Studies on the clastogenic effects of biologic stains and dyes.

We have surveyed the clastogenic potential of 12 different groups of stains and dyes totalling 48 compounds. We observed that 18 compounds induced significant increase in chromosome damage. Most of them were also found to be mutagenic, carcinogenic, or toxic in other reported studies. However, no significant studies were reported on six of them. It is concluded that these agents are potentially harzardous and should be studied further in detail.     

Evidence-based nutritional and pharmacological interventions targeting chronic low-grade inflammation in middle-age and older adults: A systematic review and meta-analysis

Growing evidence suggests chronic low-grade inflammation (LGI) as a possible mechanism underlying the aging process. Some biological and pharmaceutical compounds may reduce systemic inflammation and potentially avert functional decline occurring with aging. The aim of the present meta-analysis was to examine the association of pre-selected interventions on two established biomarkers of inflammation, interleukin-6 (IL-6), and C-reactive protein (CRP) in middle-age and older adults with chronic LGI.We reviewed the literature on potential anti-inflammatory compounds, selecting them based on safety, tolerability, acceptability, innovation, affordability, and evidence from randomized controlled trials. Six compounds met all five inclusion criteria for our systematic review and meta-analysis: angiotensin II receptor blockers (ARBs), metformin, omega-3, probiotics, resveratrol and vitamin D. We searched in MEDLINE, PubMed and EMBASE database until January 2017. A total of 49 articles fulfilled the selection criteria. Effect size of each study and pooled effect size for each compound were measured by the standardized mean difference. I² was computed to measure heterogeneity of effects across studies.The following compounds showed a significant small to large effect in reducing IL-6 levels: probiotics (−0.68 pg/ml), ARBs (−0.37 pg/ml) and omega-3 (−0.19 pg/ml). For CRP, a significant small to medium effect was observed with probiotics (−0.43 mg/L), ARBs (−0.2 mg/L), omega-3 (−0.17 mg/L) and metformin (−0.16 mg/L). Resveratrol and vitamin D were not associated with any significant reductions in either biomarker.These results suggest that nutritional and pharmaceutical compounds can significantly reduce established biomarkers of systemic inflammation in middle-age and older adults. The findings should be interpreted with caution, however, due to the evidence of heterogeneity across the studies.     

Discrimination of taste qualities among mouse fungiform taste bud cells

Multiple lines of evidence from molecular studies indicate that individual taste qualities are encoded by distinct taste receptor cells. In contrast, many physiological studies have found that a significant proportion of taste cells respond to multiple taste qualities. To reconcile this apparent discrepancy and to identify taste cells that underlie each taste quality, we investigated taste responses of individual mouse fungiform taste cells that express gustducin or GAD67, markers for specific types of taste cells. Type II taste cells respond to sweet, bitter or umami tastants, express taste receptors, gustducin and other transduction components. Type III cells possess putative sour taste receptors, and have well elaborated conventional synapses. Consistent with these findings we found that gustducin-expressing Type II taste cells responded best to sweet (25/49), bitter (20/49) or umami (4/49) stimuli, while all GAD67 (Type III) taste cells examined (44/44) responded to sour stimuli and a portion of them showed multiple taste sensitivities, suggesting discrimination of each taste quality among taste bud cells. These results were largely consistent with those previously reported with circumvallate papillae taste cells. Bitter-best taste cells responded to multiple bitter compounds such as quinine, denatonium and cyclohexamide. Three sour compounds, HCl, acetic acid and citric acid, elicited responses in sour-best taste cells. These results suggest that taste cells may be capable of recognizing multiple taste compounds that elicit similar taste sensation. We did not find any NaCl-best cells among the gustducin and GAD67 taste cells, raising the possibility that salt sensitive taste cells comprise a different population.     

Antigenic studies on an enzymatically sialylated carbohydrate: NeuAc(alpha 2-3)Gal(beta 1-3)GalNAc

Sialic acid residues are often the end moiety of the carbohydrate chain of biologically important glycoconjugates. It is difficult to study sialylated glycoconjugates because the purification of these compounds is often laborious yielding only very small amounts of oligosaccharides for study. Chemical synthesis of sialylated compounds is complicated by the labile nature of the sialic acid bond. In both of these cases the sialylated compounds would need to be conjugated to a polypeptide to be an effective immunogen, and again, such conjugation is fraught with problems due to the instability of the sialic acid linkage. We have developed a combined enzymatic and synthetic route for obtaining quantities of sialylated carbohydrates conjugated to a protein carrier in amounts sufficient for antigenic studies. The notable novelty of this protocol is the addition of sialic acid after the carbohydrate-protein conjugation step. Antiserum to the compounds was developed and after absorption, antibodies that demonstrate a requirement for sialic acid for their binding were produced and studied. CA 125 has been shown to be a prognostically significant marker for ovarian adenocarcinoma. The nature of the epitope involved has been analyzed with conflicting results. To attempt to resolve this conflict, we initiated studies on sialylated antigens with NeuAc alpha 2-3Gal beta 1-3GalNAc. This trisaccharide occupies the terminal region in a series of complex carbohydrates which have been suggested to be involved as the epitope. Hanisch et al. reported that the neuraminic acid was important for the reaction.     

A critical comparison of murine pathology and epidemiological data of TCDD, PCB126, and PeCDF

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, or dioxin) and dioxin-like compounds (DLCs) induce numerous toxicities, including developmental, endocrine, immunological, and multi-organ carcinogenic, in animals and/or humans. Multiple studies completed by the National Toxicology Program (NTP) focused on the effects caused in Harlan Sprague-Dawley rats by specific DLCs, among them the prototypical dioxin, TCDD. Because humans are exposed daily to a combination of DLCs, primarily via ingestion of food, the Toxic Equivalency Factor (TEF) was developed in order to evaluate health hazards caused by these mixtures. Herein we review the pathological effects reported in humans exposed to TCDD; 3,3',4,4',5-pentachlorobiphenyl (PCB 126); and 2,3,4,7,8,-pentachlorodibenzofuran (PeCDF) and compare them to similar changes seen in NTP murine studies performed with the same compounds. While there were differences in specific pathologies observed, clear consistency in the target organs affected (liver, oral cavity, cardiovascular system, immune system, thyroid, pancreas, and lung) could be seen in both human studies and rodent toxicity and carcinogenicity investigations.     

Applicability of the Popliteal Lymph Node Assay in the Brown-Norway Rat

A number of drugs and chemicals can induce autoimmune disorders. Previous studies suggested the popliteal lymph node (PLN) assay might be a suitable and reliable model to detect such compounds in the mouse. the applicability of this assay has been examined in the Brown-Norway rat using a pannel of positive as well as negative reference compounds.

Popliteal lymph nodes were excised and weighed seven days after subcutaneous injection of 5 mg of each compound into one footpad. Interestingly, all negative reference compounds produced no significant increase in PLN weight index whereas four positive reference compounds were associated with PLN-weight indices greater than 2.3.

However, no increase in PLN weight was noted in procainamide-and isoniazide-treated rats as previously reported in the mouse. This first set of experiments indicates that the PLN assay is applicable to Brown-Norway rats and warrants further investigation.     

Current scenario of the search for new antifungal agents to treat Candida auris infections: An integrative review

Candida auris emerges as an important causative agent of fungal infections, with worrisome mortality rates, mainly in immunocompromised individuals. This scenario is worsened by the limited availability of antifungal drugs and the increasing development of resistance to them. Due to the relevance of C. auris infections to public health, several studies aimed to discover new antifungal compounds capable of overcoming this fungus. Nonetheless, these information are decentralized, precluding the understandment of the current status of the search for new anti-C. auris compounds. Thus, this integrative review aimed to summarize information regarding anti-C. auris compounds reported in literature. After using predefined selection criteria, 71 articles were included in this review, and data from a total of 101 substances were extracted. Most of the studies tested synthetic substances, including several azoles. Moreover, drug repurposing emerges as a suitable strategy to discover new anti-C. auris agents. Few studies, however, assessed the mechanism of action and the in vivo antifungal activity of the compounds. Therefore, more studies must be performed to evaluate the usefulness of these substances as anti-C. auris therapies.     

The bleomycin amplification assay in V79 cells predicts frameshift mutagenicity of intercalative agents

We have recently reported on the use of a cell-based bleomycin amplification assay for the detection of DNA intercalating agents. In order to further validate this assay, two series of proprietary compounds were evaluated for frameshift mutagenesis in the Ames bacterial reversion system and for bleomycin amplification in the Chinese hamster V79 micronucleus system. It is shown that 10 of 11 frameshift-positive compounds were bleomycin amplifiers. These studies indicate that positive frameshift mutagenicity findings are consistent with expectations from the results of the bleomycin amplification assay, providing additional validation of the amplification assay for the detection of DNA intercalating agents. The studies also demonstrate that intercalation is necessary but not sufficient for frameshift mutagenesis since bleomycin amplifiers lacking frameshift mutagenic activity were also identified.     

Quantification of phosphocholine and glycerophosphocholine with 31P edited 1H NMR spectroscopy

Choline and the related compounds phosphocholine (PC) and glycerophosphocholine (GPC) are considered to be important metabolites in oncology. Past studies have demonstrated correlations linking the relative ratios and concentrations of these metabolites with the development and progression of cancer. Currently, in vivo and tissue ex vivo magnetic resonance spectroscopy methods have mostly centered on measuring the total concentration of these metabolites and have difficulty in differentiating between them. Here, a new scheme that uses (31)P edited (1)H spectroscopy to quantify the concentrations of choline, PC and GPC in biological samples is reported and its applicability is demonstrated using samples of human brain tumor extracts. This method is particularly well-suited for analytical situations where the PC and GPC resonances are not sufficiently resolved and/or are obscured by other metabolites. Consequently, this scheme has the potential to be used for the analysis of choline compounds in ex vivo tissue samples.     

Role of genetic polymorphisms in ACE and TNF-α gene in sarcoidosis: a meta-analysis

A great number of association studies have been performed to identify the genes involved in the etiology and prognosis of sarcoidosis. We performed a systematic review of case-control studies through the PubMed database and evaluated them for a possible inclusion into a meta-analysis in order to assess whether the reported genetic polymorphisms are the risk factors of sarcoidosis. Case-control studies with clear diagnostic criteria and interventions were included. Only investigations of a single polymorphism/gene involvement in sarcoidosis reported more than five times were selected. Aggregating data from 12 studies on ID/ACE polymorphisms, the odds ratio (OR) for sarcoidosis, if the polymorphism was considered under the dominant genetic model, was not significantly increased: 1.19 (95% CI 0.98–1.43); OR under the recessive model was 1.20 (95% CI 0.98–1.46). In seven case-control studies on −308/TNF-α polymorphism, the OR for sarcoidosis if the polymorphism considered under the dominant genetic model was significantly increased at 1.47 (95% CI 1.03–2.08); the OR under the recessive model was 1.39 (95% CI 0.67–2.90). In conclusion, the results showed that the TNF-α genotype could be a significant risk factor for sarcoidosis, whereas the risk of sarcoidosis due to the ACE genotype was not substantially elevated.     

Meta-analysis of pharmacotherapies for allergic rhinitis]

We performed meta-analysis using the data in literatures of the clinical study related to pharmacotherapies for allergic rhinitis in Japan as evidences. We extracted double-blind studies which used first-generation antihistamines, early-stage second-generation antihistamines, late-stage second-generation antihistamines and arachidonic acid metabolite-receptor antagonists as investigational drugs. In meta-analysis of first-generation antihistamines and early-stage second-generation antihistamines, significant differences between them were detected in final overall improvement and usefulness. In meta-analysis of early-stage second-generation antihistamines and late-stage second-generation antihistamines, significant differences between them were detected in usefulness and sleepiness as an adverse effect. In meta-analysis of late-stage second-generation antihistamines and arachidonic acid metabolite-receptor antagonists, significant differences between them were detected in final overall improvement and usefulness. These results indicate a historical trend in the development of drugs including measures to deal with sleepiness as an adverse effect. The arachidonic acid metabolite antagonists appeared to be promising among the oral drugs for allergic rhinitis, although data related to the arachidonic acid metabolite antagonists are still few and further collection of them is necessary.     

Die synthese reiner oligo[(hydroxy-5-nitro-1,3-phenylen)methylen]e,verbindungen mit mehreren ortho- bzw. para-nitrophenol-bausteinen im molekül

Chlormethylated nitrophenols as well as mono- and bischloromethylated bis- and tris[(hydroxy-5-nitro-1,3-phenylene)methylene] compounds were used to synthesize oligo[(hydroxy-5-nitro-1,3-phenylene)methylene]s. Chloromethylation was achieved by reaction with chloromethyl methyl ether in the presence of zinc chloride. The synthesis of the oligomeric compounds was possible with good yields by condensation of the chloromethylated compounds with a large excess of nitrophenol and zinc chloride as catalyst. Reaction conditions and different reactivities are reported. The structures of some compounds were confirmed by independent syntheses. Thus, also the structures of those compounds were ensured which are connected by unequivocal preparations with the independently synthesized compounds. All together 47 new oligo[(hydroxy-5-nitro-1,3-phenylene)methylene]s could be prepared, among them 12 dinuclear, 20 trinuclear, 13 tetranuclear and 2 pentanuclear compounds.     

Inhibition of hepatitis B virus specific DNA polymerase by intercalating agents

Intercalating agents, some of them in clinical use, were tested for their ability to inhibit the hepatitis B virus specific DNA polymerase reaction. Ethidium bromide was shown to be the strongest inhibitor among the compounds tested. Compounds in clinical use inhibited the DNA polymerase test only at high concentrations. The inhibitory activity of all compounds tested was increased when the MgCl₂ content in the reaction mixture was lowered. UV absorption studies presented no evidence that this effect was due to complex formation of magnesium and the individual compounds. The therapeutic significance of these findings is not certain and needs further work.     

Systematic reviews of sublingual immunotherapy (SLIT)

Allergic rhinitis is common worldwide, with significant morbidity and impact on quality of life. In patients who don't respond adequately to anti-allergic drugs. Subcutaneous allergen immunotherapy is effective although requires specialist administration. Sublingual immunotherapy may represent an effective and safer alternative. This Cochrane systematic review is an update of one published in 2003. We searched Cochrane ENT Group Trials Register, Central, PubMed, EMBASE, CINAHL, Web of Science, Biosis Previews, Cambridge Scientific Abstarcts, mRCT and additional sources. We included randomised, double-blind, placebo- controlled trials of sublingual immunotherapy in adults and children. Two authors selected studies and assessed them for quality. Data were put into RevMan 5.0 for a statistical analysis. We used standardised mean difference (SMD), with a random effect model to combine data. Sixty studies were included, with 49 suitable for meta-analysis. We found significant reductions in symptoms (SMD -0.49; 95%CI (-0.64 to -0.34, P < 0.00001)) and medication requirements (SMD -0.32; 95%CI (-0.43 to -0.21, P < 0.00001)) compared with placebo. None of the trials reported severe systemic reactions, anaphylaxis or use of Adrenaline. This updated review reinforces the conclusion of the original 2003 Cochrane Review that sublingual immunotherapy is effective for allergic rhinitis and appears a safe route of administration.     

Decision-making and cognitive abilities: A review of associations between Iowa Gambling Task performance,executive functions,and intelligence

The Iowa Gambling Task (IGT) has been used to study decision-making differences in many different clinical and developmental samples. It has been suggested that IGT performance captures abilities that are separable from cognitive abilities, including executive functions and intelligence. The purpose of the current review was to examine studies that have explicitly examined the relationship between IGT performance and these cognitive abilities. We included 43 studies that reported correlational analyses with IGT performance, including measures of inhibition, working memory, and set-shifting as indices of executive functions, as well as measures of verbal, nonverbal, and full-scale IQ as indices of intelligence. Overall, only a small proportion of the studies reported a statistically significant relationship between IGT performance and these cognitive abilities. The majority of studies reported a non-significant relationship. Of the minority of studies that reported statistically significant effects, effect sizes were, at best, small to modest, and confidence intervals were large, indicating that considerable variability in performance on the IGT is not captured by current measures of executive function and intelligence. These findings highlight the separability between decision-making on the IGT and cognitive abilities, which is consistent with recent conceptualizations that differentiate rationality from intelligence.     

Expanding the spectrum of rearrangements involving chromosome 19: a mild phenotype associated with a 19p13.12-p13.13 deletion

We report on a patient with a 1.2?Mb 19p13.12-p13.13 deletion. Compared to previously reported individuals with partially overlapping deletions, the propositus presented with a less severe phenotype, consisting of mild intellectual disability and behavior anomalies, with episodes of simple febrile seizures and without significant physical anomalies or major malformations. The deleted region includes 29 coding genes, some of which have already been demonstrated to be involved in cognitive processes. Mutations in two of them, CC2D1A and TECR, were recently reported to be responsible for non-syndromal, autosomal recessive intellectual disability. The residual alleles of all of these genes were submitted to sequence analysis. No sequence variants were found that could be considered pathogenic. This patient constitutes a further example of the wide phenotypic variability associated with chromosomal rearrangements, likely due to the different size of deleted/duplicated segments.     

Hardy-Weinberg equilibrium in genetic association studies: an empirical evaluation of reporting, deviations, and power

We evaluated the testing and reporting of Hardy-Weinberg equilibrium (HWE) in recent genetic association studies, detected how frequently HWE was violated and estimated the power for HWE testing in this literature. Genetic association studies published in 2002 in Nature Genetics, American Journal of Human Genetics, and American Journal of Medical Genetics were assessed. Data were analyzed on 239 biallelic associations using 154 distinct genotype distribution data sets where HWE could be tested. Any information on HWE was given only for 150 (62.8%) associations (92 (59.7%) data sets). Reanalysis of the data showed significant deviation from HWE in the disease-free controls of 20 associations (13 data sets), but only four of them (two data sets) were admitted in the published articles. Another four deviations (in two data sets) were observed in the combined sample of cases and controls of studies where both cases and controls were diseased, and none were reported in the papers. In all six tested multiallelic associations (six data sets), there was violation of HWE, but this was not admitted in the published articles. Power calculations showed that most studies conforming to HWE simply were largely underpowered to detect HWE deviation; for example, power to detect an inbreeding of magnitude F=0.10 exceeded 80% in only 11 (7%) of the data sets being tested. This empirical evidence suggests that, even in high profile genetics journals, testing and reporting for HWE is often neglected and deviations are rarely admitted in the published reports. Moreover, power is limited for HWE testing in most current genetic association studies.     

To debrief or not to debrief our heroes: that is the question

Psychological debriefing was developed in the 1980s as an approach for use with people whose work exposes them to stressful incidents. It aims to help them to process the thoughts and emotions arising from their work. Subsequently, several randomized controlled trials tested truncated forms of debriefing in a different population: primary victims of unexpected trauma. These trials, and particularly two in which debriefing appeared to be harmful, led two major reviews to warn practitioners not to offer debriefing. Consequently, many organizations have stopped providing debriefing to employees who face trauma in their routine work. This paper argues that there are at least three reasons for the apparent failure of 'debriefing' in the two studies that reported adverse effects. First, the 'debriefing' did not follow protocol in terms of timing, length, and training and independence of the debriefer. Second, the patients who were 'debriefed' reported more severe initial symptoms than those who were not. Third, 'debriefing' was used with individuals for whom it was not originally intended. Psychological debriefing is intended to be used with groups of people who have been briefed together before going on to work together in stressful situations. Such groups have reported that they find psychological debriefing helpful, and research is emerging indicating that appropriate debriefing may indeed benefit these groups. We call for reviewers to recognize the limitations of debriefing research and not to overgeneralize their conclusions.