Riluzole-Rasagiline Hybrids: Toward the Development of Multi-Target-Directed Ligands for Amyotrophic Lateral Sclerosis

Polypharmacology is a new trend in amyotrophic lateral sclerosis (ALS) therapy and an effective way of addressing a multifactorial etiology involving excitotoxicity, mitochondrial dysfunction, oxidative stress, and microglial activation. Inspired by a reported clinical trial, we converted a riluzole (1)-rasagiline (2) combination into single-molecule multi-target-directed ligands. By a ligand-based approach, the highly structurally integrated hybrids 3-8 were designed and synthesized. Through a target- and phenotypic-based screening pipeline, we identified hit compound 6. It showed monoamine oxidase A (MAO-A) inhibitory activity (IC50 = 6.9 mu M) rationalized by in silico studies as well as in vitro brain permeability. By using neuronal and non-neuronal cell models, including ALS-patient-derived cells, we disclosed for 6 a neuroprotective/neuroinflammatory profile similar to that of the parent compounds and their combination. Furthermore, the unexpected MAO inhibitory activity of 1 (IC50 = 8.7 mu M) might add a piece to the puzzle of its anti-ALS molecular profile

Temporary Closure of the Open Abdomen: A Systematic Review on Delayed Primary Fascial Closure in Patients with an Open Abdomen

Background This study was designed to systematically review the literature to assess which temporary abdominal closure (TAC) technique is associated with the highest delayed primary fascial closure (FC) rate. In some cases of abdominal trauma or infection, edema or packing precludes fascial closure after laparotomy. This "open abdomen'' must then be temporarily closed. However, the FC rate varies between techniques. Methods The Cochrane Register of Controlled Trials, MEDLINE, and EMBASE databases were searched until December 2007. References were checked for additional studies. Search criteria included (synonyms of) "open abdomen,'' "fascial closure,'' "vacuum,'' "reapproximation,'' and "ventral hernia.'' Open abdomen was defined as "the inability to close the abdominal fascia after laparotomy.'' Two reviewers independently extracted data from original articles by using a predefined checklist. Results The search identified 154 abstracts of which 96 were considered relevant. No comparative studies were identified. After reading them, 51 articles, including 57 case series were included. The techniques described were vacuum-assisted closure (VAC; 8 series), vacuum pack (15 series), artificial burr (4 series), Mesh/sheet (16 series), zipper (7 series), silo (3 series), skin closure (2 series), dynamic retention sutures (DRS), and loose packing (1 series each). The highest FC rates were seen in the artificial burr (90%), DRS (85%), and VAC (60%). The lowest mortality rates were seen in the artificial burr (17%), VAC (18%), and DRS (23%). Conclusions These results suggest that the artificial burr and the VAC are associated with the highest FC rates and the lowest mortality rate

ACSL6 Is Associated with the Number of Cigarettes Smoked and Its Expression Is Altered by Chronic Nicotine Exposure

Individuals with schizophrenia tend to be heavy smokers and are at high risk for tobacco dependence. However, the nature of the comorbidity is not entirely clear. We previously reported evidence for association of schizophrenia with SNPs and SNP haplotypes in a region of chromosome 5q containing the SPEC2, PDZ-GEF2 and ACSL6 genes. In this current study, analysis of the control subjects of the Molecular Genetics of Schizophrenia (MGS) sample showed similar pattern of association with number of cigarettes smoked per day (numCIG) for the same region. To further test if this locus is associated with tobacco smoking as measured by numCIG and FTND, we conducted replication and meta-analysis in 12 independent samples (n>16,000) for two markers in ACSL6 reported in our previous schizophrenia study. In the meta-analysis of the replication samples, we found that rs667437 and rs477084 were significantly associated with numCIG (p = 0.00038 and 0.00136 respectively) but not with FTND scores. We then used in vitro and in vivo techniques to test if nicotine exposure influences the expression of ACSL6 in brain. Primary cortical culture studies showed that chronic (5-day) exposure to nicotine stimulated ACSL6 mRNA expression. Fourteen days of nicotine administration via osmotic mini pump also increased ACSL6 protein levels in the prefrontal cortex and hippocampus of mice. These increases were suppressed by injection of the nicotinic receptor antagonist mecamylamine, suggesting that elevated expression of ACSL6 requires nicotinic receptor activation. These findings suggest that variations in the ACSL6 gene may contribute to the quantity of cigarettes smoked. The independent associations of this locus with schizophrenia and with numCIG in non-schizophrenic subjects suggest that this locus may be a common liability to both conditions

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Efficacy of cultural control measures against the banana weevil, Cosmopolites sordidus (Germar), in South Africa

The banana weevil, Cosmopolites sordidus, is the most important insect pest of banana and plantain in the world. Cultural control methods were investigated over 2 years in southern KwaZulu-Natal, South Africa. Harvesting at ground level and dissection of remnants (treatment 1), and covering the base of the mat (entire plant consisting of several meristems) with soil and moving debris to the inter-row (treatment 2), were compared to a positive control that involved treatment of plants with a registered pesticide (treatment 3), and a negative control that involved harvesting at 150 cm from the collar with no soil or sanitation amendments (treatment 4). Yield, weevil damage and pseudostem girth of plants were measured from August to November annually, while adult beetle densities were assessed over 4 weeks in October/November and April. Nematode samples were taken and analysed in October/November every year. Damage parameters included the coefficient of infestation, the percentage coefficient of infestation (PCI) at two intervals, the summed PCI value, the percentage cross-sectional damage of the central cylinder and cortex, and the mean cross-sectional damage percentage. A randomized block design with three replicates was used in the trial. The parameters were similar before the onset of the trial. Fruit yield and plant girth, corrected by nematode densities, were not significantly different in any treatment, nor were the nematodes controlled. Soil cover and recession of remnants was the only effective treatment, significantly reducing the CI, but not the adult density or the other damage parameters. Soil cover showed promise as a cultural control method because it only needs to be applied seasonally and reduced the percentage cross-sectional damage of the central cylinder, the damage parameter most closely related to yield, by 14%

A novel, non-stop mutation in FOXE3 causes an autosomal dominant form of variable anterior segment dysgenesis including Peters anomaly

Anterior segment dysgenesis (ASD) is a spectrum of disorders that affect the anterior ocular chamber. Clinical studies on a Newfoundland family over the past 30 years show that 11 relatives have a variable ocular phenotype ranging from microcornea to Peters anomaly, segregating as an autosomal dominant trait. To determine the molecular etiology of the variable ASD in this family, we sequenced nine functional candidate genes and identified 44 variants. A point mutation in FOXE3, which codes for a transcription factor involved in the formation of the lens and surrounding structures, co-segregated with the variable ocular phenotype. This novel mutation (c.959G>T) substitutes the stop codon for a leucine residue, predicting the addition of 72 amino acids to the C-terminus of FOXE3. Two recent reports have also identified non-stop mutations in FOXE3 in patients with variable ocular phenotypes and predict an extended protein. Although FOXE3 is a lens-specific gene, we successfully isolated complementary DNA from lymphoblasts of an affected family member, and our sequencing results show that the c.959T allele is absent, suggesting that it may be degraded at the RNA level. Though preliminary, our results challenge the notion that an extended FOXE3 protein causes ASD, and instead suggests a mechanism of haploinsufficiency in the case of non-stop mutations. This study adds to several reports that suggest that autosomal-dominant mutations within FOXE3 cause ASD and has important clinical utility, especially for the diagnosis of mildly affected patients