Regional and network neural activity reflect men's preference for greater socioeconomic status during impression formation.
Evidence from social psychology suggests that men compared to women more readily display and pursue control over human resources or capital. However, studying how status and gender shape deliberate impression formation is difficult due to social desirability concerns. Using univariate and multivariate fMRI analyses (n = 65), we examined how gender and socioeconomic status (SES) may influence brain responses during deliberate but private impression formation. Men more than women showed greater activity in the VMPFC and NAcc when forming impressions of high-SES (vs. low-SES) targets. Seed partial least squares (PLS) analysis showed that this SES-based increase in VMPFC activity was associated with greater co-activation across an evaluative network for the high-SES versus low-SES univariate comparison. A data-driven task PLS analysis also showed greater co-activation in an extended network consisting of regions involved in salience detection, attention, and task engagement as a function of increasing target SES. This co-activating network was most pronounced for men. These findings provide evidence that high-SES targets elicit neural responses indicative of positivity, reward, and salience during impression formation among men. Contributions to a network neuroscience understanding of status perception and implications for gender- and status-based impression formation are discussed.


Evaluation of chronic toxicity and carcinogenicity of ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate in Sprague-Dawley rats.
Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate, developed for use as a polymerization processing aid in the manufacture of fluoropolymers, was tested for its potential chronic toxicity and carcinogenicity in a 2-year oral dosing study in Sprague-Dawley rats. Male rats were given daily doses of either 0, 0.1, 1 or 50 mg/kg; females were given either 0, 1, 50 or 500 mg/kg. Body weights, food consumption and clinical signs were monitored daily; clinical pathology was conducted at designated intervals and animals were given a complete pathological evaluation after 12 months and 24 months of dosing. Normal survival was seen in all groups, no abnormal clinical signs were seen, and body weight gain was reduced only in female rats at 500 mg/kg. Both sexes at the high dose had mild decreases in red cell mass which were somewhat more pronounced in females. Clinical pathology indicative of liver injury was present in males that received 50 mg/kg and correlated with histomorphological liver changes that included both hypertrophic and degenerative/necrotic lesions. Similar histomorphological lesions were seen in the livers of females at 500 mg/kg. Previous shorter term toxicity studies have identified this chemical as a PPARα agonist and the finding of benign tumors of the liver, pancreas and/or testes in males at 50 mg/kg and females at 500 mg/kg is consistent with the rat response to peroxisome proliferators and is of questionable human relevance. Changes in the kidney, tongue, and stomach were observed only at the highest dose of 500 mg/kg in females. The no-observed-adverse-effect-level in this study lies between 1 and 50 mg/kg for males and between 50 and 500 mg/kg for females.


The effects of postnatal FSH substitution on Sertoli cell number and the sperm production capacity of the adult boar.
The role of FSH for Sertoli cell establishment and sperm production in the boar is not definitely known. In order to elucidate its function FSH was substituted postnatally in male pigs and the resulting effects on testicular histological traits and sperm production capacity were investigated when the boars had reached maturity. Six male piglets received pFSH from 18 to 48 days postnatally. Another six piglets instead received saline and served as controls. Blood samples were drawn to measure FSH, LH, testosterone and estradiol. After 28 weeks, the boars were trained to mount a dummy so that the spermatogenic capacity was tested by increasing the frequency of semen collection at the age of 30 weeks. Libido (latency time) and ejaculate criteria (volume, motility, morphological abnormalities) were determined. Thereafter the boars were killed and their testes analyzed for morphology, number of Sertoli cells, germ cells and Leydig cells as well as the ratio between mitosis and apoptosis in the tubules. FSH concentrations were twofold due to FSH application when compared to the controls. LH was low during the first 2 weeks of FSH treatment. Thereafter concentrations increased in three of the six treated animals but not in controls. Testosterone increased slightly over the application period both in the controls and the treated piglets. Estradiol levels were similar in both groups. Increased ejaculation frequency reduced sperm concentrations and sperm motility in all boars and the percentage of morphologically abnormal sperm increased. Ejaculate volumes and the time of latency were not significantly altered. No differences were observed between the controls and the FSH treated boars. The testicular parameters of both FSH- and control boars were identical for morphology, number of spermatogenic and somatic cells as well as mitosis-apoptosis equilibrium. The data demonstrated that a prolonged postnatal period of FSH concentrations does not influence the sperm production of the adult boar.


Monodisperse Macromolecules by Self-Interrupted Living Polymerization.
Biological macromolecules such as proteins and nucleic acids are monodisperse just as low-molar-mass organic compounds are. However, synthetic macromolecules contain mixtures of different chain lengths, the most uniform being generated by living polymerizations, which exhibit a maximum of 1-3% of chains with the desired length. Monodisperse natural and synthetic oligomers can be obtained in low quantities by tedious, multistep iterative methods. Here we report a methodology to synthesize monodisperse synthetic macromolecules by self-interrupted living polymerization. This methodology relies on a concept that combines supramolecular and macromolecular chemistry and differs from the conventional reactivity principles employed in the synthesis of polymers for over 100 years.


An analysis of endometrial biopsies performed for infertility.
The authors evaluated 774 endometrial biopsies that were performed for infertility. Complications arose in 3.6%. Lag of more than 2 days was found in 19%; luteal phase defect (LPD) was diagnosed in 5.7%. Most of the incidence of LPD can be predicted from chance occurrence. There was no association between abnormal biopsies and basal body temperature patterns, or between pathology, pregnancy outcome, and treatment. Exceptions included women with multiple spontaneous abortions and patients treated with clomiphene citrate (CC). An endometrial biopsy was performed in a pregnancy cycle in 4.0%, with an abortion rate not significantly different from the total study group. The authors conclude that an endometrial biopsy is relatively safe; however, the diagnostic and therapeutic consequences are limited. Endometrial biopsies may be useful only if performed in cases of habitual abortion or ovulation induction with CC.


Incidence, Clinical Characteristics, and Management of Psoriasis Induced by Anti-TNF Therapy in Patients with Inflammatory Bowel Disease: A Nationwide Cohort Study.
Psoriasis induced by anti-tumor necrosis factor-α (TNF) therapy has been described as a paradoxical side effect. To determine the incidence, clinical characteristics, and management of psoriasis induced by anti-TNF therapy in a large nationwide cohort of inflammatory bowel disease patients. Patients with inflammatory bowel disease were identified from the Spanish prospectively maintained Estudio Nacional en Enfermedad Inflamatoria Intestinal sobre Determinantes genéticos y Ambientales registry of Grupo Español de Trabajo en Enfermedad de Croh y Colitis Ulcerosa. Patients who developed psoriasis by anti-TNF drugs were the cases, whereas patients treated with anti-TNFs without psoriasis were controls. Cox regression analysis was performed to identify predictive factors. Anti-TNF-induced psoriasis was reported in 125 of 7415 patients treated with anti-TNFs (1.7%; 95% CI, 1.4-2). The incidence rate of psoriasis is 0.5% (95% CI, 0.4-0.6) per patient-year. In the multivariate analysis, the female sex (HR 1.9; 95% CI, 1.3-2.9) and being a smoker/former smoker (HR 2.1; 95% CI, 1.4-3.3) were associated with an increased risk of psoriasis. The age at start of anti-TNF therapy, type of inflammatory bowel disease, Montreal Classification, and first anti-TNF drug used were not associated with the risk of psoriasis. Topical steroids were the most frequent treatment (70%), achieving clinical response in 78% of patients. Patients switching to another anti-TNF agent resulted in 60% presenting recurrence of psoriasis. In 45 patients (37%), the anti-TNF therapy had to be definitely withdrawn. The incidence rate of psoriasis induced by anti-TNF therapy is higher in women and in smokers/former smokers. In most patients, skin lesions were controlled with topical steroids. More than half of patients switching to another anti-TNF agent had recurrence of psoriasis. In most patients, the anti-TNF therapy could be maintained.


Dephostatin, a novel protein tyrosine phosphatase inhibitor produced by Streptomyces. II. Structure determination.
Dephostatin, a novel tyrosine phosphatase inhibitor, was isolated from the culture broth of Streptomyces sp. MJ742-NF5. The structure was elucidated to be 2-(N-methyl-N-nitroso)hydroquinone by spectral and chemical analyses of dephostatin and its derivatives.


Hypoglycemic flavonoids from Selaginella tamariscina (P.Beauv.) Spring.
Six flavonoids, namely, three undescribed biflavonoids, one undescribed 8-aryl flavonoid, and two known compounds, were isolated from Selaginella tamariscina (P.Beauv.) Spring. The structures and absolute configurations of those undescribed compounds were established by NMR spectroscopy data, HRESIMS analyses and electronic circular dichroism (ECD) analyses. In addition, all the isolates were evaluated for their hypoglycemic activity in HepG2 cells. Involvenflavone H, I, and J significantly increased glucose consumption in both normal and insulin-resistant HepG2 cells. Interestingly, these three compounds can effectively upregulate the protein expression of glucokinase (GCK) and adenylate cyclases (ADCYs). These results suggested that involvenflavone H, I, and J (especially involvenflavone J) may have potent hypoglycemic activity, which also provided promising molecular targets for the treatment of diabetes.


Transcriptome alterations in peripheral blood B cells of patients with multiple sclerosis receiving immune reconstitution therapy.
Multiple sclerosis (MS) is a chronic, inflammatory and neurodegenerative disease that leads to irreversible damage to the brain and spinal cord. The goal of so-called "immune reconstitution therapies" (IRTs) is to achieve long-term disease remission by eliminating a pathogenic immune repertoire through intense short-term immune cell depletion. B cells are major targets for effective immunotherapy in MS. The aim of this study was to analyze the gene expression pattern of B cells before and during IRT (i.e., before B-cell depletion and after B-cell repopulation) to better understand the therapeutic effects and to identify biomarker candidates of the clinical response to therapy. B cells were obtained from blood samples of patients with relapsing-remitting MS (n = 50), patients with primary progressive MS (n = 13) as well as healthy controls (n = 28). The patients with relapsing MS received either monthly infusions of natalizumab (n = 29) or a pulsed IRT with alemtuzumab (n = 15) or cladribine (n = 6). B-cell subpopulation frequencies were determined by flow cytometry, and transcriptome profiling was performed using Clariom D arrays. Differentially expressed genes (DEGs) between the patient groups and controls were examined with regard to their functions and interactions. We also tested for differences in gene expression between patients with and without relapse following alemtuzumab administration. Patients treated with alemtuzumab or cladribine showed on average a > 20% lower proportion of memory B cells as compared to before IRT. This was paralleled by profound transcriptome shifts, with > 6000 significant DEGs after adjustment for multiple comparisons. The top DEGs were found to regulate apoptosis, cell adhesion and RNA processing, and the most highly connected nodes in the network of encoded proteins were ESR2, PHB and RC3H1. Higher mRNA levels of BCL2, IL13RA1 and SLC38A11 were seen in patients with relapse despite IRT, though these differences did not pass the false discovery rate correction. We show that B cells circulating in the blood of patients with MS undergoing IRT present a distinct gene expression signature, and we delineated the associated biological processes and gene interactions. Moreover, we identified genes whose expression may be an indicator of relapse risk, but further studies are needed to verify their potential value as biomarkers.


The incretin hormone GLP-1 and mechanisms underlying its secretion.
Glucagon-like peptide-1 (GLP-1) is a cell type-specific post-translational product of proglucagon. It is encoded by the proglucagon gene and released primarily from intestinal endocrine L-cells in response to hormonal, neuronal, and nutritional stimuli. In addition to serving as an incretin in mediating the effect of meal consumption on insulin secretion, GLP-1 exerts other functions in pancreatic islets, including regulation of β-cell proliferation and protection of β-cells against metabolic stresses. Furthermore, GLP-1 exerts numerous other functions in extrapancreatic organs, whereas brain GLP-1 signaling controls satiety. Herein we review the discovery of two incretins and the development of GLP-1-based drugs. We also describe the development of cellular models for studying mechanisms underlying GLP-1 secretion over the past 30 years. However, the main content of this review is a summary of studies on the exploration of mechanisms underlying GLP-1 secretion. We not only summarize studies conducted over the past three decades on elucidating the role of nutritional components and hormonal factors in regulating GLP-1 secretion, but also present a few very recent studies showing the possible role of dietary polyphenols. Finally, the emerging role of gut microbiota in metabolic homeostasis with the potential implication on GLP-1 secretion is discussed.


Pediatric burns in Western Saudi Arabia.
To conduct a cross-sectional analysis of the demographical, etiological, clinical pattern, and the outcome of pediatric burn injuries. A cross-sectional study of 459 pediatric burn patients admitted to Al-Noor Specialist Hospital in Makkah, Saudi Arabia from January 2008 to December 2010 were evaluated using a structured questionnaire. The mean age was 5.97, and the male to female ratio was 1.5:1. The most common cause was scalding (81.7%). Approximately 92.8% of patients had burn injuries involving 25% of the total body surface area, or less. The mean hospital stay was 9.51 days. Approximately 92% of patients were treated conservatively. Toddlers are at high risk of having scald burns. We also noted the number of admissions is increasing every year. Therefore, an effective scientific based prevention program is required.


Racial Disparities and Upward Trend in Bowel Preparation for Elective Colectomy in the National Surgical Quality Improvement Program Procedure Targeted Dataset: 2012 to 2018.
The primary objective of this study was to assess trends in bowel preparation among patients who had elective colectomy between 2012 and 2018. The secondary objective was to assess patient and procedure-related factors predictive of bowel preparation use or lack thereof. Numerous studies have demonstrated that bowel preparation before elective colorectal surgery can reduce the risk of postoperative complications. Studies of surgeon practices found 75% to 98% prescribe bowel preparation to their patients, although biases in the study design may lead to overestimation of bowel preparation practice. Cross-sectional study of the National Surgical Quality Improvement Program colectomy procedure targeted dataset. We included patients from 18 to 90 years old who underwent elective colectomy (n = 101,096). The primary outcomes were bowel preparation before elective colectomy, including oral antibiotic only, mechanical only, both oral and mechanical, or none. Twenty percent of patients did not do any bowel preparation before elective colectomy. Almost all covariates were independently associated with any bowel preparation, although some were not clinically relevant. The odds that Black/African American or Hispanic patients had any bowel preparation were lower than that of White patients. Additionally, the odds minimally invasive colectomy patients completed any bowel preparation was 1.46 times that of open surgery patients. This study is the first of its kind to assess trends in bowel preparation using an objective dataset. Our study highlights disparities in bowel preparation. Further studies should focus on delineating the root cause of this disparity, identifying the barriers, and finding solutions.


Anti-ulcerogenic effect of chitin and chitosan on mucosal antioxidant defence system in HCl-ethanol-induced ulcer in rats.
The anti-ulcerogenic effect of chitin and chitosan against ulcer induced by HCl-ethanol in male Wistar rats was studied. Levels of acid output, pepsin, protein, lipid peroxides and reduced glutathione and the activity of glutathione peroxidase (GPx), glutathione-S-transferase (GST), catalase (CAT) and superoxide dismutase (SOD) were determined in the gastric mucosa of normal and experimental groups of rats. A significant increase in volume and acidity of the gastric juice was observed in the ulcer-induced group of rats. Peptic activity was significantly decreased as compared with that of normal controls. In the rats pre-treated with chitin and chitosan 2% along with feed, the volume and acid output and peptic activity of gastric mucosa were maintained at near normal levels. The level of lipid peroxidation was significantly higher in the ulcerated mucosa when compared with that of normal controls. This was paralleled by a decline in the level of reduced glutathione and in the activity of antioxidant enzymes like GPx, GST, CAT and SOD in the gastric mucosa of ulcer-induced rats. Also, the levels of mucosal proteins and glycoprotein components were significantly depleted in ulcerated mucosa. The pre-treatment with chitin and chitosan was found to exert a significant anti-ulcer effect by preventing all the HCl-ethanol-induced ulcerogenic effects in experimental rats.


Stereospecificity of (+)-pinoresinol and (+)-lariciresinol reductases from Forsythia intermedia.
Pinoresinol/lariciresinol reductase catalyzes the first known example of a highly unusual benzylic ether reduction in plants; its mechanism of hydride transfer is described. The enzyme was found in Forsythia intermedia and catalyzes the presumed regulatory branch-points in the pathway leading to benzylaryltetrahydrofuran, dibenzylbutane, dibenzylbutyrolactone, and aryltetrahydronaphthalene lignans. Using [7,7'-2H2]-pinoresinol and [7,7'-2H3]lariciresinol as substrates, the hydride transfers of the highly unusual reductase were demonstrated to be completely stereospecific (> 99%). The incoming hydrides were found to take up the pro-R position at C-7' (and/or C-7) in lariciresinol and secoisolariciresinol, thereby eliminating the possibility of random hydride delivery to a planar quinone methide intermediate. As might be expected, the mode of hydride abstraction from NADPH was also stereospecific: using [4R-3H] and [4S-3H]NADPH, it was found that only the 4 pro-R hydrogen was abstracted for enzymatic hydride transfer.


Molecular size of bovine lipoprotein lipase as determined by radiation inactivation.
We have determined the size of the functional unit of bovine lipoprotein lipase by radiation inactivation. This was done in five different situations: 1) in a buffer with high salt concentration. In this situation the enzyme is relatively soluble and stable. 2) For an enzyme-heparin complex. This may reflect the physiological state of the enzyme at the vascular endothelium, where it is believed to be bound to a heparin-like molecule. 3) In the presence of lipid substrate and 4) with lipid substrate and activator protein. Here most of the enzyme is adsorbed to the substrate droplets. 5) For an enzyme-detergent complex; another model for enzyme-lipid interaction. In all five situations the enzyme activity decayed as an exponential function of radiation dose, and the target sizes were similar. The target size did not vary with the concentration of lipase protein. The combined data for bovine lipoprotein lipase yield a functional size of 72 kDa which is close to that expected for a dimer, 77 kDa.


Curcumin attenuates allergic airway inflammation by regulation of CD4+CD25+ regulatory T cells (Tregs)/Th17 balance in ovalbumin-sensitized mice.
The present study aimed to determine the protective effects and the underlying mechanisms of curcumin on ovalbumin (OVA)-induced allergic inflammation in a mouse model of allergic asthma. Asthma mice model was established by ovalbumin. A total of 60 mice were randomly assigned to six experimental groups: control, model, dexamethasone (2 mg/kg), and curcumin (50 mg/kg, 100 mg/kg, 200 mg/kg). Airway resistance (Raw) was measured by the forced oscillation technique, differential cell count in BAL fluid (BALF) was measured by Wright-Giemsa staining, histological assessment was measured by hematoxylin and eosin (HE) staining, BALF levels of Treg/Th17 cytokines were measured by enzyme-linked immunosorbent assay, Treg cells and Th17 cells were evaluated by flow cytometry (FCM). Our study demonstrated that curcumin inhibited OVA-induced increases in eosinophil count; interleukin (IL)-17A level were recovered in bronchoalveolar lavage fluid increased IL-10 level in bronchoalveolar lavage fluid. Histological studies demonstrated that curcumin substantially inhibited OVA-induced eosinophilia in lung tissue. Flow cytometry (FCM) studies demonstrated that curcumin remarkably inhibited Th17 cells and significantly increased Treg cells. The results in vivo show ovalbumin-induced significantly broke Treg/Th17 balance; curcumin treatments markedly attenuated the inflammatory in asthma model by regulating Treg/Th17 balance. Our findings support the possible use of curcumin as a therapeutic drug for patients with allergic asthma.


Increased muscle nucleoside levels associated with a novel frameshift mutation in the thymidine phosphorylase gene in a Spanish patient with MNGIE.
We studied a patient with the cardinal features of mitochondrial gastrointestinal encephalomyopathy (MNGIE). Two of his siblings showed a similar clinical picture. Muscle histochemistry displayed ragged red fibres (RRF) which were COX negative and biochemistry revealed combined defects of complexes III and IV of the mitochondrial respiratory chain. Southern-blot analysis showed multiple mtDNA deletions. Molecular analysis of the ECGF1 gene revealed the presence of a homozygous deletion of 20 base pairs in exon 10, c.1460_1479delGACGGCCCCGCGCTCAGCGG, resulting in a frameshift and synthesis of a protein larger than the wild-type. Thymidine and deoxyuridine accumulation was detected in muscle, indicating loss-of-function of thymidine phosphorylase (TP).


Metabolism of steroid-modifying anticancer agents.
The application of steroid-modifying drugs as a strategy for the treatment of hormone-dependent cancers has gained increasing popularity during the past decade. However, it is important to point out and emphasize that very few of the agents were originally designed for their current application. Most were designed for other purposes, predominantly fertility control (e.g. LHRH agonists and the antiestrogens). Nevertheless, now it is possible to integrate their actions to design rational therapies. There are many reasons for the current interest in antisteroidal drugs. The initial euphoria over the potential ability of combination chemotherapy to cure breast and prostatic carcinoma has proved to be premature. Combination chemotherapy has many severe side-effects which limits patient acceptability, especially if the patient realizes that the likelihood of a cure is remote. In the main, antisteroidal therapies do not have many side-effects and those that do, e.g. aminoglutethimide, are the focus of increased efforts in drug design to produce increased drug specificity. Finally, there is a growing realization that hormone-dependent cancer control with a nontoxic, antisteroidal therapy may be the most acceptable approach currently available for early disease management. Chemotherapy would then be reserved as the final option for treatment. The description of drug metabolism has been central to the development of synthetic LHRH analogs and an understanding of the mode of action of nonsteroidal antiestrogens and antiandrogens. The discovery of steroid synthetic pathways has been essential for the development of the aromatase inhibitors. This whole area of endeavor has now become a major focus of attention for the medicinal chemist. A new generation of agents is entering clinical evaluation which will provide a wealth of valuable information about the successful (or unsuccessful?) methods to control hormone-dependent disease. Since the success or failure of a drug can often depend upon formulation, pharmacokinetics, bioavailability or metabolism, it is our hope that this overview might help solve some of the future problems.


Chronic mesenteric ischemia: evaluation with phase-contrast cine MR imaging.
To compare superior mesenteric artery (SMA) blood flow in healthy volunteers and patients with stenoses in the fasting state and after food intake by using phase-contrast (PC) cine magnetic resonance (MR) imaging. Ten healthy subjects, four asymptomatic patients (three with 50% stenosis, one with 70% stenosis), and one symptomatic patient (with 80% stenosis) were studied. All subjects were studied after fasting at least 8 hours and 15, 30, and 45 minutes after ingesting a standard meal. In healthy volunteers, SMA blood flow at all postprandial intervals increased significantly compared with that obtained after fasting (P < or = .0005). The percentage change in SMA blood flow 30 minutes after food intake provided the best distinction between the healthy subjects, the asymptomatic patients, and the symptomatic patient. Cine PC MR imaging is an effective, noninvasive technique for measuring SMA blood flow.


Meta-analysis of epigenome-wide association studies of major depressive disorder.
Epigenetic mechanisms have been hypothesized to play a role in the etiology of major depressive disorder (MDD). In this study, we performed a meta-analysis between two case-control MDD cohorts to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) in MDD. Using samples from two Cohorts (a total of 298 MDD cases and 63 controls with repeated samples, on average ~ 1.8 samples/subject), we performed an EWAS meta-analysis. Multiple cytosine-phosphate-guanine sites annotated to TNNT3 were associated with MDD reaching study-wide significance, including cg08337959 (p = 2.3 × 10-11). Among DMPs with association p values less than 0.0001, pathways from REACTOME such as Ras activation upon Ca2+ influx through the NMDA receptor (p = 0.0001, p-adjusted = 0.05) and long-term potentiation (p = 0.0002, p-adjusted = 0.05) were enriched in this study. A total of 127 DMRs with Sidak-corrected p value < 0.05 were identified from the meta-analysis, including DMRs annotated to TNNT3 (chr11: 1948933 to 1949130 [6 probes], Sidak corrected P value = 4.32 × 10-41), S100A13 (chr1: 153599479 to 153600972 [22 probes], Sidak corrected P value = 5.32 × 10-18), NRXN1 (chr2: 50201413 to 50201505 [4 probes], Sidak corrected P value = 1.19 × 10-11), IL17RA (chr22: 17564750 to 17565149, Sidak corrected P value = 9.31 × 10-8), and NPFFR2 (chr4: 72897565 to 72898212, Sidak corrected P value = 8.19 × 10-7). Using 2 Cohorts of depression case-control samples, we identified DMPs and DMRs associated with MDD. The molecular pathways implicated by these data include mechanisms involved in neuronal synaptic plasticity, calcium signaling, and inflammation, consistent with reports from previous genetic and protein biomarker studies indicating that these mechanisms are involved in the neurobiology of depression.


The association between non-motor symptoms in Parkinson's disease and age at onset.
Age at onset is likely to be related to a wide range of problems in Parkinson's disease (PD), including cardinal motor features, motor complications and non-motor symptoms (NMS). This study investigated the effect of the age at onset on NMS. Two hundred and thirty patients were examined and classified into one of three groups based on age at onset: early onset PD (EOPD) group (<45 years), middle-age onset group (45-64 years) and old-age onset group (≥65 years). The trends relating to NMS were compared across the three groups. The EOPD and old-age onset groups were separately studied to determine their association to the appearance of non-motor features using logistic regression analysis. There were upward trends in the occurrence of dribbling (P=0.009; all P values are stated for trend), impaired taste/smelling (P=0.016), constipation (P=0.006), urinary urgency (P=0.002), nocturia (P=0.018), hallucinations (P=0.016) and acting out during dreams (P=0.011) with the increase of age at onset. Older age at onset is an independent risk factor for dementia (OR=8.42, CI 3.16-22.44), dribbling (OR=4.14, CI 1.93-8.87), impaired taste/smelling (OR=2.23, CI 1.20-4.13), constipation (OR=3.42, CI 1.88-6.24), incomplete bowel emptying (OR=2.23, CI 1.19-4.20), urinary urgency (OR=2.58 CI 1.46-4.57), nocturia (OR=2.65, CI 1.49-4.71), hallucinations (OR=5.32, CI 1.78-15.97), dizziness (OR=3.03, CI 1.59-5.79), falling (OR=3.60, CI 1.67-7.77), insomnia (OR=2.29, CI 1.28-4.11), intense vivid dreaming (OR=2.10, CI 1.21-3.66) and acting out during dreams (OR=2.23, CI 1.24-4.01). PD patients with different ages at onset present clinically different symptoms in terms of NMS. Old-age onset PD is characterized by more olfactory and sensory symptoms, autonomic symptoms, sleep disorders, dementia and psychosis compared to EOPD.


Snoring patterns during home polysomnography. A proposal for a new classification.
Snoring is a very common disorder, but, at present, there is no universally accepted classification for the condition. The main aim of this paper is to introduce a home sleep monitoring-based classification of common snoring patterns in simple snorers and in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). In total, 561 consecutive patients with a history of snoring, either simple or associated with apnea, were enrolled in this home sleep monitoring study. Analysis of the polysomnographic traces and the snoring sensor allowed the main patterns of snoring and their characteristics to be determined. Four patterns of snoring were identified. In a spectrum of increasing severity (mild, moderate or severe), snoring can be episodic, positional, continuous, or alternating, whereas in obstructive sleep apnea syndrome, the snoring events only occur between successive respiratory obstructive events. In mild snoring, the episodic pattern is the most frequent, whereas in moderate and severe snoring, the continuous snoring pattern occurs in most cases. The proposed classification of snoring patterns would be beneficial for providing a realistic disturbance index, for the selection and evaluation of the outcomes of surgical techniques.


Stereotactically guided fractionated re-irradiation in recurrent glioblastoma multiforme.
To assess the feasibility, efficacy and toxicity of fractionated stereotactic radiotherapy in the treatment of recurrent glioblastoma multiforme. From January 1995 to July 2003, 53 patients with histologically proven glioblastoma multiforme were treated at recurrence with fractionated stereotactic radiation therapy. A median dose of 36 Gy using a median fractionation of 5 x 2 Gy/week was applied. Median overall survival was 21 months, and median overall survival from the time point of re-irradiation was 8 months. The median time interval between primary and secondary radiation therapy was 10 months. In this patient population, no variables predicting longer overall survival could be determined. However, neurosurgical resection at relapse was associated with increased survival after re-irradiation (p=0.04), but left progression-free survival unaltered. Treatment was well-tolerated and no severe toxicities developed. Stereotactically guided fractionated re-irradiation is a safe and effective treatment modality in selected cases of recurring glioblastoma multiforme. Since this is not a randomized study, further evaluation in larger patient collectives is warranted. Also, based on recent results of radiochemotherapy in the treatment of primary glioblastoma multiforme, concomitant chemotherapy at relapse might be considered in the future.


Functional atropine sensitive purinergic responses in the healthy rat bladder.
While acetylcholine is regarded to be the main directly contractile transmitter substance in the urinary bladder, interactions with other transmitters likely occur. Presently, the interplay between purinergic and cholinergic signalling was investigated to unravel the involvement of the urothelium and efferent neurons in the functionally important purinergically evoked release of acetylcholine in vitro. Functional characterization of receptor subtypes involved in this interplay was also performed. In vitro organ bath experiments with electrical field stimulation (EFS) or administration of agonist were performed in the absence and presence of the neurotoxin tetrodotoxin (TTX; 5 × 10-7 M) and/or receptor antagonists, in intact and urothelium-denuded full thickness rat bladder strip preparations. Interestingly, functional contractions to ATP (10-6-10-3 M) remained unaffected by TTX, but were significantly lowered in the presence of the muscarinic antagonist atropine (10-6 M). However, in urothelium-denuded strip preparations, this latter phenomenon was not present and the ATP response remained unaltered. To rule out purinergic interference caused by break-down of ATP, experiments were performed in which the stable ATP-analogue αβMeATP (10-7-10-5 M) gave rise to functional atropine-sensitive contractions. Furthermore, contractions to ATP were not affected by P2Y6 purinoceptor blockade (by MRS2578; 10-7, 10-5 M), nor were relaxatory responses to ATP sensitive to atropine, PPADS (3 × 10-5 M) or αβMeATP. Lastly, relaxations to ADP (10-6-10-3 M) or NECA (10-8-10-5 M) were unaltered by the presence of atropine. To conclude, purinergic functional contractile, but not relaxatory, responses are supported by the cholinergic transmitter system in vitro, through non-neuronal mechanisms in the urothelium. Involved purinoceptors are of the P2X-subtype, most likely P2X1 and/or P2X3.


Mechanism of PEDF promoting the proliferation of lens epithelial cells in human eyes.
To investigate the regulation effect of pigment epithelium-derived factor (PEDF) on the growth of human lens endothelial cells (LECs) and related mechanisms in vivo and in vitro. In the part of in vivo study, 82 eyes of 82 patients with age-related cataract were included to collect the central lens anterior capsule (diameter at 5.0-5.5 mm) with the informed consent of surgery for patients. The selected specimens were divided into the LECs low density group and high density group with 20 specimens for each group based on hematoxylin and eosin staining results. The relative expression level of PEDF mRNA in LECs was detected by reverse transcription PCR. In the part of in vitro study, LEC line (HLE-B3) was cultured and 50 ng/mL PEDF was added in media for 72 h in PEDF culture group, while normally cultured cells were used as the control group. The percentage of LECs at G0 and S phases and apoptotic rate of cells were assayed by using flow cytometry with annexin Ⅴ-FITC/7-AAD double staining method. Intracellular expression of vascular endothelial growth factor (VEGF) mRNA was detected by real-time fluorescence quantitative PCR. The central anterior subcapsular LECs density and relative expression level of PEDF mRNA were lower than those of high density group. There were no significant differences between two groups (P = 0.168). The apoptotic rate in the PEDF culture group was significantly reduced in comparison with the control group (P < 0.001). In addition, the expression level of VEGF mRNA was lower in the PEDF culture group compared with the control group (P < 0.001). In human eyes, PEDF may function as cytotropic factor to promote survival of LECs through anti-apoptosis and reducing-expression of VEGF. Decrease of PEDF content in LECs probably modulates the pathophysiological process of lens cells and further cataractogenesis.


Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy.
The paradigm of a single gene associated with one specific phenotype and mode of inheritance has been repeatedly challenged. Genotype-phenotype correlations can often be traced to different mutation types, localization of the variants in distinct protein domains, or the trigger of or escape from nonsense-mediated decay. Using whole-exome sequencing, we identified homozygous variants in EMC1 that segregated with a phenotype of developmental delay, hypotonia, scoliosis, and cerebellar atrophy in three families. In addition, a de novo heterozygous EMC1 variant was seen in an individual with a similar clinical and MRI imaging phenotype. EMC1 encodes a member of the endoplasmic reticulum (ER)-membrane protein complex (EMC), an evolutionarily conserved complex that has been proposed to have multiple roles in ER-associated degradation, ER-mitochondria tethering, and proper assembly of multi-pass transmembrane proteins. Perturbations of protein folding and organelle crosstalk have been implicated in neurodegenerative processes including cerebellar atrophy. We propose EMC1 as a gene in which either biallelic or monoallelic variants might lead to a syndrome including intellectual disability and preferential degeneration of the cerebellum.


Neurophysiological evaluation of sexual dysfunction in patients operated for colorectal cancer.
Sexual dysfunction after colorectal cancer surgery may be severe and occurs in 25% to 100% of cases. Thirty-eight patients underwent colorectal resection; eight (21%) who were totally impotent and two (5%) who had ejaculatory failure were therefore studied to better understand the neurophysiological alterations related to this type of surgery. The patients were evaluated after surgery with electrophysiological testing, including examination of the sacral reflex (SR), pudendal somatosensory evoked potential (PEP), and motor evoked potential (MEP) responses. Sudomotor skin response (SSR) was also studied in a group of patients. Of the 38 patients studied, 29 showed abnormalities: six of SR, three of PEP, six of MEP, and fourteen of SSR. Only a combination of all these tests permits correct evaluation of the sexual dysfunction.


Water Recovery Rate in Short-Circuited Closed-Cycle Operation of Flow-Electrode Capacitive Deionization (FCDI).
While flow-electrode CDI is a promising desalination technology that has major advantages when the electrodes are operated in the short-circuited closed-cycle (SCC) mode, little attention has been paid to the water recovery rate, which, in the SCC mode, is determined by the need for partial replacement of the saline electrolyte of the flow electrodes. Results of this study show that an extremely high water recovery rate of ∼95% can be achieved when desalting a 1000 mg NaCl L-1 brackish influent to a potable level of 150 mg L-1. The improved performance with regard to the electrical cost is related, at least in part, to the alleviated concentration polarization at the membrane/electrolyte interface during electrosorption. In effect, the current efficiency decreases with an increase in the water recovery rate. This finding is ascribed to inevitable co-ion leakage since the flow electrodes reject ions with the same charge. In addition, water transport across the ion exchange membranes also influences the water recovery rate. The effect of partial replacement of the saline electrolyte during (semi-)continuous operation requires particular consideration because the associated dilution of the carbon content in the flow electrodes results in a decrease in process performance.


Influence of talent retention strategy on employees׳ attitude to work: Analysis of survey data.
In this data article, an analysis on the strategies for talent retention in Covenant University and the corresponding effects on employees' attitude to work was presented. The study population included the academic staff of Covenant University, which has a population of 530 employees, but a sample size was determined using Yamen׳s formula. The data obtained through survey questionnaires were analysed using Statistical Package for Social Sciences (SPSS). Linear regression was used to model the effect of talent retention strategy on employees' attitude to work. This information is made publicly available to aid empirical researches on the subject of talent management in organizations.


Calcium-permeable AMPA receptors are essential to the synaptic plasticity induced by epileptiform activity in rat hippocampal slices.
Abnormal neuronal activity during epileptic seizures alters the properties of synaptic plasticity, and, consequently, leads to cognitive impairment. The molecular mechanism of these alterations in synaptic plasticity is still unclear. In the present study, using a 4-aminopyridine (4-AP) in vitro model, we demonstrated that epileptiform activity in rat hippocampal slices initially causes substantial enhancement of field excitatory postsynaptic potential amplitude. However, the potentiation of CA3-CA1 synapses was temporary and switched to long-term depression (LTD) within an hour. Previous studies showed that transient incorporation of calcium-permeable AMPA receptors (CP-AMPARs) is crucial for the consolidation of long-term potentiation (LTP). We confirmed that, in normal conditions, the blockage of CP-AMPARs prevented the consolidation of LTP induced by theta-burst stimulation (TBS). In contrast, the blockage of CP-AMPARs preserved synaptic potentiation induced by epileptiform activity. One hour after a period of epileptiform activity in the hippocampal slices, synaptic plasticity was substantially altered, and the TBS protocol was unable to produce LTP. Moreover, if CP-AMPARs were blocked, the TBS protocol induced LTD. Our results indicate that CP-AMPARs play an essential role in the molecular mechanism of the disturbances of synaptic plasticity caused by epileptiform activity.


Hyperemesis gravidarium: Epidemiologic findings from a large cohort.
This study was undertaken to quantify the frequency, clinical course, charges, and outcomes of hyperemesis gravidarum. California birth certificate data linked with maternal and neonatal hospital discharge data in 1999 were used (N=520,739). Hyperemesis was defined by ICD-9 codes. The frequency, estimated charges, and demographic characteristics associated with hyperemesis patients were assessed. Maternal and neonatal perinatal outcomes were compared by maternal hyperemesis status. Hyperemesis complicated 2,466 of 520,739 births. The average length of stay was 2.6 days and the average charge was $5,932. Singleton hyperemesis infants were smaller (3,255 vs 3,380 g; P < .0001 and more likely to be small for gestational age (29.21% vs 20.8%; P < .0001). Hyperemesis occurs in 473 of 100,000 live births and is associated with significant charges. Infants of mothers with hyperemesis have lower birth weights and the mothers are more likely to have infants that are small for gestational age.


Differential expression of cancer-related genes by single and permanent exposure to bone morphogenetic protein 2.
Bone morphogenetic proteins (BMPs) are multifunctional regulators of various cell functions. The BMP-signalling network plays a pivotal role during embryogenesis and tumorigenesis. BMPs, e.g. BMP-2 exert their biological function in a time and concentration-dependent manner but also modulated by the context of the cellular microenvironment. In this study, we investigated the effect of a steady high level of BMP-2 versus a single application of BMP-2 on the breast cancer cell line MCF-7. The effect of the incubation regimes was analysed by DNA microarray expression profiling. Data were verified by real-time PCR. The protein expression of apoptosis-related genes was studied by western blot analysis. We found a clear difference in the altered gene expression between the constant high level and the single application of BMP-2. After grouping the genes of interest into the biological processes of Gene Ontology, the group of apoptosis-related genes like BAX, BAG5 or PKR, was predominantly affected under the single-application regime of BMP-2. Among these protein kinase R was the most prominently regulated. Further studies on the protein level showed activation of PKR after 4 h with a subsequent enhanced phosphorylation of the PKR substrate eIF2alpha for several hours. The duration of treatment and the concentration of BMP-2 affect the global expression pattern of MCF-7 cells. Among the regulated cancer-related genes, the cohort of the apoptosis-related genes showed the pronounced alterations. Our data point to a novel role of BMP-2 in the regulation of the PKR pathway in tumorigenesis.


CdGAP maintains podocyte function and modulates focal adhesions in a Src kinase-dependent manner.
Rho GTPases are regulators of the actin cytoskeleton and their activity is modulated by GTPase-activating proteins (GAPs) and guanine nucleotide exchanging factors (GEFs). Glomerular podocytes have numerous actin-based projections called foot processes and their alteration is characteristic of proteinuric kidney diseases. We reported previously that Rac1 hyperactivation in podocytes causes proteinuria and glomerulosclerosis in mice. However, which GAP and GEF modulate Rac1 activity in podocytes remains unknown. Here, using a proximity-based ligation assay, we identified CdGAP (ARHGAP31) and β-PIX (ARHGEF7) as the major regulatory proteins interacting with Rac1 in human podocytes. CdGAP interacted with β-PIX through its basic region, and upon EGF stimulation, they both translocated to the plasma membrane in podocytes. CdGAP-depleted podocytes had altered cell motility and increased basal Rac1 and Cdc42 activities. When stimulated with EGF, CdGAP-depleted podocytes showed impaired β-PIX membrane-translocation and tyrosine phosphorylation, and reduced activities of Src kinase, focal adhesion kinase, and paxillin. Systemic and podocyte-specific CdGAP-knockout mice developed mild but significant proteinuria, which was exacerbated by Adriamycin. Collectively, these findings show that CdGAP contributes to maintain podocyte function and protect them from injury.


To treat or not to treat? Current attitudes on treatment aimed at modifying the disease burden in clinically suspect arthralgia: a survey among participants of the TREAT EARLIER trial and healthcare professionals.
While awaiting therapies accomplishing rheumatoid arthritis (RA)-prevention in individuals at-risk, recent evidence supports that a 1-year methotrexate treatment may lead to sustained reduction in disease burden and subclinical joint inflammation in patients with clinically suspect arthralgia (CSA). We aimed to study the previously unexplored attitudes of CSA patients and rheumatologists on 1-year DMARD treatment in the arthralgia phase to reduce the disease burden, while not preventing RA. CSA patients who participated in the TREAT EARLIER trial, thus being expert by experience, were informed on the trial results. Thereafter they completed an anonymous questionnaire about their attitudes on treatment in the CSA phase. We used the same approach for Dutch healthcare professionals in rheumatology. The majority of trial participants (85%) considered the effects of the 1-year treatment as found in the TREAT EARLIER trial, beneficial in the symptomatic at-risk stage. 79% would recommend a 1-year methotrexate course to others with comparable joint complaints. Two-thirds indicated RA prevention and improving disease burden to be equally important treatment goals in the CSA phase. Most healthcare professionals (88%) were inclined to prescribe 1-year treatment to CSA patients aimed at long-term improvement of symptoms and functioning, while not preventing RA development. 59% believed the profits of a 1-year methotrexate course to outweigh disadvantages, for example, side effects. A considerable willingness exists among CSA patients and rheumatologists to start a 1-year treatment resulting in long-term improvement of symptoms and functioning, while not preventing RA. This emphasises the need for more research optimising treatment regimens and disease monitoring in individuals at-risk to facilitate such treatment decisions in the future, while avoiding an intervention, either limited or for a prolonged period, which may have harms that outweigh benefits. The Netherlands Trials Registry (NTR4853-trial-NL4599). EudraCT number: NL2014-004472-35.


Radiation-induced cystitis following intracavitary irradiation for superficial bladder cancer.
Intracavitary irradiation is effective in the treatment of noninvasive papillary transitional cell carcinoma and carcinoma in situ of the bladder. Mortality has not been associated with this form of therapy. The morbidity associated with intracavitary irradiation consists of mild to severe radiation cystitis and we report 2 such cases. One patient is from a series of 65 patients with noninvasive bladder tumors treated with intracavitary irradiation at this clinic since 1965. The second patient had noninvasive bladder tumors and was treated with intracavitary irradiation elsewhere. In both patients severe radiation cystitis subsequently developed, requiring simple cystectomy and urinary diversion. The potential for this serious side effect must be considered when choosing a form of therapy for patients with noninvasive papillary transitional cell carcinoma and carcinoma in situ of the bladder.


Early tactile stimulation influences the development of Alzheimer's disease in gestationally stressed APP NL-G-F adult offspring NL-G-F/NL-G-F mice.
Alzheimer's disease (AD) is associated with cerebral plaques and tangles, reduced synapse number, and shrinkage in several brain areas and these morphological effects are associated with the onset of compromised cognitive, motor, and anxiety-like behaviours. The appearance of both anatomical and behavioural symptoms is worsened by stress. The focus of this study was to examine the effect of neonatal tactile stimulation on AD-like behavioural and neurological symptoms on APP NL-G-F/NL-G-F mice, a mouse model of AD, who have been gestationally stressed. Our findings indicate that neonatal tactile stimulation improves cognition, motor skills, and anxiety-like symptoms in both gestationally stressed and non-stressed adult APP mice and that these alterations are associated with reduced Aβ plaque formation. Thus, tactile stimulation appears to be a promising non-invasive preventative strategy for slowing the onset of dementia in aging animals.


Expression of the genes encoding basic fibroblast growth factor and its receptor in human granulosa cells.
The role of basic fibroblast growth factor (bFGF) in granulosa cell ontogeny has been previously demonstrated. In this study we evaluated the possible intraovarian origin of bFGF. Human granulosa cells were maintained in primary culture and their cytoplasmic extract was purified by affinity chromatography on a heparin-sepharose column. The column was then eluted with 10 mM Tris-HCl containing increasing concentrations of NaCl. The chromatographic fractions were tested in a bioassay using bovine adrenal capillary endothelial cells (ACE) as targets. A peak of mitogenic activity was detected in the fraction eluted with the highest salt concentration. This chromatographic profile is similar to that of bFGF. The in situ synthesis of this bFGF-like protein was then demonstrated by reverse transcription-polymerase chain reaction. Using oligonucleotide primers specific for the bFGF gene, a single major band of DNA, corresponding to the expected size, was amplified. The identity of this fragment with the bFGF corresponding sequence was further demonstrated by restriction enzyme analysis. Moreover, RT-PCR was also employed to amplify a DNA band specific for the bFGF receptor gene. These data indicate that human granulosa cells are able to synthesize both bFGF and its receptor and, thus, bFGF might participate to the autocrine mechanisms regulating their growth and differentiated functions.


Effect of curcumin on the interaction between androgen receptor and Wnt/β-catenin in LNCaP xenografts.
Curcumin is a nontoxic, chemopreventive agent possessing multifaceted functions. Our previous study showed that curcumin inhibits androgen receptor (AR) through modulation of Wnt/β-catenin signaling in LNCaP cells. Therefore, we investigated the in vivo effects of curcumin by using LNCaP xenografts. LNCaP cells were subcutaneously inoculated in Balb/c nude mice. When the tumor volume reached greater than 100 mm(3), either curcumin (500 mg/kg body weight) or vehicle was administered through oral gavage three times weekly for 4 weeks. The expression of AR and intermediate products of Wnt/β-catenin were assessed. Curcumin had an inhibitory effect on tumor growth during the early period, which was followed by a slow increase in growth over time. Tumor growth was delayed about 27% in the curcumin group. The mean prostate-specific antigen (PSA) doubling time in the curcumin group was approximately twice that in the untreated group. Curcumin significantly decreased AR expression at both the mRNA and protein level. The PSA levels tended to be reduced in the curcumin group. However, there were no significant changes in expression of Wnt/β-catenin pathway intermediates. This study revealed that curcumin initially interferes with prostate cancer growth by inhibiting AR activity and possibly by reducing PSA expression. Further research is needed to investigate the plausible mechanism of the antiandrogenic action of curcumin.


Effects of intravenous infusion of a ten percent soybean emulsion on hormones, amino acids and other substrates in blood.
Acute responses in hormone and substrate concentrations to intravenous administration of a fat emulsion were studied in metabolically normal subjects. Eight subjects were infused with either a fat emulsion or an aqueous solution of glycerol for 3 h. Serum triglycerides (TG), free fatty acids (FFA), glucose, glycerol, 3-hydroxybutyrate (3-OH butyrate), insulin, thyroid hormones, plasma glucagon, norepinephrine, and amino acids were measured. The infusion of a fat emulsion induced a 30% increase in glucose and a 22% decrease in alanine together with significant elevations of TG (> 10 mM) and FFA (> 1 mM). A small increase in insulin (4 microU/ml) and a reduction in glucagon (40 pg/ml) were observed. Eight-fold increases in glycerol occurred with both the fat emulsion and glycerol infusions. The administration of a fat emulsion resulted in a 4-fold increase in 3-OH butyrate, whereas glycerol infusion reduced its level by 50%. Glycerol infusion produced no measurable effects on the substrates other than glycerol or 3-OH butyrate. No significant changes were observed in thyroid hormones or norepinephrine after either solution was given. The data suggest that acute elevation of FFA by means of intravenous fat emulsions leads to preferential oxidation of FFA and stimulates hepatic ketogenesis with resulting glucose conservation as well as inhibition of alanine production without many alterations in hormonal concentrations.


Demethylating agent decitabine disrupts tumor-induced immune tolerance by depleting myeloid-derived suppressor cells.
The immunoregulatory effect of demethylating agent decitabine (DAC) has been recognized recently. However, little is known about its impact on immune tolerance. In this study, we aimed to determine the impact of DAC on the immune tolerance induced by tumor cells. The effects of DAC on immune cells in vivo were measured by flow cytometry. Myeloid-derived suppressor cells (MDSCs) were sorted using magnetic beads and cultured in vitro. The mixed lymphocyte reaction was used to determine the immunoregulatory effect of DAC in vitro. An adoptive transfusion mouse model was established to evaluate the effect in vivo. We found that DAC treatment significantly depleted MDSCs in vivo by inducing MDSCs apoptosis. When given at a low dose, the immune effector cells were less affected by the treatment, except for MDSCs. The mixed lymphocyte reaction in vitro showed that T-cell responses were enhanced when MDSCs were depleted. Supplementation of MDSCs would attenuate this T-cell activation effect. Using an adoptive transfusion mouse model, we further demonstrated in vivo that DAC treatment could induce autologous anti-tumor immune response by depleting MDSCs. This study is the first to illustrate DAC's immunoregulatory effect on immune tolerance. The disruption of immune tolerance is due to MDSCs depletion that induces an autologous immune response in vivo. By depleting MDSCs, DAC treatment removes one of the obstacles affecting anti-tumor immune activation and warrants further experimental and clinical studies to explore its potential utility in combination with various anti-tumor immunotherapies in the future.


Paracetamol toxicity in classic homocystinuria: Effect of N-acetylcysteine on total homocysteine.
Classical homocystinuria (HCU) is caused by cystathionine β-synthase deficiency leading to impaired homocysteine transsulfuration and accumulation of homocysteine and methionine. Patients present with a wide spectrum of manifestations including ocular, skeletal, neuropsychiatric, and vascular manifestations. We report a 48-year-old female with pyridoxine-unresponsive HCU treated with betaine, cyanocobalamin, and folate. Her diet was non-restricted due to intolerance of low-methionine diet. She was admitted to hospital following a fall, with multiple fractures and subsequently developed acute liver failure with encephalopathy. Shock, sepsis, and liver ischaemia/thrombosis were excluded. In the context of glutathione depletion expected in HCU, hepatic dysfunction was presumed to be due to iatrogenic paracetamol toxicity, despite paracetamol intake at conventional therapeutic dose, with role of hypermethioninemia as a contributing factor being uncertain. Betaine was discontinued on hospital admission. N-Acetylcysteine (NAC) infusion was initiated. Plasma total homocysteine (tHcy) was 3.4 μmol/L 9 days following initiation of NAC treatment with a markedly elevated plasma methionine of 1278 μmol/L. tHcy concentration returned to pre-admission baseline after NAC was discontinued. Recovery following this episode was slow with a prolonged cholestatic phase and gradual improvement in jaundice and coagulopathy. We recommend that paracetamol should be administered cautiously in HCU patients due to underlying glutathione depletion and risk of toxicity even at therapeutic doses. NAC is clearly effective in lowering tHcy in classical HCU in the short-term however further research is required to assess clinical efficacy and use as a potential therapy in classical HCU.


High-order random Raman lasing in a PM fiber with ultimate efficiency and narrow bandwidth.
Random Raman lasers attract now a great deal of attention as they operate in non-active turbid or transparent scattering media. In the last case, single mode fibers with feedback via Rayleigh backscattering generate a high-quality unidirectional laser beam. However, such fiber lasers have rather poor spectral and polarization properties, worsening with increasing power and Stokes order. Here we demonstrate a linearly-polarized cascaded random Raman lasing in a polarization-maintaining fiber. The quantum efficiency of converting the pump (1.05 μm) into the output radiation is almost independent of the Stokes order, amounting to 79%, 83%, and 77% for the 1(st) (1.11 μm), 2(nd) (1.17 μm) and 3(rd) (1.23 μm) order, respectively, at the polarization extinction ratio >22 dB for all orders. The laser bandwidth grows with increasing order, but it is almost independent of power in the 1-10 W range, amounting to ~1, ~2 and ~3 nm for orders 1-3, respectively. So, the random Raman laser exhibits no degradation of output characteristics with increasing Stokes order. A theory adequately describing the unique laser features has been developed. Thus, a full picture of the cascaded random Raman lasing in fibers is shown.


Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections.
A diverse and well-balanced repertoire of T cells is thought to be crucial for the efficacious defence against infection with new or re-emerging pathogens throughout life. In the last third of the mammalian lifespan, the maintenance of a balanced T-cell repertoire becomes highly challenging because of the changes in T-cell production and consumption. In this Review, I question whether latent persistent pathogens might be key factors that drive this imbalance and whether they determine the extent of age-associated immune deficiency.


Health locus of control among patients operated on for colorectal cancer.
Introduction: An important factor determining health-oriented behavior is the health locus of control (HLC). Patients with cancer differ in health practices and perception of the disease.
Aim: Assessment of the influence of demographic factors and somatic symptoms of the disease on HLC in patients treated for colorectal cancer.
Materials and methods: The study included 160 people divided into patients with colorectal cancer (CRC) and healthy people. The Multidimensional Health Locus of Control Scale was used in the adaptation of Z. Juczyński. The scale includes three dimensions of health perception, which depends on internal control, impact of others and random.
 Results: The study group consisted of 80 patients with CRC (51.2% women), and the control group 80 healthy people (57.7% women). In our analysis, we found that people with CRC were significantly more dependent on their own health control on the influence of external factors, such as doctors and nurses, than healthy people (27.11±5.43 vs. 19.64±7.77; p=<0.001). Similarly, patients with CRC significantly more than healthy people considered random as a dimension responsible for HLC (23.05±5.95 vs 20.36±7.45; p=0.012). Men with CRC more than women conditioned HLC on random influence (24.21±5.94 vs. 21.95±5.91; p=0.044). People with secondary and higher education made the HLC more dependent on internal control (26.98±5.98 vs. 23.14±5.74; p=0.041).
Conclusions: Patients with CRC made their sense of health control dependent on external dimensions: influence of others and random. Men with CRC were more likely to condition their health control on random events than women. Secondary and higher education guaranteed greater autonomy in undertaking health behaviors.


One-pot synthesis of benzo[c]carbazoles by photochemical annulation of 2-chloroindole-3-carbaldehydes.
A novel and efficient procedure for the synthesis of benzo[c]carbazoles has been achieved in moderate to high yields by the one-pot photochemical annulations of 2-chloroindole-3-carbaldehydes by styrenes via photodechlorination-initiated coupling of 2-chloroindole-3-carbaldehydes with styrenes, electrocyclic reactions and deformylative aromatization in the presence of pyridine.


Inferior vena cava-tricuspid annulus isthmus is a critical site of unidirectional block during the induction of common atrial flutter.
Until recently no clinical studies had reported precise right atrium (RA) mapping when performing induction of atrial flutter (AFl). We studied the mode of tachycardia initiation in 16 patients (pts) referred for radiofrequency (RF) AFl ablation. AFl induction was performed at the beginning of the procedure (n = 10), or after previous AFl termination during RF delivery (n = 6). Detailed analysis of AFl initiation was provided by duodecapolar (Halo) and multipolar catheters positioned in the peritricuspidian region at the lateral right atrial wall (LRA), the inferior vena cavatricuspid annulus (IVC-TA) isthmus and the interatrial septum. Induction was obtained during incremental pacing (IAP) (15 pts) or programmed stimulation (1 pt) from the proximal coronary sinus (PCS). Atrial flutter with counterclockwise (CCW) RA rotation was induced in all pts by PCS pacing. During PCS IAP, at long pacing cycle lengths, impulse propagated in a clockwise (CW) direction through the IVC-TA isthmus and then upward at low (L) LRA. This led to a collision at the mid LRA with another wave front propagating in a CCW direction at the septum. IAP from PCS induced a progressive delay of propagation at the IVC-TA isthmus resulting in a prolongation of the PCS-Mid Isthmus interval from 85 +/- 29 to 151 +/- 42 msec. At same pacing cycle lengths (CL), the PCS-HLRA interval was comparatively less prolonged, from 75 +/- 12 to 105 +/- 18 msec, p = 0.0007. This preferential slowing of conduction between PCS and mid isthmus, during IAP from PCS, was associated with a displacement of the zone of collision to the Low LRA. Finally a CW functional block occurred at the IVC-TA isthmus and CCW AFl was induced through a period of transient concealed entrainment. The paced CL required to initiate flutter ranged from 290 to 180 msec and the mean CL of induced atrial flutter was 254 +/- 27 msec. The IVC-TA isthmus has decremental properties and exhibits wenckebach phenomenon during incremental PCS pacing. Initiation of a counterclockwise flutter by PCS pacing is associated with appearance of a functional unidirectional block at the IVC-TA isthmus.


Comparison Between Removable and Fixed Devices for Nonskeletal Anterior Crossbite Correction in Children and Adolescents: A Systematic Review.
To compare removable and fixed orthodontic devices in the correction of non-skeletal anterior crossbite in children and adolescents in the mixed dentition. Electronic searches were conducted in the following databases: PubMed, Web of Science, Scopus, Medline Ovid, Lilacs, US Clinical Trials, and Proquest. A hand search of the reference lists of the included articles and a Google Scholar search were also conducted. References were evaluated by 2 review authors. Articles that met the eligibility criteria were included. Data extraction, methodological quality assessment (Cochrane tool), and strength of the evidence evaluation (GRADE) were also carried out. Seven articles were included. The results showed that removable and fixed devices were equally efficacious for overjet correction. Removable and fixed devices can also present inconveniences regarding pain and discomfort levels, the accomplishment of everyday activities (leisure and school), and the performance of functions, such as chewing and speech. However, treatment time and costs were significantly lower in orthodontic therapy with fixed appliances. Sequence generation, allocation concealment, and complete outcome data were not a concern. Blinding of participants or personnel was not reported in any article, and blinding of the assessor was a concern in 2 articles. Selective reporting was a concern in 2 articles. The certainty of the evidence for overjet correction was very low. Removable and fixed orthodontic devices are efficacious for overjet correction in non-skeletal anterior crossbite. However, treatment time and costs are lower for cases treated with fixed devices.


A physical model of a supercapacitor to reveal the mechanism of the voltage recovery phenomenon.
Quickly discharged supercapacitors are often found to show voltages that increase with time ranging from minutes to several hours. People attribute this to the special structure of the supercapacitor; however, we propose an alternative explanation. A physical model was developed to explain the phenomenon and further reveal the working mechanism of supercapacitor discharge, thus providing a guide for improving the performance of supercapacitors.


Therapy response assessment after radioembolization of patients with hepatocellular carcinoma--comparison of MR imaging with gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid and gadobutrol.
To compare the utility of gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid (Gd-EOB-DTPA), a liver-specific magnetic resonance (MR) imaging contrast agent, versus gadobutrol for treatment response evaluation of hepatocellular carcinoma (HCC) after radioembolization. This prospective study included 50 patients with HCC undergoing radioembolization. All patients underwent contrast-enhanced computed tomography (CT) and MR imaging with gadobutrol and Gd-EOB-DTPA on 2 consecutive days before radioembolization and 30 days, 90 days, 180 days, and 270 days after radioembolization. The standard of reference indicating tumor progression was CT combined with either α-fetoprotein or γ-glutamyltransferase. Gadobutrol-enhanced MR imaging, Gd-EOB-DTPA-enhanced MR imaging without late phase imaging (Gd-EOB-DTPA-), and Gd-EOB-DTPA-enhanced MR imaging with late phase imaging (Gd-EOB-DTPA+) were evaluated by 2 radiologists in consensus using a 4-point scale: 1 = definitely no tumor progression; 2 = probably no tumor progression; 3 = probably tumor progression; 4 = definitely tumor progression. Diagnostic accuracy was assessed with receiver operating characteristic analysis. Tumor progression was detected in 14 of 82 study visits according to the reference standard. Pairwise comparison of the area under the curve showed a tendency toward a larger area under the curve for Gd-EOB-DTPA+ compared with gadobutrol (P = .056). Sensitivity and specificity were higher in Gd-EOB-DTPA+ (0.929 and 0.971) than in Gd-EOB-DTPA- (0.786 and 0.941) or gadobutrol (0.643 and 0.956). In 2 cases, tumor progression was detected by Gd-EOB-DTPA+ and by an increase in α-fetoprotein, but not by CT, gadobutrol, or Gd-EOB-DTPA-. Gd-EOB-DTPA+ MR imaging was not inferior to gadobutrol-enhanced MR imaging in therapy response evaluation after radioembolization and may allow a more accurate detection of early HCC recurrence in single cases.


Ionic liquid associated with ultrasonic-assisted extraction: A new approach to obtain carotenoids from orange peel.
The aim of this study was to develop a new method for carotenoid extraction from orange peel, using ionic liquid (IL) to replace conventional organic solvents, assisted by ultrasound. Four different IL were tested: 1-butyl-3-methylimidazolium chloride ([BMIM][Cl]), 1-n-butyl-3-methylimidazolium hexafluorophosphate ([BMIM][PF6]), 1-n-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]), and 1-hexyl-3-methylimidazolium chloride ([HMIM][Cl]). Response surface methodology was applied in order to optimize the carotenoid extraction conditions, and Amberlite XAD-7HP resin was used to separate the carotenoids from the IL, allowing their recovery. Determination of carotenoids was carried out by high-performance liquid chromatography coupled to photodiode array and mass spectrometry detectors (HPLC-DAD-MSn). Thermal stability at different temperatures (60 °C and 90 °C) and peroxyl radical scavenging activity of the carotenoid extracts obtained with acetone and IL were evaluated. [BMIM][Cl] was the most effective IL, leading to a total carotenoid content of 32.08 ± 2.05 μg/g, while 7.88 ± 0.59 μg/g of dry matter was obtained by acetone extraction. IL and carotenoid recoveries using XAD-7HP resin were in the range of 59.5-63.8% and 52.2-58.7%, respectively. A carotenoid extract was successfully obtained with IL, finally isolated just by using ethanol, besides being more stable and presenting higher antioxidant activity than that obtained with acetone.


MRI: the development of T2 contrast with rapid field echo sequences.
The soft tissue contrast obtained in fast imaging using rapidly repeated partial saturation sequences is usually based on differences in T1. We describe here an extension of the method which results in the development of clinically useful T2-based contrast.


Natural Infection of the Wild Canid Lycalopex gymnocercus by the Protozoan Rangelia vitalii, the Agent of Canine Rangeliosis.
Rangelia vitalii is a piroplasmid that causes canine rangeliosis, a severe hemorrhagic disease of domestic dogs in South America. We report about R. vitalii infecting a pampas fox (Lycalopex gymnocercus). The fox, which developed a fatal illness, was also infected by Hepatozoon canis and Capillaria hepatica.


Outcomes of an Integrated Multidisciplinary Clinic for People with Functional Neurological Disorder.
Functional neurological disorder (FND) is a disabling condition which has poor prognosis without treatment. This study aimed to evaluate the effectiveness of an outpatient integrated multidisciplinary intervention for the condition. This study aimed to assess the outcomes of a pilot integrated multidisciplinary treatment clinic for FND with motor symptoms. Patients were seen simultaneously by a neurology doctor, a physiotherapist, a clinical psychologist, and sometimes a psychiatrist. The primary endpoint was change in quality of life measured by Short Form-36 (SF-36). Secondary outcomes were change in work and social participation measured by the Work and Social Adjustment Scale (WSAS), ability to participate in full-time or part-time employment, self-rated understanding of FND, and self-rated agreement with the diagnosis of FND. Over the year, 13 patients were recruited to the clinic, and 11 agreed to participate in the outcome study. Statistically significant improvements in quality of life were seen across seven out of eight domains of the SF-36, with improvements in individual domains of between 23 and 39 points (of a possible 100). Mean Work and Social Adjustment Scale score halved from 26 to 13 (worst possible is 40). Of the 12 patients treated, one began to work again after complete unemployment, and two who had been working reduced hours due to disability resumed full time work. No patients had worsened occupational status. This intervention is associated with substantial improvements in quality of life and function, and may be more amenable to delivery at non-specialist centers than other described interventions for FND.


Resveratrol has anti-leukemic activity associated with decreased O-GlcNAcylated proteins.
CLL cells are characterized by high levels of proteins that are post-translationally modified by O-linked β-N-acetylglucosamine (O-GlcNAc) moieties, but it is not clear whether O-GlcNAc is a relevant therapeutic target. The neutraceutical resveratrol is cytotoxic to chronic lymphocytic leukemia cells in vitro. In this study, we found that resveratrol has therapeutic activity as a single agent in vivo in both human chronic lymphocytic leukemia patients and mice with erythroleukemia. Blood and splenic O-GlcNAc levels reflected the changes in tumor burden. Resveratrol directly lowered O-GlcNAc levels in leukemia cells through proteasomal activation, but increasing O-GlcNAc levels in vitro did not prevent cell death. These findings suggest that resveratrol has potential as a novel treatment for some forms of chronic and acute leukemia, and the measurement of O-GlcNAc levels could be a surrogate marker for therapeutic responses.


Chloro-cobalt complexes with pyridyl-ethyl-derived di-aza-cyclo-alkanes.
Syntheses are described for the blue/purple complexes of cobalt(II) chloride with the tetra-dentate ligands 1,4-bis-[2-(pyridin-2-yl)eth-yl]piperazine (Ppz), 1,4-bis-[2-(pyridin-2-yl)eth-yl]homopiperazine (Phpz), trans-2,5-dimethyl-1,4-bis-[2-(pyridin-2-yl)eth-yl]piperazine (Pdmpz) and tridentate 4-methyl-1-[2-(pyridin-2-yl)eth-yl]homopiperazine (Pmhpz). The CoCl2 complexes with Ppz, namely, {μ-1,4-bis-[2-(pyridin-2-yl)eth-yl]piperazine}bis-[di-chlorido-cobalt(II)], [Co2Cl4(C18H24N4)] or Co2(Ppz)Cl4, and Pdmpz (structure not reported as X-ray quality crystals were not obtained), are shown to be dinuclear, with the ligands bridging the two tetra-hedrally coordinated CoCl2 units. Co2(Ppz)Cl4 and {di-chlorido-{4-methyl-1-[2-(pyridin-2-yl)eth-yl]-1,4-di-aza-cyclo-hepta-ne}cobalt(II) [CoCl2(C13H21N3)] or Co(Pmhpz)Cl2, crystallize in the monoclinic space group P21/n, while crystals of the penta-coordinate mono-chloro chelate 1,4-bis-[2-(pyr-id-in-2-yl)eth-yl]piperazine}chlorido-cobalt(II) perchlorate, [CoCl(C18H24N4)]ClO4 or [Co(Ppz)Cl]ClO4, are also monoclinic (P21). The complex {1,4-bis-[2-(pyridin-2-yl)eth-yl]-1,4-di-aza-cyclo-hepta-ne}di-chlorido-cobalt(II) [CoCl2(C19H26N4)] or Co(Phpz)Cl2 (P ) is mononuclear, with a penta-coordinated CoII ion, and entails a Phpz ligand acting in a tridentate fashion, with one of the pyridyl moieties dangling and non-coordinated; its displacement by Cl- is attributed to the solvophobicity of Cl- toward MeOH. The penta-coordinate Co atoms in Co(Phpz)Cl2, [Co(Ppz)Cl]+ and Co(Pmhpz)Cl2 have substantial trigonal-bipyramidal character in their stereochemistry. Visible- and near-infrared-region electronic spectra are used to differentiate the two types of coordination spheres. TDDFT calculations suggest that the visible/NIR region transitions contain contributions from MLCT and LMCT character, as well as their expected d-d nature. For Co(Pmhpz)Cl2 and Co(Phpz)Cl2, variable-temperature magnetic susceptibility data were obtained, and the observed decreases in moment with decreasing temperature were modelled with a zero-field-splitting approach, the D values being +28 and +39 cm-1, respectively, with the S = 1/2 state at lower energy.


Effect of aflatoxin B1 treatment in vivo on the in vitro activity of hepatic and extrahepatic glutathione S-transferase.
The effect of aflatoxin B1 (AFB1) on the glutathione S-transferase activity (GST) and on non-protein thiol levels of different tissues was studied in adult male Wistar rats. Animals received a single dose of the toxin (100 or 500 micrograms/kg body wt., p.o.), and were studied 6 or 24 h after administration. GST was determined in liver, renal cortex, duodenum, jejunum-ileum and distal ileum, using 3 substrates: 1-chloro-2,4-dinitrobenzene (CDNB), trans-4-phenyl-3-buten-2-one (PBO) and 1,2-epoxyethylbenzene (STOX). The non-protein thiol content of all tissues tested increased with the lowest dose at 6 h, returning to normal values at 24 h, while the higher dose produced a significant decrease in reduced thiol levels at 6 h, returning to normal values at 24 h. AFB1 administration induced, independently of dose and tissue, total GST (CDNB) and epoxide-transferase activity (STOX) while A--C-type transferases (PBO) were inhibited. Almost all activities returned to normal values at 24 h. In cases of enzyme induction there was in general an increase in Vmax and a decrease in apparent Km. The opposite was seen in cases of inhibition. In conclusion, the results provide evidence that extrahepatic GST could be important in the overall process of detoxification of AFB1. The behavior seen in hepatic and extrahepatic tissues revealed the functions of catalysis (B-type transferases) and covalent bond formation, as well as inactivation by probable AFB1 metabolites (A--C-type transferases).


[Hepatitis B virus replication status and its response to surgery for tumor in hepatocellular carcinoma patients with positive markers of HBV].
To investigate the status of hepatitis B virus (HBV) activity in patients with hepatocellular carcinoma (HCC) and its response to surgical interventions for tumor in HBV positive HCC patients. We analyzed HBV marker results and detected HBV DNA in sera of 97 HCC patients (pre-operation 66 cases, post-operation 31 cases) with polymerase chain reaction (PCR) assay. We also investigated the HBV DNA titer in sera before and one week after operation in 20 HCC patients with positive HBV markers by quantitative polymerase chain reaction (Q-PCR). HBV DNA positive rate in sera was 40.9% and 64.52% in the two subgroup respectively (P < 0.05). HBV DNA titer in sera increased after operation (P < 0.01). The infection rate of HBV in Chinese HCC patients is very high. The replication of hepatitis B virus is strong in partial HBV marker positive HCC patients and surgical interventions may promote the virus replication.


A deletion of heterochromatin only of the Y chromosome in an azoospermic male.
A patient with a deletion of the distal portion of the long arm (q21) of chromosome Y is described clinically and cytogenetically. The proband has a normal male habitus but with azoospermia. The proband was investigated because of infertility. Male relatives were also investigated cytogenetically. The deleted Y chromosome was measured and compared with the normal Y of male family members. The results suggest that no Y euchromatin was lost.


Evaluation of cochlear implant electrode scalar position by 3 Tesla magnet resonance imaging.
The estimation of scalar electrode position is a central point of quality control during the cochlear implant procedure. Ionic radiation is a disadvantage of commonly used radiologic estimation of electrode position. Recent developments in the field of cochlear implant magnets, implant receiver magnet position, and MRI sequence usage allow the postoperative evaluation of inner ear changes after cochlear implantation. The aim of the present study was to evaluate the position of lateral wall and modiolar cochlear implant electrodes using 3 T MRI scanning. In a prospective study, we evaluated 20 patients (10× Med-El Flex 28; 5× HFMS AB and 5× SlimJ AB) with a 3 T MRI and a T2 2D Drive MS sequence (voxel size: 0.3 × 0.3 × 0.9 mm) for the estimation of the intracochlear position of the cochlear implant electrode. In all cases, MRI allowed a determination of the electrode position in relation to the basilar membrane. This observation made the estimation of 19 scala tympani electrode positions and a single case of electrode translocation possible. 3 T MRI scanning allows the estimation of lateral wall and modiolar electrode intracochlear scalar positions.


Lateral cortical notching in specific cases of delayed unions or nonunions after intertrochanteric and reversed fractures.
Stabilization of both intertrochanteric and reversed trochanteric fractures is commonly performed by proximal femoral nailing. However, biomechanics significantly differ between these two fracture types. In this study we report on the occurrence of delayed union or nonunion after inter- or reversed trochanteric fractures in eight patients (7 females and 1 male). Mean age was 73.3 years (range 63-82). The interval between initial operation and first intervention ranged between 4.3 and 15.0 months (mean 8.4 months). Failure of bone healing may cause permanent strain on the implant leading to nail breakage, which we observed in three of these eight cases. Dynamization is part of the general treatment concept for delayed union and nonunion after intramedullary fracture fixation. Normally it is performed by removal of interlocking screws or by occupying a 'dynamic' interlocking hole. We can show, however, that some types of inter- and reversed trochanteric fractures develop a characteristic kind of nonunion at the level of the lesser trochanter. This condition causes pain while walking and includes the risk of implant failure due to material fatigue. In these cases dynamization may be blocked by the cortex of the distal fragment directly contacting the prominent lag screw or its sleeve. We describe a procedure we call "lateral notching", which is needed to make distal conventional dynamization effective and to allow for bone healing.


Multiple melanotic schwannoma.
Melanotic schwannoma is a rare pigmented neural tumor most commonly occurring in the paraspinal region. In a small minority of instances, melanotic schwannoma may have multiple nodules. Here, a 52-year-old woman is presented with multiple melanotic schwannomas of paraspinal region.


Gene expression profiles of bladder cancers: evidence for a striking effect of in vitro cell models on gene patterns.
In order to assess the effect of in vitro models on the expression of key genes known to be implicated in the development or progression of cancer, we quantified by real-time quantitative PCR the expression of 28 key genes in three bladder cancer tissue specimens and in their derived cell lines, studied either as one-dimensional single cell suspensions, two-dimensional monolayers or three-dimensional spheroids. Global analysis of gene expression profiles showed that in vitro models had a dramatic impact upon gene expression. Remarkably, quantitative differences in gene expression of 2-63-fold were observed in 24 out of 28 genes among the cell models. In addition, we observed that the in vitro model which most closely mimicked in vivo mRNA phenotype varied with both the gene and the patient. These results provide evidence that mRNA expression databases based on cancer cell lines, which are studied to provide a rationale for selection of therapy on the basis of molecular characteristics of a patient's tumour, must be carefully interpreted.


Intracellular pH of isolated rat diaphragm muscle with metabolic and respiratory changes of extracellular pH.
Relationships between intracellular and extracellular pH isolated rat diaphragms were determined both during respiratory and metabolic changes of extracellular pH. Metabolic changes of extracellular pH were produced by varying bicarbonate concentration of the suspending Krebs-Ringer solution and respiratory changes were produced by varying PCO2 of the suspending medium. At any defined extracellular pH, the bicarbonate concentration ratios between intracellular and extracellular space were the same during both metabolic and respiratory changes of extracellular pH. However, when extracellular pH varied within 7.15 and 7.4 intracellular pH remained essentially constant. In order to maintain the intracellular pH constant during extracellular pH changes, a bicarbonate efflux during metabolic changes from the intracellular compartment, and a bicarbonate influx during respiratory changes to the intracellular compartment must occur. The maintenance of identical intracellular/extracellular bicarbonate concentration ratios regardless of the mechanisms of extracellular pH changes (metabolic or respiratory) suggests an active mechanism for the transport of bicarbonate or H-+ ions.


Synthesis of new thiazolylmethoxyphenyl pyrimidines and antihyperglycemic evaluation of the pyrimidines, analogues isoxazolines and pyrazolines.
New thiazolylmethoxyphenyl pyrimidines (7a-g) have been conveniently synthesized with better yields by cyclocondensing 3-(4-((2-phenylthiazol-4-yl)methoxy)phenyl)-1-(4-substituted phenyl)prop-2-en-1-ones (4a-g) with thiourea in aqueous emulsion of tetradecyltrimethylammonium bromide (TTAB) at 80 °C. Antihyperglycemic activity of the new thiazolylmethoxyphenyl pyrimidines (7a-d), thiazolylmethoxyphenyl pyrazolines (5a-d) and thiazolylmethoxyphenyl isoxazolines (6a-d) has been evaluated in sucrose loaded rat model. Among these compounds; 5a, 5c, 6b, 7c and 7d have displayed noticeable antihyperglycemic activity. Pyrimidines and pyrazolines have displayed better antihyperglycemic activity than the analogues isoxazolines.


The correspondence between morphometric MRI and metabolic profile in Rasmussen's encephalitis.
Volumetric magnetic resonance imaging (MRI) atrophy is a hallmark of Rasmussen's encephalitis (RE). Here, we aim to investigate voxel-wise gray matter (GM) atrophy in RE, and its associations with glucose hypometabolism and neurotransmitter distribution utilizing MRI and PET data. In this study, fifteen RE patients and fourteen MRI normal subjects were included in this study. Voxel-wise GM volume and glucose metabolic uptake were evaluated using structural MRI and FDG-PET images, respectively. Spatial Spearman's correlation was performed between GM atrophy of RE with FDG uptake alterations, and neurotransmitter distributions provided in the JuSpace toolbox. Compared with the control group, RE patients displayed extensive GM volume loss not only in the ipsilateral hemisphere, but also in the frontal lobe, basal ganglia, and cerebellum in the contralateral hemisphere. Within the RE group, the insular and temporal cortices exhibited significantly more GM atrophy on the ipsilesional than the contralesional side. FDG-PET data revealed significant hypometabolism in areas surrounding the insular cortices in the ipsilesional hemisphere. RE-related GM volumetric atrophy was spatially correlated with hypomebolism in FDG uptake, and with spatial distribution of the dopaminergic and serotonergic neurotransmitter systems. The spatial concordance of morphological changes with metabolic abnormalities suggest FDG-PET offers potential value for RE diagnosis. The GM alterations associated with neurotransmitter distribution map could provide novel insight in understanding the neuropathological mechanisms and clinical feature of RE.


Human prostate cancer cell death by novel anticancer compounds, apoptosis-inducing nucleosides from CD57+ HLA-DR(bright) natural suppressor cell line.
We validated the induction of apoptosis in human prostate cancer PC3 cells by apoptosis-inducing nucleosides (AINs) released from the CD57(+)HLA-DR(bright)-natural suppressor (57.DR-NS) cell line. We analyzed the molecular signaling pathway during AINs-induced apoptosis in PC3 cells. Direct and indirect co-cultures between 57.DR-NS and PC3 cells were performed. AINs were isolated by high-performance liquid chromatography (HPLC) from 57.DR-NS cell cultures. Apoptosis in PC3 cells was analyzed by DNA fragmentation, sub-G(1) DNA content with flow cytometry, and terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL) method. The DNA strand breaks and activation of caspase-3 in PC3 cells were measured by DNA unwinding and flow cytometry assay. The 57.DR-NS cell line generated apoptosis in PC3 cells via AINs. AINs isolated from 57.DR-NS cell cultures induced apoptosis in PC3 cells. Furthermore, we found DNA strand breaks followed by activation of caspase-3 during AINs-induced apoptosis in PC3 cells. The data obtained here indicated that AINs could induce apoptosis in PC3 cells through DNA strand breaks and activation of caspase-3.


In vivo imaging of the human thyroid with a positron camera using 124I.
A high-density avalanche chamber (HIDAC) positron camera was used for tomographic imaging of the human thyroid in vivo. Images were made 7 and 24 h after the oral administration of the positron-emitting radionuclide, sodium iodide 124I (with activities varying between 0.3 and 1 mCi), to patients scheduled for either partial thyroidectomy or radioiodine treatment. The results of thyroid imaging performed on 38 patients and their clinical relevance are discussed; as an illustration, three typical cases are presented. In Graves' disease, it was found that, whereas standard 131I and 124I scintigrams showed a diffuse goitre, positron images indicated a marked heterogeneity of the activity distribution, with "cold" areas in 8 out of the 11 cases studied. In conventional scintigrams, multinodular goitre showed a non-uniform radioiodine distribution, while positron images revealed considerable regional differences of activity uptake, with hot and cold areas in all of the 13 cases studied. As a consequence of the high spatial resolution of the camera [2.5 mm full width at half maximum (FWHM)], the functional volume of the thyroid may be estimated from 2 mm-thick transverse tomographic sections to within about 13%. This estimate may be compared with the measured volume after partial thyroidectomy, and in a follow-up scan, a further estimate can be made of the residual thyroid tissue remaining within the patient's body. In the case of radioiodine treatment in Graves' disease and multinodular goitre, the appropriate therapeutic dose of 131I can calculated according to the functional volume of the thyroid estimated from 124I tomographic images.


Effects of 3-deazaadenosine on antibody-dependent cellular cytoxicity and phagocytosis: reciprocal inhibition and augmentation of these functions in various effector cell populations.
3-Deazaadenosine (3-DAA), an inhibitor of S-adenosyl-L-homocysteine hydrolase, caused a dose-dependent inhibition of antibody-dependent cellular cytotoxicity (ADCC) against erythrocyte target cells of mouse spleen effector cells and complete Freund's adjuvant-induced peritoneal exudate cells. Inhibition of ADCC was accompanied by a proportional augmentation of antibody-dependent phagocytosis (ADø). When resident peritoneal cells were used as the source of effectors, ADø was inhibited by 3-DAA without augmentation of ADCC. Long-term (overnight) preincubation studies showed that the effect of 3-DAA on peritoneal ADø increased with time and was irreversible. Peritoneal exudate cells elicited by sodium caseinate mediated both antibody-dependent and -independent (spontaneous) phagocytosis. 3-DAA was shown as a potent and irreversible inhibitor of spontaneous phagocytosis. Inhibition of phagocytosis in these cell preparations resulted in augmentation of ADCC. In most of these effector cell populations, effects of 3-DAA were potentiated by the presence of L-homocysteine thiolactone.


The occurrence of click-evoked oto-acoustic emissions ("Kemp echoes") in normal-hearing ears.
Altogether 210 normal-hearing ears were screened regarding the possibility of producing click-evoked oto-acoustic emissions ("Kemp echoes"). Only a limited number of these ears displayed an emission. This finding limits the useful application of this technique as a method to define cochlear functioning.


The evolution of domestic pets and companion animals.
The process of domestication, which began 12,000 years ago, before the beginnings of agriculture, continues as humans and domestic animals coexist, interact, and profoundly influence the shape of each other's social spaces. Although its beginnings were simple, this process has become increasingly complex. Attention to relationships between humans and companion animals commonly focuses on dogs and cats; however, companion animals and pets take various shapes in numerous places with and have diverse, overlapping functions and specializations.


Ecotoxicological impacts of effluents generated by oil sands bitumen extraction and oil sands lixiviation on Pseudokirchneriella subcapitata.
The exploitation of Athabasca oil sands deposits in northern Alberta has known an intense development in recent years. This development has raised concern about the ecotoxicological risk of such industrial activities adjacent to the Athabasca River. Indeed, bitumen extraction generated large amounts of oil sands process-affected water (OSPW) which are discharged in tailing ponds in the Athabasca River watershed. This study sought to evaluate and compare the toxicity of OSPW and oil sands lixiviate water (OSLW) with a baseline (oil sands exposed to water; OSW) on a microalgae, Pseudokirchneriella subcapitata, at different concentrations (1.9, 5.5, 12.25, 25 and 37.5%, v/v). Chemical analyses of water-soluble contaminants showed that OSPW and OSLW were enriched in different elements such as vanadium (enrichment factor, EF=66 and 12, respectively), aluminum (EF=64 and 15, respectively), iron (EF=52.5 and 17.1, respectively) and chromium (39 and 10, respectively). The toxicity of OSPW on cells with optimal intracellular esterase activity and chlorophyll autofluorescence (viable cells) (72h-IC 50%<1.9%) was 20 times higher than the one of OSW (72h-IC 50%>37.5%, v/v). OSLW was 4.4 times less toxic (IC 50%=8.5%, v/v) than OSPW and 4.5 times more toxic than OSW. The inhibition of viable cell growth was significantly and highly correlated (<-0.7) with the increase of arsenic, beryllium, chromium, copper, lead, molybdenum and vanadium concentrations. The specific photosynthetic responses studied with JIP-test (rapid and polyphasic chlorophyll a fluorescence emission) showed a stimulation of the different functional parameters (efficiency of PSII to absorb energy from photons, size of effective PSII antenna and vitality of photosynthetic apparatus for energy conversion) in cultures exposed to OSPW and OSLW. To our knowledge, our study highlights the first evidence of physiological effects of OSPW and OSLW on microalgae.


Feasibility of a novel approach for rapid detection of simulated bloodstream infections via enzymatic template generation and amplification (ETGA)-mediated measurement of microbial DNA Polymerase activity.
Bloodstream infections (BSIs) caused by bacteria and fungi are associated with significant morbidity and mortality. Currently, blood culture is the gold standard for confirming a suspected BSI, but has the drawback of lengthy time-to-detection (TTD) required for indicating the presence of microbes. Detection of conserved microbial nucleic acid sequences within blood culture samples via PCR has been demonstrated to offer potential for reducing the TTD of BSI; however, these approaches have various other limitations. We report a novel approach toward rapid detection of microbes from simulated BSI via differential hematopoietic cell lysis followed by enzymatic template generation and amplification (ETGA)-mediated measurement of microbial DNA polymerase extension activity. The differential cell lysis procedure effectively reduced the level of detectable DNA polymerase extension activity associated with human-derived hematopoietic cells present in blood culture samples taken from healthy donors. After treatment with the differential cell lysis procedure, the ETGA assay detected a panel of clinically prevalent bacteria and Candida albicans from spiked blood culture samples. The ETGA blood culture method also reduced by threefold the TTD required for simulated BSI, compared with a continuous-monitoring blood culture instrument. In summary, these findings demonstrate the feasibility of an innovative approach toward a rapid, sensitive, and universal screen for microbes within blood culture samples. Potential for clinical application and automation are also addressed.