity, and it is found that the energy balance principle (EBP) overestimates the vibration amplitudes because it cannot take the influences of the geometrical nonlinearity and span length into account. The obtained results may provide some instructions for the prevention design of aeolian vibration.


The macrophage scavenger receptor SR-AI/II and lung defense against pneumococci and particles.
The class A macrophage scavenger receptor SR-AI/II is implicated as a pattern recognition receptor for innate immunity, but its functional role in lung defense has not been studied. We used mice genetically deficient in SR-AI/II and their wild-type C57BL/6 counterparts to investigate the contribution of this receptor to defense against pneumococcal infection and inhaled particles. SR-AI/II deficiency caused impaired phagocytosis of fluorescent bacteria in vivo, diminished clearance of live bacteria from the lungs, and substantially increased pneumonic inflammation. Survival studies also showed increased mortality in SR-AI/II-deficient mice with pneumococcal lung infection. Similarly, after challenge of the airways with TiO(2) particles, SR-AI/II-deficient mice showed increased proinflammatory cytokine levels in lung lavage fluid and a more pronounced neutrophilic inflammation. The data indicate that the lung macrophage class A scavenger receptor SR-AI/II contributes to innate defense against bacteria and inhaled particles.


A case of acute poststreptococcal glomerulonephritis complicated by interstitial nephritis related to streptococcal pyrogenic exotoxin B.
This paper presents the case of a patient who developed acute kidney injury and nephrotic syndrome following streptococcal cutaneous infection. He presented with microhematuria, severe proteinuria and systemic edema 5 days after infection. Blood examination showed elevated creatinine level, hypocomplementemia, and elevated anti-streptolysin O level. Renal biopsy revealed endocapillary proliferative glomerulonephritis with tubulointerstitial nephritis (TIN). Immunofluorescence revealed C3-dominant glomerular staining, while electron microscopy showed hump-shaped subepithelial deposits. The patient was therefore diagnosed with poststreptococcal glomerulonephritis. The unique histological feature was C3 deposition in the tubular basement membrane (TBM), in which we detected streptococcal pyrogenic exotoxin B (SpeB), a nephritogenic antigen produced by streptococci. No nephritis-associated plasmin receptor or plasmin activity was evident in the TBM. These nephritogenic antigens and upregulation of plasmin activity were observed in glomeruli. This case suggests that TIN after poststreptococcal infection might be partially attributable to SpeB toxicity.