Exploration of the influence of surface proteins on the probiotic activity of Lactobacillus pentosus HC-2 in the Litopenaeus vannamei midgut via label-free quantitative proteomic analysis.
Our previous work showed that using Lactobacillus pentosus HC-2 as a probiotic could improve the growth performance, immune response, gut bacterial diversity and disease resistance of Litopenaeus vannamei. However, the probiotic mechanism had not been fully characterized. In the present study, histology and proteomic analysis were performed to explore the influence of HC-2 surface protein on its probiotic effects on L. vannamei after feeding either the intact surface proteins, the probiotic treated with lithium chloride (LiCl) to remove noncovalently bound surface proteins or no probiotic for four weeks. Histological observation found that feeding with normal HC-2 obviously improved the intestinal histology and enhanced the protective effect against pathogen damage, but feeding with LiCl-treated HC-2 did not improve the intestinal environment. A total of over 2764 peptides and 1118 uniproteins were identified from the L. vannamei midgut; 211 proteins were significantly differentially expressed in the normal HC-2 group compared with the control group; 510 proteins were significantly differentially expressed in the LiCl-treated HC-2 group compared with the control group, and 458 proteins were significantly differentially expressed in the LiCl-treated HC-2 group compared with the normal HC-2 group. GO/KEGG enrichment analysis of the significantly different proteins demonstrated that feeding normal HC-2 mainly induced immune response, metabolic, cell adhesion and cell-cell signaling-related protein upregulation, which contributed to bacterial adhesion and colonization in the midgut to improve the shrimp immune system and growth, but these proteins were suppressed after the shrimp were fed bacteria deprived of surface proteins. Taken together, these results indicate that the surface proteins were indispensable for HC-2 to execute probiotic effects in the shrimp midgut.


Study of removal of Direct Yellow 12 by cadmium oxide nanowires loaded on activated carbon.
In this research, cadmium oxide nanowires loaded on activated carbon (CdO-NW-AC) has been synthesized by a simple procedure and characterized by different techniques such as XRD, SEM and UV-vis spectrometry. This new adsorbent has been efficiently utilized for the removal of the Direct Yellow 12 (DY-12) from wastewater. To obtain maximum DY-12 removal efficiency, the influences of variables such as pH, DY-12 concentration, amount of CdO-NW-AC, contact time, and temperature have been examined and optimized in a batch method. Following the variable optimization, the experimental equilibrium data (at different concentration of DY-12) was fitted to conventional isotherm models such as Langmuir, Freundlich and Tempkin. The applicability of each method is based on the R(2) and error analysis for each model. It was found that the experimental equilibrium data well fitted to the Langmuir isotherm model. The dependency of removal process to time and the experimental data follow second order kinetic model with involvement of intraparticle diffusion model. The negative value of Gibbs's free energy and positive value of adsorption enthalpy show the spontaneous and endothermic nature of adsorption process.


Curability of patients with lymph node metastases from extremity soft-tissue sarcoma.
Lymph node metastases (LNM) rarely occur in adult extremity soft-tissue sarcoma (STS), affecting approximately 5% of patients. To the authors' knowledge, few studies to date have evaluated the prognosis and survival of patients with LNM. A retrospective review was performed of a single-center, prospectively collected STS database. Demographic, treatment, and oncologic data for patients with STS of the extremity with LNM were obtained from clinical and radiographic records. Of 2689 patients with extremity STS, a total of 120 patients (4.5%) were diagnosed with LNM. LNM occurred most frequently among patients diagnosed with clear cell sarcoma (27.6%), epithelioid sarcoma (21.9%), rhabdomyosarcoma (17.3%), angiosarcoma (14.0%), and extraskeletal myxoid chondrosarcoma (9.3%). A total of 98 patients (81.7%) underwent LNM surgical resection. Patients with isolated LNM had a greater 5-year overall survival (57.3%) compared with patients with American Joint Committee on Cancer (AJCC) eighth edition stage IV STS with only systemic metastases (14.6%) or both LNM and systemic disease (0%; P < .0001). Patients with isolated LNM had an overall survival rate (52.9%) similar to that of patients with localized AJCC stage III tumors (ie, large, high-grade tumors) (49.3%) (P = .8). Patients with late, isolated, metachronous LNM had a 5-year overall survival rate (61.2%) that was similar to that of patients with isolated synchronous LNM at the time of presentation (53.6%) (P = .4). Many different types of STS develop LNM. Patients with extremity STS with isolated LNM should not be considered as having stage IV disease as they are according to the current AJCC eighth edition classification because they have significantly better survival than those with systemic metastases. Patients with isolated, late, metachronous LNM have a survival similar to that of patients with isolated synchronous LNM at the time of presentation. The results of the current study demonstrated that patients diagnosed with isolated lymph node metastases have a prognosis similar to that of patients diagnosed with localized American Joint Committee on Cancer stage III soft-tissue sarcomas, which also equates to a significantly better overall survival compared with patients with systemic metastases. Therefore, the authors recommend modifications to the most recent eighth edition of the American Joint Committee on Cancer staging system to clearly distinguish patients with isolated lymph node metastases to acknowledge their better prognosis compared with those with systemic metastases.


Immunocytochemical localization on neuropeptides in the fornix of rat, monkey and man.
Using specific antisera and immunocytochemical methods VIP, CCK, substance P, methionine-enkephalin, neurotensin and somatostatin-like immunoreactive fibers were found within the fornix and fimbria in 3 species (rat, monkey and human). Neither methionine-enkephalin- nor substance P-containing cell bodies were located within the hippocampus and so fibers containing these peptides are presumably hippocampal afferents, probably arising in the septum or caudal hypothalamus. VIP, CCK, neurotensin and somatostatin fibers may be hippocampal efferents arising from cell bodies within the subiculum.


The dioxin and peroxisome proliferator-activated receptors: nuclear receptors in search of endogenous ligands.
Dioxins and peroxisome proliferators represent two diverse classes of xenobiotic compounds that induce transcription of specific genes encoding cytochrome P-450 drug-metabolizing enzymes. Signal transduction by these chemicals is mediated by two distinct nuclear receptors, one of which has recently been demonstrated to be a member of the steroid hormone receptor superfamily of ligand-activated transcription factors. However, no endogenous ligand has so far been identified for either of these nuclear receptors. Lorenz Poellinger, Martin Göttlicher and Jan-Ake Gustafsson review properties of both these xenobiotic receptor systems and discuss how the molecular details in the receptor activation pathways compare with those of nuclear hormone receptors.


Performance of endoscopic ultrasound for diagnosis of agenesis of the dorsal pancreas: a case report.
Agenesis of the dorsal pancreas is a rare congenital pancreatic malformation. We herein describe a 67-year-old woman with a 5-day history of lower back pain who was eventually diagnosed with agenesis of the dorsal pancreas. Abdominal computed tomography showed an enlarged pancreatic head, but the pancreatic body and tail were invisible. The magnetic resonance imaging findings were similar to the computed tomography findings. Magnetic resonance cholangiopancreatography showed that the major pancreatic duct was mildly dilated but otherwise normal. Endoscopic ultrasound revealed absence of the pancreatic body and tail, an enlarged head of the pancreas, and mild pancreatic duct dilation. The final diagnosis was dorsal pancreatic agenesis.


The differential expression of lamin epitopes during mouse spermatogenesis.
The presence of lamin proteins in mouse spermatogenic cells has been examined by using an anti-lamin AC and an anti-lamin B antisera which recognize somatic lamins A and C, and somatic lamin B, respectively. Anti-lamin B binds to the nuclear periphery of all cell types examined, including Sertoli cells, primitive type A spermatogonia, preleptotene, leptotene, zygotene and pachytene spermatocytes, and round spermatids. In sperm nuclei, the antigenic determinants are localized to a narrow domain of the nucleus. However, after removing the perinuclear theca, anti-lamin B localizes to the entire nuclear periphery in a punctate pattern, suggesting that it is binding to determinants previously covered by the theca constituents. On immunoblots anti-lamin B reacts with a approximately 68 kD polypeptide in all germ cells and, to a lesser extent, with four additional polypeptides present only in meiotic and post-meiotic nuclear matrices. Anti-lamin AC also reacts with the perinuclear region of the somatic cells in the testes, in particular, those of the interstitium and also the Sertoli cells of the seminiferous epithelium. In contrast to anti-lamin B, anti-lamin AC does not bind to the germ cells at any stage of spermatogenesis. In addition, nuclear matrix proteins from isolated spermatogenic cells do not bind anti-lamin AC on immunoblots, suggesting the lack of reactivity is not due to the masking of any antigenic sites. These data demonstrate that germ cells contain lamin B throughout spermatogenesis, even during meiosis and spermiogenesis when the nuclear periphery lacks a distinct fibrous lamina.


Region-of-interest-based analysis of clustered BOLD MRI data in experimental arthritis.
BOLD MRI provides functional information based on minimal changes. Problems inherent in data processing of the very low signal-to-noise-ratio of BOLD experiments have created obstacles for validation of certain techniques using standard strength-field MR scanners. Measures of diagnostic accuracy of clustered data are directly related to the reading parameters used to define regions-of-interest (ROIs). Our primary aim was to determine the combination of ROI-related reading parameters that provides highest accuracy for discrimination of presence or absence of arthritis in acute and subacute stages of the disease using paired comparisons of BOLD MRI data. Six male New Zealand white rabbits were injected with albumin into one knee and saline into the contralateral knee, 3 animals had albumin injected into only one of the knees, 2 had saline injected into one of the knees, and 3 animals were not injected. The rabbits' knees underwent BOLD MRI on days 1 and 28 after induction of arthritis, except for the knees of 3 animals (albumin- vs saline-injected knees, n = 2 animals; saline- vs noninjected knees, n = 1 animal) that died before expected and had only the first MRI examination done. Percentage of activated voxels and differences in on-and-off signal intensities were the BOLD MRI methods applied. Data were analyzed using anatomic-driven small ROI, voxel-chaser-driven small ROI and anatomic-driven large ROI techniques. Diagnostic areas-under-the curve (AUCs) were obtained only for acute arthritis and only when percentage of activated voxels was used. Low threshold, positive voxel activations and small ROIs generated the largest AUCs (AUC +/- SE, .911 +/- .092, P = .014) using either anatomic-driven or voxel-chaser-driven techniques. A sensitivity analysis confirmed the importance of threshold as a parameter for analysis. Low threshold, positive voxel activations and small ROIs constituted the set of reading parameters that provided the most accurate BOLD MRI results.


Protective role of microglial HO-1 blockade in aging: Implication of iron metabolism.
Heme oxygenase-1 (HO-1) is an inducible enzyme known for its anti-inflammatory, antioxidant and neuroprotective effects. However, increased expression of HO-1 during aging and age-related neurodegenerative diseases have been associated to neurotoxic ferric iron deposits. Being microglia responsible for the brain's innate immune response, the aim of this study was to understand the role of microglial HO-1 under inflammatory conditions in aged mice. For this purpose, aged wild type (WT) and LysMCreHmox1△△ (HMOX1M-KO) mice that lack HO-1 in microglial cells, were used. Aged WT mice showed higher basal expression levels of microglial HO-1 in the brain than adult mice. This increase was even higher when exposed to an inflammatory stimulus (LPS via i.p.) and was accompanied by alterations in different iron-related metabolism proteins, resulting in an increase of iron deposits, oxidative stress, ferroptosis and cognitive decline. Furthermore, microglia exhibited a primed phenotype and increased levels of inflammatory markers such as iNOS, p65, IL-1β, TNF-α, Caspase-1 and NLRP3. Interestingly, all these alterations were prevented in aged HMOX1M-KO and WT mice treated with the HO-1 inhibitor ZnPPIX. In order to determine the effects of microglial HO-1-dependent iron overload, aged WT mice were treated with the iron chelator deferoxamine (DFX). DFX caused major improvements in iron, inflammatory and behavioral alterations found in aged mice exposed to LPS. In conclusion, this study highlights how microglial HO-1 overexpression contributes to neurotoxic iron accumulation providing deleterious effects in aged mice exposed to an inflammatory insult.


Probabilistic numerical discrimination in mice.
Previous studies showed that both human and non-human animals can discriminate between different quantities (i.e., time intervals, numerosities) with a limited level of precision due to their endogenous/representational uncertainty. In addition, other studies have shown that subjects can modulate their temporal categorization responses adaptively by incorporating information gathered regarding probabilistic contingencies into their time-based decisions. Despite the psychophysical similarities between the interval timing and nonverbal counting functions, the sensitivity of count-based decisions to probabilistic information remains an unanswered question. In the current study, we investigated whether exogenous probabilistic information can be integrated into numerosity-based judgments by mice. In the task employed in this study, reward was presented either after few (i.e., 10) or many (i.e., 20) lever presses, the last of which had to be emitted on the lever associated with the corresponding trial type. In order to investigate the effect of probabilistic information on performance in this task, we manipulated the relative frequency of different trial types across different experimental conditions. We evaluated the behavioral performance of the animals under models that differed in terms of their assumptions regarding the cost of responding (e.g., logarithmically increasing vs. no response cost). Our results showed for the first time that mice could adaptively modulate their count-based decisions based on the experienced probabilistic contingencies in directions predicted by optimality.


Quinalizarin inhibits adipogenesis through down-regulation of transcription factors and microRNA modulation.
Protein kinase CK2 is induced early in adipogenesis whereas later on, this kinase seems to be dispensable. Here, we have analysed how CK2 might be involved in early steps of differentiation of 3T3-L1 cells. 3T3-L1 cells were differentiated to adipocytes in the absence or presence of quinalizarin. The expression and localization of important transcription factors was analysed by Western blot and immunofluorescence. DNA binding capacity and transactivation was analysed with pull-down assays and with luciferase reporter experiments, respectively. mRNA was detected with qRT-PCR, miRNAs with Northern hybridization and qRT-PCR. We show that clonal expansion was considerably repressed upon inhibition of CK2 with quinalizarin. Moreover, to prevent adipogenesis CK2 inhibition had to take place before day 4 of differentiation. Neither the expression at the protein or at the RNA level nor the subcellular localization of the transcription factors C/EBPβ and C/EBPδ was affected by CK2 inhibition. There was, however, a drastic reduction in the mRNA and protein levels of C/EBPα and PPARγ2. Upon inhibition of CK2, we found a significant up-regulation of the level of the microRNAs miR-27a and miR-27b, which are known to target PPARγ mRNA. Time course experiments revealed that CK2 seems to be required at early time points after the induction of differentiation. One important target of CK2 was identified as PPARγ, which is down-regulated after inhibition of CK2. This is the first report about i) cellular targets of CK2 during adipogenesis and ii) a role of CK2 in microRNA regulation.


Day case cardiac catheterisation using the Sones technique.
Cardiac catheterisation using the Sones technique was planned as a day case procedure in 855 of 1662 consecutive patients admitted for cardiac catheterisation. Of these, 810 (95%) were discharged the same day. Forty-five (5%) needed overnight hospitalization, 34 for reasons connected with the procedure and 11 for other reasons. No serious complications occurred and there were no deaths. The cost of day stay was approximately half that incurred using overnight stay. Thus, cardiac catheterisation using the Sones technique on a day case basis is safe and may produce significant cost efficiency.


An immunohistochemical study of Whipple's disease using the immunoperoxidase technique.
Formalin-fixed, paraffin-embedded jejunal, lymph nodal, and splenic tissues were obtained from four patients with Whipple's disease. Using antisera to a variety of bacteria, sections were stained by the immunoperoxidase technique. Positive staining was obtained with antiserum to streptococcus group B in all tissues examined. The distinctive pattern of staining was similar to the findings of previous workers using fluorescein-labeled antibodies. However, when rigorous controls for specificity were applied in this study, it was not possible to confirm the presence of streptococcus B antigen in the tissues. The discrepancy between the specificity of the technique on control and test sections is interesting and emphasizes the need for adequate controls when the immunoperoxidase technique is used to look for microorganisms in tissues. It is suggested that the unknown microorganism observed in the macrophages of patients with Whipple's disease has been altered in some way to resemble streptococcus B antigenically or that it shares common antigens with streptococcus B.


Deep Brain Stimulation of the Internal Pallidum in Lesch-Nyhan Syndrome: Clinical Outcomes and Connectivity Analysis.
Lesch-Nyhan syndrome (LNS) is a rare genetic disorder characterized by a deficiency of hypoxanthine-guanine phosphoribosyltransferase enzyme. It manifests during infancy with compulsive self-mutilation behavior associated with disabling generalized dystonia and dyskinesia. Clinical management of these patients poses an enormous challenge for medical teams and carers. We report our experience with bilateral deep brain stimulation (DBS) of the globus pallidus internus (GPi) in the management of this complex disorder. Preoperative and postoperative functional assessment data prospectively collected by a multidisciplinary pediatric complex motor disorders team, including imaging, neuropsychology, and neurophysiology evaluations were analyzed with regards to motor and behavioral control, goal achievement, and patient and caregivers' expectations. Four male patients (mean age 13 years) underwent DBS implantation between 2011 and 2018. Three patients received double bilateral DBS electrodes within the posteroventral GPi and the anteromedial GPi, whereas one patient had bilateral electrodes placed in the posteroventral GPi only. Median follow-up was 47.5 months (range 22-98 months). Functional improvement was observed in all patients and discussed in relation to previous reports. Analysis of structural connectivity revealed significant correlation between the involvement of specific cortical regions and clinical outcome. Combined bilateral stimulation of the anteromedial and posteroventral GPi may be considered as an option for managing refractory dystonia and self-harm behavior in LNS patients. A multidisciplinary team-based approach is essential for patient selection and management, to support children and families, to achieve functional improvement and alleviate the overall disease burden for patients and caregivers.


A label-free photoelectrochemical immunosensor for detection of the milk allergen β-lactoglobulin based on Ag2S -sensitized spindle-shaped BiVO4/BiOBr heterojunction by an in situ growth method.
Food allergies have become a nonnegligible food safety issue, and milk allergies are one of the most common food allergies, that has attracted large consumer attention. In this work, a novel label-free photoelectrochemical (PEC) immunosensor for the detection of the allergen β-lactoglobulin (β-LG) in dairy products was designed that used the specific recognition of allergen β-LG and antibodies in dairy products in combination with biosensing technology. Here, Ag2S-sensitized spindle-shaped BiVO4/BiOBr heterojunction was fixed on the surface of the ITO electrode as an excellent photoactive substrate and effectively improved the photocurrent responses and sensitivity. Thioglycolic acid (TGA) was used as a linker to immobilize the β-LG antibody on the surface of the electrode. The photocurrent was detected at different antigen concentrations, which realized the quantitative testing of β-LG. Under the optimal experimental conditions, the PEC immunosensor proved an ideal linear relationship ranging from 10 pg/mL to 100 ng/mL, with a low detection limit of 3.7 pg/mL. The designed immunosensor showed good stability, a wide linear range, high sensitivity and good reproducibility and could be used for the detection of actual samples. The PEC immunosensor had a strong ability to specifically recognize β-LG, which was not affected by other proteins in the milk without pretreatment. Meanwhile, the developed immunosensor provided a promising PEC detection platform and reference idea for the detection of other proteins in milk.


Further study on spectrophotometric determination of CO--Hb in post-mortem blood.
The method for spectrophotometric determination of CO--Hb in blood on the basis of difference in absorbancies of deoxy- and carboxy-hemoglobin reported previously [1] was further improved. The total blood hemoglobin content was determined by the azide-methemoglobin method instead of the well-known cyanmethemoglobin method. This method was found to be useful even if applied to old or putrefied blood samples.


Reproductive effort and success of wild female mallards: does male quality matter?
In accordance with the differential allocation hypothesis, females are expected to increase their reproductive investment when mated to high-quality males. In waterfowl, reproductive, investment increased when captive female mallards (Anas platyrhynchos) were mated to more attractive males, but information for wild ducks is lacking. Studies of waterfowl mating systems have focused primarily on the importance of plumage coloration of males and female mate choice, whereas investigations of reproductive ecology examine female attributes and virtually ignore the role of males in investment decisions. Here, we used unique data for 253 pairs of wild mallards to test whether females mated to high-quality males would increase reproductive effort and reproduce more successfully. We derived measurements of female and male body size and condition, and indices of male plumage quality, and related these traits to patterns of reproductive effort and performance of females. Consistent with predictions, yearling females nested earlier and had higher nest survival when mated to males with better plumage scores. Furthermore, when paired with larger bodied males, yearling females renested more often, and nest and brood survival increased among older females. Although the strength of male effects varied with breeding stage and female age or experience, this is one of a few studies to demonstrate an additive effect of male quality on investment and success of females, in free-ranging birds.


Randomized dose-controlled study of topiramate as first-line therapy in epilepsy.
To evaluate the efficacy and tolerability of topiramate as monotherapy, using a dose-controlled study design. We conducted a multinational, randomized, double-blind trial in adults and children (> or =6 years old) with epilepsy that was not being treated when randomized to 400 or 50 mg/day topiramate as target maintenance dosages. In addition to > or =2 lifetime unprovoked seizures, patients had to have one or two partial-onset seizures or generalized-onset tonic-clonic seizures in the 3-month retrospective baseline. The primary efficacy end point was time to first seizure; a secondary efficacy measure was the seizure-free rate at 6 months and 1 year. Double-blind treatment continued until 6 months after the last patient was randomized. Kaplan-Meier survival analyses for time to first seizure (intent-to-treat, n = 470) favored 400 mg/day over 50 mg/day (P = 0.0002) as a target maintenance dosage. The first evaluation point with a significant difference (P = 0.046) favoring the higher dose was at day 14 when patients were receiving 100 or 25 mg/day. The probability of being seizure-free at 6 months was 83% in patients randomized to 400 mg/day and 71% in those randomized to 50 mg/day (P = 0.005). Seizure-free rates at 12 months were 76% and 59%, respectively (P = 0.001). Differences favoring the higher dose were significant in patients with partial-onset seizures (P = 0.009) and in those with generalized-onset tonic-clonic seizures (P = 0.005). The most common dose-related adverse events were paresthesia, weight loss, and decreased appetite. Discontinuations due to cognitive-related adverse events were 2% in the 50-mg group and 7% in the 400-mg group. Overall, 7% and 19%, respectively, discontinued with adverse events during the median treatment duration of 9 months. Topiramate is effective as monotherapy in adults and children. Because a therapeutic effect emerges during titration, clinicians should adjust dosages in step-wise fashion with intermediate stopping points, e.g., 100 mg/day, to evaluate patient response and achieve the optimal maintenance dosage.


Activity of syngeneic complement for revealing antibody-induced cytotoxicity against a rat hepatoma.
The cytotoxicity of tumour-bearer serum against a transplanted aminoazodye-induced rat hepatoma was revealed using normal rat serum as the source of complement as assessed using a short-term 51Cr release test. The tumour-bearing rat was not deficient in a functional complement system and direct cytolysis against hepatoma cells was demonstrated following admixture of tumour cells and serum with no additional complement. No tumour growth was observed in animals receiving subcutaneous transfer of cells treated with tumour-bearer serum, although when heat-inactivated (56 C for 60 min) or normal sera were used, there was no modification of tumour development. The present findings indicate that the tumour-bearing animal contains both antibodies and complement sufficient for tumour lysis, although the full contribution of serum-mediated cytotoxicity in imposing immunological constraints upon tumour growth remains to be elucidated.


Contactless Measurement of Sheet Resistance of Nanomaterial Using Waveguide Reflection Method.
Conductive nanomaterials are widely studied and used. The four-point probe method has been widely used to measure nanomaterials' sheet resistance, denoted as . However, for materials sensitive to contamination or physical damage, contactless measurement is highly recommended if not required. Feasibility of evaluation using a one-port rectangular waveguide working on the microwave band in a contact-free mode is studied. Compared with existed waveguide methods, the proposed method has three advantages: first, by introducing an air gap between the waveguide flange and the sample surface, it is truly contactless; second, within the specified range of , the substrate's effect may be neglected; third, it does not require a matched load and/or metallization at the sample backside. Both theoretical derivation and simulation showed that the magnitude of the reflection coefficient decreased monotonously with increasing . Through calibration, a quantitative correlation of and was established. Experimental results with various conductive glasses showed that, for in the range of ~10 to 400 Ohm/sq, the estimation error of sheet resistance was below ~20%. The potential effects of air gap size, sample size/location and measurement uncertainty of are discussed. The proposed method is particularly suitable for characterization of conductive glass or related nanomaterials with in the range of tens or hundreds of Ohm/sq.


Renal manifestations of Kawasaki's disease.
Renal sonographic evaluation of seven patients with mucocutaneous lymph node syndrome were performed and correlated with clinical and laboratory data either supporting or not supporting renal disease associated with this entity. Four of seven patients demonstrated significant elevations of the BUN, creatinine and/or significant proteinuria. These four patients had renal sonographic findings of increased cortical echogenicity, enlarged kidneys and enhanced corticomedullary differentiation. This complication of mucocutaneous lymph node syndrome has heretofore not been noted.


Biological Basis for Amyloidogenesis in Alzheimer's Disease.
Certain cellular proteins normally soluble in the living organism under certain conditions form aggregates with a specific cross-β sheet structure called amyloid. These intra- or extracellular insoluble aggregates (fibers or plaques) are hallmarks of many neurodegenerative pathologies including Alzheimer's disease (AD), Huntington's disease, Parkinson's disease, prion disease, and other progressive neurological diseases that develop in the aging human central nervous system. Amyloid diseases (amyloidoses) are widespread in the elderly human population, a rapidly expanding demographic in many global populations. Increasing age is the most significant risk factor for neurodegenerative diseases associated with amyloid plaques. To date, nearly three dozen different misfolded proteins targeting brain and other organs have been identified in amyloid diseases and AD, the most prevalent neurodegenerative amyloid disease affecting over 15 million people worldwide. Here we (i) highlight the latest data on mechanisms of amyloid formation and further discuss a hypothesis on the amyloid cascade as a primary mechanism of AD pathogenesis and (ii) review the evolutionary aspects of amyloidosis, which allow new insight on human-specific mechanisms of dementia development.


Sequential dose injections. A new technique for technetium-99m colloid gastrointestinal bleeding studies.
For Tc-99m colloid bleeding studies to be positive, the patient must be actively bleeding while the colloid is circulating in the blood pool. A simple technique of sequential dose injections (SDI) is presented where five injections of 2 mCi each are made at 5-minute intervals. Image acquisition is performed after each injection. This technique results in an increase in the effective plasma residence time of the colloidal particles from 10-15 minutes to 35-40 minutes. A case report is presented in which the bleeding site was identified only after the fifth serial injection of a fractionated dose of Tc-99m microaggregated albumin colloid.


Effect of structure-directing agents on facile hydrothermal preparation of hierarchical γ-Al2O3 and their adsorption performance toward Cr(VI) and CO2.
Hierarchical flower-like and sphere-like mesoporous γ-Al2O3 microparticles were successfully prepared by a facile hydrothermal method followed by a calcination process using sodium aluminate as aluminum source, urea as precipitating agent, and Pluronic F127 (EO106PO70EO106), polyacrylic acid sodium (PAAS), and mixed F127-PAAS as structure-directing agents (SDAs), respectively. Effects of the SDAs on the phase structure, morphology, textural properties, surface alkaline, and the adsorption performance toward Cr(VI) and CO2 of the as-prepared samples were comparatively studied by X-ray diffraction (XRD), scanning electron microscope (SEM), transmission electron microscope (TEM), N2 adsorption-desorption, CO2 temperature programmed desorption (CO2-TPD), and UV-Vis spectrophotometric method. The results indicate that the sphere-like γ-Al2O3 obtained by using F127 as the SDA shows the best adsorption performance toward Cr(VI) with a high adsorption rate of 95% and adsorption capacity of 5.7 mg/g when the adsorption reaches equilibrium for 4h at room temperature. However, the flower-like γ-Al2O3 obtained by using PAAS as the SDA has the biggest CO2 adsorption capacity of 1.04 mmol/g at room temperature. This work provides a simple and practical way to prepare potentially bifunctional γ-Al2O3 adsorbent for the removal of pollutants in water and air treatment from cheap sodium aluminate by using different SDAs.


"Your help isn't helping me!" Unhelpful workplace social support, strain, and the role of individual differences.
While the reception of social support at work is generally considered a net positive for employees, researchers have identified that particular kinds of social support, such as unhelpful workplace social support (UWSS), tend to evoke stress and contribute to strain for recipients. Although (Gray et al. Work and Stress, 34(4), 359-385, 2020), when validating the novel UWSS measure, uncovered relations between UWSS and various outcomes, more research is needed to further understand the impacts of UWSS. Furthermore, the extant social support literature is currently lacking in its understanding of how individual differences strengthen or weaken the relations such support has with strain. Drawing from the Theory of Stress as Offense to Self (Semmer et al. Occupational Health Science, 3(3), 205-238. 10.1007/s41542-019-00041-5, 2019), we, through two studies (N 1 = 203, N 2 = 277), further explore the relations of UWSS, focusing on behavioral and psychological strain, and examine how these relations are influenced by relevant individual differences (e.g., Big Five traits). Results from our first study replicate key findings from (Gray et al. Work and Stress, 34(4), 359-385, 2020), providing additional validity evidence for the novel measure of UWSS, and demonstrate that UWSS is related to various types of behavioral strain. Our second study shows that the strength of these deleterious relations varies based on characteristics of the recipient of UWSS. Altogether, the present research contributes to the literature on social support as a stressor by elucidating further the effects of UWSS, and, perhaps more importantly, for whom UWSS is particularly deleterious.


CPT2-mediated fatty acid oxidation inhibits tumorigenesis and enhances sorafenib sensitivity via the ROS/PPARγ/NF-κB pathway in clear cell renal cell carcinoma.
Kidney cancer is a common kind of tumor with approximately 400,000 new diagnoses each year. Clear cell renal cell carcinoma (ccRCC) accounts for 70-80% of all renal cell carcinomas. Lipid metabolism disorder is a hallmark of ccRCC. With a better knowledge of the importance of fatty acid oxidation (FAO) in cancer, carnitine palmitoyltransferase 2 (CPT2) has gained prominence as a major mediator in the cancer metabolic pathway. However, the biological functions and mechanism of CPT2 in the progression of ccRCC are still unclear. Herein, we performed assays in vitro and in vivo to explore CPT2 functions in ccRCC. Moreover, we discovered that CPT2 induced FAO, which inhibited the generation of reactive oxygen species (ROS) by increasing nicotinamide adenine dinucleotide phosphate (NADPH) production. Additionally, we demonstrated that CPT2 suppresses tumor proliferation, invasion, and migration by inhibiting the ROS/ PPARγ /NF-κB pathway. Gene set enrichment analysis (GSEA) and drug sensitivity analysis showed that high expression of CPT2 in ccRCC was associated with higher sorafenib sensitivity, which was also validated in vitro and in vivo. In summary, our results suggest that CPT2 acts as a tumor suppressor in the development of ccRCC through the ROS/PPARγ/NF-κB pathway. Moreover, CPT2 is a potential therapeutic target for increasing sorafenib sensitivity in ccRCC.


Infants of drug addicts: at risk for child abuse, neglect, and placement in foster care.
In a methadone maintenance program for pregnant, drug dependent women, an investigation was undertaken (1) to study the occurrence of violence experienced by the women as children and as adults and (2) to lean whether those who report past violence/abuse are more likely to neglect and/or abandon their children to the care of others. Subjects included 178 drug dependent women who completed a Violence Questionnaire and 70 comparable, but drug-free women. Results revealed that a history of violence or abuse is related to drug abuse and also to the placement of one's child(ren) in foster care.


Validation of the modified Bosniak classification system to risk stratify pediatric cystic renal masses: An international, multi-site study from the pediatric urologic oncology working group of the societies for pediatric urology.
Pediatric cystic renal lesions are challenging to manage as little is known about their natural course. A modified Bosniak (mBosniak) classification system has been proposed for risk stratification in pediatric patients that takes ultrasound (US) and/or computed tomogram (CT) characteristics into account. However, literature validating this system remains limited. To determine if the mBosniak classification system correlates with pathologic diagnoses. The hypothesis is that mBosniak classification can stratify the risk of malignancy in children with renal cysts. Patients treated for cystic renal masses with available imaging and pathology between 2000 and 2019 from five institutions were identified. Clinical characteristics and pathology were obtained retrospectively. Characteristics from the most recent US, CT, and/or magnetic resonance imaging (MRI) were recorded. Reviewers assigned a mBosniak classification to each scan. mBosniak scores 1/2 were considered low-risk and 3/4 high-risk. These groups were compared with pathology (classified as benign, intermediate, malignant). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (+LR), and negative likelihood ratio (-LR) were calculated to assess this categorization as a screening tool to guide surgical intervention. Agreement between imaging modalities was also explored. 99 patients were identified. High-risk imaging findings were correlated with malignant or intermediate pathology with a sensitivity of 88.3%, specificity of 84.6%, PPV of 89.8%, NPV of 82.5%, +LR of 5.7, and -LR of 0.14. The sensitivity for detecting malignant lesions only was 100%. There was substantial agreement between US/CT (n = 55; κ = 0.66) and moderate agreement between US/MRI (n = 20; κ = 0.52) and CT/MRI (n = 13; κ = 0.47). The mBos classification system is a useful tool in predicting the likelihood of benign vs. intermediate or malignant pathology. The relatively high sensitivity and specificity of the system for prediction of high-risk lesions makes this classification applicable to clinical decision making. In addition, all malignant lesions were accurately identified as mBosniak 4 on imaging. This study adds substantial data to the relatively small body of literature validating the mBosniak system for risk stratifying pediatric cystic renal lesions. Pediatric cystic renal lesions assigned mBosniak class 1/2 are mostly benign, whereas class 3/4 lesions are likely intermediate or malignant pathology. We observed that the mBosniak system correctly identified pathology appropriate for surgical management in 88% of cases and did not miss malignant pathologies. There is substantial agreement between CT and US scans concerning mBos classification.


Quantification of myocardial infarct size after coronary reperfusion by serum cardiac myosin light chain II in conscious dogs.
The effects of early coronary artery reperfusion on the relation between the extent of myocardial infarction and serum levels of cardiac myosin light chain II or plasma creatine kinase levels were evaluated in the conscious dog. Hydraulic occluders were placed on the left anterior descending arteries of 38 dogs. Seven to 10 days later, myocardial infarction was produced. Coronary reperfusion was performed 3 hours (group A1, n = 13) and 6 hours (group A2, n = 12) after the occlusion. In the other 13 dogs, coronary occlusion was sustained throughout the course of the experiment (group B). Seven days after the occlusion, the heart was cut from the apex to the base into 4-mm slices, and infarct size was determined macroscopically. Rapid appearance and early peaking of creatine kinase were observed in group A. Cumulative release of creatine kinase significantly correlated with infarct size in group A (infarct size ranged from 0.1 to 20.1 g, r = 0.90) and group B (from 0.6 to 26.8 g, r = 0.91). However, since creatine kinase release in group A was greater in comparison with that from infarcts of the same size in group B, the slope of the regression line for group A was significantly steeper (p less than 0.05). Cardiac myosin light chain II appeared as early as creatine kinase did and continued to be elevated for 7 days. A very close relation was observed between infarct size and total cardiac myosin light chain II release (r = 0.87 for group A, and r = 0.88 for group B) or peak level of light chain II (r = 0.85 for group A, and r = 0.81 for group B). In addition, the slopes of the regression lines for infarct size and both peak and total release of light chain II did not differ between group A and group B. On histological examination, viable myocardium was frequently observed in the epicardium of the ischemic area in group A1; therefore, infarct size was greater in group B than in group A1 (p less than 0.05). Also, myocardial creatine kinase content in the epicardium of the center of the ischemic area in group A1 was greater than that in group B. Cardiac myosin light chain II release in group A1 was less than that in group B, whereas no difference was found in plasma creatine kinase release among groups A1, A2, and B.(ABSTRACT TRUNCATED AT 250 WORDS)


In chromaffin cells, the mammalian Sec1p homologue is a syntaxin 1A-binding protein associated with chromaffin granules.
Membrane proteins of the synaptic vesicle and the presynaptic plasma membrane together with soluble proteins form a secretory fusion complex conserved from yeast to neurons (Söllner, T., Whiteheart, S. W., Brunner, M., Erdjument-Bromage, H., Geromanos, S., Tempst, P., and Rothman, J. E. (1993) Nature 362, 318-324). Two of the membrane proteins have been localized in chromaffin cells, which secrete catecholamines stored in chromaffin granules. Syntaxin 1A and 1B are found in a plasma membrane-enriched fraction, whereas synaptobrevin is concentrated on the granules. Recombinant syntaxin 1A has been used in an affinity chromatography assay to isolate syntaxin receptor proteins of the chromaffin granules. Solubilized granule membranes contain a single protein with high affinity for syntaxin 1A. Sequencing revealed partial homology with Sec1p, a hydrophilic yeast protein acting late in the secretory process. Genetic suppressor analyses predicted the interaction of Sec1p with Sso1p, a yeast homologue of syntaxin 1A, and with Sec4p, a homologue of rab3A (Aalto, M., Ronne, H., and Keränen, S. (1993) EMBO J. 12, 4095-4104). Although rab3A is present on chromaffin granules, we did not detect it bound to syntaxin 1A together with the mammalian Sec1p homologue (mSec1). The mSec1 peptide sequences are almost identical with respective sequences of a soluble protein, termed Munc-18, reported to be the only brain protein with affinity for recombinant syntaxin 1A (Hata, Y., Slaughter, C. A., and Südhof, T. C. (1993) Nature 366, 347-351). The mSec1/Munc-18 may be a receptor protein for syntaxin 1A on the transmitter vesicles mediating their interaction with the plasma membrane in docking and fusion.


Comparison of the solid-phase extraction efficiency of a bounded and an included cyclodextrin-silica microporous composite for polycyclic aromatic hydrocarbons determination in water samples.
Solid-phase extraction is one of the most important techniques for sample purification and concentration. A wide variety of solid phases have been used for sample preparation over time. In this work, the efficiency of a new kind of solid-phase extraction adsorbent, which is a microporous material made from modified cyclodextrin bounded to a silica network, is evaluated through an analytical method which combines solid-phase extraction with high-performance liquid chromatography to determine polycyclic aromatic hydrocarbons in water samples. Several parameters that affected the analytes recovery, such as the amount of solid phase, the nature and volume of the eluent or the sample volume and concentration influence have been evaluated. The experimental results indicate that the material possesses adsorption ability to the tested polycyclic aromatic hydrocarbons. Under the optimum conditions, the quantification limits of the method were in the range of 0.09-2.4μgL(-1) and fine linear correlations between peak height and concentration were found around 1.3-70μgL(-1). The method has good repeatability and reproducibility, with coefficients of variation under 8%. Due to the concentration results, this material may represent an alternative for trace analysis of polycyclic aromatic hydrocarbons in water trough solid-phase extraction.


A novel approach for evaluating nerve function in healthy elderly persons: a pilot study.
Motor nerve function decreases with age and can cause abnormalities in motor function. Using newly designed methods, we used evoked electromyograms to evaluate change in motor nerve function. Motor function was assessed by grip strength, timed up-and-go test, 5-m normal walk, and 5-m fastest walk. In addition, motor nerve conduction velocity was calculated by measuring latency differences (NCV) in elderly and young subjects. We also investigated motor nerve conduction velocity by correlation coefficient (NCVCC) and the difference between NCV and NCVCC (DNCV). Significant differences were observed in the motor function of elderly and young persons in grip strength, the timed up-and-go test, and the 5-m fastest walk; however, no difference was observed in the 5-m normal walk test. NCVCC was lower than NCV in both elderly and young. The correlation coefficient peak of the NCVCC calculation was lower in elderly than in young. A negative correlation was observed between correlation coefficient peak and DNCV in elderly subjects. NCVCC compares the overall shape of compound muscle action potential and reflects not only the fastest motor unit, but also the motor nerve conduction velocity of other motor unit components. A significant negative correlation between DNCV and the correlation coefficient peak was observed only in elderly subjects, suggesting that older individuals, including those that maintain a high level of physical strength, experience a loss of motor nerve function. Thus, changes in motor nerve function among elderly persons can potentially be further examined for clinical use.


Beyond Medical Treatment: Surgical Treatment of Gout.
Medical treatment with urate-lowering therapy (ULT) is efficacious. A recent publication suggested that surgery in gout is more prevalent than previously reported. This revelation led us to review what is known about surgical treatment of gout. The Google Scholar database (January 1, 2014-January 1, 2020) found 104 publications with a total of 169 gout patients, with an average disease duration of 6.7 years. Most (68%) were not on ULT. The mean pre-operative serum urate levels were 9.19 mg/dL. One hundred thirteen patients underwent tophi excision, while in 33 patients, tophi were found during surgery. The majority of the surgeries were performed in Asia and Europe. Most patients were not taking ULT at the time of surgery, leading to hyperuricemia. This can result in tophi reformation post-surgery. The role of surgery should be a last-line treatment and until recently has only been demonstrated through case reports.


Prognostic factors and the effect of treatment with radioactive iodine and external beam radiation on patients with differentiated thyroid cancer seen at a single institution over 40 years.
To assess the prognostic factors and the role of radioactive iodine (RAI) and external beam radiotherapy (RT) in patients with differentiated thyroid cancer. A retrospective review of 729 patients treated between 1958 and 1998. The median follow-up was 11.3 years (range 0.3-39.8 years). Primary outcomes included time to cause-specific survival and time to local-regional relapse. Baseline and treatment variables were assessed for statistical significance using the Cox proportional hazards model. The 10-year cause-specific survival (CSS) was 87.3% and the 10-year local-regional relapse-free rate (LRFR) was 84.9%. In multivariate analysis there was no statistically significant improvement in CSS with more aggressive treatment (i.e. more extensive surgery, the administration of RAI and/or RT). By multivariate analysis the use of RAI resulted in a statistically significant improvement in LRFR (hazard ratio 0.5; 95% confidence interval 0.3-0.8; P = 0.007). In low-risk patients at AJCC stage I < or = 45 years, there was no apparent benefit from RAI. For patients over 60, with extrathyroid extension but no gross residual disease (n = 70), adjuvant external RT resulted in statistically significantly higher CSS (10-year CSS 81.0%vs. 64.6%, P = 0.04) and LRFR (10-year LRFR 86.4%vs. 65.7%, P = 0.01). The use of RAI was associated with improved LRFR but not in low-risk patients. External beam RT improved LRFR and CSS in high-risk patients.


Sequence-dependent growth-inhibitory effects of the in vitro combination of fluorouracil, cisplatin, and dipyridamole.
The present study was designed to analyze the growth-inhibitory effects of the combination of fluorouracil (FUra), cisplatin (CDDP), and dipyridamole (DP). These toxic effects were assessed on the human breast-carcinoma cell line MCF-7 using the MTT (tetrazolium bromide) assay in 96-well culture dishes. Data were analyzed using the median-effect principle. The drug combinations tested included FUra concentrations ranging from 0.8 to 800 nmol/l, CDDP concentrations of 0.3-30 mumol/l, and DP concentrations of 2-200 mumol/l. A total of 189 different experimental conditions were tested, including different sequences of administration, with being DP applied before, simultaneously with, or after the two antitumor drugs. Synergistic cytotoxic interactions were found between FUra and CDDP, FUra and DP, and CDDP and DP as well as when the three drugs were combined. The sequence of exposure did not influence the growth-inhibitory activity of the combination FUra-CDDP but altered the effect of combinations of either FUra or CDDP with DP, since at lower concentrations the effect shifted from synergism to antagonism when DP was added simultaneously with CDDP and after the two antitumor drugs. However, the interaction was shown to be truly synergistic by median-effect analysis when the two antitumor drugs were simultaneously associated, with no change in the synergistic effect being observed for the three DP administration sequences.


Action range of BMP is defined by its N-terminal basic amino acid core.
During early development, cells receive positional information from neighboring cells to form tissue patterns in initially uniform germ layers. Ligands of the transforming growth factor (TGF-beta) superfamily are known to participate in this pattern formation. In particular, activin has been shown to act as a long-range dorsalizing signal to establish a concentration gradient in Xenopus. In contrast, BMP-2 and BMP-4, other members of the family, appear to influence and induce ventral fates only where they are expressed. This raises a question as to how the action of BMPs is tightly restricted to the region within and around the cells that produce them. Here, we have demonstrated that a basic core of only three amino acids in the N-terminal region of BMP-4 is required for its restriction to the non-neural ectoderm as its expression domain. Our results also suggest that heparan sulfate proteoglycans bind to this basic core and thus play a role in trapping BMP-4. The present study is the first to identify the critical domain of BMP that is responsible for its interaction with the extracellular environment that restricts its diffusion in vivo.


Gabapentin can significantly improve dystonia severity and quality of life in children.
Gabapentin has been used in the management of neuropathic pain, epilepsy and occasionally movement disorders. A four-year retrospective, observational study analysed the use of gabapentin for severe dystonia in children at the Evelina London Children's Hospital. Motor severity was classified according to the Gross Motor Function Classification System (GMFCS), Dystonia Severity Assessment Plan (DSAP) and levels of impairment in activities of daily living were graded according to the WHO International Classification of Functioning, Disability and Health, Children & Youth version (ICF-CY) before and after gabapentin. The majority of the 69 children reported were level 5 GMFCS (non-ambulant). The DSAP grade fell significantly from grade 3 before to grade 1 after gabapentin. Significant improvements in median ICF-CY grades were seen following gabapentin in sleep quality, sleep amount, mood & agreeableness, pain, general muscle tone, involuntary muscle contractions and seating tolerance (p < 0.01 in all areas). A significantly higher mean dose of 18.1 mg/kg/dose (SD: 13.3) for dystonia, compared to 7.61 mg/kg/dose (SD: 4.14) for pain relief without dystonia (z = -2.54, p = 0.011) was noted. Gabapentin may significantly ameliorate dystonia severity and improve activities of daily living and quality of life in children with severe dystonia.


Bilateral congenital absence of internal iliac arteries, prominent lumbar arteries, and a ruptured mycotic aneurysm of the abdominal aorta.
A 46-year-old man was admitted for surgery on a ruptured mycotic abdominal aortic aneurysm. Emergency repair was performed, during which certain anomalies were noted. First, the bifurcation of the aorta was posterior to the left common iliac vein. Second there were no internal iliac arteries. Also, there were prominent lumbar arteries compensating for the absent internal iliac arteries bilaterally. This, we consider, is the first reported case of congenitally absent bilateral internal iliac arteries.


Tetrahydroindoles as Multipurpose Screening Compounds and Novel Sirtuin Inhibitors.
Indoles are privileged structures in medicinal and bioorganic chemistry that are particularly well suited to serve as platforms for diversity. Among many other therapeutic areas, the indole scaffold has been used to design aromatic compounds useful to interfere with enzymes engaged in the regulation of substrate acylation status, such as sirtuins. However, the planarity of the indole ring is not necessarily optimal for all target enzymes, especially when functionalization with aromatic side chains is required. Replacement of flat scaffolds by nonplanar molecular cores dominated by sp3 hybridization is a common strategy to avoid the disadvantages associated with poor solubility and high promiscuity, while covering less-well-explored areas of chemical space. Thus, we synthesized fragment-like tetrahydroindoles suitable for fragment-based drug discovery as well as a well-characterized small library intended as multipurpose screening compounds. For proof of principle, these compounds were screened against sirtuins 1-3, enzymes known to be addressable by indoles. We found that 2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamides are potent and selective SIRT2 inhibitors. Compound 16 t displayed an IC50 value of 0.98 μm and could serve as exquisite starting point for hit-to-lead profiling.


Maternal obesity in prolonged pregnancy: Labor, mode of delivery, maternal and fetal outcomes.
Obesity is currently not a medical indication for elective induction of labor although obese patients may not be eligible for expectant management after 41 W G. Few data on labor and complications in this population undergoing prolonged pregnancy are known. The objective of our study was to evaluate labor, mode of delivery, maternal and fetal outcomes in prolonged pregnancy in obese patients compared to normal body mass index (BMI). It was a retrospective cohort study in patients who, after prolonged pregnancy gave birth to a single fetus, in cephalic presentation, between the first of January 2002 and December 31, 2018 in the Caen University Hospital Center. Patient's characteristics were compared within each BMI class using uni- and multivariate analysis with regression logistics models. Overall, 9159 patients were included. Term of birth and spontaneous labor calculated rates were significantly increased in case of obesity (p < 0.001). The adjusted Odds Ratio (ORa) for induced labor in class III obesity was 1.73 [1.13-2.66]. After induction of labor, 83.0 % patients with normal BMI delivered vaginally versus 61.8 % in case of class III obesity (p < 0.001). The ORa for an emergency cesarean was 3.39 [2.04-5.63] and 1.78 [1.06-2.99] for neonatal morbidity in class III obesity. Morbid obese patients do not belong to a low risk patient's group when pregnancy is prolonged. Elective induction in case of morbid obesity may entail less risk than allowing the pregnancy to progress after 41 W G or even 39 W G. Further randomized prospective studies are nevertheless required.


Bilateral intracranial fibrous xanthoma.
We present a case of fibrous xanthoma in a 6-year-old boy who showed disturbance of consciousness and signs of increased intracranial pressure. A computed tomographic (CT) scan showed bitemporal enhanced masses and hydrocephalus. The patient was operated on in two stages. The tumors were located intradurally and extracerebrally and were firmly attached to the dura mater at the base of the middle fossa. Glial fibrillary acidic protein stain was negative, and histologic examination suggested a diagnosis of bilateral fibrous xanthoma. Postoperative CT scan showed residual tumors and an enlarged choroid plexus adjacent to it. A CT scan at 12 years of age showed no enhanced tumor, but disclosed bitemporal high-density areas and diffuse brain atrophy; the choroid plexus reverted to normal size. The patient showed mental and physical retardation, perhaps owing to the compression of the hypothalamus during early childhood. This would appear to be the first known case of bilateral intracranial fibrous xanthoma.


Improving embryo selection using a computer-automated time-lapse image analysis test plus day 3 morphology: results from a prospective multicenter trial.
To assess the first computer-automated platform for time-lapse image analysis and blastocyst prediction and to determine how the screening information may assist embryologists in day 3 (D3) embryo selection. Prospective, multicenter, cohort study. Five IVF clinics in the United States. One hundred sixty women ≥ 18 years of age undergoing fresh IVF treatment with basal antral follicle count ≥ 8, basal FSH <10 IU/mL, and ≥ 8 normally fertilized oocytes. A noninvasive test combining time-lapse image analysis with the cell-tracking software, Eeva (Early Embryo Viability Assessment), was used to measure early embryo development and generate usable blastocyst predictions by D3. Improvement in the ability of experienced embryologists to select which embryos are likely to develop to usable blastocysts using D3 morphology alone, compared with morphology plus Eeva. Experienced embryologists using Eeva in combination with D3 morphology significantly improved their ability to identify embryos that would reach the usable blastocyst stage (specificity for each of three embryologists using morphology vs. morphology plus Eeva: 59.7% vs. 86.3%, 41.9% vs. 84.0%, 79.5% vs. 86.6%). Adjunctive use of morphology plus Eeva improved embryo selection by enabling embryologists to better discriminate which embryos would be unlikely to develop to blastocyst and was particularly beneficial for improving selection among good-morphology embryos. Adjunctive use of morphology plus Eeva also reduced interindividual variability in embryo selection. Previous studies have shown improved implantation rates for blastocyst transfer compared with cleavage-stage transfer. Addition of Eeva to the current embryo grading process may improve the success rates of cleavage-stage ETs.


Dynamic variation and inhalation exposure of organophosphates esters and phthalic acid esters in face masks.
The coronavirus pandemic (COVID-19) has posed a huge global health threat since December 2019. Wearing face masks is known as an effective measure for controlling the wide spread of COVID-19 and its variants. But on the other hand, face masks could be a potential source of organophosphate esters (OPEs) and phthalic acid esters (PAEs) as they are extensively added in masks. However, knowledge associated with the occurrence as well as inhalation risks of OPEs and PAEs in masks is limited. In this study, OPEs and PAEs were determined in different types of mask samples collected from the local market. OPEs and PAEs were detected in mask samples ranging from 36.7 to 855 ng/g, and from 251 to 3830 ng/g, respectively. Relatively lower OPEs and PAEs concentrations were observed in disposable mask for toddlers. Simulated inhalation experiment indicated that the mass loss of OPEs and PAEs was 136 and 3910 ng/mask in disposable masks, 71.9 and 763 ng/mask in disposable mask for toddlers, 924 and 1020 ng/mask in N95 mask after 12 h, respectively. Significantly negative correlations were exhibited between the decrement of OPEs in masks and the increment of OPEs in corresponding polyurethane foams (PUFs) during the course, elucidating OPEs released from masks could be well captured by PUFs. With regard to the variation over time, predominant OPE and PAE analogues showed semblable release and absorption tendency in mask and corresponding PUF. Inhalation exposure risk of OPEs and PAEs was estimated based on the increment of pollutants in PUF. The estimated daily intakes (EDIs), hazard index (HI) and carcinogenic risk (CR) were also calculated and they were within the threshold levels. This study provides the evidence of OPEs and PAEs releasing from the face masks during wearing and unveiled a potential source of OPEs and PAEs exposure to humans.


Lysine production byBrevibacterium linens and its mutants: Activities and regulation of enzymes of the lysine biosynthetic pathway.
Activity and regulation of key enzymes of the lysine biosynthetic pathway were investigated inBrevibacterium linens, a natural excretor of lysine, its lysine-overproducing homoserine auxotroph (Hom(-1)) and its auxotrophic and multianalogue-resistant high-yielding mutant (AEC NV 20(r)50). The activity of aspartate kinase (AK) and aspartaldehydate dehydrogenase (AD) was maximum during the mid-exponential phase of growth and decreased therafter. The mutants showed 10 and 20% more activity of AK and AD than the wild-type lysine excretor.B. linens (natural excretor) has a single AK and AD repressed and inhibited bivalently by lysine and threonine. Lysine slightly repressed and inhibited dihydrodipicolinate synthase (DS) and diaminopimelate decarboxylase (DD) of the wild type and of the mutant Hom(-1). The mutant AEC NV 20(r)50 showed DS and DD to be insensitive to lysine inhibition and repression. Persistence of a major part of the maximal activity of these enzymes during the late stationary phase of growth allowed prolonged synthesis and excretion of lysine. Stepwise addition of resistance to the different analogues of lysine in the mutant AEC NV20(r)50 resulted in an increase of enzyme activity and reduced repressibilities of enzymes that contributed to the high yield of lysine.


Adding cancer antigen 125 screening to gray scale sonography for predicting specific diagnosis of benign adnexal masses in premenopausal women: is it worthwhile?
The purpose of this study was to assess whether a single determination of the serum cancer antigen 125 (CA-125) level provides additional information to sonography for specific diagnosis of benign adnexal masses in premenopausal women. We conducted a retrospective study comprising 1058 premenopausal women (mean age, 34.8 years) with histologically proven benign adnexal masses. All women had undergone transvaginal sonography and serum CA-125 determination within 1 week before surgery and tumor removal. According to "pattern recognition" analysis, a presumptive diagnosis was provided on gray scale transvaginal sonography for all masses. Positive and negative likelihood ratios were calculated for gray scale sonography and gray scale sonography plus CA-125. Eighty-five women had bilateral masses (1143 masses analyzed). In 7 women with bilateral masses, the histologic diagnoses of the masses were discordant and were excluded. Histologic diagnoses were as follows: endometrioma, n = 452; dermoid cyst, n = 180; serous cyst, n = 158; hemorrhagic cyst, n = 119; mucinous cyst, n = 54; hydrosalpinx, n = 37; and other, n = 109. The median CA-125 level was significantly higher in endometrioma (71.9 IU/mL; range: 5-2620 IU/mL) and hydrosalpinx (59.2 IU/mL; range, 5-601 IU/mL) compared to all other tumor types (P < .001). The CA-125 level was 35 IU/mL or higher in 74% of endometriomas, 58% of hydrosalpinges, 34% of hemorrhagic cysts, 18% of mucinous cysts, 14% of dermoid cysts, and 8% of serous cysts. The positive and negative likelihood ratios for sonography and sonography plus CA-125 (335 IU/mL) for each kind of tumor were not statistically different except for endometrioma, for which the positive likelihood ratio for sonography plus CA-125 (55.0; 95% confidence interval, 27.5-109.9) was significantly higher than for sonography alone (19.2; 95% confidence interval, 13.6-27.1). Cancer antigen 125 screening does not add useful information for specific diagnosis of benign adnexal tumors, except for endometrioma. An elevated CA-125 level significantly increases the probability of such a lesion.


Gemcitabine (GEM) and vindesine (VDS) in advanced non-small cell lung cancer (NSCLC): a phase II study in elderly or poor performance status patients.
The aim of the study was to assess the activity and tolerability of the combination of gemcitabine (GEM) and vindesine (VDS) in elderly or poor performance patients with advanced non-small cell lung cancer. Forty four patients (36 males and 8 females with a median age of 70 years and a median Karnofsky performance score of 60) were recruited between January 1998 and June 2001; 9 (20.5%) were stage IIIB patients and 35 (79.5%) were stage IV patients; 20 (45.5%) had squamous carcinoma and 24 (54.5%) non-squamous carcinoma. The patients received GEM 1000 mg/m(2) and VDS 3mg/m(2) (max 5mg) on days 1 and 8 every 3 weeks, and were all evaluable for response and toxicity: 17 (38.6%) were partial responders, 17 (38.6%) experienced stable disease, and 10 (22.3%) progressive disease. Grade 3-4 anemia, neutropenia and thrombocytopenia were observed in, respectively, 6.8, 9.1 and 2.3% of the patients, and grade 2-3 fatigue, paresthesias and skin toxicity in, respectively, 11.4, 20.4 and 2.3%. After a median follow-up of 54 months, 43/44 patients died; median survival was 12 months, and a clinical benefit was observed in 54.5% of cases. GEM plus VDS is an active and well-tolerated schedule.


Featuring advanced translational strategies: Principles, techniques, devices and applications.
The ever-emerging developments and innovations on the advanced translational strategies for diagnosing and treating fatal human diseases are substantially re-shaping our future and improving the human health quality. This special issue published several mini-review manuscripts covering fundamental principles, techniques, devices and applications in the related fields. Several investigators including basic research scientists and medical doctors have described recent breakthroughs in the fields of cancer therapy, biomedical engineering, material sciences and their translational medicine from-bench-to-bed into clinical uses.


Effects of Seismic Air Guns on Pallid Sturgeon and Paddlefish.
Pallid sturgeon and paddlefish were placed at different distances from a seismic air gun array to determine the potential effects on mortality and nonauditory body tissues from the sound from a single shot. Fish were held 7 days postexposure and then necropsied. No fish died immediately after sound exposure or over the postexposure period. Statistical analysis of injuries showed no differences between the experimental and control animals in either type or severity of injuries. There was also no difference in injuries between fish exposed closest to the source compared with those exposed furthest from the source.


Application of synthetic magnetic resonance imaging and DWI for evaluation of prognostic factors in cervical carcinoma: a prospective preliminary study.
To determine the values of quantitative metrics derived from synthetic MRI (SyMRI) and apparent diffusion coefficient (ADC) in evaluating the prognostic factors of cervical carcinoma (CC). In this prospective study, 74 patients with pathologically confirmed CC were enrolled. Pretreatment quantitative metrics including T1, T2 and ADC values were obtained from SyMRI and diffusion-weighted imaging (DWI) sequences. The values of all metrics were compared for different prognostic features using Student's t-test or Mann-Whitney U-test. The receiver operating characteristic (ROC) curve and multivariate logistic regression analysis were utilized to evaluate the diagnostic performance of quantitative variables. T1 and T2 values of parametrial involvement (PMI)-negative were significantly higher than those of PMI-positive (p = 0.002 and < 0.001), while ADC values did not show a significant difference. The area under curve (AUC) of T1 and T2 values for identifying PMI were 0.743 and 0.831. Only the T2 values showed a significant difference between the lymphovascular space involvement (LVSI)-negative and LVSI-positive (p < 0.001), and the AUC of T2 values for discriminating LVSI was 0.814. The differences of T1, T2, and ADC values between the well/moderately and the poorly differentiated CC were significant (all p < 0.001). The AUCs of T1, T2 and ADC values for predicting differentiation grades were 0.762, 0.830, and 0.808. The combined model of all metrics proved to achieve good diagnostic performance with the AUC of 0.866. SyMRI may be a potential noninvasive tool for assessing the prognostic factors such as PMI, LVSI, and differentiation grades in CC. Moreover, the overall diagnostic performances of synthetic quantitative metrics were superior to the ADC values, especially in identifying PMI and LVSI. This is the first study to assess the utility of SyMRI-derived parameters and ADC value in evaluating the prognostic factors in CC.


The role of tachykinins in air ventilation-induced bronchoconstriction in postmortem guinea pigs.
To investigate the relationship between tachykinins and air ventilation-induced airway constriction after heart ligation, 26 guinea pigs were divided into three groups: Group 1, control (n = 15); Group 2, tachykinin depletion via pretreatment with capsaicin (n = 7); and Group 3, isocapnic ventilation (n = 4). To examine the age effect, the first two groups were further separated into two subgroups: young (n = 12) and mature (n = 10). Animals were anesthetized with pentobarbital, sternotomized and artificially ventilated with room air or with 5% CO2 gas mixture. Before (baseline) and after heart ligation, tidal volume and transpulmonary pressure (Ptp) were recorded during ventilation, and the maximal expiratory flow-volume curve was periodically obtained. Minimal volume (lung volume at Ptp = 0) was determined by neon dilution. Within 30 min after heart ligation in the control group, air ventilation significantly decreased dynamic compliance, vital capacity, peak maximal expiratory flow, maximal expiratory flow at 50% total lung capacity, and forced expiratory volume in 0.2 sec. Tachykinin depletion significantly prevented, whereas isocapnic (5% CO2) ventilation failed to alter, the above changes. Young and mature subgroups showed similar results. Our data indicate that air ventilation after heart ligation induced severe airway constriction and that this bronchoconstriction can be prevented by tachykinin depletion.


Network pharmacology-based study on the mechanism of Schisandra chinensis for treating Alzheimer's disease.
Alzheimer's disease (AD) is a mental illness that poses a serious threat to human health worldwide. Schisandra chinensis is a natural herb that can treat the effects of AD, but its specific mechanism is still unclear. The purpose of this study was to explore the potential components and pharmacological pathways of S. chinensis in the treatment of AD. In this study, we investigated the compound of S. chinensis and the effects of it on AD by network pharmacology. Meanwhile, the potential mechanism was proved in vitro. The results showed that S. chinensis contained 173 compounds. Compound-target network confirmed that (E)-9-Isopropyl-6-Methyl-5,9-Decadiene-2-One, 1-Phenyl-1,3-Butanedion, nootkatone and phenyl-2-Propanone were the main chemical constituents which highly aimed at APOE, CACNA1D, GRIN2A, and PTGS2. KEGG and GO enrichment analysis indicated that the main pathways involved neural-related signaling pathways and functions, such as nicotine addiction, GABAergic synapse, Ca2+ signaling pathway, AD, and so on. Validation experiments showed that nootkatone was able to exert anti-apoptotic effects related to Ca2+ signaling pathway by inhibiting nitric oxide production, enhancing the activity of antioxidant enzymes, upregulating the expression of anti-oxidation and anti-apoptotic proteins in vitro. These results illustrated that S. chinensis could regulate neuronal apoptosis through the calcium signaling pathway to exert anti-AD by integrating multi-component, multi-target and multi-pathway.


Evaluation of rapid methods for diagnosis of tuberculosis in slaughtered free-range pigs.
Free-range pigs can be infected by Mycobacterium tuberculosis complex (MTC) and may contribute to the spread of bovine tuberculosis (bTB). In the present study, the diagnostic values of bacteriological culture, a duplex real-time quantitative PCR and an antibody ELISA were evaluated in an abattoir study of submandibular lymph nodes and serum samples from 73 pigs with and without lesions consistent with bTB. The duplex qPCR was an accurate method for diagnosis of TB in pigs (specificity 100%; sensitivity 80%). Combining qPCR with histopathology improved sensitivity and had very good concordance (κ = 0.94) with the reference method. Serological results suggest that the antibody ELISA can be used for monitoring herds but not individuals.


Proteomic characterization of the fibroin-based silk fibers produced by weaver ant Camponotus textor.
The fibroin-based silk fibers of weaver ants are an alternative biomaterial to be investigated and explored for potential biomedical applications. In this context, the silk fibers from the nest of the weaver ant Camponotus textor was solubilized and fractionated by gel permeation. The different fractions were collected, pooled and submitted to analysis with a series of biochemical methods, nuclear magnetic resonance (NMR) spectroscopy, analytical proteomic strategies, and data treatment with bioinformatic tools to perform the structural characterization of the fibroin-based silk fibers produced by the ant. Our data demonstrated the identification of one fibroin proteoform in the ant silk fibers. The protein chracterized as a glycoprotein with MW around 40 kDa and presenting 66% (w/w) of total sugars attached to it through O-linked carbohydrates. The 3D of protein was modeled, revealing a structure predominantly constituted of coiled-coil secondary units in the whole model, featuring at least four superhelices (arrangement with multiple α-helices). The scientific outcomes reported herein may be relevant for the development of novel approaches for the synthetic or recombinant production of novel silk-based polymers for biomedical applications. BIOLOGICAL SIGNIFICANCE: The present investigation significantly expanded knowledge regarding to the fibroin-based silk fibers from weaver ants, contributing to improvements in our understanding of the properties and characteristics of these silk fibers. For example, as reported here, carbohydrates were detected in the ants' silk for the first time presenting the fibroin as a glycoprotein. Moreover, the 3D structure provided new insights into the secondary structures considering the whole model of the protein.


Identity change and informed consent.
In this paper, I focus on a kind of medical intervention that is at the same time fascinating and disturbing: identity-changing interventions. My guiding question is how such interventions can be ethically justified within the bounds of contemporary bioethical mainstream that places great weight on the patient's informed consent. The answer that is standardly given today is that patients should be informed about the identity effects, thus suggesting that changes in identity can be treated like 'normal' side effects. In the paper, I argue that this approach is seriously lacking because it misses important complexities going along with decisions involving identity changes and consequently runs into mistakes. As a remedy I propose a new approach, the 'perspective-sensitive account', which avoids these mistakes and thus provides the conceptual resources to systematically reflect on and give a valid consent to identity-changing interventions.


Understanding Statistical Noise in Research: 3. Noise in Regression Analysis.
In regression analysis, the adjusted R2 value describes the proportion of the variance in the dependent variable that is explained by the independent variables in the equation. What remains is unexplained or residual variance. Residual variance has two components: the contribution of unmeasured variables (residual confounding) and measurement error (noise). These concepts are explained using examples.


Content of red blood-cell sialic acid in BW 35 blood donors. Relation to magnesium concentration and pyruvate kinase activity.
Previous studies have shown that the concentration of red blood cell (RBC) magnesium is significantly lower in subjects carrying an HLA-BW 35 antigen (p less than 0.001) than in non-carriers. As this finding might be related to modifications of the RBC membrane sialoglycoconjugates, RBC sialic acid was comparatively determined in BW 35+ and BW 35- subjects. Pyruvate-kinase activity mean RBC volume, and reticulocyte count have also been determined in order to estimate whether some significant variations in the level of these age markers could be detected between the HLA BW 35+ and BW 35- subjects. A significant negative correlation between sialic acid and RBC magnesium concentrations was observed for the whole population tested (n 57, p less than 0.005), 61% of the BW 35+ and only 25% of the BW 35- individuals having sialic acid values above, and magnesium values below the overall mean (p less than 0.01). The variance of mean RBC volume was also larger for the BW 35+ group. Other determinations did not show any significant variations, suggesting that the results are not related to RBC age.


Effects of Cognitive Functions on Speech Recognition in Noise in Cochlear Implant Recipients.
There are substantial differences in speech recognition performance of adult cochlear implant (CI) recipients. This study investigated the effects of cognitive function on speech recognition in CI recipients. The verbal working memory of 36 adults with unilateral CIs was tested using digit span tests. Attention and inhibition abilities were assessed by using the Stroop test (both congruent and incongruent tasks). Speech recognition in noise was measured using the Turkish matrix test. A moderate negative correlation was observed between the critical signal-to-noise ratio obtained via speech recognition in noise test and the digit span test scores (backward and digit span total scores). There was no correlation between Stroop test scores and speech recognition in noise in CI recipients. The findings indicated that verbal working memory correlated well with speech recognition outcomes in adult CI recipients and that higher working memory capacity led to better speech recognition performance in noise.


Licensed to elongate: a molecular mechanism for MLL-based leukaemogenesis.
The RNA polymerase II (Pol II) elongation factor (ELL) was the first translocation partner of mixed lineage leukaemia (MLL) for which a biochemical function was determined. It was therefore proposed that the regulation of the elongation stage of transcription could be fundamental to MLL-based leukaemogenesis. Recent studies have identified ELL complexed with several of the translocation partners of MLL in a transcriptional super elongation complex (SEC). These studies provide evidence for the importance of the regulation of Pol II elongation in disease pathogenesis and suggest that MLL chimaeras function by licensing Pol II transcription elongation without the appropriate checkpoints.


Variations during the gonotrophic cycle in the titer of the myotropic ovulation hormone and the response of the ovarian muscles in Rhodnius prolixus.
The response of the ovarian muscles to a standard preparation of the myotropic ovulation factor from identified neurosecretory cells in the brain of Rhodnius prolixus increases after feeding in both virgin and mated females. This increase is unaffected by removal of the neurosecretory cells and by increases imposed on the resting tension of the ovaries used in the bioassay. The hemolymph titer of the myotropic activity as determined by bioassay exhibits a peak after feeding in both mated and virgin females. A second peak, corresponding both with the principal bout of ovulation/oviposition and with a corresponding peak in ovarian motility previously observed in vivo, is observed only in mated females. It is concluded that the changes in ovarian motility associated with ovulation in Rhodnius are a consequence primarily of variations in the hemolymph titer of the myotropic ovulation hormone from neurosecretory cells in the brain.


Endoscopy in pediatric gastroenterology.
Seventy two endoscopies of the upper gastrointestinal tract and one hundred and fifteen colonoscopies were performed in children aged nine months to seventeen years. The experience gained with different types of endoscopes suggests that endoscopy of the upper gastrointestinal tract should be only performed with pediatric instruments. These are: GIF-P2(1) (max. outer diameter 9 mm) and TX-7(2) (max. outer diameter 10mm). For colonoscopy, the ideal pediatric instrument is not yet available. Sigmoidocoloscopes like the CFMB1 (length 1115 mm) and the F-91-S2 (length 650 mm) are suitable for older children.


Qualitative Differences Between the Semi-separable and the "Almansi-Type" Stokes Stream Function Expansions in the Study of Biological Fluids.
The creeping motion of a Newtonian fluid around particles simulating the relative motion of biological fluids such as blood plasma flow past red blood cells can be modeled through Stokes equations in spheroidal coordinates. By employing a stream function ψ, the irrotational and the rotational Stokes flow are described through a second- and a fourth-order elliptic-type partial differential equations: E2ψ = 0 and E4ψ = 0, respectively. Firstly, the complete set of the solution expansion has been obtained, in terms of particular combinations of Gegenbauer functions, in separable and semiseparable forms. Each of these terms, the so-called eigenflow, represents in a clearly and distinct way either rotational or irrotational type of flow. This information is of great value in the study of biofluids, as it may be correlated to characteristics observed in various diseases. Secondly, the Almansi-type solution is obtained as a kind of perturbation of the irrotational flow solution implying that no clear identification of the kind of flow is available. In the present manuscript, we demonstrate the advantages of the semiseparable form of solution and provide a reduction formula from the "Almansi-type" solution to the semiseparable one, indicating a way of revealing the hidden physical information.


Ichthyosiform eruption in a patient with Dubowitz syndrome.
Dubowitz syndrome is a rare autosomal recessive disorder characterized by intrauterine and postnatal growth retardation, microcephaly, moderate mental retardation, typical craniofacial anomalies, and eczematous skin lesions. We report a case of Dubowitz syndrome associated with ichthyosiform skin changes.


Human aspirated epididymal spermatozoa: ultrastructural, immunological, kinetic study and fertilization ability. MESA Italian Group.
The analysis of ultrastructural, kinetic and immunological characters of spermatozoa aspirated from the proximal segments of the epididymis of patients with congenital absence of vas deferens showed that most of them are defective. These spermatozoa, utilized in different procedures of assisted reproduction, showed a reduced fertilization rate. The data obtained in this study seem to indicate that CAV affects the development and functional properties of epididymal spermatozoa.


Bisulfite-Free Sequencing of 5-Hydroxymethylcytosine with APOBEC-Coupled Epigenetic Sequencing (ACE-Seq).
Here, we provide a detailed protocol for our previously published technique, APOBEC-Coupled Epigenetic Sequencing (ACE-Seq), which localizes 5-hydroxymethylcytosine at single nucleotide resolution using nanogram quantities of input genomic DNA. In addition to describing suggested troubleshooting workflows, these methods include four important updates which should facilitate widespread implementation of the technique: (1) additionally optimized reaction conditions; (2) redesigned quality controls which can be performed prior to resource-consumptive deep sequencing; (3) confirmation that the less active, uncleaved APOBEC3A (A3A) fusion protein, which is easier to purify, can be used to perform ACE-Seq ; and (4) an example bioinformatic pipeline with suggested filtering strategies. Finally, we have provided a supplementary video which gives a narrated overview of the entire method and focuses on how best to perform the snap cool and A3A deamination steps central to successful execution of the method.


Normal Gamma Glutamyl Transferase Levels at Presentation Predict Poor Outcome in Biliary Atresia.
Gamma-glutamyl transferase levels (GGT) are typically elevated in biliary atresia (BA), but normal GGT levels have been observed. This cohort of "normal GGT" BA has neither been described nor has the prognostic value of GGT level on outcomes in BA. We aimed to describe outcomes of a single-centre Australian cohort of infants with BA and assess the impact of GGT level at presentation on outcomes in BA. Infants diagnosed with BA between 1991 and 2017 were retrospectively analysed. Outcomes were defined as survival with native liver, liver transplantation (LT), and death. Patients were categorized into normal (<200I U/L) or high GGT groups based on a mean of 3 consecutive GGT values done before Kasai portoenterostomy (KPE). Baseline parameters, age at surgery, clearance of jaundice (COJ), and outcomes were compared between the 2 groups. One hundred thirteen infants underwent KPE at median 61 (30-149) days. At a median follow-up of 14.2 (0.9-26.3) years, 35% (39/113) patients were surviving with native liver, 55% (62/113) underwent LT and 11% (12/113) died pretransplant. 12.3% (14/113) patients had normal GGT. Age at KPE and time to COJ were similar between normal and high GGT groups. Normal GGT group had shorter time from KPE to LT (11 vs 18 months, P = 0.02), underwent LT at a younger age (14 vs 20 months, P = 0.04), and had poorer transplant-free survival (P = 0.04) than high GGT group. 12.3% of infants with BA had normal GGT levels at diagnosis. Low GGT levels at presentation in BA was associated with a poorer outcome.


Vestibular reflex changes following aminoglycoside induced ototoxicity.
The effects of aminoglycoside-induced changes on the vestibular system were evaluated in three subjects who suffered significant damage over the course of treatment. Measurements of vestibulo-ocular reflex (VOR) function were made using sinusoidal and pseudorandom rotational stimuli between 0 to 5 days after initiation of drug therapy, during drug therapy, and up to 579 days following drug administration. All subjects tested at baseline evaluations had normal VOR function. During aminoglycoside therapy there was a precipitous drop in both the VOR time and gain constants. The decline in VOR function was larger at lower stimulus frequencies compared to high frequencies, resulting in a relative preservation of function in the high frequencies. Over a period of about a year, VOR high frequency gains recovered to within normal limits. However, the VOR time constants showed only a modest recovery and remained well below the normal range.


Efficacy and safety of novel oral anticoagulants versus low molecular weight heparin in cancer patients with venous thromboembolism: A systematic review and meta-analysis.
Novel Oral Anticoagulants (NOACs) have been considered for treating cancer-related venous thromboembolism (VTE), but safety issues have been raised. We performed a systematic review and pairwise meta-analysis of the efficacy and safety of NOACs versus low molecular weight heparin (LMWH) in this setting. Four randomized controlled trials were included, providing data on 2894 patients. Compared to LMWH, NOACs were associated with a significantly lower risk of VTE recurrence and were not associated with an increased risk of major bleedings (MB). NOACs were non inferior to LMWH for a composite outcome of VTE recurrence and MB, pulmonary embolism recurrence and all-cause mortality; however, NOACs were associated with an increased risk of clinically relevant nonmajor bleedings (CRNMB) and gastrointestinal MB. In conclusion, in patients with cancer-related VTE, NOACs are effective and safe in reducing VTE recurrence compared to LMWH. An increased risk of CNRMB and GI MB should nonetheless be considered.


Mitochondrial complex III in larval stage of Echinococcus multilocularis as a potential chemotherapeutic target and in vivo efficacy of atovaquone against primary hydatid cysts.
Echinococcus multilocularis employs aerobic and anaerobic respiration pathways for its survival in the specialized environment of the host. Under anaerobic conditions, fumarate respiration has been identified as a promising target for drug development against E. multilocularis larvae, although the relevance of oxidative phosphorylation in its survival remains unclear. Here, we focused on the inhibition of mitochondrial cytochrome bc1 complex (complex III) and evaluated aerobic respiratory activity using mitochondrial fractions from E. multilocularis protoscoleces. An enzymatic assay revealed that the mitochondrial fractions possessed NADH-cytochrome c reductase (mitochondrial complexes I and III) and succinate-cytochrome c reductase (mitochondrial complexes II and III) activities in the aerobic pathway. Enzymatic analysis showed that atovaquone, a commercially available anti-malarial drug, inhibited mitochondrial complex III at 1.5 nM (IC50). In addition, culture experiments revealed the ability of atovaquone to kill protoscoleces under aerobic conditions, but not under anaerobic conditions, indicating that protoscoleces altered their respiration system to oxidative phosphorylation or fumarate respiration depending on the oxygen supply. Furthermore, combined administration of atovaquone with atpenin A5, a quinone binding site inhibitor of complex II, completely killed protoscoleces in the culture. Thus, inhibition of both complex II and complex III was essential for strong antiparasitic effect on E. multilocularis. Additionally, we demonstrated that oral administration of atovaquone significantly reduced primary alveolar hydatid cyst development in the mouse liver, compared with the untreated control, indicating that complex III is a promising target for development of anti-echinococcal drug.


Peptidomics methods for the identification of peptidase-substrate interactions.
Peptidases have important roles in controlling physiological signaling through their regulation of bioactive peptides. Understanding and controlling bioactive peptide regulation is of great biomedical interest and approaches that elucidate the interplay between peptidases and their substrates are vital for achieving this goal. Here, we highlight the utility of recent peptidomics approaches in identifying endogenous substrates of peptidases. These approaches reveal bioactive substrates and help characterize the biochemical functions of the enzyme. Most recently, peptidomics approaches have been applied to address the challenging question of identifying the peptidases responsible for regulating specific bioactive peptides. Since peptidases are of great biomedical interest, these approaches will begin to impact our ability to identify new drug targets that regulate important bioactive peptides.


Structural basis of polyamine transport by human ATP13A2 (PARK9).
Polyamines are small, organic polycations that are ubiquitous and essential to all forms of life. Currently, how polyamines are transported across membranes is not understood. Recent studies have suggested that ATP13A2 and its close homologs, collectively known as P5B-ATPases, are polyamine transporters at endo-/lysosomes. Loss-of-function mutations of ATP13A2 in humans cause hereditary early-onset Parkinson's disease. To understand the polyamine transport mechanism of ATP13A2, we determined high-resolution cryoelectron microscopy (cryo-EM) structures of human ATP13A2 in five distinct conformational intermediates, which together, represent a near-complete transport cycle of ATP13A2. The structural basis of the polyamine specificity was revealed by an endogenous polyamine molecule bound to a narrow, elongated cavity within the transmembrane domain. The structures show an atypical transport path for a water-soluble substrate, in which polyamines may exit within the cytosolic leaflet of the membrane. Our study provides important mechanistic insights into polyamine transport and a framework to understand the functions and mechanisms of P5B-ATPases.


Synthesis and anticancer activity of novel 2-pyridyl hexahyrocyclooctathieno[2,3-d]pyrimidine derivatives.
A series of new 2-pyridyl hexahydrocycloocta [4,5]thieno[2,3-d]pyrimidines with different substituents as C-4 position was synthesized. The anticancer activity of the newly synthesized compounds was tested in vitro using a two-stage process utilizing 60 different human tumor cell lines representing leukemia, melanoma and cancers of lung, colon, central nervous system, ovary, kidney, prostate as well as breast. Compounds 4a, 6a, 7a, 7d and 7g showed potent anticancer activity at low concentrations against most of the used human tumor cell lines comparable with doxorubicin as standard potent anticancer drug (average log10 GI50 over all cell lines = -6.85). Also, compound 4b was selective against SNB-75 (CNS cancer) log10 GI50 = -5.57. Interestingly, compound 7e exhibited promising selectivity against 13 tumor cell lines showing growth inhibition percentages between 54.05 and 89.23.


Immunotoxicological investigation of the effects of a pesticide; cypermethrin.
The effects of a synthetic pyrethroid pesticide cypermethrin on the immune system were studied. The effect of a daily oral administration of 1/40, 1/20 and 1/10 of LD50 was studied in rabbits for its influence on the humoral immune response after vaccination with Salmonella typhi, as well as on cell-mediated immunity. The two higher doses induced a significant dose-dependent decrease of serum antibody titers. The skin redness measured in the tuberculin skin test showed the same dose-dependent tendency. In subacute experiments with rats, a significant dose-dependent decrease was observed both in the anti-ovalbumin titer of blood sera measured in passive hemagglutination test and in the autologous rosette-formation of T-lymphocytes in groups fed the higher doses.


Reduced densities of sodium-dependent [3H] hemicholinium-3 binding sites in hippocampus of developmental rats following perinatal low-level lead exposure.
We investigated the effect of perinatal, low-level lead exposure on [3H]hemicholinium-3 (HC-3) binding in the hippocampus of postnatal rat. Rat pups were maternally lead-exposed from gestational day 16 through postnatal day 28 (PN28). In control animals, the [3H]HC-3 binding sites increased from 7 fmol/mg protein at postnatal day 1 (PN1) to 14 and 35 fmol/mg protein at PN7 and PN14, respectively, and reached adult values of 50 fmol/mg protein, at PN21 and PN28. In lead-exposed litters, the [3H]HC-3 binding was reduced by 30-40% throughout the early postnatal development and remained 40% below control values in PN60 animals, one month after termination of lead exposure. The Pb-induced reduction in HC-3 binding was associated with a similar decrease in ChAT activity and was comparable to the effect of localized lesion of medial septum. Septal cell counts in the lead-exposed PN21 rats indicated a 22% reduction in the number of ChAT-immunoreactive cells in the medial septum/vertical diagonal band (MS/vDB) complex although cell numbers in the horizontal limb of the diagonal band (hDB) were not altered. These results suggest that perinatal, low-level lead exposure results in a reduced density of cholinergic nerve terminals in the hippocampus, either due to impaired development or degeneration of the cholinergic projection neurons in the MS/vDB complex.