Effects of exercise therapy for the treatment of symptomatic full-thickness supraspinatus tears on in vivo glenohumeral kinematics.
The high incidence of rotator cuff disease combined with high failure rates for nonoperative treatment of full-thickness rotator cuff tears underlines the importance of improving nonoperative management of rotator cuff tears. The study objective was to assess changes in in vivo glenohumeral kinematics of patients with a symptomatic full-thickness supraspinatus tear before and after a 12-week exercise therapy program. It was hypothesized that successful exercise therapy would result in improved kinematics (smaller translations and increased subacromial space). Five patients were recruited for the study and underwent dynamic stereoradiography analysis before and after a 12-week exercise therapy protocol to measure changes in glenohumeral joint translations and subacromial space during coronal plane abduction. Strength and patient-reported outcomes (American Shoulder and Elbow Surgeons; Disabilities of the Arm, Shoulder and Hand; Western Ontario Rotator Cuff Index) were also evaluated. After therapy, no subject went on to receive surgery. It was found that the contact path length of the humerus translating on the surface of the glenoid was reduced by 29% from 67.2% ± 36.9% glenoid height to 43.1% ± 26.9% glenoid height (P = .036) after therapy. Minimum acromiohumeral distance showed a small increase from 0.9 ± 0.6 mm to 1.3 ± 0.8 mm (P = .079). Significant improvements in strength and patient-reported outcomes were also observed (P < .05). Successful exercise therapy for treatment of small full-thickness supraspinatus tears results in improvements in glenohumeral joint kinematics and patient-reported outcomes through increases in rotator cuff muscle strength and joint stability. This study may enable identification of prognostic factors that predict the response of a patient with a rotator cuff tear to exercise therapy.


Nuclear deprimerones (low molecular weight peptides controlling gene expression) are associated with DNA and nuclear RNA.
Isolated, deproteinized nucleic acids from calf thymus and rat liver nuclei were fractionated on Bio-Gel A-5m into DNA and RNA fractions. Extraction of deproteinized DNA and nuclear RNA with 80% ethanol at pH 9.5 yielded low molecular weight peptides (deprimerones) capable of inhibiting DNA transcription in a cell-free system. The extracted peptidic fractions were further fractionated on a Sephadex G-25 column and collected as a fraction of mol. wt. between 1 500 and 600. The yield of DNA deprimerones was about 30 microgram/mg DNA and of nuclear RNA deprimerones 150-200 microgram/mg RNA (measured by amino acid composition). The nucleoplasm contained a negligible amount of free, soluble peptides (about 18 microgram/g tissue). The DNA and RNA deprimerones were characterized by their amino acid composition and by two-dimensional thin layer chromatography on cellulose gel plates which yielded two major and two minor fractions. DNA deprimerones isolated in this way are very similar, if not identical, to the affinity DNA deprimerones isolated from a nuclear extract on DNA-cellulose but differ from RNA deprimerones. DNA and RNA deprimerones were also compared with the nuclear deprimerones extracted directly from the lysed nuclei. Their amino acid composition is different from both DNA and nuclear RNA deprimerones. Two-dimensional thin layer chromatography on cellulose plates yielded about ten fractions (spots) with various amino acid composition and inhibitory activity for cell-free transcription.


Alterations of brain tissue in fetal rats exposed to nicotine in utero: possible involvement of nitric oxide and catecholamines.
Histopathological changes in the brains of embryos from female rats treated with nicotine during pregnancy and possible involvement of nitric oxide (NO) and catecholamines in the nicotine-induced abnormalities of developing brain were investigated. Sexually mature female Wistar rats were given 1, 2, and 3 mg/kg nicotine hydrogen tartrate (NHT) subcutaneously for 20 days after mating. Levels of cotinine, a nicotine metabolite, in the maternal plasma increased dose-dependently. Fetus and fetal brain weights were significantly lower in all nicotine-treated groups. Light microscopy of hippocampal CA1 area showed a decrease in the number of cells per unit area. Electron microscopy of the same region revealed a dose-dependent increase in intracytoplasmic edema, mitochondrial swelling, dilation of rough endoplasmic reticulum, nuclear configurative abnormalities, and condensation of the nuclear chromatin. Nitrate + nitrite levels in fetal brain homogenates were significantly lower in the groups treated with 2 and 3 mg/kg NHT. Norepinephrine and normetanephrine (NMN) levels were significantly higher in 2 and 3 mg/kg NHT groups, as well as dopamine, 3-methoxy-4-hydroxyphenylethyleneglycole (MHPG), and dihydroxyphenylacetic acid levels in the 3-mg/kg NHT group. In conclusion, maternal nicotine exposure may lead to structural abnormalities of the fetal brain tissue and may result in decreased levels of NO and increased levels of catecholamines and their metabolites.


Association between social capital and suicide ideation, plan and attempt among men living with HIV in China.
Better understanding of the relationship between social capital and risk of suicide is essential for suicide prevention and control among people living with HIV (PLWH). Participants were 494 male PLWH recruited with a venue-based method from Wuhan in China. Data were collected using a self-reported questionnaire during November 2015 and January 2016. Social capital was measured using the short-version Personal Social Capital Scale. Multivariate logistic regression was used to assess the association between social capital and suicidal ideations post HIV+ diagnosis and in the past month, as well as suicide plan and attempt. Scatter plots showed a nonlinear trend in the prevalence of the three suicide measures along with social capital. Logistic regression analyses stratified by quartiles of social capital indicated a significant nonlinear association between social capital and the risk of suicide. The estimated odds ratio [95% CI] of suicidal ideation was 0.87 [0.51.1.42], 0.68 [0.40, 1.14] and 0.24 [0.12, 0.46] for the second, third and fourth quartile of social capital scores respectively with the first quartile as the reference. Similar results were observed for suicidal ideation in the past month and suicidal plan/attempt. Findings of this study suggest that social capital is only associated with lower suicidal ideation at very high levels of social capital. If verified with longitudinal data, this finding suggests an effective suicide prevention intervention among male PLWH must foster social capital to a level greater than average.


A new series of pyridazinone derivatives as cholinesterases inhibitors: Synthesis, in vitro activity and molecular modeling studies.
The pyridazinone nucleus has been incorporated into a wide variety of therapeutically interesting molecules to transform them into better drugs. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are known to be serine hydrolase enzymes responsible for the hydrolysis of acetylcholine (ACh). Inhibition of cholinesterases is an effective method to curb Alzheimer's disease. Here, we prepared 12 new 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(nonsubstituted/4-substituted benzenesulfonohydrazide) derivatives and evaluated their inhibitory effects on AChE/BChE in pursuit of potent dual inhibitors for Alzheirmer's Disease. We also tried to get insights into binding interactions of the synthesized compounds in the active site of both enzymes by using molecular docking approach. We obtained our compounds by the reaction of various substituted/nonsubstituted benzenesulfonic acid derivatives with 6-substitutedphenyl-3(2H)-pyridazinone-2-yl acetohydrazide and determined their anticholinesterase activities according to the Ellman's method. Molecular docking studies were done using Glide and the results were evaluated on Maestro (Schrödinger, LLC, New York, NY, 2019). The title compounds showed moderate inhibition at 100 μg/ml against both enzymes, yet with better activity against BChE. Compound VI2a emerged as a dual inhibitor with 25.02% and 51.70% inhibition against AChE and BChE, respectively. This study supports that novel pyridazinone derivates may be used for the development of new BChE inhibitory agents. It was less potent than the reference drugs, yet promising for further modifications as a lead. The ability of the compounds to adopt energetically more favourable conformations and to engage in more key interactions in the ECBChE active gorge explains their better activity profile against ECBChE.


Induced expression of melittin, an antimicrobial peptide, inhibits infection by Chlamydia trachomatis and Mycoplasma hominis in a HeLa cell line.
As the number of pathogenic microbial strains resistant to different antibiotics increases, amphipathic peptides with antimicrobial activity are promising agents for the therapy of infectious diseases. This work deals with the effect of an amphipathic antimicrobial peptide, melittin, expressed within recombinant plasmid vectors, on infection with urogenital pathogens Chlamydia trachomatis and Mycoplasma hominis in HeLa cell culture. Recombinant plasmid constructs with the melittin gene under the control of the tetracycline-responsive promoter of human cytomegalovirus were obtained. We showed inhibition of C. trachomatis and M. hominis infection after the introduction of recombinant plasmid vectors expressing the melittin gene into the infected cell culture.


Increased marble-burying behavior in ethanol-withdrawal state: modulation by gonadotropin-releasing hormone agonist.
A characteristic behavior in alcohol abstinence state indicates the possibility of obsessive-compulsive behavior in alcoholics. Ethanol is known to reduce hypothalamic synthesis, release, and mRNA expression of gonadotropin-releasing hormone (GnRH) that modulates serotonergic, dopaminergic, and glutamatergic systems, which experience adaptive changes on chronic exposure to ethanol. Such changes are also evident in obsessive-compulsive disorder. Therefore, it was proposed to investigate the effect of ethanol-withdrawal on marble-burying behavior in mice, particularly because it simulates some aspects of obsessive-compulsive behavior; further, the influence of GnRH agonist was studied on the same. Ethanol-withdrawal state was induced after its chronic administration, and marble-burying behavior was observed at 0, 6, 24, 48, and 96 h interval. Further, the influence of leuprolide--a GnRH agonist (50-600 microg/kg, s.c.) or fluoxetine (5-30 mg/kg, i.p.) was investigated on ethanol-withdrawal-induced changes in marble-burying behavior. The results indicated that ethanol-withdrawal led to a gradual increase in marble-burying behavior upto 48 h with peak at 24 h interval. Administration of leuprolide (100-600 microg/kg, s.c.), 30 min prior to 24 h interval, dose dependently reduced ethanol-withdrawal-induced increase in marble-burying behavior, and this effect was comparable to that of fluoxetine (15 and 30 mg/kg, i.p.). Further, twice daily administration of leuprolide (50 microg/kg, s.c), concomitant with ethanol, prevented the gradual increase in marble-burying behavior after ethanol-withdrawal and this effect was comparable to fluoxetine (5 mg/kg, i.p.). In conclusion, ethanol-withdrawal on chronic administration increases marble-burying behavior in mice; its development and expression is attenuated by leuprolide.


Fungal esophagitis associated with tuberculous pericarditis in an human immunodeficiency virus-positive patient: a case report.
Opportunistic infections are frequent in people living with the human immunodeficiency virus who either do not have access to antiretroviral therapy (ART) or use it irregularly. Tuberculosis is the most frequent infectious disease in PLHIV and can predispose patients to severe fungal infections with dire consequences. We describe the case of a 35-year-old Brazilian man living with human immunodeficiency virus (HIV) for 10 years. He reported no adherence to ART and a history of histoplasmosis with hospitalization for 1 month in a public hospital in Natal, Brazil. The diagnosis was disseminated Mycobacterium tuberculosis infection. He was transferred to the health service in Recife, Brazil, with a worsening condition characterized by daily fevers, dyspnea, pain in the upper and lower limbs, cough, dysphagia, and painful oral lesions suggestive of candidiasis. Lymphocytopenia and high viral loads were found. After screening for infections, the patient was diagnosed with tuberculous pericarditis and esophageal candidiasis caused by Candida tropicalis. The isolated yeasts were identified using the VITEK 2 automated system and matrix-assisted laser desorption/ionization time-of-flight-mass spectrometry. Antifungal microdilution broth tests showed sensitivity to fluconazole, voriconazole, anidulafungin, caspofungin, micafungin, and amphotericin B, with resistance to fluconazole and voriconazole. The patient was treated with COXCIP-4 and amphotericin deoxycholate. At 12 days after admission, the patient developed sepsis of a pulmonary focus with worsening of his respiratory status. Combined therapy with meropenem, vancomycin, and itraconazole was started, with fever recurrence, and he changed to ART and tuberculostatic therapy. The patient remained clinically stable and was discharged with clinical improvement after 30 days of hospitalization. Fungal infections should be considered in patients with acquired immunodeficiency syndrome as they contribute to worsening health status. When mycoses are diagnosed early and treated with the appropriate drugs, favorable therapeutic outcomes can be achieved.


Effect of dietary linoleate on synthesis and degradation of fatty acid synthetase from rat liver.
The induction of fatty acid synthetase activity in rat liver is markedly reduced by feeding a diet containing a source of linoleate. Within 48 h after changing from a fat-free, high carbohydrate diet to one containing 15% by weight of safflower oil, the specific activity of rat liver fatty acid synthetase is approximately 2-fold lower than that from rats fed a fat-free diet througout. In contrast, feeding a diet containing 15% hydrogenated coconut oil, a source of saturated fatty acids, or 5% methyl oleate for the same length of time has little effect on the activity of the enzyme. The rate of synthesis of the enzyme is reduced by safflower oil feeding from the fat-free (control) level and after 48 h is approximately one-half that of the control. The rate of degradation of fatty acid synthetase is markedly increased in the safflower oil-fed animals over the control; the half-lives are 1.8 days and 3.8 days, respectively. It is suggested that polyunsaturated fatty acids, or a product derived from them, may directly or indirectly regulate the transcription or translation (or both) of fatty acid synthetase messenger RNA.


Disruption of Brainstem Structural Connectivity in REM Sleep Behavior Disorder Using 7 Tesla Magnetic Resonance Imaging.
Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is one of the earliest manifestations of α synucleinopathies. Brainstem pathophysiology underlying REM sleep behavior disorder has been described in animal models, yet it is understudied in living humans because of the lack of an in vivo brainstem nuclei atlas and to the limited magnetic resonance imaging (MRI) sensitivity. To investigate brainstem structural connectivity changes in iRBD patients by using an in vivo probabilistic brainstem nuclei atlas and 7 Tesla MRI. Structural connectivity of 12 iRBD patients and 12 controls was evaluated by probabilistic tractography. Two-sided Wilcoxon rank-sum test was used to compare the structural connectivity indices across groups. In iRBD, we found impaired (Z = 2.6, P < 0.01) structural connectivity in 14 brainstem nuclei, including the connectivity between REM-on (eg, subcoeruleus [SubC]) and REM sleep muscle atonia (eg, medullary reticular formation) areas. The brainstem nuclei diagram of impaired connectivity in human iRBD expands animal models and is a promising tool to study and possibly assess prodromal synucleinopathy stages. © 2021 International Parkinson and Movement Disorder Society.


Spatial-temporal dynamics of NDVI and Chl-a concentration from 1998 to 2009 in the East coastal zone of China: integrating terrestrial and oceanic components.
Annual normalized difference vegetation index (NDVI) and chlorophyll-a (Chl-a) concentration are the most important large-scale indicators of terrestrial and oceanic ecosystem net primary productivity. In this paper, the Sea-viewing Wide Field-of-view Sensor level 3 standard mapped image annual products from 1998 to 2009 are used to study the spatial-temporal characters of terrestrial NDVI and oceanic Chl-a concentration on two sides of the coastline of China by using the methods of mean value (M), coefficient of variation (CV), the slope of unary linear regression model (Slope), and the Hurst index (H). In detail, we researched and analyzed the spatial-temporal dynamics, the longitudinal zonality and latitudinal zonality, the direction, intensity, and persistency of historical changes. The results showed that: (1) spatial patterns of M and CV between NDVI and Chl-a concentration from 1998 to 2009 were very different. The dynamic variation of terrestrial NDVI was much mild, while the variation of oceanic Chl-a concentration was relatively much larger; (2) distinct longitudinal zonality was found for Chl-a concentration and NDVI due to their hypersensitivity to the distance to shoreline, and strong latitudinal zonality existed for Chl-a concentration while terrestrial NDVI had a very weak latitudinal zonality; (3) overall, the NDVI showed a slight decreasing trend while the Chl-a concentration showed a significant increasing trend in the past 12 years, and both of them exhibit strong self-similarity and long-range dependence which indicates opposite future trends between land and ocean.


Efficient Gaussian sample specific network marker discovery and drug enrichment analysis validation.
Identifying stable gene markers at an individual level can help to understand the genetic mechanisms of each individual patient and accomplish personalized medicine. In this paper, we propose an efficient framework to identify sample-specific markers. Gene expression data first is transformed to a corresponding likelihood matrix to alleviate inherent noise besides adding population information to each sample. Then those significantly differential genes or gene pairs are further mapped to a STRING network for analysis by assuming that the likelihood of each gene or gene pairs in the control group follows a Gaussian distribution. The proposed method is applied to three benchmark datasets including lung adenocarcinoma, kidney renal clear cell carcinoma, and uterine corpus endometrial carcinoma. It is found that disease gene markers identified by the proposed methods outperform the previous sample-specific network (SSN) method in both subtyping and survival analysis. Furthermore, we exploit the application of the subtype markers in following drug selection. The difference of the enriched drug set may reflect some underlying mechanisms of the subtypes and shed light on selecting appropriate drugs for each cancer subtype.


Association between household fuel combustion and diabetes among middle-aged and older adults in China: A cohort study.
Few studies examined the associations of household fuel combustion with incident diabetes. The current study emphasizes the association of domestic fuel combustion with diabetes among middle- and older- Chinese. The data was extracted from a national and prospective cohort, the China Health and Retirement Longitudinal Study (CHARLS), which enrolled adults ≥ 45 years. A total of 4610 and 5570 participants were involved in heating and cooking-related analyses. Multivariable logistic models were conducted to assess the association of domestic fuel combustion for heating and cooking with diabetes. Furthermore, we also examined whether it differed from switching fuel types. Subgroup and interaction analyses were performed based on covariates to examine the robustness and find potential effect modifiers. After about 5-year follow-up, 592 and 716 diabetes were diagnosed in heating and cooking-related analyses. Compared to cleaner fuel users, those who used solid fuel for heating [OR (95 % CI):1.32 (1.05-1.66)] maintained higher risks of incident diabetes. In addition, participants who were exposed to solid fuel for both heating and cooking [OR (95 % CI):1.55 (1.17-2.06)] might have further elevated diabetic risk. Those risks are likely to be attenuated if people switched cooking fuel from solid to cleaner [OR (95 % CI): 0.68 (0.53-0.89)]. Home solid fuel use for heating is associated with an increased risk of incident diabetes. If solid fuel was concurrently used for both cooking and heating, those risks might be further elevated. Interestingly, as compared to solid fuel users, the participants switching cooking fuel types from solid to cleaner presented reduced diabetic risk.


Comparison of haemodialysis (HD) and post dilution haemofiltration (HF) on an unselected dialysis population.
In a comparison of post-dilution haemofiltration (HF) with routine haemodialysis (HD) HF was found to be technically feasible and without difficulty a method of treating end-stage renal failure patients. HF offers the theoretical benefit of a high removal rate of middle molecules at the expense of measured small molecule clearances. The reported improvement in blood pressure and hyperphosphataemia in HF could not be found in our unselected population. The better tolerance to fluid removal during HF may be due to the linear weight loss during treatment but cannot be attributed to constancy in serum osmolality HF (3 X 20-23L ultrafiltrate/week) seems to be an adequate treatment for small patients. In large, heavy patients without significant residual renal function the ultrafiltration volume has to be increased in relation to body weight. HF was found to be superior to HD in patients with fluid removal problems and frequent hypotensive episodes during HD.


Surface modification of chitosan with Ni(II) Schiff base complex: A new heterogeneous catalyst for the synthesis of xanthones.
A new biocomposite of chitosan, chitosan-supported di(pyridine-2-yl)methanone-Ni(II) complex, CS-DPM-Ni, is synthesized for the first time. The biocomposite is thoroughly characterized by FTIR, PXRD, XPS, FESEM, EDX, TGA, ICP-OES, and elemental analysis. The synthesized composite is successfully used as a heterogeneous catalyst in the synthesis of a library of xanthone derivatives by the intermolecular catalytical coupling of 2-substituted benzaldehydes and phenols. The catalyst could be retrieved from the reaction mixture by simple filtration and reused for up to four catalytic cycles. All products were isolated in good to high yields (65-90 %) with good turnover numbers (TONs), and fully characterized by 1H and 13C{1H} NMR spectroscopy. The green chemistry metrics values for the reaction were discerned and found to be close to the ideal values.


Healthcare worker-related MRSA cluster in a German neonatology level III ICU: a true European story.
Here we investigated a cluster of eight newly Methicillin-resistant Staphylococcus aureus (MRSA)-colonized neonates at an ICU, and present data on molecular strain characterization as well as the source identification process in which we analyze the impact of MRSA-colonized HCWs. Molecular strain characterization revealed a unique pattern which was identified as spa-type t 127--an extremely rare strain type in Germany. Environmental sampling and screening of parents of colonized neonates proved negative. However, staff screening identified one healthcare worker (HCW; 1/134) belonging to a group of recently employed Romanian HCWs who was colonized with the spa 127 strain. Subsequent screening also detected MRSA in 9/51 Romanian HCWs (18%) and 7/9 (14% of all) isolates showed the same molecular pattern as the index case (spa/PFGE type). All carriers were successfully decolonized, after which no new patient cases occurred. As a result, we have now implemented a universal screening programme of all new employees as part of our infection control management strategy. MRSA-colonized HCWs can act as a source for in hospital transmission. Since HCWs from high endemic countries are particular prone to being colonized, they may pose a risk to patients.


Racial/Ethnic Differences in Contemporaneous Use of Mental Health and Substance Use Treatment Among Individuals Experiencing Both Mental Illness and Substance Use Disorders.
This study examined whether the well-established racial/ethnic differences in mental health service utilization among individuals with mental illness are reflected in the treatment utilization patterns of individuals experiencing both mental illness and substance use disorders, particularly in regards to the use of contemporaneous mental health and substance abuse treatment. Using pooled data from the National Survey on Drug Use and Health (2009-2013), the patterns of mental health and substance use treatment utilization of 8748 White, Black, or Latino individuals experiencing both mental illness and substance use disorders were analyzed. Multinomial logistic regression was conducted to test the relationships among racial/ethnic groups and the receipt of contemporaneous treatment, mental health treatment alone, and substance use treatment alone as compared with no treatment utilization. Results indicated that Black and Latino respondents were less likely to receive contemporaneous treatment than Whites respondents. Also, significantly associated with outcomes were several interactions between race/ethnicity and predisposing, need and enabling factors known to be associated with service utilization. The findings suggest that an underlying mechanism of racial/ethnic differences among individuals with co-occurring mental illness and substance use disorders in the treatment utilization may differ by the specific types of treatment and between Blacks and Latinos. Therefore, efforts to reduce these disparities should consider specialty in each treatment settings and heterogeneity within diverse racial/ethnic groups.


Decreased antibody response following immunization with enantiomorphic synthetic polypeptides.
The ability to decrease the antibody response to poly(Glu52Lys33Tyr15) in the DA and PVG strains of rats by prior immunization with its D-amino acid enantiomorph poly(DGlu48DLys38DTyr14) was tested as part of a continuing investigation into the role of optical isomerism in the ability of an antigen to induce an antibody response. The results showed that prior immunization with the D-amino acid polymer decreased the immune response to the isomeric L-polypeptide in both strains.


Carbon dynamics and their link to dissolved organic matter quality across contrasting stream ecosystems.
Streams represent active components of the carbon cycle as emitters of carbon dioxide (CO2) and methane to the atmosphere at a global scale. However, the mechanisms and governing factors of these emissions are still largely unknown, especially concerning the effect of land use. We compared dissolved and gaseous carbon dynamics in streams bordered by contrasting types of land use, specifically agriculture and forest. Carbon dioxide and methane partial pressures (pCO2 and pCH4, respectively) in the water body and carbon emissions via both gases were studied for 24h during four field expeditions. pCH4 did not differ between the two system types. pCO2 was constantly oversaturated in all streams and significantly higher in agricultural streams (annual mean 4282 ppm) compared to forest streams (annual mean 2189 ppm) during all seasons. However, emissions of CO2 were not significantly different between the stream types due to significantly higher gas transfer velocity in forest compared to agricultural streams. pCO2 was significantly positively correlated to the concentrations of dissolved organic carbon, dissolved nitrogen and soluble reactive phosphorus in the water. Furthermore, pCO2 was correlated to optical parameters of dissolved organic matter (DOM) quality, e.g., it increased with indicators of molecular size and an allochthonous fluorescent component identified by Parallel Factor Analysis (PARAFAC). This study demonstrates that different forms of land use may trigger a cascade of effects on the carbon production and emission of streams linked to changes in DOM quality.


Conversion of senescent cartilage into a pro-chondrogenic microenvironment with antibody-functionalized copper sulfate nanoparticles for efficient osteoarthritis therapy.
The development of osteoarthritis (OA) correlates with the expansion of senescent cells in cartilage, which contributes to an inflammatory microenvironment that accelerates matrix degradation and hampers cartilage generation. To address OA, we synthesized small copper sulfide nanoparticles functionalized with anti-beta-2-microglobulin antibodies (B2M-CuS NPs) that catalyze the formation of toxic •OH from H2O2 via peroxidase-like activity. These B2M-CuS NPs are specifically targeted to induce apoptosis in senescent chondrocytes while showing no toxicity toward normal chondrocytes. Furthermore, B2M-CuS NPs enhance the chondrogenesis of normal chondrocytes. Thus, B2M-CuS NPs can effectively treat OA by clearing senescent chondrocytes and promoting cartilage regeneration after intra-articular injection into the knee joints of surgery-induced OA mice. This study uses smart nanomaterials to treat OA with a synergistic strategy that both remodels senescent cartilage and creates a pro-chondrogenic microenvironment.


GSK461364A suppresses proliferation of gastric cancer cells and induces apoptosis.
Polo-like kinase 1 (PLK1) is crucial in regulating cell division and has been shown to have an oncogenic function in several cancers. Since PLK1 overexpression is closely related to tumorigenesis and has been correlated with poor clinical outcomes, specific inhibition of PLK1 in cancer cells is a promising approach for developing new anticancer drugs. In this context, the aim of the present study was to evaluated the potential cytotoxic effects of GSK461364A, a competitive inhibitor for PLK1, in gastric cancer cell line SNU-1 cells and explored its cytotoxic mechanism. The cells were exposed to GSK461364A at different concentrations ranging from 1 to 40 μM for 24 h, and it showed considerable cytotoxicity with an IC50 value of 4.34 μM. The treatment of SNU-1 cells with GSK461364A results in cell cycle arrest at the G2/M phase, decreased mitochondrial membrane potential, and increased apoptosis as indicated by Annexin V binding assay. In addition, GSK461364A treatment significantly increased the total oxidant (TOS) level, a signal of oxidative stress, and increased cleaved PARP and 8-oxo-dG levels as an indicator of DNA damage. ELISA experiments evaluating Bax, BCL-2, and cleaved caspase 3 also confirmed the apoptotic effect of GSK461364A. Current findings suggest that GSK461364A may be a chemotherapeutic agent in patients with gastric cancer. Nevertheless, more research is needed to evaluate GSK461364A as a cancer treatment drug.


The effects of probenecid on the disposition of risperidone and olanzapine in healthy volunteers.
The metabolic pathways of most xenobiotics and endogenous compounds can be divided into phase 1 (oxidative, reductive, and hydrolytic) and phase 2 (glucuronidation, sulfate conjugation, glycine and glutathione conjugation, and acetylation and methylation) processes. Oxidative metabolism by the cytochrome P450 system has been intensively investigated compared with glucuronidation and other conjugation pathways. The primary aim of this study was to evaluate the disposition of olanzapine or risperidone in healthy volunteers with and without coadministration of the uridine diphosphoglucuronate-glucuronosyltransferase inhibitor probenecid. We hypothesized that olanzapine disposition would be altered as a result of decreased glucuronidation, whereas risperidone disposition would be relatively unaffected. Our objective was to investigate whether this interaction would occur in 12 healthy volunteers, aged 22 to 42 years, who participated in a single-dose, randomized, 4-period, double-blind, crossover study receiving a single dose of either 5 mg olanzapine or 1 mg risperidone with and without 500 mg probenecid (8 doses over 4 days). Multiple blood samples were analyzed by means of liquid chromatography-tandem mass spectrometry or HPLC to assess the 48-hour time course of risperidone and olanzapine. Urine was assayed for free and glucuronidated drugs. When olanzapine was administered with probenecid, statistically significant differences were observed between plasma pharmacokinetic parameters compared with olanzapine administered alone (maximum concentration, P <.05; area under the plasma concentration-time curve from time zero to 24 hours, P <.01). Clearance was not significantly different between the treatment phases. Risperidone pharmacokinetic parameters were not significantly different (all parameters, P >.05). Inhibition of uridine diphosphoglucuronate-glucuronosyltransferase appeared to influence the disposition of olanzapine but not risperidone. Phase 2 metabolism may significantly influence the disposition of antipsychotic drugs and may be an important aspect of the variability in metabolism, participation in drug-drug interactions, and clinical response to some antipsychotic agents.


[Identification of mutations in the asporogenic yeast Candida tropicalis using intrageneric fusion of protoplasts].
The possibility of genetic identification of mutations in asporogenic yeast by the technique of intrageneric fusion of yeast protoplasts of Candida tropicals and Saccharomyces cerevisiae has been demonstrated for Candida tropicals strains G5-9 (Ade- Leu-) and G32-4 (Leu-). The mutations to auxotrophy ade- in the strain G5-9 and leu- in G32-4 of Candida tropicals are allelic to ade2 and leu1 mutations in the genes of Saccharomyces cerevisiae yeast. The allelic character of adenine auxotrophy mutation in Candida tropicals and ade2 mutation in Saccharomyces cerevisiae is confirmed by the absence of AIR-carboxylase activity in cellular extract from the strain G5-9.


ERK1/2-SOX9/FOXL2 axis regulates ovarian steroidogenesis and favors the follicular-luteal transition.
Estradiol and progesterone are the primary sex steroids produced by the ovary. Upon luteinizing hormone surge, estradiol-producing granulosa cells convert into progesterone-producing cells and eventually become large luteal cells of the corpus luteum. Signaling pathways and transcription factors involved in the cessation of estradiol and simultaneous stimulation of progesterone production in granulosa cells are not clearly understood. Here, we decipher that phosphorylated ERK1/2 regulates granulosa cell steroidogenesis by inhibiting estradiol and inducing progesterone production. Down-regulation of transcription factor FOXL2 and up-regulation of SOX9 by ERK underpin its differential steroidogenic function. Interestingly, the incidence of SOX9 is largely uncovered in ovarian cells and is found to regulate FOXL2 along with CYP19A1 and STAR genes, encoding rate-limiting enzymes of steroidogenesis, in cultured granulosa cells. We propose that the novel ERK1/2-SOX9/FOXL2 axis in granulosa cells is a critical regulator of ovarian steroidogenesis and may be considered when addressing pathophysiologies associated with inappropriate steroid production and infertility in humans and animals.


Gemcitabine and cisplatin-induced tumor lysis syndrome in a patient with gallbladder carcinoma: A case report.
We report a case of tumor lysis syndrome (TLS) in a patient with gallbladder carcinoma. TLS has not been reported in association with this type of tumor. TLS typically occurs in cases of highly proliferative hematological malignancies and small cell carcinoma. Two factors that may have contributed to TLS in this case include multifactorial mild acute renal failure shortly before the administration of chemotherapy and the aggressive morphology of the gallbladder carcinoma, which was a poorly differentiated sarcomatoid variant. This case raises concern for the development of TLS in certain types of patients with solid tumors.


1-Methyl-4-phenyl-pyridinium-induced inhibition of nicotinamide adenosine dinucleotide cytochrome c reductase.
The effect of 1-methyl-4-phenyl-pyridinium (MPP+), the main toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a parkinsonism-causing neurotoxin, upon the activity of nicotinamide adenine dinucleotide (NADH) cytochrome c reductase (EC 18.104.22.168) and upon that of glutathione reductase (EC 126.96.36.199) was monitored spectrophotometrically. For the cytochrome c reductase, the increase in absorbance of reduced cytochrome c was measured at 550 nm; for evaluating glutathione reductase, the absorbance of nicotinamide adenine dinucleotide phosphate (NADPH) was followed at 340 nm. MPP+ but not MPTP reversibly inhibited NADH cytochrome c reductase, but not glutathione reductase. This may be a direct mechanism of cell toxicity by this neurotoxin.


Diode laser cyclophotocoagulation: role in the management of refractory pediatric glaucomas.
To report the efficacy and complications of diode laser cyclophotocoagulation (cyclodiode) in the management of refractory pediatric glaucomas. Noncomparative interventional case series. Pediatric patients with uncontrolled glaucoma. Seventy-seven eyes of 61 patients underwent cyclodiode. Mean age was 7.4 years (range, 0.4-17 years). Intraocular pressure (IOP), visual acuity, complications. Diagnoses included aphakic glaucoma, congenital glaucoma, juvenile chronic arthritis, aniridia, anterior segment dysgenesis, and Sturge-Weber syndrome. Sixty percent of eyes were aphakic, and 64% had undergone at least one previous surgical procedure for glaucoma. Patients underwent a mean of 2.3 treatment sessions per eye (maximum, 8 sessions). Mean pretreatment IOP was 32.0 mmHg. After one treatment session, 62% had a clinically useful reduction in IOP (<22 mmHg or by 30%), but this had fallen to 37% by 12 months. With repeat cyclodiode, 72% had a clinically useful reduction in IOP for a year or more (mean, 8.4-month interval between treatments). Aphakic eyes had a more sustained IOP reduction (P < 0.01 log rank test). Of treatment failures, 13% had no useful IOP response, and three eyes developed subsequent retinal detachment and loss of vision. No other eyes lost vision because of cyclodiode-related complications. In 5.5% of the treatment sessions there was a significant posttreatment inflammatory episode. Cyclodiode treatment did not enable a reduction in the number of medications. With repeated treatment, cyclodiode can provide effective control of IOP. However, the success rate is lower than with adults, and younger eyes may recover from treatment more rapidly. Although response may be temporary, cyclodiode has a lower rate of severe adverse effects than surgical modalities and has roles as a temporizing measure, as an adjunct to surgery, or in managing selected patients in whom surgery is undesirable because of a high risk of surgical complications.


Extraosseous tumor uptake of 99m technetium phosphate compounds in children with abdominal neuroblastoma.
Sixteen patients with abdominal neuroblastoma had 99m Technetium Phosphate Compounds (99m TC-PC) bone scans as a preoperative evaluation for metastatic disease. Ten patients (62%) had extraosseous tumor uptake while six patients (38%) did not. There was no difference in the incidence of tumor calcification, tumor necrosis or hydronephrosis in the two groups. However, VMA levels were significantly higher in the group with extraosseous tumor uptake. Various bone seeking radionuclides are compared to 99m TC-PC and possible mechanism for extraosseous uptake of such radionuclides are postulated. Awareness of the frequency of such uptake should reduce the possibility of errors in the interpretation of bone scans in patients with neuroblastoma.


Comparison of gut microbiome profile in patients with schizophrenia and healthy controls - A plausible non-invasive biomarker?
The human gut microbiome regulates brain function through the microbiome-gut-brain axis and is implicated in several neuropsychiatric disorders. However, the relationship between the gut microbiome and the pathogenesis of schizophrenia (SCZ) is poorly defined, and very few studies have examined the effect of antipsychotic treatment response. We aim to study the differences in the gut microbiota among drug-naïve (DN SCZ) and risperidone-treated SCZ patients (RISP SCZ), compared to healthy controls (HCs). We recruited a total of 60 participants, from the clinical services of a large neuropsychiatric hospital, which included DN SCZ, RISP SCZ and HCs (n = 20 each). Fecal samples were analyzed using 16s rRNA sequencing in this cross-sectional study. No significant differences were found in taxa richness (alpha diversity) but microbial composition differed between SCZ patients (both DN and RISP) and HCs (PERMANOVA, p = 0.02). Linear Discriminant Analysis Effect Size (LEfSe) and Random Forest model identified the top six genera, which significantly differed in abundance between the study groups. A specific genus-level microbial panel of Ruminococcus, UCG005, Clostridium_sensu_stricto_1 and Bifidobacterium could discriminate SCZ patients from HCs with an area under the curve (AUC) of 0.79, HCs vs DN SCZ (AUC: 0.68), HCs vs RISP SCZ (AUC: 0.93) and DN SCZ vs RISP SCZ (AUC: 0.87). Our study identified distinct microbial signatures that could aid in the differentiation of DN SCZ, RISP SCZ, and HCs. Our findings contribute to a better understanding of the role of the gut microbiome in SCZ pathophysiology and suggest potential targeted interventions.


Prognostic value of tumor regression during radiotherapy for head and neck cancer: a prospective study.
Prospective evaluation of tumor regression during external irradiation for head and neck squamous cell carcinomas and its association with long-term local control. Two hundred twenty-eight patients with histologically confirmed squamous cell carcinoma [oral cavity: 59 (26%), oropharynx: 65 (29%), hypopharynx: 37 (16%), larynx: 67 (29%)] were included between January 1986 and December 1990. Curative intent external irradiation delivered 65-70 Gy over a period of 7 weeks (five 2 Gy fractions per week). Tumor regression was evaluated clinically and endoscopically every week. Tumor regression, assessed at 2 weeks, was as follows: no response: 62 (30%), 25% response: 121 (59%); 50% response: 23 (11%). At 5 weeks, 9 (4%) patients showed 0-25% regression, 75 (33%) showed 50% regression, 115 (50%) showed 75% regression, and 29 (13%) showed complete regression. Median follow-up was 79 months (range: 6-96 months). The local control probability was 68% (62-74%) at 2 years, 65% (59-70%) at 5 years. Univariate analysis showed that, at 2 weeks, local control was significantly different between the nonresponders and the patients with 25% or greater response (p < 0.025) and that, at the fifth week, local control was very different between the major responders (75 and 100%) and the minor responders (0-50%) (p < 0.0001). Multivariate analysis (Cox Proportional Hazards Model) showed that the probability of local relapse was significantly and independently increased for minor regression at 5 weeks [Relative risk (RR) of failure was 2.3 (1.4-3.7)], for nonlaryngeal tumors [RR: 2.4 (1.3-4.5)], and for Stage T3-T4 [RR:2.4 (1.4-4)]. Three prognostic groups can, therefore, be proposed: 1) low risk of recurrence when regression > or = 75% and laryngeal tumor or T1-T2 tumors in other sites: 106 (46.5%) patients, 2-year local control probability: 84% (77-92%); 2) high risk of recurrence: regression < or = 50% and T3-T4 nonlaryngeal tumors: 44 (19%) patients, 2-year local control probability: 27% (13-41%); 3) intermediate risk of recurrence: 78 (34.5%) patients, 2-year local control probability: 69% (58-80%). The present study suggests that tumor regression during external radiotherapy is an independent predictive factor of local control in head and neck carcinomas.


Linear multidimensional liquid chromatography in the preparative scale purification of calmodulin from brain extract.
Rapid preparative scale purification of calmodulin from crude bovine brain extract is achieved in a single chromatographic run by physically coupling two different liquid chromatography columns which employ different separation mechanisms. In this case columns packed with newly commercialized 40-microns silica-based hydrophobic interaction and 5-microns micron silica-based weak anion-exchange chromatography media were used. The only sample preparation required for conducting this purification procedure is the addition of salt to the crude brain supernatant to promote the initial binding of calmodulin to the hydrophobic interaction chromatography media. Chromatography carried out on such linear arrangements of columns has been referred to as linear multidimensional liquid chromatography.


[Evidence basis of psychotherapy for schizophrenia patients in Germany].
Little is known about the degree of implementation of evidence-based psychotherapy in routine care of people with schizophrenia in Germany. First, results of studies on the efficacy of psychotherapy in the treatment of schizophrenia are summarised. Second, the degree of implementation of psychotherapeutic practices in the routine care of schizophrenics is assessed through a systematic literature search and analyses of several data sets. There is substantial evidence for the efficacy of cognitive-behavioural interventions in the treatment of schizophrenia. The paucity of data on the degree of implementation suggests a wide gap between evidence and practice. Barriers to implementation are outlined and discussed. There is a need for more studies on epidemiological and long-term effectiveness of health care.


Antibiotic Prophylaxis for Prosthetic Joint Patients Undergoing Invasive Dental Procedures: Time for a Rethink?
In the United States, it has been common practice to recommend that dentists provide antibiotic prophylaxis (AP) before invasive dental procedures (IDPs) to prevent late periprosthetic joint infections (LPJIs) in patients who have prosthetic arthroplasties despite lack of evidence for a causal relationship between IDP and LPJI and a lack of evidence for AP efficacy. A recent study quantified the IDP incidence over the 15-month period prior to LPJI hospital admissions in the United Kingdom for which dental records were available. A case-crossover analysis compared IDP incidence in the 3 months before LPJI admission with the preceding 12 months. The English population was used because guidelines do not recommend AP and any relationship between IDPs and LPJI should be fully exposed. No significant positive association was identified between IDPs and LPJI. Indeed, the incidence of IDPs was lower in the 3 months before LPJI hospital admission than that in the preceding 12 months. In the absence of a significant positive association between IDPs and LPJI, there is no rationale to administer AP before IDPs in patients with prosthetic joints, particularly given the cost and inconvenience of AP, the risk of adverse drug reactions, and the potential for unnecessary AP use that promotes antibiotic resistance. These results should reassure orthopedic surgeons and their patients that dental care of patients who have prosthetic joints should focus on maintaining good oral hygiene rather than on recommending AP for IDPs. Moreover, it should also reassure those in other countries where AP is not recommended that such guidance is sufficient.


Nasolacrimal polyurethane stent: complications with CT correlation.
To evaluate initial results in patients with epiphora secondary to obstruction of the nasolacrimal duct treated by placement of a polyurethane stent, and to discuss the technical problems and complications arising during the procedure, with visualization of the anatomy of the drainage apparatus using computed tomography (CT). We inserted 20 polyurethane Song stents under fluoroscopic guidance after dacryocystography in 19 patients with grade 3-4 epiphora caused by idiopathic obstruction of the nasolacrimal duct. CT scans were obtained following stent placement in all patients. We focus on the technical problems and complications that arose during these procedures. During negotiation of the guidewire past the obstruction at the level of the junction of the duct with the lacrimal sac, the guidewire created a false passage in a posterior suborbital direction in two cases and towards the posterior midline in another. In all cases the guidewire was withdrawn and reinserted through the proper anatomic route without further difficulty or complications. In two cases the stent was improperly positioned wholly or partially outside the nasolacrimal system (one medially, one posteriorly). In one case the stent was removed and reinserted; in the other it remains in place and functional. CT was performed in all these cases to ensure proper anatomic alignment and determine what had gone wrong. The epiphora was completely resolved in 13 cases and partially relieved in four; there were three cases of stent obstruction. Epistaxis of short duration (1 hr) occurred in seven patients and headache in one. Treatment of epiphora with polyurethane stents is a technique that is well tolerated by patients and achieves a high success rate, yet problems in placement may be encountered. Though no major consequences for patients are involved, cognizance of such difficulties is important to avoid incorrect positioning of stents.


Risk factors for cytomegalovirus disease in seropositive renal transplant recipients; a single-center case-controlled study.
Risk factors for cytomegalovirus (CMV) disease in renal transplant recipients have been evaluated in industrialized countries with relatively low CMV seroprevalence. We aimed to determine which factors are related to this illness in a high CMV seroprevalence country. A case-control study was performed with data from a 5-year follow-up of 260 kidney transplant recipients at our center. Odds ratios were calculated using the Mantel-Haenszel method. A total of 25 cases of CMV disease occurred during the study period. Recipient age greater than 55 years old (odds ratio: 4.95, 95% CI: 1.44-17.0) and use of thymoglobulin (odds ratio: 4.84; 95% CI: 1.10-21.39) were the only independent predictors for CMV disease. There was not any relationship between the previous serologic status of both donor and receptor and the occurrence of CMV disease. We did not observe any association between the immunosuppressive regimens and CMV disease, except for thymoglobulin. Only recipient age and thymoglobulin administration were related to CMV disease. Further studies are needed to determine if prophylactic treatment confers clinical benefit in this subset of patients.


Protective effect and mechanism of rebamipide on NSAIDs associated small bowel injury.
To investigate the protective effect and mechanism of rebamipide on NSAIDs associated intestinal injury. Intestinal injury was induced in Sprague Dawley rats by intragastric administration of diclofenac with rebamipide intervention, and LPS and TAK-242 were given intraperitoneally respectively. The expression of TLR4/NF-κB and the related proteins in the intestinal mucosa were detected. 55 patients taking NSAIDs and diagnosed as NSAIDs associated small intestinal injury were recruited as NSAIDs group. Another 55 patients without NSAIDs and no obvious abnormality in the small bowel served as the control group. The macroscopic and histological scores of the small intestinal mucosa in the rebamipide pretreatment group were significantly lower compared to the diclofenac group (p < 0.01). The expressions of Tollip, ZO-1 and Claudin-1 in the diclofenac group were down-regulated compared with that in the control group, while they increased significantly in the rebamipide pretreatment group (p < 0.01). The expressions of TLR4/NF-κBp65, IL-1β, IL-6, IL-8, and TNF-α significantly increased in the model group while they were down-regulated in the rebamipide pretreatment group (p < 0.05). Administration of LPS 1 h after diclofenac aggravated small intestinal damage, and increased expression of IL-1β, IL-6, IL-8 and TNF-α. Administration of rebamipide did not effectively reverse intestinal injury induced by diclofenac and LPS. In contrast, pretreatment with TAK-242 significantly inhibited damage and prevented the increased expression of the cytokines. The expression of TLR4 and NF-κBp65 in the patients with NSAIDs associated intestinal injury was significantly higher than that in the control group (p < 0.01), while the expression of Tollip was decreased (p < 0.01). Rebamipide effectively alleviated intestinal mucosa injury by probably suppressing the TLR4/NF-κB signaling pathway and the decreasing of ZO-1 and Claudin-1 induced by diclofenac.


Hazard report. Incorrect measurement of uterine cavity while using Hologic NovaSure endometrial ablation system can result in patient injury.
If the uterine cavity is improperly or inaccurately measured during use of the Hologic NovaSure endometrial ablation system, it could result in thermal or perforation injuries. This article describes some of these injuries and offers guidance on reducing their likelihood.


Late ovarian relapse of TEL/AML1 positive ALL confirming that TEL deletion is a secondary event in leukemogenesis.
We describe here a late extramedullary ovarian relapse in an 18-year-old female who was diagnosed with hypotetraploid cell acute lymphoblastic leukaemia (cALL) at the age of 6. At both occurrences of the disease cells were analyzed by morphology, immunophenotyping, cytogenetics and molecular methods. TEL/AML1 was detected by RT-PCR and FISH analysis in both events. We demonstrated, using detection of IGH/TCR rearrangements and TEL/AML1 breakpoints sequencing that the cells were clonally related. Moreover, interphasic FISH using TEL and AML1 probes showed the loss of a second TEL at the time of relapse. This observation confirms that TEL/AML1 alone is not sufficient to trigger ALL and that TEL deletion is a secondary event in leukemogenesis. To our knowledge, it is the first complete description of extramedullary ALL relapse combining all methodologies.


Shared extracellular vesicle miRNA profiles of matched ductal pancreatic adenocarcinoma organoids and blood plasma samples show the power of organoid technology.
Extracellular vesicles (EV) are considered as a promising diagnostic tool for pancreatic ductal adenocarcinoma (PDAC), a disease with a poor 5-year survival that has not improved in the past years. PDAC patient-derived 3D organoids maintain the intratumoral cellular heterogeneity, characteristic for the tumor in vivo.Thus, they represent an ideal in vitro model system to study human cancers. Here we show that the miRNA cargo of EVs from PDAC organoids largely differs among patients. However, we detected a common set of EV miRNAs that were present in matched organoids and blood plasma samples of individual patients. Importantly, the levels of EV miR-21 and miR-195 were higher in PDAC blood EV preparations than in healthy controls, albeit we found no difference compared to chronic pancreatitis (CP) samples. In addition, here we report that the accumulation of collagen I, a characteristic change in the extracellular matrix (ECM) in both CP and PDAC, largely increases EV release from pancreatic ductal organoids. This provides a possible explanation why both CP and PDAC patient-derived plasma samples have an elevated amount of CD63 + EVs. Collectively, we show that PDAC patient-derived organoids represent a highly relevant model to analyze the cargo of tumor cell-derived EVs. Furthermore, we provide evidence that not only driver mutations, but also changes in the ECM may critically modify EV release from pancreatic ductal cells.


Effects of exogenous abscisic acid on oil content, fatty acid composition, biodiesel properties and lipid components in developing Siberian apricot (Prunus sibirica) seeds.
Previous studies in Siberian apricot (Prunus sibirica) seed kernel (SASK) have suggested the involvement of abscisic acid (ABA) signaling pathway in oil accumulation. However, there are few reports on the effects of ABA on the metabolism of fatty acids (FA) in seed development. Here, we first evaluated the response of developing SASK to ABA treatment, with a focus on oil content, FA composition, biodiesel properties, lipid compounds and gene expressions. Compared with control samples, the application of exogenous ABA increased the total oil content by 6.55% in mature SASK. The C18:1 content markedly increased in ABA treatment, and conversely C16:0 decreased. Exogenous ABA also improved the biodiesel properties of SASK oil, making it better suited to the specifications of biodiesel standards. Furthermore, the molecular species of phosphatidylcholine (PC), phosphatidic acid (PA), diacylglycerol (DAG) and triacylglycerol (TAG) were detected using lipidomics analysis. The 18:1/18:1 was the main component in PA, PC and DAG, while the main components of 18:1/18:1/18:2, 18:1/18:1/18:3, 18:2/18:2/18:2 and 18:1/18:1/18:1 in TAG. Most lipid species gradually increased with SASK maturity. In addition, the relative contents of TAG-18:1/18:1/18:2 and TAG-18:1/18:1/18:1 in developing SASK increased with the application of exogenous ABA. We also detected elevated gene expression of key genes involved in ABA chemical pathway, which likely affected FA biosynthesis and accumulation. Our results provide insight into the effects of ABA on the oil accumulation in developing SASK, which has direct applications to improving the quality of SASK-derived biodiesel.


Analysis of antibodies to surface epitopes of contactin-2 in multiple sclerosis.
Contactin-2 was recently identified as an autoantigen targeted by T-cells and autoantibodies in multiple sclerosis (MS). Here we analyzed the frequency of antibodies to contactin-2 (contactin-2-ab) by a cell-based assay in the serum from 105 MS patients and at least 5 years of follow-up (19 clinically isolated syndromes, 51 relapsing-remitting, 20 secondary-progressive, and 15 primary-progressive). Contactin-2-ab were detected in 4 (7.8%) relapsing-remitting patients. Clinical and magnetic resonance imaging characteristics were not significantly different from the rest of relapsing-remitting patients. In conclusion, contactin-2-ab are identified in a minority of MS patients but their presence is not associated with a particular clinical-radiological profile.


A case of renal γ2 heavy-chain deposition disease accompanied by rapid progressive renal failure.
The recently described heavy-chain deposition disease (HCDD) is a comparatively rare monoclonal immunoglobulin disorder characterized histopathologically by glomerular and tubular basement membrane deposition of nonamyloidotic monoclonal heavy chains without associated light chains. We have described a case of γ2-HCDD presenting with proteinuria, microhematuria, severe hypertension, and rapidly progressive renal failure, which serum creatinine level was only 1.52 mg/dL in early stage HCDD, and the clinicopathologic features of this case have been compared with other reported cases of γ2-HCDD. Renal biopsy disclosed nodular sclerosing glomerulopathy. Immunofluorescence analysis revealed IgG2 (2+) heavy chain and C3 (+) in the mesangium and along the capillary walls and tubular basement membranes without IgA, IgM, κ and λ light chains. Electron microscopy revealed electron-dense deposits along the glomerular and tubular basement membranes as well as in the mesangium. Moreover, regardless of therapy, the condition of the patient progressively deteriorated, with less than 3 months of renal survival. Rapid progressive renal failure was a common feature in both cases of γ2-HCDD. We propose that a possible link exists between prognosis of renal HCDD and the subclass of heavy chain deposited in the kidney.


A 5-Minute Delay From Bolus Injection to Infusion Halves Plasma Concentration of Tissue Plasminogen Activator.
Reducing the time between onset of cerebral infarction and treatment with tissue plasminogen activator improves the prognosis of patients with cerebral infarction. Diverse dosing protocols have been developed with the aim of reducing the time to bolus injection; however, only a few studies have investigated the methods and effects of the interrupted time between bolus and post-bolus infusion. We evaluated the impact of the interrupted time on pharmacokinetic parameters. We calculated the changes in alteplase concentration after a bolus injection with high precision, in relation to different interval times. Simulations were performed using the linpk package of the statistical analysis software R. Post-bolus infusion was initiated at 0-, 5-, 15-, and 30-min intervals after bolus dosing. The calculation interval was set as 6 s. Alteplase concentration rose to 1.23 mg/mL after bolus dosing. However, it dropped to 0.53 mg/mL (43.4%) during a 5-min interval, 0.27 mg/mL (22.23%) during a 15-min interval, and 0.10 mg/mL (8.38%) during a 30-min interval. Because of the short half-life of alteplase, even a short delay in initiating post-bolus infusion can cause a significant reduction in serum alteplase concentration.


Retrovirus and lentivirus vector design and methods of cell conditioning.
Retroviruses are useful tools for the efficient delivery of genes to mammalian cells, owing to their ability to stably integrate into the host cell genome. Over the past few decades, retroviral vectors have been used in gene therapy clinical trials for the treatment of a number of inherited diseases and cancers. The earliest retrovirus vectors were based on simple oncogenic gammaretroviruses such as Moloney murine leukemia virus (MMLV) which, when pseudotyped with envelope proteins from other viruses such as the gibbon ape leukemia virus envelope protein (GALV) or vesicular stomatitis virus G protein (VSV-G), can efficiently introduce genes to a wide range of host cells. However, gammaretroviral vectors have the disadvantage that they are unable to efficiently transduce nondividing or slowly dividing cells. As a result, specific protocols have been developed to activate cells through the use of growth factors and cytokines. In the case of hematopoietic stem cells, activation has to be carefully controlled so that pluripotency is maintained. For many applications, gammaretroviral vectors are being superseded by lentiviral vectors based on human immunodeficiency virus type-1 (HIV-1) which has additional accessory proteins that enable integration in the absence of cell division. In addition, retroviral and lentiviral vector design has evolved to address a number of safety concerns. These include separate expression of the viral genes in trans to prevent recombination events leading to the generation of replication-competent viruses. Further, the development of self-inactivating (SIN) vectors reduces the potential for transactivation of neighboring genes and allows the incorporation of regulatory elements that may target gene expression more physiologically to particular cell types.


Structural characteristics and biological activity of lactic acid bacteria exopolysaccharides separated by ethanol/(NH4)2SO4 ATPS.
Exopolysaccharides (EPS) from lactic acid bacteria (LAB) as edible and safe bioproducts with health benefits have become an interesting topic. In this study, aqueous two-phase system (ATPS) was established using ethanol and (NH4)2SO4 as phase-forming substances to separate and purify LAB EPS from Lactobacillus plantarum 1.0665. The operating conditions were optimized by a single factor and response surface method (RSM). The results indicated that an effectively selective separation of LAB EPS was achieved by the ATPS consisted of 28 % (w/w) ethanol and 18 % (w/w) (NH4)2SO4 at pH 4.0. Under optimized conditions, the partition coefficient (K) and recovery rate (Y) were well matched with the predicted value of 3.83 ± 0.019 and 74.66 ± 1.05 %. The physicochemical properties of purified LAB EPS were characterized by various technologies. According to the results, LAB EPS was a complex polysaccharide with a triple helix structure mainly composed of mannose, glucose and galactose in the molar ratio of 1.00: 0.32: 0.14, and it proved that the ethanol/(NH4)2SO4 system had good selectivity for LAB EPS. In addition, LAB EPS displayed excellent antioxidant activity, antihypertension activity, anti-gout capacity and hypoglycemic activity in vitro analysis. The results suggested that LAB EPS could be a dietary supplement applied in functional foods.


Nitric oxide alters renal function and guanosine 3',5'-cyclic monophosphate.
Endothelium-derived relaxing factor (EDRF) activates soluble guanylate cyclase, resulting in an increase in vascular smooth muscle guanosine 3',5'-cyclic monophosphate (cGMP) levels, which correlates with its relaxing effect. Using a microdialysis technique, we investigated changes in right and left renal interstitial fluid cGMP levels in response to right intrarenal administration of an EDRF inhibitor, NG-monomethyl-L-arginine (L-NMMA). Studies were conducted in anesthetized dogs (n = 5) in metabolic balance at a sodium intake of 40 meq/day. Urine was collected directly from the right and left ureters individually. Changes in the right and left urinary cGMP excretion and renal function in response to cumulative doses of L-NMMA were studied. In the right kidney, 20-100 micrograms/kg/min L-NMMA caused 1) a dose-dependent decrease in renal interstitial fluid and urinary cGMP levels (p less than 0.0001 and p less than 0.001, respectively), 2) antinatriuresis (p less than 0.01), 3) antidiuresis (p less than 0.01), 4) a decrease in renal blood flow (p less than 0.01) and glomerular filtration rate (p less than 0.01), and 5) a decrease in fractional sodium excretion (p less than 0.01). No changes in left renal interstitial fluid and urinary cGMP levels or excretory and hemodynamic function were observed during right intrarenal administration of L-NMMA at 20 and 60 micrograms/kg/min.(ABSTRACT TRUNCATED AT 250 WORDS)


MiR-525-5p Repressed Metastasis and Anoikis Resistance in Cervical Cancer via Blocking UBE2C/ZEB1/2 Signal Axis.
Accumulating evidence indicated that miRNAs are important regulators involved in cancer biology. We aimed to investigate the biological functions and potentially underlying molecular mechanism of miR-525-5p in CC. RT-PCR and Western blot assay were performed to detect mRNA and protein expression. Cell proliferation, anoikis resistance, and cell invasion were analyzed. We observed that the expression of miR-525-5p was declined in several CC cell lines. Additionally, introduction of miR-525-5p dramatically hampered cell viability, invasiveness, and migration ability through modulating epithelial-to-mesenchymal transition (EMT) marked genes as reflected by the upregulation of E-cadherin, as well as the downregulation of vimentin and N-cadherin. Furthermore, administration of miR-525-5p markedly reduced anchorage-independent growth and anoikis resistance accompanied by a decrease in the expression of anti-apoptotic protein Bcl-2 and an increase in the expression of pro-apoptotic protein Bax, C-caspase 3, and C-PARP1. Most importantly, analysis using publicly available algorithms predicted that UBE2C was a direct and functional target of miR-525-5p. Luciferase assays coupled with RT-PCR and Western blot analysis further verified that miR-525-5p negatively regulated UBE2C expression. Interestingly, miR-525-5p modulated ZEB1/2 expression via targeting UBE2C. Mechanically, administration of UBE2C partially blunted the salutary effects of miR-525-5p on invasive ability, EMT, and anoikis resistance, indicating that miR-525-5p acts as a tumor suppressor in CC largely through repression of UBE2C/ZEB1/2 signaling. Taken together, our data identify a novel signaling axis of miR-525-5p/UBE2C/ZEB1/2 in repressing EMT and anoikis resistance, and likely serve as a potential therapeutic target for CC metastasis and prognosis as well as a therapeutic application.


Isolation and characterization of the gene coding for human cytidine deaminase.
The human gene coding for cytidine deaminase (CD), the enzyme which catalyzes the deamination of cytidine and deoxycytidine to uridine and deoxyuridine, was isolated and structurally characterized. CD is a single copy gene with a length of 31 kb and consists of four exons. Exon-intron junctions do not bracket functional domains of the encoded protein as the boundary between exons 2 and 3 interrupts the catalytically important zinc-finger domain, which is well conserved along phylogenesis. 5'-RACE and RNase mapping experiments identify one major and multiple other minor transcription initiation sites, which are present in placenta as well as in the myeloid cell lines, HL-60 and U937. The 5'-flanking region of the gene contains an orientation-dependent functional promoter and is characterized by the presence of several potential sites for the binding of known transcriptional factors.


[Activity of certain dehydrogenases in accumulation and continuous-flow culture of paraffin-oxidizing yeast of the genus Candida].
Lability of NADP- and NAD-dependent glutamate dehydrogenases and malate dehydrogenases has been demonstrated during a change of the physiological activity of yeast Candida guilliermondii in the exponential phase of growth. Variations in the isoenzyme spectrum of the enzymes and total dehydrogenase activity of the yeast has been found during their transition from the accumulative to the continuous cultivation. Changes in the physiological state of yeast during their growth are accompanied by a rearrangement of the isoenzyme spectrum of malate dehydrogenase and glutamate dehydrogenases.


In vitro activity of cycloSal-nucleoside monophosphates and polyhydroxycarboxylates against orthopoxviruses.
Because variola virus might be used as a pathogen in biological attacks, there is an urgent need to provide effective antiviral drugs for the treatment of orthopoxvirus infections. Thus, the aim of the present study was to test the antiviral activity of 3 pro-nucleotides of the acyclic nucleoside analogues aciclovir (ACV), 3 of penciclovir (PCV) and 38 of the cyclic nucleoside analogue brivudin (BVDU), on the basis of cycloSaligenyl-nucleoside monophosphate approach against vaccinia virus and cowpox virus in vitro. In further experiments, 13 synthetic humic acid-like polymers, so-called polyhydroxycarboxylates, were examined. Antiviral screening was performed by means of the plaque reduction assay and for quantification of the cytotoxicity of the test compounds the XTT-based tetrazolium reduction assay EZ4U was used. As result, three cycloSal-monophosphate derivatives of ACV proved to be potent inhibitors of both vaccinia virus and cowpox virus replication in vitro. Among the tested monophosphate derivatives of cycloSal-PCV and cycloSal-BVDU, selected substances showed a promising antiviral activity against vaccinia virus and cowpox virus. For the polyanionic compounds, no relevant antiviral activity was detected. In conclusion, by the delivery of nucleoside monophosphates from neutral, membrane-permeable prodrugs on the basis of the cycloSaligenyl-nucleotide concept, different ACV, PCV and BVDU derivatives can act as potent and selective inhibitors of orthopoxvirus replication. However, most of the cycloSal-monophosphate derivatives of BVDU had a higher cytotoxicity than their parent nucleosides.


The cardiac sodium channel gene SCN5A and its gene product NaV1.5: Role in physiology and pathophysiology.
The gene SCN5A encodes the main cardiac sodium channel NaV1.5. This channel predominates the cardiac sodium current, INa, which underlies the fast upstroke of the cardiac action potential. As such, it plays a crucial role in cardiac electrophysiology. Over the last 60years a tremendous amount of knowledge regarding its function at the electrophysiological and molecular level has been acquired. Furthermore, genetic studies have shown that mutations in SCN5A are associated with multiple cardiac diseases (e.g. Brugada syndrome, Long QT syndrome, conduction disease and cardiomyopathy), while genetic variation in the general population has been associated with differences in cardiac conduction and risk of arrhythmia through genome wide association studies. In this review we aim to give an overview of the current knowledge (and the gaps therein) on SCN5A and NaV1.5.


Mutations in the catalytic subunit of class IA PI3K confer leukemogenic potential to hematopoietic cells.
Constitutive activation of the phosphoinositide 3-kinase (PI3K)-AKT pathway is observed in up to 70% of acute myelogenous leukemia. To investigate the relevance of an intrinsic PI3K-AKT pathway activation in hematopoietic malignancies, we analysed the effect of point mutations in the catalytic (p110alpha) and regulatory (p85alpha) subunit of class IA PI3K. We demonstrated that mutations in the helical (E542K, E545A) and kinase domain (H1047R) of p110alpha constitutively activate the PI3K-AKT pathway and lead to factor-independent growth of early hematopoietic cells. Proliferation and survival of the cells were inhibited in a time- and dose-dependent manner using either PI3K or AKT inhibitors. The mammalian target of rapamycin (mTOR) was demonstrated to be important for mitogenic, but not antiapoptotic signaling of mutant p110alpha. In a syngenic mouse model, hematopoietic cells expressing mutated p110alpha induced a leukemia-like disease characterized by anemia, neoplastic infiltration of hematopoietic organs and 90% mortality within 5 weeks, whereas activated mutants of the receptor tyrosine kinase c-KIT led to 100% mortality within 10 days. Our data show that point mutations in the p110alpha subunit of class IA PI3K confer factor independence to hematopoietic cells in vitro and leukemogenic potential in vivo, but have lower transforming activity than a deregulated class III receptor tyrosine kinase.


Technologies for deriving primary tumor cells for use in personalized cancer therapy.
For decades, immortal cancer cell lines have constituted an accessible, easily usable set of biological models to investigate cancer biology and explore the potential efficacy of anticancer drugs. However, numerous studies have suggested that these cell lines poorly represent the diversity, heterogeneity, and drug-resistant tumors occurring in patients. The derivation and short-term culture of primary cells from solid tumors have thus gained significant importance in personalized cancer therapy. This review focuses on our current understanding and the pros and cons of different methods for primary tumor cell culture. Furthermore, various culture matrices such as biomimetic scaffolds and chemically defined media supplemented with essential nutrients, have been prepared for different tissues. These well-characterized primary tumor cells redefine cancer therapies with high translational relevance.


Dermal psoriasis involving an oral split-skin graft. Case report.
Psoriasis is a chronic inflammatory skin disease which very rarely affects the oral cavity. It has many forms of expression on cutaneous and mucosal surfaces. This paper describes an unusual case of psoriasis with oral involvement affecting the skin graft used to reconstruct an oral mucosal defect. Diagnosis was based on clinical and microscopic findings and confirmed by the concurrent cutaneous disease.


[Biomarkers and risk factors of cardiovascular system disease in diabetes mellitus type 2].
The content of glycated hemoglobin, a biomarker of diabetes in patients with type 2 diabetes correlates with risk factors for cardiovascular disease: hypertension, BMI and ratio of total cholesterol to HDL cholesterol. Therefore, increase in glycosylated hemoglobin should be considered a predictor of cardiovascular disease in patients with type 2 diabetes.


Lanthanide metal-organic frameworks with nitrogen functional sites for the highly selective and sensitive detection of NADPH.
A series of isostructural Ln-MOFs, namely Eu(BPDC-xN)(x = 0, 1, 2), with different numbers of nitrogen atoms were designed and synthesized. Due to the strong affinity between the bare phosphate group of NADPH and nitrogen functional sites, the highly selective and sensitive detection of NADPH was realized. Furthermore, as the number of sites was increased, the sensitivity significantly increased, with a detection limit as low as 0.43 μM.


Omic approaches to pediatric bone sarcomas.
Over the last decade, next-generation sequencing technologies have improved our ability to assess biological aspects, at genomic and transcriptomic levels, on a large scale- and have been increasingly used for the management of adult cancers. However, their efficacy and feasibility within pediatrics is still under investigation. "Omic" approaches represent an opportunity to understand the oncogenic mechanisms driving the onset and progression of bone sarcoma and improve the clinical management of young patients with bone sarcomas. This review focuses on the current genomic and transcriptomic characteristics of managing pediatric patients, affected by Ewing sarcoma and osteosarcoma.


Flexible cyclic-olefin with enhanced dipolar relaxation for harsh condition electrification.
Flexible large bandgap dielectric materials exhibiting ultra-fast charging-discharging rates are key components for electrification under extremely high electric fields. A polyoxafluoronorbornene (m-POFNB) with fused five-membered rings separated by alkenes and flexible single bonds as the backbone, rather than conjugated aromatic structure typically for conventional high-temperature polymers, is designed to achieve simultaneously high thermal stability and large bandgap. In addition, an asymmetrically fluorinated aromatic pendant group extended from the fused bicyclic structure of the backbone imparts m-POFNB with enhanced dipolar relaxation and thus high dielectric constant without sacrificing the bandgap. m-POFNB thereby exhibits an unprecedentedly high discharged energy density of 7.44 J/cm3 and high efficiency at 150 °C. This work points to a strategy to break the paradox of mutually exclusive constraints between bandgap, dielectric constant, and thermal stability in the design of all-organic polymer dielectrics for harsh condition electrifications.


Effect of Different Early Oxygenation Levels on Clinical Outcomes of Patients Presenting in the Emergency Department With Severe Traumatic Brain Injury.
Despite the almost universal administration of supplemental oxygen in patients presenting in the emergency department (ED) with severe traumatic brain injury, optimal early oxygenation levels are unknown. Therefore, we aimed to examine the effect of different early oxygenation levels on the clinical outcomes of patients presenting in the emergency department with severe traumatic brain injury. We performed a secondary analysis of the Resuscitation Outcomes Consortium Traumatic Brain Injury Hypertonic Saline randomized controlled trial by including patients with Glasgow Coma Scale ≤8. Early oxygenation levels were assessed by the worst value of arterial partial pressure of oxygen (PaO2) during the first 4 hours of presentation in the emergency department. The primary outcome was 6-month neurologic status, as assessed by the Extended Glasgow Outcome Scale. A binary logistic regression was utilized, and an odds ratio (OR) with 95% (95% confidence intervals) was calculated. A total of 910 patients were included. In unadjusted (crude) analysis, a PaO2 of 101 to 250 mmHg (OR, 0.59 [0.38 to 0.91]), or 251 to 400 mmHg (OR, 0.53 [0.34 to 0.83]) or ≥401 mmHg (OR, 0.31 [0.20 to 0.49]) was less likely to be associated with poor neurologic status when compared with a PaO2 of ≤100 mmHg. This was also the case for adjusted analyses (including age, pupillary reactivity, and Revised Trauma Score). High oxygenation levels as early as the first 4 hours of presentation in the emergency department may not be adversely associated with the long-term neurologic status of patients with severe traumatic brain injury. Therefore, during the early phase of trauma, clinicians may focus on stabilizing patients while giving low priority to the titration of oxygenation levels.


Crossed views of burden and emotional distress of cancer patients and family caregivers during palliative care.
Studies regarding natural caregivers' burden (CB) in palliative situations, as well as its determinants and consequences, have been numerous during the last 20 years. Yet, studies regarding how terminally ill cancer patients perceive their CB (self-perceived burden, SPB) are less common. This study aims to assess the links between CB and SPB evaluated by means of the very same items. It also aims at identifying the determinants of potential differences between CB and SPB and their consequences on emotional distress among both members of the dyad. Sixty cancer patients from a palliative care unit and their principal natural caregiver completed questionnaires concerning the subjective burden of the caregiver, their own personal emotional distress and that of the other member of the dyad. Globally, patients had a good perception of their CB, although a little overestimated, except for their difficulties in managing their time. Caregivers overestimated patients' distress. The minimisation by patients of CB was a source of emotional distress for the latter, and the perception of being a burden to others was a source of depression for patients. These results did not depend on the nature of the relationship between patients and their caregivers. This data confirmed the need to study the experiences of the patient-caregiver dyad as well as their communication of their respective experiences, with a prospect to offer clinical interventions to optimise the quality of life and health of patients and their close relatives.Copyright © 2015 John Wiley & Sons, Ltd.


Expression and purification of two alternative peptides for mechano-growth factor in Escherichia coli.
Two genes, MGFc (40) and MGFc (24), encoding different E peptides of mechano-growth factor (MGF), were obtained by a four-step PCR strategy and subcloned into pRSETC and pGEX-6p-1. Recombinant MGFc(40) protein (4 mg l(-1)) was expressed and purified by affinity chromatography using His60 Ni Superflow. Recombinant MGFc(24) protein was purified using a glutathione-Sepharose 4B column. After enzymatic cleavage of the GST-tail, 1 mg MGFc(24) protein l(-1) was obtained. MGFc(40) and MGFc(24), which are involved in proliferation and differentiation, stimulated cell proliferation and inhibited cell differentiation of C2C12 cells.


Epithelial cell surface morphology in the endolymphatic sac: a scanning electron microscopic study in the mouse.
The apical, lateral and basal surface structures of the epithelial cells in the murine endolymphatic sac were studied using the freeze-cracking technique and scanning electron microscopy. In this way, it was possible to visualize the luminal surface and the interior of the cell simultaneously. The light epithelial cells, with their smooth rounded nuclei and many mitochondria, had numerous microvilli on their apical cell surface, whereas the dark epithelial cells, with indented nuclei, had only a few such microvilli. The lateral surfaces of these cells were flat, with few projections facing a dilated lateral intercellular space.


Computer navigation for revision of unicompartmental knee replacements to total knee replacements: the results of a case-control study of forty six knees comparing computer navigated and conventional surgery.
The revision of unicompartmental knee replacements (UKRs) to total knee replacements (TKRs) using computer navigation is a little-known technique. The principal objective of this study was to analyse the radiological position of implants in revision of UKR to TKR comparing the results of surgery aided by computer navigation (CAS) with conventional surgery (CS). Our hypothesis was that computer navigation would improve the position of the implants. This is a retrospective single surgeon series. Forty-six patients (46 knees) with an average age 73 ± eight years (53-93) between January 1995 and December 2014 were included. The two groups were made up of 23 patients each and are comparable in terms of age, sex, side of surgery, age of the UKR, cause of failure and HKA angle before surgery. All patients were reviewed by two independent observers. In the CAS group, the average hip-knee-ankle (HKA) angle was 179.2 ± 2.2° (175-184°). The average medial tibial mechanical angle (TMA) was 88.4 ± 1.6° (84-90°) and the medial femoral mechanical angle (FMA) was 91 ± 2° (87- 94°). The tibial slope was 88.7 ± 1.1° (87-90°). In the CS group, the average HKA angle was 179.9 ± 1.9° (175-183°), the TMA was on average 89.1 ± 1.3° (87-93°) and the FMA was 90.6 ± 1.5° (87-93°). The tibial slope was 87.8 ± 4.9° (85-95°). There was no statistically significant difference between the two groups on any of the radiological parameters studied. Our radiological target of a post-operative HKA angle of 180 ± 3° was obtained in 87.5% of cases in the CS group and 92.4% of cases in the CAS group. This slight difference in favour of the computer-assisted group was not statistically significant, and we cannot therefore confirm our initial hypothesis, at least in the hands of an experienced surgeon. However, the quality of the results in the CAS group suggest that this technique could provide precious assistance to less experienced surgeons performing this surgery.


A feasibility study of a PET/MRI insert detector using strip-line and waveform sampling data acquisition.
We are developing a time-of-flight Positron Emission Tomography (PET) detector by using silicon photo-multipliers (SiPM) on a strip-line and high speed waveform sampling data acquisition. In this design, multiple SiPMs are connected on a single strip-line and signal waveforms on the strip-line are sampled at two ends of the strip to reduce readout channels while fully exploiting the fast time response of SiPMs. In addition to the deposited energy and time information, the position of the hit SiPM along the strip-line is determined by the arrival time difference of the waveform. Due to the insensitivity of the SiPMs to magnetic fields and the compact front-end electronics, the detector approach is highly attractive for developing a PET insert system for a magnetic resonance imaging (MRI) scanner to provide simultaneous PET/MR imaging. To investigate the feasibility, experimental tests using prototype detector modules have been conducted inside a 9.4 Tesla small animal MRI scanner (Bruker BioSpec 94/30 imaging spectrometer). On the prototype strip-line board, 16 SiPMs (5.2 mm pitch) are installed on two strip-lines and coupled to 2 × 8 LYSO scintillators (5.0 × 5.0 × 10.0 mm3 with 5.2 mm pitch). The outputs of the strip-line boards are connected to a Domino-Ring-Sampler (DRS4) evaluation board for waveform sampling. Preliminary experimental results show that the effect of interference on the MRI image due to the PET detector is negligible and that PET detector performance is comparable with the results measured outside the MRI scanner.


Novel anticoagulants for non-valvular atrial fibrillation.
Non-valvular atrial fibrillation is a major cause of strokes in patients of all ages. Warfarin has been the mainstay anticoagulant for stroke prevention for many years. Warfarin use is limited by frequent monitoring and drug interactions. New oral anticoagulants have been investigated in recent large randomised trials: direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban and apixaban). These new anticoagulants do not require regular monitoring. Dabigatran and rivaroxaban have been shown to be non-inferior, whilst apixaban has been shown to be superior to warfarin in terms of stroke and systemic embolism. There are practical issues of cost, lack of availability on the Pharmaceutical Benefits Scheme currently, and a lack of reversal agents. These new oral anticoagulants may revolutionise anticoagulation for stroke prevention in non-valvular atrial fibrillation.


pH-responsive copolymers based on pluronic P123-poly(β-amino ester): Synthesis, characterization and application of copolymer micelles.
A novel amphiphilic and pH-responsive copolymer, pluronie P123-poly(β-amino ester) (P123-PAE), was firstly designed and synthesized using a Michael-type step polymerization. Nano-sized polymeric micelles based on P123-PAE block copolymer were prepared by self-assembly. Curcumin (Cur), a potential cancer therapy drug, was efficiently encapsulated into the P123-PAE micelles to enhance anticancer efficacy. The obtained Cur loaded P123-PAE micelles (Cur-P123-PAE) presented a spherical shape and high drug loading (18.4%). Interestingly, when the media pH decreased from 7.4 to 5.5, the particle size of the micelles shrank from 152.5nm to 122.1nm due to the protonation of PAE blocks, and the zeta potential of the P123-PAE micelles changed from weakly positive (1.5mV) to highly positive (9.0mV) over a pH range from 7.4 to 5.5. In vitro drug release studies demonstrated that the release rate of Cur was markedly influenced by pH. In vitro cytotoxicity tests showed that all the blank micelles were non-toxic. Cur-P123-PAE exhibited similar antitumor effect against MCF-7 and HepG2 cells compared to solubilized Cur solution. Using Coumarin-6 as a fluorescence probe, it was observed that Cur-P123-PAE micelles experienced longer circulation followed by accumulation at tumor tissues with stronger fluorescence intensity. The results of pharmacokinetics studies showed that the P123-PAE micelles could significantly prolong the retention time of Cur in vivo.


An intramedullary ependymal cyst in a 71-year-old woman.
An intraspinal ependymal cyst of the thoracolumbar spinal cord was found in a 71-year-old woman with a history of right side abdominal pain since the age of 18. The late discovery of the cyst is related to the extremely slow evolution of this type of cyst in the absence of spinal trauma. Etiopathogenic problems are discussed after a review of the literature.


Dysexecutive syndrome in amnesic mild cognitive impairment: a multicenter study.
Executive functions (EF) in Alzheimer's disease (AD), classically related to the prefrontal cortex, have been forgotten in mild stages, given more importance to temporal lobe associated disorders, such as memory. The study of disexecutive syndrome (DS) has been relegated to advanced stages of the disease. Our goal is to demonstrate that EF are already present in amnesic mild cognitive impairment (aMCI). Furthermore, we are interested in knowing whether poor scores in EF tests are related to the progression to AD or another kind of dementia. We studied patients with aMCI (n = 81) and healthy controls (n = 142) from neurological departments of several centers of Basque Country with a cross-sectional design. Patients underwent a complete neuropsychological evaluation, neuroimaging testing APOE genotype and 3 year of prospective follow-up. In the first visit, patients with aMCI showed more alterations in tests that evaluate EF such as Stroop, trail-making and categorical verbal fluency. More alterations were also found in NPI scale (P <0.05). Stroop and Trail-Making test were not associated with the future development of AD, but fluency (p = 0.01) and apathy (p = 0.031) did. No patient developed a different kind of dementia different from AD. DS is a broad concept not confined to frontal lobes, and can be found in early stages of aMCI. DS impacts negatively on patient autonomy and may have prognostic value.


Spreading Depressions and Periinfarct Spreading Depolarizations in the Context of Cortical Plasticity.
Studies of cortical function-recovery require a comparison between normal and post-stroke conditions that lead to changes in cortical metaplasticity. Focal cortical stroke impairs experience-dependent plasticity in the neighboring somatosensory cortex and usually evokes periinfarct depolarizations (PiDs) - spreading depression-like waves. Experimentally induced spreading depressions (SDs) affect gene expression and some of these changes persist for at least 30 days. In this study we compare the effects of non-stroke depolarizations that impair cortical experience-dependent plasticity to the effects of stroke, by inducing experience-dependent plasticity in rats with SDs or PiDs by a month of contralateral partial whiskers deprivation. We found that whiskers' deprivation after SDs resulted in normal cortical representation enlargement suggesting that SDs and PiDs depolarization have no influence on experience-dependent plasticity cortical map reorganization. PiDs and the MMP-9, -3, -2 or COX-2 proteins, which are assumed to influence metaplasticity in rats after stroke were compared between SDs induced by high osmolarity KCl solution and the PiDs that followed cortical photothrombotic stroke (PtS). We found that none of these factors directly caused cortical post-stroke metaplasticity changes. The only significant difference between stoke and induced SD was a greater imbalance in interhemispheric activity equilibrium after stroke. The interhemispheric interactions that were modified by stroke may therefore be promising targets for future studies of post-stroke experience-dependent plasticity and of recuperation studies.


Ecotoxicological risks of metals in the subsistence food garden soils of Watut River floodplains, Papua New Guinea.
Exorbitant concentrations of toxic metals in the soil from anthropogenic activities are environmental hazards and key health risk concerns to humans. The subsistence food garden soils have minimum anthropogenic interventions. The ecotoxicological risk potentials of the metals in subsistence food garden settings are unexplored. The metals (Cr, Cu, Pb, and Ni) concentration were assessed in the surface soil fractions (2 mm and 0.2 mm) of food gardens (N = 20) on the floodplains of Watut River, Papua New Guinea. The threshold limits, index of geo-accumulation (Igeo), contamination factor (CF), pollution load index (PLI), and potential ecological risk index (PERI) served as potential risk indicators of metals. Regardless of soil particle size, the descending order of median metals concentration was Cr > Cu > Ni > Pb. The concentration of Cu and Ni in the soil particles exceeded the WHO threshold limits in 100% and 50% of the food garden soils, respectively. Metal enrichment led to severe pollution in 100% gardens (Igeo > 5). Cr, Cu, and Ni contamination factors were > 1 in 95% of the food gardens. The PERI values indicated a lower ecological risk of the metals (PERI < 100). The median concentration of Cu, Igeo, and CF values for Cu in the 2 mm soil particles were significantly greater than in 0.2 mm. The results suggested exposure of subsistence food gardens soils to geogenic metal contamination and the need to carefully choose appropriate soil particle size for the soil health assessments.


Asian American and Pacific Islander breast and cervical carcinoma screening rates and healthy people 2000 objectives.
Breast carcinoma is the number one cause of cancer-related mortality among Asian American and Pacific Islander (AAPI) women, and for certain subgroups cervical carcinoma is among the top three causes. Yet AAPI women have the lowest cancer screening and early detection rates of all ethnic groups. The practice of merging AAPI data hides significant variation among AAPI groups, and the groups at highest risk for late presentation of disease become invisible. To the authors' knowledge, this study is the first report of disaggregated national data for breast and cervical carcinoma screening in AAPI subpopulations. The authors used data from the National Health Interview Survey (NHIS 1993 and 1994) and evaluated major socioeconomic and access variables associated with screening practices. Healthy People 2000 (HP2000) criteria were used to evaluate the most recent NHIS screening rates for AAPIs as one group and for six distinct subgroups compared with HP2000 criteria. The sample included 2756 non-Hispanic AAPI and 64,196 non-Hispanic white women age 18 years or older in the 1993 and 1994 NHIS. The effects of socioeconomic and access-to-care indicators on screening were explored. Breast and cervical carcinoma screening rates for AAPIs were below those for white women and well below national goals and guidelines. Lack of insurance, low income, and lack of a usual source of care had a significantly greater negative impact on AAPIs than on white women, indicating that AAPIs may be more vulnerable to structural barriers to cancer control efforts. AAPI women have very low rates of breast and cervical screening, which increases their chances of later stage disease presentation. To reach the Healthy People 2000 objectives, targeted efforts are needed to increase cancer screening among AAPI women overall and specific subgroups in particular.


Isolated vestibular syndromes due to brainstem and cerebellar lesions.
Dizziness/vertigo is the most common symptoms of posterior circulation strokes. Isolated vestibular symptoms and signs without other neurologic deficits have been found in infarctions involving the brainstem and cerebellum. In the brainstem, infarctions responsible for isolated vestibular syndrome are usually restricted to the dorsal portion that contains the vestibular nucleus and the nucleus prepositus hypoglossi. Cerebellar lesions confined to the flocculus, tonsil, and nodulus also produce isolated vertigo and imbalance. The cerebellar peduncle, as a conduit between the brainstem and cerebellum, can also produce isolated vestibular syndrome when damaged. Recognition of these isolated central vestibular syndromes aids in defining the function of each structure and in localizing the involved neural structures based upon the vestibular and ocular motor findings.