Enteral or parenteral nimodipine treatment: a comparative pharmacokinetic study.
BACKGROUND AND STUDY AIMS/OBJECT: Oral nimodipine is recommended to reduce poor outcome related to aneurysmal subarachnoid hemorrhage (SAH). In addition, animal experiments and clinical trails revealed a beneficial effect of enteral and parenteral nimodipine for the regeneration of cranial nerves following skull base, laryngeal, and maxillofacial surgery. Despite these findings there is a lack of pharmacokinetic data in the literature, especially concerning its distribution in nerve tissue. Samples were taken from a consecutive series of 57 patients suffering from skull base lesions and treated with nimodipine prophylaxis from the day before surgery until the seventh postoperative day. Both groups received standard dosages for enteral (n = 25) and parenteral (n = 32) nimodipine . Nimodipine levels were measured in serum, cerebrospinal fluid (CSF), and tissue samples, including vestibular nerves. Nimodipine levels were significantly higher following parenteral as compared with enteral administration for intraoperative serum (p < 0.001), intraoperative CSF (p < 0.001), tumor tissues (p = 0.01), and postoperative serum (p < 0.001). In addition, nimodipine was significantly more frequently detected in nerve tissue following parenteral administration (Fisher's exact test, p = 0.015). From a pharmacokinetic point of view, parenteral nimodipine medication leads to higher levels in serum and CSF. Furthermore, traces are more frequently found in nerve tissue following parenteral as compared with enteral nimodipine administration, at least in the early course.


Interaction of Religion/Spirituality With Internalized HIV Stigma, Depression, Alcohol Use, and Sexual Risk Among Black Men Who Have Sex With Men: The 6 City HPTN 061 Study.
Black men who have sex with men (BMSM) remain at highest risk for HIV in the United States. Internalized HIV stigma and depression contribute to substance use and condomless anal intercourse (CAI). Religion and spirituality (R/S) are associated with decreased HIV-related risk behaviors for some groups, but their impact among BMSM is uncertain. We investigated the main and moderating roles of R/S on pathways from internalized HIV stigma to CAI while under the influence of drugs. We used baseline data from 1511 BMSM from the HIV Prevention Trials Network (HPTN) 061 study to examine the associations between internalized HIV stigma, depressive symptoms, alcohol use, and CAI while under the influence of drugs, adjusting for covariates in generalized structural equation models. We then tested whether R/S moderated the association between (1) internalized HIV stigma and depressive symptoms, (2) depressive symptoms and alcohol use, and (3) alcohol use and CAI while under the influence of drugs. Spiritual beliefs [F(1,2) = 9.99, P < 0.001], spiritual activities [F(1,2) = 9.99, P < 0.001], and religious attendance [F(1,2) = 9.99, P < 0.001] moderated the pathway between internalized HIV stigma and depressive symptoms. As internalized HIV stigma increased, those with lower spiritual activity scores experienced significantly higher increases in depressive symptoms compared with those with higher spiritual activity scores whose depressive symptom scores remained unchanged [stigma × spiritual activities B = -0.18 (SE = 0.07), P < 0.001]. Religion and spirituality were protective against CAI among BMSM. Future intervention research should explore ways to incorporate religious and/or spiritual activities to reduce internalized HIV stigma as one way to reduce depressive symptoms among BMSM.


Periodontal health of the elderly people in South East local government area in Ibadan, Nigeria.
Health problems involving physical and mental conditions directly or indirectly affect the oral health of the elderly. Other ways in which physical and mental health conditions influence their health result from the various drug prescriptions given for these ailments. Periodontal health is the most affected. Various studies have demonstrated that the elderly have the highest rate of gingival bleeding, calculus deposits and periodontal pocketing. It is the aim of this study to determine the health of the supporting tissues of the teeth using periodontal indices such as the C.PI.T.N and mobility index. The study was carried out on 690 elderly individuals (403 males and 287 females) who were 65 years and above living in various wards in the South East Local Government Area of Ibadan (S.E.L.G.A). A multistage sampling technique was used to select elderly individuals for the study. Two interviewers, 2 record clerks and 2 examiners were trained and the examiners were calibrated. The elderly individuals were interviewed and examined concurrently. The results highlighted the high prevalence of periodontal disease in the elderly in this local government area. Only 5.2% were free from periodontal disease. 94.8% had one or another stage of periodontal disease. It also demonstrated the poor oral cleanliness among these elderly. More than 42% had gross accumulation of calculus. Among the elderly in this local government area, 21.6% and 28.8% had shallow and deep pockets, respectively whilst 39.3% had one or more mobile teeth. Pockets and excessive mobility of the teeth represent advance stages of periodontitis. Majority (70.4%) of the elderly in the study claimed they use chewing sticks to maintain oral hygiene. The pattern of deposit of calculus along the interdental surfaces, mesio and distobuccal surfaces as well as lingual surfaces, question the effectiveness of the chewing stick in cleaning these surfaces. This study confirms findings of other authors, on oral hygiene in Nigeria. There is an urgent need to establish a community based outreach programme to prevent and treat periodontal disease among the elderly in this local government area.


Microvascular function predicts cardiovascular events in primary prevention: long-term results from the Firefighters and Their Endothelium (FATE) study.
Biomarkers of atherosclerosis may refine clinical decision making in individuals at risk of cardiovascular disease. The purpose of the study was to determine the prognostic significance of endothelial function and other vascular markers in apparently healthy men. The cohort consisted of 1574 men (age, 49.4 years) free of vascular disease. Measurements included flow-mediated dilation and its microvascular stimulus, hyperemic velocity, carotid intima-media thickness, and C-reactive protein. Cox proportional hazard models evaluated the relationship between vascular markers, Framingham risk score, and time to a first composite cardiovascular end point of vascular death, revascularization, myocardial infarction, angina, and stroke. Subjects had low median Framingham risk score (7.9%). Cardiovascular events occurred in 71 subjects (111 events) over a mean follow-up of 7.2±1.7 years. Flow-mediated dilation was not associated with subsequent cardiovascular events (hazard ratio, 0.92; P=0.54). Both hyperemic velocity (hazard ratio, 0.70; 95% confidence interval, 0.54 to 0.90; P=0.006) and carotid intima-media thickness (hazard ratio, 1.45; confidence interval, 1.15 to 1.83; P=0.002) but not C-reactive protein (P=0.35) were related to events in a multivariable analysis that included Framingham risk score (per unit SD). Furthermore, the addition of hyperemic velocity to Framingham risk score resulted in a net clinical reclassification improvement of 28.7% (P<0.001) after 5 years of follow-up in the intermediate-risk group. Overall net reclassification improvement for hyperemic velocity was 6.9% (P=0.24). In men, hyperemic velocity, the stimulus for flow-mediated dilation, but not flow-mediated dilation itself was a significant risk marker for adverse cardiovascular outcomes. The prognostic value was additive to traditional risk factors and carotid intima-media thickness. Hyperemic velocity, a newly described marker of microvascular function, is a novel tool that may improve risk stratification of lower-risk healthy men.


Adherence to accelerometry measurement of community ambulation poststroke.
The step activity monitor (SAM) quantifies steps taken in the home and community by patient populations. Although the SAM has been used to study individuals after stroke, adherence to the use of SAMs has not been addressed. Participants' adherence to wearing the monitor is critical for obtaining accurate assessments. The purpose of this study was to determine the rate of and predictors for inferred adherence to the use of the SAM after stroke. A cross-sectional design was used. Community-dwelling individuals (n=408) 2 months after stroke with moderate-to-severe gait impairment (gait speed of ≤0.8 m/s) were studied. Step activity was assessed for 2 days with the SAM. Inferred adherence was established in 3 periods: 6:00 am to 12:00 pm, 12:01 pm to 6:00 pm, and 6:01 pm to 12:00 am. Adherence was defined as activity recorded in all 3 periods. The percentage of participant adherence for the first day, second day, both days, and either day was calculated. Demographic and clinical characteristics of adherers and nonadherers were compared. Independent adherence predictors were identified by means of stepwise logistic regression. Inferred adherence rates for the first day, second day, both days, and either day were 68%, 61%, 53%, and 76%, respectively. Upper and lower extremity impairment, balance control, and endurance were significantly different between adherers and nonadherers. On the other hand, older age, greater balance self-efficacy, and better walking endurance were significant predictors of adherence. Participants were individuals with subacute stroke. Therefore, the findings of this study may not be generalized to individuals during the acute and chronic phases of stroke recovery. Strategies to improve adherence are needed when collecting data for more than 1 day and in samples with younger individuals and those with low levels of balance self-efficacy and walking endurance.


A large deletion in the matrix domain of the human immunodeficiency virus gag gene redirects virus particle assembly from the plasma membrane to the endoplasmic reticulum.
Morphogenesis of retroviruses involves assembly of the structural Gag and Gag-Pol polyproteins with subsequent budding of the virus particle from the plasma membrane and proteolytic cleavage by the viral proteinase. The matrix (MA) domain, representing the N-terminal segment of Gag, plays a critical role in this process. We constructed an in-frame deletion in the MA coding region (lacking codons 16 to 99) of the human immunodeficiency virus (HIV) type 1 gag gene. Following transient transfection of the complete proviral DNA carrying the deletion, the mutant polyprotein was synthesized and proteolytically processed like the wild-type polyprotein. However, release of virus particles was reduced approximately 10-fold. The extracellular particles that were released did not contain viral glycoproteins and were noninfectious. Electron micrographs revealed budding of virus particles into the endoplasmic reticulum (ER) of transfected cells and large numbers of particles within the ER. These particles were all immature and morphologically indistinguishable from intracisternal A-type particles, a class of murine endogenous retrovirus elements. Budding structures at the plasma membrane were rarely seen and only a few extracellular particles were observed, but in contrast to those in the ER, these particles had the morphology of mature particles, similar to that of wild-type HIV, except for the lack of surface projections.


The number of catalytic sites in acetylcholinesterase.
By using two methods of titration, the number of active sites in acetylcholinesterase was determined. Either stepwise inhibition of the enzyme by an irreversible inhibitor, namely di-isopropyl phosphorofluoridate, or direct measurement of the concentration of active sites by titration with o-nitrophenyl dimethylcarbamate yielded an equivalent weight of approx. 130000 for an active site in acetylcholinesterase. This indicates two sites per molecule, since the native enzyme has a molecular weight of 260000.


Endoscopic Therapy of Gastric Varices: Safety and Efficacy of N-Butyl-2-Cyanoacrylate Injection.
Background Upper gastrointestinal bleeding (UGIB) is a common medical emergency that results in significant morbidity, mortality, and socioeconomic burden. Both types of cardio-fundal varices, gastro-esophageal varix 2 (GOV2) and isolated gastric varices type 1 (IGV1), can cause massive bleeding and often are difficult to treat compared to the other types of gastric varices. Endoscopic variceal band ligation (EVBL) is a less effective treatment modality for gastric varices than esophageal varices and is associated with high re-bleeding rates. N-butyl-2-cyanoacrylate (Histoacryl) injection is an effective and potential treatment option for fundal varices. This study aims to evaluate the safety and efficacy of n-butyl-2-cyanoacrylate injection therapy in cardio-fundal varices. Objective To assess the efficacy and safety of n-butyl-2-cyanoacrylate injection therapy for fundal varices. Methods This retrospective observational cohort study was conducted at the Department of Gastroenterology, Allied Teaching Hospital, Gujranwala, over one year. All patients, irrespective of age and gender, presenting with UGIB and in whom fundal varices were diagnosed on gastroscopy followed by n-butyl 2-cyanoacrylate injection therapy were included in this study. The efficacy and safety of Histoacryl therapy were assessed by analyzing successful hemostasis, frequency of re-bleeding, obliteration, and regression of fundal varices on repeat endoscopy. Adverse events such as re-bleeding and mortality related to fundal variceal treatment were documented. Results A total of 60 patients were included in the study. Of these, 70% had IGV1, while the remaining 30% had GOV2. Hemostasis was achieved in 100% of patients following n-butyl-2-cyanoacrylate injection. Successful obliteration with regression of varices was observed in 91.3% of patients. Various adverse events were observed, with abdominal pain being the most common observed complication in 18.3% of participants. However, only 8.3% of participants developed re-bleeding due to ulcer formation at the injection site, and no death occurred directly due to fundal variceal treatment. Conclusion N-butyl-2-cyanoacrylate injection therapy is a lifesaving, effective, and safe intervention for controlling bleeding from cardio-fundal varices, leading to improved health status and a consequent decrease in episodes of recurrent bleeding. Its side effects are few and infrequent. However, larger-scale studies are needed to further evaluate the safety and effectiveness of n-butyl-2-cyanoacrylate injection therapy. These studies will be crucial in establishing comprehensive guidelines for the management of fundal varices.


Investigating endogenous µ-opioid receptors in human keratinocytes as pharmacological targets using novel fluorescent ligand.
Opioids in skin function during stress response, regeneration, ageing and, particularly in regulating sensation. In chronic pruritus, topical treatment with Naltrexone changes μ-opioid receptor (μ-OR) localization to relieve itch. The molecular mechanisms behind the effects of Naltrexone on μ-OR function in reduction of itching behavior has not been studied. There is an immediate need to understand the endogenous complexity of μ-OR dynamics in normal and pathological skin conditions. Here we evaluate real-time behavior of μ-OR-Endomorphine complexes in the presence of agonist and antagonists. The μ-OR ligand Endomorphine-1 (EM) was conjugated to the fluorescent dye Tetramethylrhodamine (TAMRA) to investigate the effects of agonist and antagonists in N/TERT-1 keratinocytes. The cellular localization of the EM-TAMRA was followed through time resolved confocal microscopy and population analysis was performed by flow cytometry. The in vitro analyses demonstrate fast internalization and trafficking of the endogenous EM-TAMRA-μ-OR interactions in a qualitative manner. Competition with Endomorphine-1, Naltrexone and CTOP show both canonical and non-canonical effects in basal and differentiated keratinocytes. Acute and chronic treatment with Naltrexone and Endomorphine-1 increases EM-TAMRA binding to skin cells. Although Naltrexone is clinically effective in relieving itch, the mechanisms behind re-distribution of μ-ORs during clinical treatments are not known. Our study has given insight into cellular mechanisms of μ-OR ligand-receptor interactions after opioid agonist and antagonist treatments in vitro. These findings potentially offer opportunities in using novel treatment strategies for skin and peripheral sensory disorders.


Repression of African swine fever virus polyprotein pp220-encoding gene leads to the assembly of icosahedral core-less particles.
African swine fever virus (ASFV) polyprotein pp220, encoded by the CP2475L gene, is an N-myristoylated precursor polypeptide that, after proteolytic processing, gives rise to the major structural proteins p150, p37, p34, and p14. These proteins localize at the core shell, a matrix-like virus domain placed between the DNA-containing nucleoid and the inner envelope. In this study, we have examined the role of polyprotein pp220 in virus morphogenesis by means of an ASFV recombinant, v220i, containing an inducible copy of the CP2475L gene regulated by the Escherichia coli repressor-operator system. Under conditions that repress pp220 expression, the virus yield of v220i was about 2.6 log units lower than that of the parental virus or of the recombinant grown under permissive conditions. Electron microscopy revealed that pp220 repression leads to the assembly of icosahedral particles virtually devoid of the core structure. Analysis of recombinant v220i by immunoelectron microscopy, immunoblotting, and DNA hybridization showed that mutant particles essentially lack, besides the pp220-derived products, a number of major core proteins as well as the viral DNA. On the other hand, transient expression of the CP2475L gene in COS cells showed that polyprotein pp220 assembles into electron-dense membrane-bound coats, whereas a mutant nonmyristoylated version of pp220 does not associate with cellular membranes but forms large cytoplasmic aggregates. Together, these findings indicate that polyprotein pp220 is essential for the core assembly and suggest that its myristoyl moiety may function as a membrane-anchoring signal to bind the developing core shell to the inner viral envelope.


A Dedifferentiation Strategy to Enhance the Osteogenic Potential of Dental Derived Stem Cells.
Dental stem cells (DSCs) holds the ability to differentiate into numerous cell types. This property makes these cells particularly appropriate for therapeutic use in regenerative medicine. We report evidence that when DSCs undergo osteogenic differentiation, the osteoblast-like cells can be reverted back to a stem-like state and then further differentiated toward the osteogenic phenotype again, without gene manipulation. We have investigated two different MSCs types, both from dental tissues: dental follicle progenitor stem cells (DFPCs) and dental pulp stem cells (DPSCs). After osteogenic differentiation, both DFPCs and DPSCs can be reverted to a naïve stem cell-like status; importantly, dedifferentiated DSCs showed a greater potential to further differentiate toward the osteogenic phenotype. Our report aims to demonstrate for the first time that it is possible, under physiological conditions, to control the dedifferentiation of DSCs and that the rerouting of cell fate could potentially be used to enhance their osteogenic therapeutic potential. Significantly, this study first validates the use of dedifferentiated DSCs as an alternative source for bone tissue engineering.


Microbial synthesis of gold nanoparticles using the fungus Penicillium brevicompactum and their cytotoxic effects against mouse mayo blast cancer C 2 C 12 cells.
Microorganisms, their cell filtrates, and live biomass have been utilized for synthesizing various gold nanoparticles. The shape, size, stability as well as the purity of the bio synthesized nanoparticles become very essential for application purpose. In the present study, gold nanoparticles have been synthesized from the supernatant, live cell filtrate, and biomass of the fungus Penicillium brevicompactum. The fungus has been grown in potato dextrose broth which is also found to synthesize gold nanoparticles. The size of the particles has been investigated by Bio-TEM before purification, following purification and after storing the particles for 3 months under refrigerated condition. Different characterization techniques like X-ray diffraction, Fourier transform infrared spectroscopy, and UV-visible spectroscopy have been used for analysis of the particles. The effect of reaction parameters such as pH and concentration of gold salt have also been monitored to optimize the morphology and dispersity of the synthesized gold nanoparticles. A pH range of 5 to 8 has favored the synthesis process whereas increasing concentration of gold salt (beyond 2 mM) has resulted in the formation of bigger sized and aggregated nanoparticles. Additionally, the cytotoxic nature of prepared nanoparticles has been analyzed using mouse mayo blast cancer C(2)C(12) cells at different time intervals (24, 48, and 72 h) of incubation period. The cells are cultivated in Dulbecco's modified Eagle's medium supplemented with fetal bovine serum with antibiotics (streptopenicillin) at 37°C in a 5% humidified environment of CO(2). The medium has been replenished every other day, and the cells are subcultured after reaching the confluence. The viability of the cells is analyzed with 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide method.


Non-viral gene therapy for spinal cord regeneration.
Spinal cord injury (SCI) normally results in life-long disabilities and a broad range of secondary complications. Advances in therapeutic delivery during the past few decades offer hope for such victims. However, the limited functional improvement shown in in vivo studies hinders effective therapeutic application in clinical practice. Recent studies showed that gene vectors can transfect cells present in the lesion of an injured spinal cord (endogenous cells) and thereby produce therapeutic molecules with long-lasting biological effects that promote neural tissue regeneration. In this article we review recent advances in non-viral gene delivery into neural cells and their use for gene therapy in SCI.


Photic sensitization is mediated by cortico-accumbens pathway in rats with trigeminal neuropathic pain.
Exposure to light stimuli may trigger or exacerbate perception of pain, also known as a common yet debilitating symptom of photophobia in patient with chronic orofacial pain. Mechanism underlying this phenomenon of photic sensitization in neuropathic condition remains elusive. Here, we found that rats developed hypersensitivity to normal light illumination after establishment of chronic constriction injury of infraorbital nerve (ION-CCI) model, which can be attenuated by blocking the exposure of photic stimulation. Additionally, this behavioral phenotype of light-sensitivity impairment was associated with overexpression of anterior cingulate cortex (ACC) c-fos positive neurons, enhancement of neural excitability in the ACC neurons and its excitatory synaptic transmission between nucleus accumbens (NAc). Optogenetic and chemogenic silencing of ACC-NAc pathway improved trigeminal sensitization in responses to light stimuli by decreasing spontaneous pain-like episodes in ION-CCI animals. In contrast, selective activation of ACC-to-NAc circuits enhanced photic hypersensitivity in dark environment. Thus, our data provided novel role of ACC and its projection to NAc in bidirectional modulation of photic sensation, which may contribute to the understanding of photic allodynia in trigeminal neuropathic pain status.


Cross-Language Influences in the Processing of Multiword Expressions: From a First Language to Second and Back.
The present study investigated cross-language influences in the processing of binomial expressions (knife and fork), from a first language (L1) to a second language (L2) and from L2 to L1. Two groups of unbalanced bilinguals (Chinese/L1-English/L2 and English/L1-Chinese/L2) and a control group of English monolinguals performed a visual lexical decision task that incorporated unmasked priming. To assess cross-language influences, we used three types of expressions: congruent binomials (English binomials that have translation equivalents in Chinese), English-only binomials, and Chinese-only binomials translated into English. Lexical decision latencies to the last word (fork) in a binomial (knife and fork) were compared with response latencies to the same word in a matched control phrase (spoon and fork). We found that (1) Chinese-English bilinguals showed a significant priming effect for congruent binomials but no facilitation for English-only binomials, (2) English-Chinese bilinguals showed a trend toward priming for congruent binomials, which did not reach statistical significance, and no priming for English-only binomials, (3) English monolinguals showed comparable priming for congruent and English-only binomials. With respect to the Chinese-only binomials, none of the three participant groups showed priming for translated Chinese-only binomials over controls. These findings suggest that L1 influences the processing of L2 binomials, and that there may be some cross-linguistic influence in the opposite direction, i.e., from L2 to L1, although to a lesser extent.


The effect of acute serotonergic modulation on rectal motor function in diarrhea-predominant irritable bowel syndrome and healthy controls.
Irritable bowel syndrome (IBS) patients suffer from visceral hypersensitivity and show increased activity in the brain emotional arousal network following a rectal stimulus, compared with controls. Serotonergic activity can be decreased by acute tryptophan depletion (ATD), which increases visceral perception and also increases activity in the brain's emotional arousal network during rectal stimulation. Treatment with a serotonin reuptake inhibitor such as citalopram is effective in some IBS patients. Hence, serotonergic modulation alters visceral perception. However, it is not clear whether serotonergic modulation alters rectal motor function. The aims of the study were to evaluate the effect of the administration of ATD and citalopram on rectal motor function in diarrhea-predominant IBS (d-IBS) patients and controls using a barostat procedure. Following a randomized, double-blind placebo-controlled crossover design, an ATD and citalopram experiment was conducted. Fourteen d-IBS patients and 14 healthy, matched (age, sex, BMI) controls participated. Rectal volume (RV), adaptive relaxation (RAR), and compliance (RC) were determined using a barostat procedure. d-IBS patients showed significantly decreased RV (P<0.04), RAR (P<0.03), and RC (P=0.05) compared with the controls. ATD and citalopram did not influence RV, RAR, or RC significantly (all P's>0.1). d-IBS patients have disturbed rectal pressure-volume relations. Visceral perception in IBS is associated with both increased activity in the brain's emotional arousal network and decreased RC. Acutely decreasing or increasing serotonergic activity does not affect these characteristics in d-IBS patients or healthy controls. The pathophysiology in d-IBS contains both a rectal motor component and a central neuropsychologic component.


Reconsidering anhedonia in depression: lessons from translational neuroscience.
Anhedonia is a core symptom of major depressive disorder (MDD), the neurobiological mechanisms of which remain poorly understood. Despite decades of speculation regarding the role of dopamine (DA) in anhedonic symptoms, empirical evidence has remained elusive, with frequent reports of contradictory findings. In the present review, we argue that this has resulted from an underspecified definition of anhedonia, which has failed to dissociate between consummatory and motivational aspects of reward behavior. Given substantial preclinical evidence that DA is involved primarily in motivational aspects of reward, we suggest that a refined definition of anhedonia that distinguishes between deficits in pleasure and motivation is essential for the purposes of identifying its neurobiological substrates. Moreover, bridging the gap between preclinical and clinical models of anhedonia may require moving away from the conceptualization of anhedonia as a steady-state, mood-like phenomena. Consequently, we introduce the term "decisional anhedonia" to address the influence of anhedonia on reward decision-making. These proposed modifications to the theoretical definition of anhedonia have implications for research, assessment and treatment of MDD.


Overall Survival of Hepatocellular Carcinoma Patients Underwent Radiofrequency Ablation (RFA) Treatment: a Retrospective Cohort Study from Two Referral Hospitals in Indonesia.
Radiofrequency ablation (RFA) is one of the curative modality therapies commonly used for the early stage of HCC management. Although numerous studies have reported the outcome of RFA around the world, the data regarding the usage of RFA for the early and intermediate stage of HCC remains limited. Hence, the study aimed to report the survival rate of the early and intermediate stage HCC patients who underwent RFA in two tertiary referral hospitals in Jakarta, Indonesia. A retrospective cohort study was conducted in Cipto Mangunkusumo and Medistra multicenter hospital in Jakarta, Indonesia. The patients with HCC BCLC A and B who underwent RFA treatments between January 2015 to December 2017 were recruited for the study. Baseline characteristics of patients were collected from the medical record. Survival analysis was calculated using the Kaplan Meier. p value result was obtained from the log-rank test. Sub-analysis of factors associated with the survival was also included in this study. There were 62 patients enrolled in this study (32.3% were BCLC A and 67.7% were BCLC B). Forty-six out of 62 patients (74.2%) were reported to have RFA as their first line of treatment, while 12 (25.8%) were reported to have a combination of RFA and other therapy modalities. All these patients were follow-up with an average duration of 27 months. The survival rate of liver cancer due to HCC for 12 and 36 months in patients who received RFA was 82.3% and 57.8%, respectively. Moreover, BCLC staging of liver cancer and response after RFA was significantly associated with survival. RFA still can be used as initial modality therapy nor combination with another therapy for the early and intermediate stage of HCC. BCLC staging and response after RFA had shown to be the independent factors related to survival.


Effects of quercetin on oxidative stress and memory retrieval in kindled rats.
Flavonoids are a class of polyphenolic compounds present in fruits and vegetables. Several studies have demonstrated a relationship between the consumption of flavonoid-rich diets and the prevention of human diseases including neurodegenerative disorders. Thus, we assessed the effect of quercetin (3,3',4',5,7-pentahydroxyflavone) on oxidative stress and memory retrieval using a step-through passive avoidance task in kindled rats. Quercetin (25, 50, and 100 mg/kg) was administered intraperitoneally (i.p.) before pentylenetetrazole (PTZ) every other day prior to the training. Retention tests were performed to assess memory in rats. Compared to control, pretreatment with 50 mg/kg of quercetin could attenuate seizure severity from the beginning of the kindling experiment by lowering the mean seizure stages. Moreover, quercetin 50 mg/kg significantly increased the step-through latency of the passive avoidance response compared to the control in the retention test. Malondialdehyde (MDA) levels were significantly increased in the quercetin groups compared to the PTZ group in the hippocampus and cerebral cortex following PTZ kindling. In the quercetin groups, higher sulfhydryl (SH) contents were not observed compared to the PTZ group. These results indicate that quercetin at a specific dose results in decreased seizure severity during kindling and performance improvement in a passive avoidance task in kindled rats. All doses of quercetin led to increased oxidative stress in the hippocampi and cerebral cortices of kindled rats.


Screening of ordinary commercial varieties of apple fruits under different storage conditions for their potential vascular and metabolic protective properties.
Epidemiological studies reported that apple consumption is associated with a decrease of cardiovascular and metabolic dysfunction, probably due to the polyphenols and fibers present in this fruit. The storage conditions and genetic origin of apples have been reported to influence their content and, as a consequence, their pharmacological properties. The present study evaluated the influence of varieties and storage conditions of traditional and highly appreciated apples including Gala, Golden Delicious, Granny Smith and Pink Lady varieties after harvest and storage under classic cold conditions, under a controlled atmosphere, or under extreme ultra-low oxygen conditions. Thus, a multi-parametric screening on cell models associated with vascular and metabolic dysfunctions - such as endothelial and smooth muscle cells, hepatocytes, adipocytes and macrophages - in relation to the apple polyphenol content has been developed. This strategy demonstrated that, overall, peeled apple samples exhibited a vascular tropism and acted mainly on proliferation and oxidative stress in endothelial and smooth muscle cells. Apple extracts appeared to be less effective on adipocytes and macrophages, but they exhibited antioxidant properties in hepatocytes. Among the varieties, Gala and Golden Delicious were the most efficient against the processes involved in the development of atherosclerosis. Concerning storage conditions, most of the apple varieties were more efficient under harvest conditions, while they could not be discriminated under all other cold conditions and the concentration used, except for the Gala samples. Interestingly, pharmacological properties were associated with the polyphenol profiles of freeze dried apple flesh powder. The present report revealed the potential use of some apple extracts as effective food supplements or nutraceuticals for the prevention and/or management of cardiovascular and metabolic diseases.


Importance of Postprandial Glucose in Relation to A1C and Cardiovascular Disease.
IN BRIEF This article reviews the evidence regarding the impact of postprandial glucose (PPG) on overall A1C and its relation to cardiovascular disease (CVD). To date, four randomized, controlled trials have evaluated the impact of PPG reduction on CVD; however, only one of these successfully demonstrated a positive effect. Despite this, epidemiological evidence does indicate a cardiovascular benefit of PPG reduction, and agents that can be used to manage PPG in people with type 2 diabetes are also discussed.


Clinical signs associated with earlier diagnosis of children with autism Spectrum disorder.
The objective of this study is to gain new insights into the relationship between clinical signs and age at diagnosis. We utilize a new, large, online survey of 1743 parents of children diagnosed with ASD, and use multiple statistical approaches. These include regression analysis, factor analysis, and machine learning (regression tree). We find that clinical signs that most strongly predict early diagnosis are not necessarily specific to autism, but rather those that initiate the process that eventually leads to an ASD diagnosis. Given the high correlations between symptoms, only a few signs are found to be important in predicting early diagnosis. For several clinical signs we find that their presence and intensity are positively correlated with delayed diagnosis (e.g., tantrums and aggression). Even though our data are drawn from parents' retrospective accounts, we provide evidence that parental recall bias and/or hindsight bias did not play a significant role in shaping our results. In the subset of children without early deficits in communication, diagnosis is delayed, and this might be improved if more attention will be given to clinical signs that are not necessarily considered as ASD symptoms. Our findings also suggest that careful attention should be paid to children showing excessive tantrums or aggression, as these behaviors may interfere with an early ASD diagnoses.


Leukoencephalopathy with brain stem and spinal cord involvement and high lactate: a genetically proven case with distinct MRI findings.
Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a recently described disorder with autosomal recessive mode of inheritance. Lately, mutations in the DARS2 gene, which encodes mitochondrial aspartyl-tRNA synthetase, have been found as the underlying defect. We report a 19-year-old male patient with cerebellar, pyramidal and dorsal column dysfunctions and specific magnetic resonance imaging (MRI) and characteristic magnetic resonance spectroscopy (MRS) abnormalities. The patient was compound-heterozygous for two mutations in DARS2. MRI showed selective involvement of cerebral and cerebellar white matter and superior and inferior cerebellar peduncles, without contrast enhancement. The U-fibers were spared. The sensory and the pyramidal tracts were affected over their entire length. Involvement of the intraparenchymal trajectories of the trigeminal nerves and mesencephalic trigeminal tracts was demonstrated. In the spinal cord, signal abnormalities were identified in the dorsal columns and the lateral corticospinal tracts. Proton-MRS of the frontal and cerebellar white matter showed elevated lactate, reduced N-acetylaspartate, increased myoinositol and mildly elevated choline. In LBSL, distinct MRI findings should lead to the diagnosis, which can be confirmed by the analysis of the disease gene DARS2.


Vasovagal syncope: an update on the latest pharmacological therapies.
Syncope is an abrupt loss of consciousness in response to reduced perfusion to the brain. Neurocardiogenic or vasovagal syncope results from a complex neurologic reflex, and treatments to prevent recurrence attempt to modulate aspects of that reflex. Pharmacologic treatments for vasovagal syncope address the syncope reflex in multiple ways. Fludrocortisone and sodium chloride increase systemic fluid volume. Midodrine, β blockers and norepinephrine transport inhibitors modulate the sympathetic nervous system. Other treatments for syncope modulate other neurotransmitters or affect heart rate. The most recent trials evaluating established and novel therapies are reviewed. To reduce recurrence of vasovagal syncope, conservative measures are first line. If these fail to prevent recurrence, the most promising medical therapy includes midodrine. Randomized placebo-controlled data evaluating fludrocortisone, midodrine and β blockers in older patients are awaited. Because of the significance of the placebo effect in this condition, any treatment must be evaluated in a randomized double-blind placebo-controlled trial before being accepted as effective.


Kaposi's sarcoma in a young homosexual man. Association with angiofollicular lymphoid hyperplasia and a malignant lymphoproliferative disorder.
Recent reports have described an unexpected number of cases of a virulent form of a Kaposi's sarcoma (KS) as well as acquired immunodeficiency in young homosexual men. A 31-year-old man initially had a benign disorder, angiofollicular lymphoid hyperplasia. Kaposi's sarcoma then developed, and he died of a malignant lymphoproliferative disorder. We believe that this is unique among the recently described cases of KS in homosexual men because of the occurrence of this second malignancy. It may be that similar cases will be recognized in this population.


Engineering of thioesterase YciA from Haemophilus influenzae for production of carboxylic acids.
Acyl-CoA-thioesterases, which hydrolyze acyl-CoA-esters and thereby release the respective acid, have essential functions in cellular metabolism and have also been used to produce valuable compounds in biotechnological processes. Thioesterase YciA originating from Haemophilus influenzae has been previously used to produce specific dicarboxylic acids from CoA-bound intermediates of the ethylmalonyl CoA pathway (EMCP) in Methylorubrum extorquens. In order to identify variants of the YciA enzyme with the capability to hydrolyze so far inaccessible CoA-esters of the EMCP or with improved productivity, we engineered the substrate-binding region of the enzyme. Screening a small semi-rational mutant library directly in M. extorquens yielded the F35L variant which showed a drastic product level increase for mesaconic acid (6.4-fold) and 2-methylsuccinic acid (4.4-fold) compared to the unaltered YciA enzyme. Unexpectedly, in vitro enzyme assays using respective M. extorquens cell extracts or recombinantly produced thioesterases could not deliver congruent data, as the F35L variant showed strongly reduced activity in these experiments. However, applied in an Escherichia coli production strain, the protein variant again outperformed the wild-type enzyme by allowing threefold increased 3-hydroxybutyric acid product titers. Saturation mutagenesis of the codon for position 35 led to the identification of another highly efficient YciA variant and enabled structure-function interpretations. Our work describes an important module for dicarboxylic acid production with M. extorquens and can guide future thioesterase improvement approaches. KEY POINTS: • Substitutions at position F35 of YciAHI changed the productivity of YciA-based release of carboxylic acid products in M. extorquens AM1 and E. coli. • YciAHI F35N and F35L are improved variants for dicarboxylic production of 2-methylsuccinic acid and mesaconic acid with M. extorquens AM1. • In vitro enzyme assays did not reveal superior properties of the optimized protein variants.


Pilot Study of a Single Dose of Orally Administered Tapentadol Suspension in Hispaniolan Amazon Parrots (Amazona ventralis).
Tapentadol is an analgesic agent that acts as both a µ-opioid receptor agonist and a norepinephrine reuptake inhibitor. It is a common therapeutic agent in human medicine for management of acute and chronic pain, and it is currently being investigated for use in veterinary medicine. Tapentadol was evaluated in Hispaniolan Amazon parrots (Amazona ventralis) because there is only 1 other oral opioid-like analgesic agent, tramadol, which has been evaluated in an avian species. The effectiveness of tramadol after administration to a patient involves a complex physiologic metabolism and has been found to have variable pharmacokinetics between species. Because of the lack of active metabolites from tapentadol, less interspecific variation was expected. Seven Hispaniolan Amazon parrots were used to evaluate the pharmacokinetics of tapentadol after a single 30 mg/kg PO administration of a compounded 5 mg/mL tapentadol suspension. Blood samples were collected before (time 0) and 0.25, 0.5, 0.75, 1, 1.5, 3, and 6 hours after administration, following a balanced, incomplete-block design. Plasma tapentadol concentrations were measured by high-pressure liquid chromatography with mass spectrometry. Results revealed detectable plasma concentrations in only 2 of 7 birds (29%), and the bird with the highest plasma levels had a peak concentration (Cmax) of 143 ng/mL and a half-life (T 1/2) of 24.8 minutes. The variable plasma concentrations and short half-life of this drug in Hispaniolan Amazon parrots suggests that this drug would be of limited clinical use in this species; however, it is possible that this drug will be more bioavailable in other avian species.


A multivariate analysis of mortality and hospital admissions with high-flux dialysis.
The use of high-flux dialysis in clinical practice increased rapidly despite an absence of reports on the clinical effectiveness of the technique. Mortality and hospital admission rates of patients treated with high-flux dialysis were evaluated and compared with those of patients treated with conventional dialysis in a hospital-based renal dialysis unit in northern California. By use of a retrospective, cross-over design, 253 patients enrolled in the dialysis unit from January 1987 to January 1991 were studied. During this period, 107 patients were treated with high-flux dialysis for at least 1 month, and all but 17 of them had received conventional dialysis before switching to high-flux dialysis. The remaining 146 patients were treated with only conventional dialysis. Of the 80 patients who died during the study period, 69 were receiving conventional dialysis and 11 were receiving high-flux dialysis. The multivariate analyses, adjusted for age, gender, ethnic background, type of renal failure, comorbid conditions, and duration of ESRD, showed that annual mortality was substantially less for patients treated with high-flux dialysis compared with that for patients treated with conventional dialysis (7 versus 20%; P < 0.001). The difference in the rate of hospital admissions was not statistically significant. In this nonexperimental study, methods were applied to control for selectivity bias and other factors that might confound the apparent treatment effect. The findings suggest that the potential benefits of high-flux dialysis are sufficient to justify further confirmation in a randomized, controlled trial.


Different views about the nature of gender-related asymmetries in tasks based on biological or artefact categories.
Sex-related asymmetries in the ability to process different semantic categories have been reported both in normal subjects and in brain-damaged patients, but the nature of these asymmetries is still controversial. Some authors suggest that these differences might be due to social-role related familiarity factors, whereas others attribute them to inborn neural differences rooted in evolution. Drawing in part on this second line of thought, some authors have suggested that gender-related asymmetries might be due to differences in stimulus processing between men and women, namely, to the tendency of females to focus mainly on perceptual features and of males to focus equally on both perceptual and functional features. To test this hypothesis, we asked 53 male and 65 female undergraduate students to evaluate the relevance of a number of perceptual and functional features in the representation of various kinds of biological and artefact categories. Contrary to the hypothesis, evaluation of the weight of different sources of knowledge in representing living and artefact categories was similar in males and females.


Understanding the association between parental attitudes and the practice of female genital mutilation among daughters.
Female genital mutilation is a harmful traditional practice that violates girls' right to health and overall well-being. Most research cites social acceptance, marriageability, community belonging, proof of virginity, curbing promiscuity, hygiene, and religion as motivations for the practice. It is generally assumed that individual attitudes of parents and other family members have an impact on decisions related to the cutting of girls, and that such attitudes are influenced by social norms. The aim of this study is to understand how parental attitudes towards the practice of female genital mutilation influence decision making related to the cutting of girls. Data from 15 Demographic and Health Surveys were analyzed to assess whether couples with at least one living daughter aged 0 to 14 years share the same opinions about the continuation of the practice, and to what extent couples' opinions are associated with the risk of daughters being cut. The analysis reveals that a significant percentage of couples hold discordant opinions on the continuation of the practice including in countries where the practice is very common. While a daughter's likelihood of being cut is much higher when both parents think the practice should continue, the analysis also shows that many cut girls have parents who oppose the practice. It further suggests that female genital mutilation is more prevalent among daughters whose mothers want the practice to continue and whose fathers are opposed or undecided, compared to daughters with fathers who are the sole parent supporting its continuation. Understanding the extent to which parental opinions influence decisions and which girls are most likely to be cut is essential for developing appropriate interventions aimed at promoting the abandonment of the practice.


In vivo CD8+ T cell CRISPR screening reveals control by Fli1 in infection and cancer.
Improving effector activity of antigen-specific T cells is a major goal in cancer immunotherapy. Despite the identification of several effector T cell (TEFF)-driving transcription factors (TFs), the transcriptional coordination of TEFF biology remains poorly understood. We developed an in vivo T cell CRISPR screening platform and identified a key mechanism restraining TEFF biology through the ETS family TF, Fli1. Genetic deletion of Fli1 enhanced TEFF responses without compromising memory or exhaustion precursors. Fli1 restrained TEFF lineage differentiation by binding to cis-regulatory elements of effector-associated genes. Loss of Fli1 increased chromatin accessibility at ETS:RUNX motifs, allowing more efficient Runx3-driven TEFF biology. CD8+ T cells lacking Fli1 provided substantially better protection against multiple infections and tumors. These data indicate that Fli1 safeguards the developing CD8+ T cell transcriptional landscape from excessive ETS:RUNX-driven TEFF cell differentiation. Moreover, genetic deletion of Fli1 improves TEFF differentiation and protective immunity in infections and cancer.


Does anemia matter? Anemia, morbidity, and mortality in older adults: need for greater recognition.
Anemia is common and under recognized in older adults and associated with increased morbidity and mortality. Estimates of prevalence of anemia in older adults vary considerably based on the setting, gender, age and definition used and likely to increase further based on aging trends. Rather than simply a consequence of aging, anemia is a marker of underlying disease, requiring investigation for an etiology. A cause is discernible in at least two-thirds of cases; management involves addressing the underlying disease process, replacement of deficient nutrients or the use of erythropoietic factors.


Surface-based brain morphometry and diffusion tensor imaging in schizoaffective disorder.
The profile of grey matter abnormalities and related white-matter pathology in schizoaffective disorder has only been studied to a limited extent. The aim of this study was to identify grey- and white-matter abnormalities in patients with schizoaffective disorder using complementary structural imaging techniques. Forty-five patients meeting Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria and Research Diagnostic Criteria for schizoaffective disorder and 45 matched healthy controls underwent structural-T1 and diffusion magnetic resonance imaging to enable surface-based brain morphometry and diffusion tensor imaging analyses. Analyses were conducted to determine group differences in cortical volume, cortical thickness and surface area, as well as in fractional anisotropy and mean diffusivity. At a threshold of p = 0.05 corrected, all measures revealed significant differences between patients and controls at the group level. Spatial overlap of abnormalities was observed across the various structural neuroimaging measures. In grey matter, patients with schizoaffective disorder showed abnormalities in the frontal and temporal lobes, striatum, fusiform, cuneus, precuneus, lingual and limbic regions. White-matter abnormalities were identified in tracts connecting these areas, including the corpus callosum, superior and inferior longitudinal fasciculi, anterior thalamic radiation, uncinate fasciculus and cingulum bundle. The spatial overlap of abnormalities across the different imaging techniques suggests widespread and consistent brain pathology in schizoaffective disorder. The abnormalities were mainly detected in areas that have commonly been reported to be abnormal in schizophrenia, and to some extent in bipolar disorder, which may explain the clinical and aetiological overlap in these disorders.


Effect of Homeopathic Preparations on Lettuce, Parasitized or Not by Meloidogyne enterolobii.
There are relatively few scientific works on the use of homeopathy to manage plant pathogens, particularly nematodes. A handful of studies focused on Meloidogyne spp. parasitizing vegetables have brought contradictory results on nematode control and enhancement of plant tolerance to parasitism. Our goal was to assess the effect of Cina-a well-known anti-nematode ingredient-on Meloidogyne enterolobii parasitizing lettuce. Cina was applied daily on nematode-inoculated plants, from the seedling stage until harvest. We tested an evenly spaced range of Hahnemannian concentrations (c), which were applied though irrigation with a constant dose of the ingredient. Several absolute and relative controls were employed to allow the assessment of the effect of Cina on nematode reproduction and lettuce growth. Cina affected growth of non-parasitized plants, both positively and negatively; this effect was modulated by the c applied and the thermal stress suffered by the plants in one of the assays. The effect of Cina on the growth of nematode-parasitized plants was neutral or negative. Cina reduced nematode reproduction by 25-36%. Based on the moderate negative effect of Cina on M. enterolobii reproduction, it seems this ingredient may be useful as a complementary strategy for Meloidogyne control. But Cina did not enhance the tolerance of lettuce to Meloidogyne spp.


[Markers of periodontal diseases and sensitivity to taromentine in patients with aggressive periodontitis].
The aim of the research was to study sensitivity of specific microorganisms from the periodontal pockets of patients with rapidly progressive periodontal disease to Taromentine. 95 patients aged 21 to 35 years (50 women (52,6+/-33,62) and 45 men (47,36+/-3,62)) with rapidly progressive form of periodontal desease were observed. Porphiromonas gingivalis was identifide in 83 out of 95 patients (87,36+/-2,06). Prevotella intermedia - in 31 patients (32,6+/-2,750); Actinobacillus actinomycetemcomitans - in 23 patients (24,2+/-2,050); Bacteroides forsythus - in 19 patients (20,0+/-2,360); Treponema denticola - in 16 patients (16,84+/-2,190); Candida - in 11 patients (11,57+/-1,80). The sensitivity of all cultures to Taromentine was investigated: 134 (77,9+/-1,89) out of 183 identified markers demonstrated sensitivity to Taromentine. Demostrated sensitivity to Taromentine: 64 (37,2+/-1,06) out of 83 identified cultures of Porphiromonas gingivalis, 24 (13,95+/-1,85) out of 31 identified cultures of Prevotela intermedia, 18 (10,47+/-1,05) out of 23 identified cultures of Actinobacillus actinomycetemcomitans, 15 (8,7+/-1,86) out of 19 identified cultures of Bacteroides forsythus, and 13 (7,84+/-1,09) out of 16 identified cultures of Treponema denticola. Totally 38 (22,1+/-1,59) out of 172 identified periodontal markers demonstrated resistence to Taromentine. The results of analysis showed that Taromentine could be recommended in complex treatment of periodontal diseases.


An official systematic review of the European Respiratory Society/American Thoracic Society: measurement properties of field walking tests in chronic respiratory disease.
This systematic review examined the measurement properties of the 6-min walk test (6MWT), incremental shuttle walk test (ISWT) and endurance shuttle walk test (ESWT) in adults with chronic respiratory disease. Studies that report the evaluation or use of the 6MWT, ISWT or ESWT were included. We searched electronic databases for studies published between January 2000 and September 2013. The 6-min walking distance (6MWD) is a reliable measure (intra-class correlation coefficients ranged from 0.82 to 0.99 in seven studies). There is a learning effect, with greater distance walked on the second test (pooled mean improvement of 26 m in 13 studies). Reliability was similar for ISWT and ESWT, with a learning effect also evident for ISWT (pooled mean improvement of 20 m in six studies). The 6MWD correlates more strongly with peak work capacity (r=0.59-0.93) and physical activity (r=0.40-0.85) than with respiratory function (r=0.10-0.59). Methodological factors affecting 6MWD include track length, encouragement, supplemental oxygen and walking aids. Supplemental oxygen also affects ISWT and ESWT performance. Responsiveness was moderate to high for all tests, with greater responsiveness to interventions that included exercise training. The findings of this review demonstrate that the 6MWT, ISWT and ESWT are robust tests of functional exercise capacity in adults with chronic respiratory disease.


Green biomimetic preparation of efficient Ag-ZnO heterojunctions with excellent photocatalytic performance under solar light irradiation: a novel biogenic-deposition-precipitation approach.
Herein, we report a unique single-step biogenic deposition precipitation (BDP) approach as a straightforward route for producing efficient Schottky contact between noble metal nanoparticles and wide-band-gap semiconductors. Successful preparation of Ag-ZnO heterojunctions using fennel seed extract (FSE) has been described. The effective biomolecules available in the seeds functioned as novel biogenic materials for the precipitation of adsorbed silver ions (Ag+) on ZnO particles as metallic silver (Ag0). The as-prepared composite materials were characterized using diffuse reflectance spectroscopy (DRS), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), energy dispersive X-ray (EDX) study, X-ray photoelectron spectroscopy (XPS), photoluminescence spectroscopy (PL) and high-resolution transmission electron microscopy (HR-TEM). The biogenically prepared Ag-ZnO nanocomposites exhibited excellent photocatalytic activity towards reduction/degradation of colored (rhodamine B (Rh-B) dye) as well as colorless (chlorpyrifos pesticide) pollutants when irradiated under solar light. Among the prepared photocatalysts, 3 wt% Ag-ZnO hybrid composite showed the best photocatalytic activity by efficiently degrading hazardous organic pollutants within a very short time. The superior photocatalytic performance of biogenically prepared Ag-ZnO heterojunctions can be ascribed to the clean production of steady and efficient Schottky contact between plasmonic AgNPs and semiconducting ZnO NPs.


The association of abnormal cerebellar function in children with developmental coordination disorder and reading difficulties.
Children with developmental coordination disorder/dyspraxia (DCD) are at high risk of reading and writing delay. The difficulties with motor skills are heterogeneous and many children have features of poor cerebellar function, reflected in problems with posture, balance and fast accurate control of movement. This study confirmed a high level of parental reporting of reading and writing delay in a clinical group of 23 children with DCD, defined on the basis of both clinical examination and standardized testing of motor function. Direct measurement of reading delay, identified still further children in the group. Those children with reading delay had associated findings typical of phonological awareness difficulties. The children also underwent a standardized test of neurological function and although they all had difficulties with cerebellar function, no distinctive pattern emerged for those whose presentation was complicated by delayed reading and writing. Both the children with DCD and 136 typically developing children, completed the pilot parental questionnaire on gross motor skills. The three skills of catching a ball, jumping on a moving playground roundabout and handwriting, distinguished the children with DCD. This study therefore confirms that children with DCD should be assessed for difficulties in phonological awareness. Additionally, children aged between 7 and 12 years are on the whole, highly competent in a range of gross motor skills and further study might determine whether a simple parental questionnaire might detect children who would benefit from further assessment. The study also suggests that all the children with DCD have cerebellar dysfunction and further work with a larger group might determine particular patterns associated with reading delay.


Similarities and differences in the neural representations of abstract concepts across English and Mandarin.
Recent research suggests there is a neural organization for representing abstract concepts that is common across English speakers. To investigate the possible role of language on the representation of abstract concepts, multivariate pattern analytic (MVPA) techniques were applied to fMRI data to compare the neural representations of 28 individual abstract concepts between native English and Mandarin speakers. Factor analyses of the activation patterns of the 28 abstract concepts from both languages characterized this commonality in terms of a set of four underlying neurosemantic dimensions, indicating the degree to which a concept is verbally represented, internal to the person, contains social content, and is rule-based. These common semantic dimensions (factors) underlying the 28 concepts provided a sufficient basis for reliably identifying the individual abstract concepts from their neural signature in the other language with a mean rank accuracy of 0.65 (p < .001). Although the neural dimensions used for representing abstract concepts are common across languages, differences in the meaning of some individual concepts can be accommodated in terms of differential salience of particular dimensions. These semantic dimensions constitute a set of neurocognitive resources for abstract concept representations within a larger set of regions responsible for general semantic processing.


The natural flavorprotein electron acceptor of trimethylamine dehydrogenase.
The isolation and partial characterization of a flavoprotein which functions as the electron acceptor of trimethylamine dehydrogenase (EC 188.8.131.52) from a methylotrophic bacterium is described. It has a molecular weight of 77,000 and is composed of two dissimilar subunits. All preparations examined contained only 1 mol of FAD/mol of the flavoprotein. Trimethylamine dehydrogenase, in the presence of trimethylamine or dithionite, reduced the flavoprotein to a stable anionic semiquinone form. No evidence for the participation of the fully reduced flavoprotein in catalysis could be obtained.


Cerebrospinal fluid metabolomics identifies 19 brain-related phenotype associations.
The study of metabolomics and disease has enabled the discovery of new risk factors, diagnostic markers, and drug targets. For neurological and psychiatric phenotypes, the cerebrospinal fluid (CSF) is of particular importance. However, the CSF metabolome is difficult to study on a large scale due to the relative complexity of the procedure needed to collect the fluid. Here, we present a metabolome-wide association study (MWAS), which uses genetic and metabolomic data to impute metabolites into large samples with genome-wide association summary statistics. We conduct a metabolome-wide, genome-wide association analysis with 338 CSF metabolites, identifying 16 genotype-metabolite associations (metabolite quantitative trait loci, or mQTLs). We then build prediction models for all available CSF metabolites and test for associations with 27 neurological and psychiatric phenotypes, identifying 19 significant CSF metabolite-phenotype associations. Our results demonstrate the feasibility of MWAS to study omic data in scarce sample types.


The antidoping control in horseraces in Italy.
The results and the improvement of the analytical procedures adopted for the control of doping in horses will be reported. This control has been systematically carried out in Italy for about 10 years in the laboratories of Italian Federation of Sport and Medicine in which the biological samples for the control of doping in various sport activities (football, cycling, athletics etc.) are also examined. In this way it is possible to use the same instruments for all these similar problems and compare the results. The analytical procedure is based on the following steps: 1) Extraction of the samples (mainly urine but sometimes blood or saliva). 2) Screening tests by thin-layer chromatography. 3) Confirmatory tests by gas chromatography on different columns and also by gas chromatography coupled with mass spectrometry. These single steps will be separately discussed, and practical problems encountered will be presented.


Cerebellar processing of sensory inputs primes motor cortex plasticity.
Plasticity of the human primary motor cortex (M1) has a critical role in motor control and learning. The cerebellum facilitates these functions using sensory feedback. We investigated whether cerebellar processing of sensory afferent information influences the plasticity of the primary motor cortex (M1). Theta-burst stimulation protocols (TBS), both excitatory and inhibitory, were used to modulate the excitability of the posterior cerebellar cortex and to condition an ongoing M1 plasticity. M1 plasticity was subsequently induced in 2 different ways: by paired associative stimulation (PAS) involving sensory processing and TBS that exclusively involves intracortical circuits of M1. Cerebellar excitation attenuated the PAS-induced M1 plasticity, whereas cerebellar inhibition enhanced and prolonged it. Furthermore, cerebellar inhibition abolished the topography-specific response of PAS-induced M1 plasticity, with the effects spreading to adjacent motor maps. Conversely, cerebellar excitation had no effect on the TBS-induced M1 plasticity. This demonstrates the key role of the cerebellum in priming M1 plasticity, and we propose that it is likely to occur at the thalamic or olivo-dentate nuclear level by influencing the sensory processing. We suggest that such a cerebellar priming of M1 plasticity could shape the impending motor command by favoring or inhibiting the recruitment of several muscle representations.


iDog: an integrated resource for domestic dogs and wild canids.
The domestic dog (Canis lupus familiaris) is indisputably one of man's best friends. It is also a fundamental model for many heritable human diseases. Here, we present iDog (http://bigd.big.ac.cn/idog), the first integrated resource dedicated to domestic dogs and wild canids. It incorporates a variety of omics data, including genome sequences assemblies for dhole and wolf, genomic variations extracted from hundreds of dog/wolf whole genomes, phenotype/disease traits curated from dog research communities and public resources, gene expression profiles derived from published RNA-Seq data, gene ontology for functional annotation, homolog gene information for multiple organisms and disease-related literature. Additionally, iDog integrates sequence alignment tools for data analyses and a genome browser for data visualization. iDog will not only benefit the global dog research community, but also provide access to a user-friendly consolidation of dog information to a large number of dog enthusiasts.


Wave-swept coralliths of Saba Bank, Dutch Caribbean.
During a recent reef coral survey at the submarine Saba Bank (Eastern Caribbean), an uncommon and diverse assemblage of unattached scleractinian corals (coralliths) was encountered, which has not been reported from the Atlantic before. Four different types of these free-living (unattached) corals were distinguished. They were observed on a relatively flat seafloor (15-20 m deep) with poor coral cover and full exposure to oceanic swell. Much of the substratum was not consolidated and consisted mainly of sand and fragments of branching coralline algae. One of the four types is the (1) anthocyathus stage in the life history of the free-living species Manicina areolata and Meandrina danae. The other three are coralliths formed as ecophenotypic varieties: (2) spheroidal-amoeboidal (= globular and (sub)massive) in Porites astreoides, Siderastrea radians, S. siderea, and Stephanocoenia intersepta; (3) tumbleweed-like (= globular and ramose) in Porites divaricata and P. furcata; and (4) discoidal (flat and circular with short branches) in Madracis decactis and possibly in M. cf. auretenra. This assemblage of free-living corals is likely related to a combination of abiotic factors consisting of wave exposure (swell), depths that waves can reach, a horizontal sea floor with little relief, an unconsolidated substratum, and low coral cover.


Towards vaporized molecular discrimination: a quartz crystal microbalance (QCM) sensor system using cobalt-containing mesoporous graphitic carbon.
A recent study on nanoporous carbon based materials (J. Am. Chem. Soc. 2012, 134, 2864) showed that the presence of abundant graphitized sp(2) carbon species in the frameworks led to higher affinity for aromatic hydrocarbons than their aliphatic analogues. Herein, improved understanding of the sensitive and selective detection of aromatic substances by using mesoporous carbon (MPC)-based materials, combined with a quartz crystal microbalance (QCM) sensor system, was obtained. MPCs were synthesized by direct carbonization of mesoporous polymers prepared from resol through a soft templating approach with Pluronic F127. The carbon-based frameworks can be graphitized through the addition of a cobalt source to the precursor solution, according to the catalytic activity of the cobalt nanoparticles formed during the carbonization process. From the Raman data, the degree of the graphitization was clearly increased by increasing the cobalt content and elevating the carbonization temperature. From a QCM study, it was proved that the highly graphitized MPCs exhibited a higher affinity for aromatic hydrocarbons than their aliphatic analogues. By increasing the degree of graphitization in the carbon-based pore walls, the MPCs showed both larger adsorption uptake and faster sensor response towards toxic benzene and toluene vapors.


Uncovering Pharmacological Opportunities for Cancer Stem Cells-A Systems Biology View.
Cancer stem cells (CSCs) represent a small fraction of the total cancer cell population, yet they are thought to drive disease propagation, therapy resistance and relapse. Like healthy stem cells, CSCs possess the ability to self-renew and differentiate. These stemness phenotypes of CSCs rely on multiple molecular cues, including signaling pathways (for example, WNT, Notch and Hedgehog), cell surface molecules that interact with cellular niche components, and microenvironmental interactions with immune cells. Despite the importance of understanding CSC biology, our knowledge of how neighboring immune and tumor cell populations collectively shape CSC stemness is incomplete. Here, we provide a systems biology perspective on the crucial roles of cellular population identification and dissection of cell regulatory states. By reviewing state-of-the-art single-cell technologies, we show how innovative systems-based analysis enables a deeper understanding of the stemness of the tumor niche and the influence of intratumoral cancer cell and immune cell compositions. We also summarize strategies for refining CSC systems biology, and the potential role of this approach in the development of improved anticancer treatments. Because CSCs are amenable to cellular transitions, we envision how systems pharmacology can become a major engine for discovery of novel targets and drug candidates that can modulate state transitions for tumor cell reprogramming. Our aim is to provide deeper insights into cancer stemness from a systems perspective. We believe this approach has great potential to guide the development of more effective personalized cancer therapies that can prevent CSC-mediated relapse.


Hypertension and coronary artery disease in non-insulin dependent diabetes--cause and effect?
There is a log-linear increase in the risk of coronary heart disease with elevation of levels of blood pressure. Allowing for the phenomenon of regression dilution bias, this corresponds to around a 20 to 25% increase in risk for each 5 to 6 mm Hg elevation in usual diastolic blood pressure. In diabetic subjects, a similar relationship occurs, but of somewhat lesser degree. Recent overviews of therapy suggest that in nondiabetics, reducing blood pressure reverses around 50% of the excess coronary heart disease risk, but this has not yet been conclusively shown in patients with diabetes. The reduction in risk with therapy is a prerequisite to defining the antecedent as a causal influence on outcome, but it is as likely that the incomplete reversibility of excess risk represents other pathways of connection between hypertension and coronary heart disease as a consequent of iatrogenic effects of current treatments. Several alternative mechanisms are outlined, and the suggestion is made that only in the context of randomized controlled studies could the possible benefits on coronary heart disease of agents influencing such mechanisms be assessed.


The giant organelles in beige and Chediak-Higashi fibroblasts are derived from late endosomes and mature lysosomes.
Chediak-Higashi Syndrome (CHS) is an autosomal recessive disease affecting secretory granules and lysosomes-like organelles. In CHS fibroblasts, acidic organelles are abnormally large and clustered in the perinuclear area. We have analyzed fibroblast cell lines from a CHS patient and from the murine model for CHS, the beige mouse, to determine which lysosome-like compartments are affected. Uptake of neutral red showed that in both beige and CHS cell lines, the acidic organelles were markedly clustered in the perinuclear region of the cells. Giant organelles (> 4 microns) were observed in a fraction of the cells, and these were more dramatic in the beige fibroblasts than in the CHS fibroblasts. The total dye uptake of both mutant cell lines was similar to their respective wild type fibroblasts, suggesting that the overall volume of acidic compartments is unaffected by the disorder. Histochemistry and immunofluorescence showed that the giant organelles in both beige and CHS fibroblasts were positive for cathepsin D, lysosome-associated membrane protein (LAMP) 1, LAMP 2, and a 120-kD lysosomal glycoprotein, all marker proteins for late endosomes and lysosomes. The giant organelles were also negative for transferrin receptor and mannose-6-phosphate receptor, and most of them were also negative for rab 7. This distribution of marker proteins shows that the giant organelles in both beige and CHS are derived from late compartments of the endocytic pathway. This conclusion was confirmed using endocytic tracers. BSA was transported to the giant organelles, but only after long incubation times, and only at 37 degrees C. alpha 2-Macroglobulin was taken up and degraded at similar rates by CHS or beige cells and their respective wild type control cells. Taken together, our results indicate that the mutation in CHS specifically affects late endosomes and lysosomes, with little or no effect on early endosomes. Although the mutation clearly causes mislocalization of these organelles, it appears to have little effect on their endocytic and degradative functions.


Irradiation of necrotic cancer cells, employed for pulsing dendritic cells (DCs), potentiates DC vaccine-induced antitumor immunity against high-grade glioma.
Dendritic cell (DC)-based immunotherapy has yielded promising results against high-grade glioma (HGG). However, the efficacy of DC vaccines is abated by HGG-induced immunosuppression and lack of attention toward the immunogenicity of the tumor lysate/cells used for pulsing DCs. A literature analysis of DC vaccination clinical trials in HGG patients delineated the following two most predominantly applied methods for tumor lysate preparation: freeze-thaw (FT)-induced necrosis or FT-necrosis followed by X-ray irradiation. However, from the available clinical evidence, it is unclear which of both methodologies has superior immunogenic potential. Using an orthotopic HGG murine model (GL261-C57BL/6), we observed that prophylactic vaccination with DCs pulsed with irradiated FT-necrotic cells (compared to FT-necrotic cells only) prolonged overall survival by increasing tumor rejection in glioma-challenged mice. This was associated, both in prophylactic and curative vaccination setups, with an increase in brain-infiltrating Th1 cells and cytotoxic T lymphocytes (CTL), paralleled by a reduced accumulation of regulatory T cells, tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC). Further analysis showed that irradiation treatment of FT-necrotic cells considerably increased the levels of carbonylated proteins - a surrogate-marker of oxidation-associated molecular patterns (OAMPs). Through further application of antioxidants and hydrogen peroxide, we found a striking correlation between the amount of lysate-associated protein carbonylation/OAMPs and DC vaccine-mediated tumor rejection capacity thereby suggesting for the first time a role for protein carbonylation/OAMPs in at least partially mediating antitumor immunity. Together, these data strongly advocate the use of protein oxidation-inducing modalities like irradiation for increasing the immunogenicity of tumor lysate/cells used for pulsing DC vaccines.


Co-amorphous formation of piroxicam-citric acid to generate supersaturation and improve skin permeation.
The objective of this study was to prepare a co-amorphous formulation of piroxicam (PIR), a non-steroidal anti-inflammatory drug, and citric acid (CA), and evaluate its skin permeation ability. A spray-drying method was employed to prepare the co-amorphous formulation and its physical properties were characterized. X-ray powder diffraction and thermal analysis confirmed a homogeneous amorphous state, and the infrared spectra revealed intermolecular interactions between PIR and CA, suggesting formation of a co-amorphous formulation of PIR and CA. The PIR-CA co-amorphous formulation exhibited no crystallization for 60 days at 4/25/40°C with silica gel. The PIR-CA co-amorphous formulation increased the solubility of PIR in polyethylene glycol 400 compared with that of the pure drug, and physical mixture (PM) of PIR and CA, confirming a supersaturated state in the formulation. The PIR-CA co-amorphous formulation demonstrated higher skin permeation than PIR alone or PM of PIR and CA, and the flux value was consistent with the degree of saturation. Thus, the increase in the skin permeation of PIR from the PIR-CA co-amorphous formulation directly depended on the increased thermodynamic activity by supersaturation in the absence of interactions between the drug and co-former in the vehicle.


[A phase II multicenter study of gemcitabine in non small cell lung cancers].
Gemcitabine is a novel pyrimidine nucleoside whose activity has been demonstrated on solid tumors. We report here the results of a multicentre phase II trial of gemcitabine in chemonaive patients with inoperable non small cell lung cancer (NSCLC). Gemcitabine was given weekly at a dose of 1,250 mg/m2 administered as a 30 min intravenous infusion, for 3 weeks followed by 1 week of rest (1 cycle). All the 161 patients included were evaluable for toxicity and 151 of them were evaluable for efficacy. The majority of patients had a stage IIIb (31.1%) or stage IV (64.6%) disease; 10.6%, 83.2% and 6.2% of patients had a WHO performance status (PS) 0, 1, and 2, respectively. Adenocarcinoma accounted for 52.2% of cases and squamous cell carcinoma for 43.5% of cases. Three complete responses and 30 partial responses gave an objective response (OR) rate of 21.8% (95% confidence interval; 15.5-29.3%). All responses were validated by an independent Oncology Review Board. Median duration of response was 7.6 months. Median time to progression was 4.6 months (3.3 months in non responders and 7.6 months in responders). Median survival was 7.3 months in non responders and 13.4 months in responders (p < 0.001), which gave an overall median survival of 8.9 months (95% CI: 0.1-21.9 months) in the entire study population. An improvement of symptoms and personal state was also observed. Treatment was well tolerated. Neutropenia was the only dose limiting toxicity. WHO grade 3 or 4 neutropenia occurred in 19.6% and 5.7% of patients, respectively. With a 21.8% OR rate, this multicentre study confirms the activity of gemcitabine as a single agent in patients with inoperable NSCLC. Its good tolerance and original mode of action make gemcitabine a drug of choice in the therapeutic strategy of these tumors.


Benzothiazole hydrazones of furylbenzamides preferentially stabilize c-MYC and c-KIT1 promoter G-quadruplex DNAs.
The stabilization of G-quadruplex DNA structures by using small molecule ligands having simple structural scaffolds has the potential to be harnessed for developing next generation anticancer agents. Because of the structural diversity of G-quadruplexes, it is challenging to design stabilizing ligands, which can specifically bind to a particular quadruplex topology. To address this, herein, we report the design and synthesis of three benzothiazole hydrazones of furylbenzamides having different side chains (ligands 1, 2 and 3), which show preferential stabilization of promoter quadruplex DNAs (c-MYC and c-KIT1) having parallel topologies over telomeric and duplex DNAs. The CD melting study revealed that all the ligands, in particular ligand 2, exhibit higher stabilization toward parallel promoter quadruplexes (ΔTm = 10-15 °C) as compared to antiparallel promoter quadruplex (h-RAS1), telomeric quadruplex and duplex DNAs (ΔTm = 0-3 °C). FID assay and fluorimetric titration results also reveal the preferential binding of ligands toward c-MYC and c-KIT1 promoter quadruplex DNAs over telomeric and duplex DNAs. Validating these results further, Taq DNA polymerase stop assay showed IC50∼ 6.4 μM for ligand 2 with the c-MYC DNA template, whereas the same for the telomeric DNA template was found to be >200 μM. Molecular modeling and dynamics studies demonstrated a 1 : 1 binding stoichiometry in which stacking and electrostatic interactions play important roles in stabilizing the c-MYC G-quadruplex structure. Taken together, the results presented here provide new insights into the design of structurally simple scaffolds for the preferential stabilization of a particular G-quadruplex topology.


Taxonomy of the zodiac loaches, Mesonoemacheilus triangularis, M. tambaraparniensis and M. periyarensis, endemic to the Western Ghats of India (Teleostei: Nemacheilidae).
The Nemacheilid loaches, Noemacheilus triangularis tambaraparniensis and Nemacheilus periyarensis have been widely considered to be synonyms of the zodiac loach, Mesonoemacheilus triangularis. An integrative taxonomic investigation based on topotypic material, involving molecular analysis of two mitochondrial genes (cytochrome oxidase subunit 1 and cytochrome b), multivariate morphometric analysis based on non-metric multidimensional scaling and non-parametric multivariate analysis of variance suggests that the three species are in fact distinct.


Modulation of Immune Signaling and Metabolism Highlights Host and Fungal Transcriptional Responses in Mouse Models of Invasive Pulmonary Aspergillosis.
Incidences of invasive pulmonary aspergillosis, an infection caused predominantly by Aspergillus fumigatus, have increased due to the growing number of immunocompromised individuals. While A. fumigatus is reliant upon deficiencies in the host to facilitate invasive disease, the distinct mechanisms that govern the host-pathogen interaction remain enigmatic, particularly in the context of distinct immune modulating therapies. To gain insights into these mechanisms, RNA-Seq technology was utilized to sequence RNA derived from lungs of 2 clinically relevant, but immunologically distinct murine models of IPA on days 2 and 3 post inoculation when infection is established and active disease present. Our findings identify notable differences in host gene expression between the chemotherapeutic and steroid models at the interface of immunity and metabolism. RT-qPCR verified model specific and nonspecific expression of 23 immune-associated genes. Deep sequencing facilitated identification of highly expressed fungal genes. We utilized sequence similarity and gene expression to categorize the A. fumigatus putative in vivo secretome. RT-qPCR suggests model specific gene expression for nine putative fungal secreted proteins. Our analysis identifies contrasting responses by the host and fungus from day 2 to 3 between the two models. These differences may help tailor the identification, development, and deployment of host- and/or fungal-targeted therapeutics.


Air-liquid interface biofilm formation by psychrotrophic pseudomonads recovered from spoilt meat.
The ability to colonise the surface of liquids has obvious advantages for bacteria and biofilm formation at the meniscus and air-liquid (A-L) interface is common amongst environmental pseudomonads. Bacteria from this genus also colonise raw meat and in this work the ability of these to produce biofilms was assessed. Sixty isolates were recovered from vacuum-packed venison, phenotypically characterised and shown by hierarchical cluster analysis to represent a diverse collection of psychrotrophic spoilt venison-associated pseudomonads. Of these, 12 % were found to produce biofilms limited to the meniscus region of the microcosm walls, 31 % produced attached biofilms with significant extensions across the A-L interface and 45 % produced unattached 'floating' biofilms. A combined statistical analysis of growth, biofilm strength and attachment levels revealed that growth affected strength but not attachment, and that there was a significant relationship between attachment and strength. Some environmental pseudomonads are known to utilise cellulose as a biofilm matrix component and here 28 % of the SVP isolates were found to express cellulose by epifluorescent microscopy. This survey suggests that biofilm formation may be more common in psychrotrophic meat-associated isolates than amongst the wider pseudomonad community from which spoilage bacteria might be recruited. This may reflect a selective advantage of bacterial aggregations such as biofilms in environments subject to high levels of physical disturbance. Aggregations may be more resistant to competition and dehydration stress than individual bacteria, whilst fragments of these aggregations may prove more effective in the colonisation of new habitats.


Prior Anterior Cruciate Ligament Reconstruction Effects on Future Total Knee Arthroplasty.
The impact of prior anterior cruciate ligament (ACL) reconstruction on total knee arthroplasty (TKA) has rarely been studied. The objective of this study was to compare intraoperative characteristics in patients who underwent TKA with pre-existing hardware from prior ACL reconstruction with a matched cohort control group. A retrospective study of patients who had undergone primary TKA with pre-existing hardware from prior ACL reconstruction was performed from June 2012 through June 2017. These patients were 2-to-1 matched to the ACL group based on similar patient demographic and provider variables. Outcomes investigated included operative time, estimated blood loss (EBL), and postoperative complications. One hundred one patients met the inclusion/exclusion criteria. The mean age was 54 ± 9 years, and the mean body mass index was 32.6 ± 6.5 kg/m2. The ACL group was divided into 4 subgroups: group 1, no pre-existing hardware removed (22 TKAs); group 2, pre-existing hardware removed from the femur only (8 TKAs); group 3, pre-existing hardware removed from the tibia only (45 TKAs); and group 4, pre-existing hardware removed from both the femur and tibia (26 TKAs). There was no statistical difference in EBL and postoperative complication between the ACL group and controls. Statistical differences were detected between 2 subgroups regarding mean operative time variables: ACL group 3 (74 ± 23 minutes; control: 64 ± 21 minutes, P = .020) and group 4 (79 ± 24 minutes; control: 65 ± 19 minutes, P = .010). Hardware retained, especially on the tibia, from prior ACL reconstruction has a major impact on TKA surgical procedure operative time but not on EBL and/or complications.


Small RNA-induced INTS6 gene up-regulation suppresses castration-resistant prostate cancer cells by regulating β-catenin signaling.
Small RNAs play an important role in gene regulatory networks. The gene suppressive effect of small RNAs was previously the dominant focus of studies, but during the recent decade, small RNA-induced gene activation has been reported and has become a notable gene manipulation technique. In this study, a putative tumor suppressor, INTS6, was activated by introducing a promoter-targeted small RNA (dsRNA-915) into castration-resistant prostate cancer (CRPC) cells. Unique dynamics associated with the gene upregulation phenomenon was observed. Following gene activation, cell proliferation and motility were suppressed in vitro. Downregulation of Wnt/β-catenin signaling was observed during the activation period, and the impairment of β-catenin degradation reversed the tumor suppressor effects of INTS6. These results suggest the potential application of small activating RNAs in targeted gene therapy for CRPC.


Genomewide Study of Salivary MicroRNAs for Detection of Oral Cancer.
MicroRNAs (miRNAs) in human saliva have recently demonstrated to be potential biomarkers for diagnosis purposes. However, lack of well-characterized/matched clinical groups and lack of suitable endogenous control (EC) for salivary extracellular miRNA detection and normalization are among the restrictions of applying salivary-based miRNA biomarker discovery. In the present study, we examined the differential expression pattern of miRNAs among 4 groups of subjects-including patients with oral squamous cell carcinoma (OSCC), patients with OSCC in remission (OSCC-R), patients with oral lichen planus, and healthy controls (HCs)-using a genomewide high-throughput miRNA microarray. First, we systematically screened 10 pooling samples and 34 individual samples of different groups to find a proper EC miRNA. We then investigated the genomewide expression patterns of differentially expressed miRNAs in saliva of different groups using NanoString nCounter miRNA expression assay and real-time quantitative polymerase chain reaction, followed by construction of receiver operating characteristic curves to determine the sensitivity and specificity of the assay. We identified miRNA-191 as a suitable EC miRNA with minimal intergroup and intragroup variability, and we used it for normalization. Of more than 700 miRNAs tested, 13 were identified as being significantly deregulated in saliva of OSCC patients compared to HCs: 11 miRNAs were underexpressed (miRNA-136, miRNA-147, miRNA-1250, miRNA-148a, miRNA-632, miRNA-646, miRNA668, miRNA-877, miRNA-503, miRNA-220a, miRNA-323-5p), and 2 miRNAs were overexpressed (miRNA-24, miRNA-27b). MiRNA-136 was underexpressed in both OSCC vs. HCs and OSCC vs. OSCC-R. MiRNA-27b levels were significantly higher in OSCC patients compared to those found in HCs, patients with OSCC-R, and patients with oral lichen planus and served as a characteristic biomarker of OSCC. Receiver operating characteristic curve analyses showed that miRNA-27b could be a valuable biomarker for distinguishing OSCC patients from the other groups. Our novel findings established a reliable EC miRNA for salivary-based diagnostic and indicate that the salivary miRNA profiles are discriminatory in OSCC patients.


[n]-Oligourea-Based Green Sorbents with Enhanced CO2 Sorption Capacity.
A new series of [n]-oligoureas ([n]-OUs, n=4, 7, 10, and 12) green solid sorbents was prepared following a base-catalyzed, microwave-assisted oligomerization reaction. The materials were characterized by NMR and IR spectroscopy, elemental analysis, thermogravimetric analysis, differential scanning calorimetry, and XRD. Decomposition temperatures at 50 % weight loss (Td50 ) were ca. 350 °C for all oligomers. Urea and urethane functional groups indicated by IR spectroscopy confirmed the formation of the sorbent. The CO2 capturing capacities were determined at 35 °C and 1.0 bar (gravimetric method). Accordingly, [10]-OU had the highest CO2 sorption capacity among the others (18.90 and 22.70 mg CO 2 gsorbent (-1) ) at two different activation temperatures (60 or 100 °C, respectively). Chemisorption was the principal mechanism for CO2 capture. Cyclic CO2 sorption/desorption measurements were carried out to test the recyclability of [10]-OU. Activating the sample at 60 °C, three stable CO2 sorption cycles were achieved after running the first cycle.


[Optimization endoscopy of esophagus pathology on the basis of computerized system of narrow band image segmentation].
In the article possibility of application and results of practical usage colored segmentation narrow band images of esophagus are presented. Algorithm of narrowband endoscopy of upper gastrointestinal tract using automatized pathology discrimination has been developed. Method of automatized discrimination of pathological focus has been carried out during esophagogastroduodenoscopy on 238 patients. Positive increase of diagnostics effectiveness of narrow band endoscopy has been registered in esophagus pathology diagnostics. Statistic analysis of narrow band images esophagus has been carried out. The usage of mathematic modeling has shown the possibility of discrimination of normal and pathological areas for obtaining objective estimation of mucous esophagus condition.


Gastric leiomyosarcoma. Prognostic factors and surgical management.
Information on gastric leiomyosarcoma, such as important prognostic factors, patterns of disease recurrence, and optimal methods of treatment, are derived from limited patient experience. We address these questions, with specific focus on whether an advantage could be demonstrated for radical resection compared with wide local excision, by retrospectively investigating 53 patients who underwent surgical treatment at Mayo Clinic, Rochester, Minn. Abdominal pain and/or gastrointestinal bleeding associated with an intramural or exogastric mass were typical features of this disease. Only tumor size and histologic grade were statistically significant prognostic factors. With analysis of survival curves and patterns of recurrence, neither the addition of lymphadenectomy nor the wider tumor-free margins of a radical gastrectomy seemed superior to the more conservative local excision. Therefore, wide local excision remains the preferred treatment when technically feasible.


Expanding the toolbox of ADHD genetics. How can we make sense of parent of origin effects in ADHD and related behavioral phenotypes?
Genome-wide association (GWA) studies have shown that many different genetic variants cumulatively contribute to the risk of psychiatric disorders. It has also been demonstrated that various parent-of-origin effects (POE) may differentially influence the risk of these disorders. Together, these observations have provided important new possibilities to uncover the genetic underpinnings of such complex phenotypes. As POE so far have received little attention in neuropsychiatric disorders, there is still much progress to be made. Here, we mainly focus on the new and emerging role of POE in attention-deficit hyperactivity disorder (ADHD). We review the current evidence that POE play an imperative role in vulnerability to ADHD and related disorders. We also discuss how POE can be assessed using statistical genetics tools, expanding the resources of modern psychiatric genetics. We propose that better comprehension and inspection of POE may offer new insight into the molecular basis of ADHD and related phenotypes, as well as the potential for preventive and therapeutic interventions.


Integrated Return-To-Field and Targeted Trap-Neuter-Vaccinate-Return Programs Result in Reductions of Feline Intake and Euthanasia at Six Municipal Animal Shelters.
For decades, animal shelters in the U.S. have sought to reduce the number of cats that are impounded and euthanized. Since the 1990s, low-cost sterilization campaigns aimed at owned cats have achieved varying levels of success in meeting these objectives. Over a similar time period, the use of trap-neuter-vaccinate-return (TNVR), as a humane alternative to the lethal management of stray and feral cats, has proliferated. Because of the limited scope of many TNVR programs, the impacts of such efforts on shelter metrics have often proven difficult to measure. In the past decade, two new variants of TNVR, return-to-field (RTF) and high-impact targeting, have exhibited the capacity to contribute to significant reductions in shelter intake and euthanasia. The present study examines changes in feline intake and euthanasia, as well as impacts on associated metrics, at municipal shelters located in six diverse U.S. communities after integrated programs of RTF and targeted TNVR (collectively termed "community cat programs," CCPs) were implemented. A total of 72,970 cats were enrolled in six 3-year CCPs, 71,311 of whom (98%) were sterilized, vaccinated, and returned to their location of capture or adopted. A median reduction of 32% in feline intake, as well as a median decline of 83% in feline euthanasia occurred across the six CCPs; median feline live-release rate increased by 53% as a result of these simultaneous declines in cat admissions and euthanasia. The integration of RTF and targeted TNVR protocols appears to result in greater feline intake and euthanasia reductions than programs lacking such an integrated approach.