3D QSAR studies on 5-(2-methylbenzimidazol-1-yl)-N-alkylthiophene-2-carboxamide derivatives as P. falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors

Malaria is currently one of the world’s most severe endemic diseases, responsible for majority of morbidity and mortality. A large number of drugs are available for its treatment; however, the development of resistance has become more widespread with most of the frontline drug therapies. Inhibitors of PfDHODH have proven efficacy for the treatment of malaria. 3D QSAR studies on some 5-(2-methylbenzimidazol-1-yl)-N-alkylthiophene-2-carboxamide derivatives as PfDHODH inhibitors were performed by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods to rationalize the structural requirements responsible for the inhibitory activity of these compounds. The alignment strategy was used for these compounds by means of Distill function defined in SYBYL x 1.2. The best CoMFA and CoMSIA models obtained for the training set were statistically significant with q ² of 0.669 and 0.727, cross-validated coefficient (r ² _cv) of 0.603 and 0.698, and conventional coefficients (r ²) of 0.971 and 0.966, respectively. Both the models were validated by an external test set of five compounds giving satisfactory prediction (r ² _pred) of 0.799 and 0.815 for CoMFA and CoMSIA models, respectively. Further the robustness of the model was verified by bootstrapping analysis. Generated CoMFA and CoMSIA models provide useful information for the design of novel inhibitors with better PfDHODH inhibitory activity.     

Effects of Marathi-Hindi bilingualism on neuropsychological performance

The present study aimed to examine if bilingualism affects executive functions and verbal fluency in Marathi and Hindi, two major languages in India, with a considerable cognate (e.g., activity is actividad in Spanish) overlap. A total of 174 native Marathi speakers from Pune, India, with varying levels of Hindi proficiency were administered tests of executive functioning and verbal performance in Marathi. A bilingualism index was generated using self-reported Hindi and Marathi proficiency. After controlling for demographic variables, the association between bilingualism and cognitive performance was examined. Degree of bilingualism predicted better performance on the switching (Color Trails-2) and inhibition (Stroop Color-Word) components of executive functioning; but not for the abstraction component (Halstead Category Test). In the verbal domain, bilingualism was more closely associated with noun generation (where the languages share many cognates) than verb generation (which are more disparate across these languages), as predicted. However, contrary to our hypothesis that the bilingualism "disadvantage" would be attenuated on noun generation, bilingualism was associated with an advantage on these measures. These findings suggest distinct patterns of bilingualism effects on cognition for this previously unexamined language pair, and that the rate of cognates may modulate the association between bilingualism and verbal performance on neuropsychological tests.     

Polymorphism of the thiopurine S-methyltransferase gene in African- Americans

The molecular basis for the genetic polymorphism of thiopurine S - methyltransferase (TPMT) has been estab-lished for Caucasians, but it remains to be elucidated in African populations. In the current study, we determined TPMT genotypes in a population of 248 African-Americans and compared it with allele frequencies in 282 Caucasian Americans. TPMT genotype was determined in all individuals with TPMT activity indicative of a heterozygous genotype (</=10.1 U/ml pRBC, n = 23African- Americans, n = 21 Caucasians) and a control group with TPMT activity indicative of a homozygous wild-type genotype (>10.2 U/ml pRBC, n = 23 African-Americans, n = 21 Caucasians). No mutant alleles were found in the high activity control groups. The overall mutant allele frequencies were similar in African-Americans and Caucasians (4.6 and 3.7% of alleles, respectively). However, while TPMT*3C was the most prevalent mutant allele in African-Americans (52.2% of mutant alleles), it represented only 4.8% of mutant alleles in Caucasians ( P < 0.001). In contrast, TPMT*3A and TPMT*2 were less common in African-Americans (17.4 and 8.7% of mutant alleles), whereas TPMT*3A was the most prevalent mutant allele in Caucasians (85.7% of mutant alleles). A novel allele ( TPMT*8 ), containing a single nucleotide transition (G644A), leading to an amino acid change at codon 215 (Arg-->His), was found in one African-American with intermediate activity. These data indicate that the same TPMT mutant alleles are found in American black and white populations, but that the predominant mutant alleles differ in these two ethnic groups.      

Molecular characteristics of two esophageal carcinosarcomas: a hint for theclonality of carcinomatic and sarcomatic tumor components

AIM To study the clonality of the esophageal carcinosarcoma by using molecular approaches.METHODS Two esophageal carcinosarcomas were included in the study. Tumor area from dysplasticlesion, squamout cell carcinoma, basaloid cell carcinoma and spindle cell elements were microdissectedseparately. Each element was analyzed with 14 microsatellite markers and direct sequenced for p53 gene andras gene mutation.RESULTS Both tumors displayed a typical histologic feature of carcinosarcoma. Both cases showed thedivergent differentiation by immunohistochemistry study. In case 1 the identical LOH at p53 and hMLH1 lociwas detected. The heterogenous LOH was detected only in carcinosarcoma at RB1 and BRCA1 loci, whilethe LOH at ACTC locus was seen only in sarcoma. The same mutation of the splice site of exon 6-intron 6displayed in the two tumor elements. In case 2, a coordinate LOH at RB locus was demonstrated in threetypes of tumor elements: sqamous carcinoma, basaloid carcinoma and spindle cell element. A heterogenousLOH was seen only in spindle cells at TAP1 locus. No mutation in exon 5-8 of p53 gene has been found incase 2. No mutation of K-ras gene was found.CONCLUSION Although the different differentiation, the two elements of esophageal carcinosarcoma mayhave a single clonality. The p53 gene mutation occurred before the two differentiation directions switched.The distinct molecular genotype can be determined through molecular biological analysis. The microsatelliteprofiling can serve as an approach to find out which genetic alteration occurs before or after thedifferentiation is determines.     

The Water-Drinking Test Revisited: An Analysis of Test Results in Subjects with Glaucoma

Purpose: The Water-Drinking Test (WDT) has been shown to predict the diurnal IOP change. This study evaluates the factors that may affect the WDT results. Methods: This study was conducted on 203 glaucoma patients who had undergone trabeculectomy (53) or tube surgery (31), or had a medically controlled open-angle (82) or closed-angle (37) glaucoma. IOP was measured at baseline and then every 15 minutes over a one-hour period after drinking water. The main outcome measures were IOP change (increase in IOP from baseline) at all measurement time points, IOP peak (highest IOP after drinking water), IOP fluctuation (difference between IOP peak and baseline), and assessing the association of these IOPs with a patient’s demographic and management modalities. Results: The mean age of the participants was 54±18 years, and 113 (56%) were male. Female patients showed greater IOP fluctuation than males (7.28 vs. 5.92 mm Hg; P=0.016), and a greater IOP peak (22.7 vs. 20.1 mm Hg; P=0.001). The observed associations between gender and IOP changes were only significant in <50 years. IOP at 60 minutes was greater in tube than trabeculectomy (5.6 vs. 3.1 mm Hg; P=0.007). The number of topical medications showed a direct independent association with IOP changes (P<0.001). Compared to other classes of topical medications, latanoprost showed lower WDT-IOP profile (P=0.0003). Conclusions: WDT-IOP change was diminished in subjects on latanoprost, and was greater in females <50 years, and those on greater number of medications.     

Ecstasy cannot be assumed to be 3,4-methylenedioxyamphetamine (MDMA)

LINKED ARTICLES

This is a rebuttal by the authors (Green et al., pp. 1523–1536 of this issue) to a commentary by Parrott, pp. 1518–1520 of this issue. To view the article by Green et al. visit http://dx.doi.org/10.1111/j.1476-5381.2011.01819.x. To view the commentary by Parrott visit http://dx.doi.org/10.1111/j.1476-5381.2012.01941.xWe thank Prof Parrott (Parrott 2012) for his interest in our review (Green et al., 2012). Our main aim was to discuss the problems that arise in interpreting data obtained when administering 3,4-methylenedioxymethamphetamine (MDMA) to experimental animals in terms of possible clinical consequences and vice versa, not to disparage the evidence that Ecstasy is neurotoxic in humans. We presented evidence that the pharmacokinetics of MDMA in rats and primates are fundamentally different from the pharmacokinetics of the drug in humans. Because the plasma half-life of the drug in rats is 10 times shorter than in humans, the acute adverse events in rats may be minimal compared with those in humans, and this includes body temperature and endocrine changes. Conversely, the rapid metabolism of the drug in rats to form neurotoxic metabolites may result in more severe long-term effects in that species than those that may occur in humans.We had no intention of suggesting that there was no evidence for some recreational Ecstasy users presenting with evidence of 5-HT neurotoxicity, albeit it is clear from the literature that some of this evidence remains open to several interpretations. What we did claim was that pure 3,4-methylenedioxymethamphetamine (MDMA) taken alone was unlikely to cause 5-HT neurotoxicity in man. Here we must emphasize the term MDMA, as it is crucial to our discussion. Parrott, in contrast, uses the term ‘Ecstasy/MDMA’ several times when discussing neurotoxicity (Parrott, 2012). This association of Ecstasy with MDMA is one of the major problems of translation that we addressed. The Ecstasy tablet that most recreational users buy and ingest is not necessarily MDMA. Indeed, in many cases, it clearly is not. The tablet is often adulterated with other compounds, and one investigation identified no less than 14 substances other than MDMA in Ecstasy tablets, which users nevertheless presumably believed contained only MDMA (Vogels et al., 2009). Many of the adulterants identified were also psychoactive and included compounds structurally related to MDMA such as 3,4-methylenedioxyethylamphetamine and 2-methylamino-1-(3,4-methylenedioxyphenyl)butane, which have poorly researched pharmacology and toxicology. In addition, most recreational users of Ecstasy also knowingly ingest other psychoactive compounds such as alcohol and cannabis. Alcohol, for example, alters the pharmacokinetics of MDMA (Hamida et al., 2009). While, as Parrott states, clinical studies have attempted to allow for these confounding factors in any examination of the physical and psychological effects of MDMA in humans, such analysis is always limited not only by the other compounds the evaluators are unaware of, but also drugs perhaps not even considered to be relevant by the user and therefore not disclosed. It is unlikely that coffee and ‘energy drinks’ such as Red Bull are always disclosed, but there is now good preclinical evidence that caffeine, which incidentally has also been found as an adulterant in Ecstasy tablets, enhances both the hyperthermia and neurotoxicity induced in rats by MDMA (Camarasa et al., 2006; Vanattou-Saïfoudine et al., 2010). And this brings us to the crux of the problem and weakness of all the clinical data cited by Parrott (2012). A basic tenet of all good clinical pharmacology is accurate knowledge of the doses administered, frequency of administration and any confounding factors such as other drugs being consumed. None of these data are available with any precision in the clinical studies quoted. Of course one has some indication as to dose (although as Vogels et al., (2009) reported, the dose contained in illicitly obtained tablets is highly variable) and frequency of drug ingestion, but this information is generally obtained from the user whose recall is likely to be limited or who decides to obfuscate. Crucially, the information can never take into account the problem of drug tablet adulteration. The fact that hair or urine samples detect MDMA merely shows the user has consumed the drug, not how much or when or what other drugs were taken concurrently.We never suggested that MDMA exposure was not going to be associated with physical or psychological change. However such changes are not necessarily associated with long-term neurotoxic damage. We have shown that long-term behavioural effects can occur in rats both with and without 5-HT neurotoxicity (Fone et al., 2002; Bull et al., 2003; Rodsiri et al., 2011). It is interesting that Parrott approvingly quotes the Verheyden et al. (2003) study in support of his contention that neurotoxic damage has occurred. Because this study noted that the majority of persons reporting chronic psychiatric problems reported ‘improved mental health’ after quitting the drug, this surely allows us to conclude that the drug had produced subacute changes rather than any that could be associated with long-term neurotoxic damage.A further limitation to any clinical study is that one cannot perform prospective studies with the aim of investigating whether long-term neurotoxic events occur, so weaknesses arise with regard to any psychological abnormalities observed. Are persons with high risk of psychiatric problems more likely to misuse the drug, or does the drug induce changes in high-risk individuals? If high risk also happened to be associated with 5-HT abnormalities in the brains, then any conclusion that MDMA has induced neurotoxicity is spurious.We most certainly did not suggest that MDMA acted as a neurotoxin only under conditions of severe hyperthermia as is stated by Parrot in his sixth paragraph (Parrott, 2012). We have been involved in many studies on the effects of MDMA on body temperature in rats (see Docherty and Green, 2010) including one that demonstrated that neurotoxicity can occur in the absence of hyperthermia (O''Shea et al., 1998) and another that showed that hyperthermia worsens neurotoxic damage (Green et al., 2004). In our review, what we did propose was that because of the very different pharmacokinetics of MDMA in rats and humans, it is probable that humans would suffer serious or fatal adverse events at plasma levels below those likely to be required to induce 5-HT neurotoxicity.We emphasize again that we are not denying the clinical observations reviewed by Parrott, but conclude that the effects seen cannot be ascribed solely to the effects of MDMA, as he seems to be proposing. We also repeat our contention that MDMA in combination with other drugs may induce neurotoxicity and this could be said to be supported by the clinical studies quoted by Parrott.Finally, we can but assume that Parrott concurs with our principal conclusion that ‘the doses currently being used to investigate the possible therapeutic benefits of MDMA are unlikely to produce any severe acute or importantly any long-term neurotoxic damage in the human brain’ as he used such a dose (100 mg or approximately 1.4 mg·kg ⁻¹) in one of his recent studies in human volunteers (Parrott et al., 2011).     

Health‐Led Interventions in the Early Years to Enhance Infant and Maternal Mental Health: A Review of Reviews

Background: Increasing recognition of the importance of maternal mental health and early parenting in optimising the later mental health of the child has given rise to new ways of working during the perinatal period. Aims: The objective of this review is to identify effective health‐led interventions to support parents, parenting and the parent‐infant relationship during the perinatal period, 1 and beyond. Method: A systematic search of key electronic databases was undertaken to identify secondary and primary sources of data addressing the research question. Twenty‐four reviews addressed the effectiveness of interventions delivered during the postnatal period in promoting closeness and sensitive parenting, infant sensory and perceptual capabilities, and positive parenting, and in addressing infant regulatory problems, maternal mental health problems, and parent‐infant relationship problems. Conclusions: A number of methods of working are recommended as part of a model of progressive‐universalism beginning ante‐natally and continuing through the first two post‐natal years, and beyond. The implications for universal, targeted and specialist healthcare services are explored, alongside the role and contribution of CAMHS practitioners.