Disentangling the roles of aneuploidy, chromosomal instability and tumour heterogeneity in developing resistance to cancer therapies.

Aneuploidy is defined as the cellular state of having a number of chromosomes that deviates from a multiple of the normal haploid chromosome number of a given organism. Aneuploidy can be present in a static state: Down syndrome individuals stably maintain an extra copy of chromosome 21 in their cells. In cancer cells, however, aneuploidy is usually present in combination with chromosomal instability (CIN) which leads to a continual generation of new chromosomal alterations and the development of intratumour heterogeneity (ITH). The prevalence of cells with specific chromosomal alterations is further shaped by evolutionary selection, for example, during the administration of cancer therapies. Aneuploidy, CIN and ITH have each been individually associated with poor prognosis in cancer, and a wealth of evidence suggests they contribute, either alone or in combination, to cancer therapy resistance by providing a reservoir of potential resistant states, or the ability to rapidly evolve resistance. A full understanding of the contribution and interplay between aneuploidy, CIN and ITH is required to tackle therapy resistance in cancer patients. However, these characteristics often co-occur and are intrinsically linked, presenting a major challenge to defining their individual contributions. Moreover, their accurate measurement in both experimental and clinical settings is a technical hurdle. Here, we attempt to deconstruct the contribution of the individual and combined roles of aneuploidy, CIN and ITH to therapy resistance in cancer, and outline emerging approaches to measure and disentangle their roles as a step towards integrating these principles into cancer therapeutic strategy.

The prognostic value of delta-lactate in critically ill children.

AIM: This study aimed to test delta-lactate (ΔL) as a short-term risk stratification method in critically ill children. METHODS: An exploratory study of patients admitted to paediatric intensive care unit (PICU) was conducted. ΔL was calculated as the difference between the maximum lactate concentrations on Days 1 and 2. According to the ΔL cutoff, two groups were considered: low mortality risk (LMR) - ΔL ≥ 0.05 mmol/L - and high mortality risk (HMR) - ΔL < 0.05 mmol/L. RESULTS: Mortality, both during PICU stay and at 28 days, was statistically associated with elevated serum lactate on D1 and D2, per se. For the 93 cases with elevated lactate on Day 1, and a ΔL cutoff of 0.05 mmol/L, the area under the ROC curve was 0.698 (95% confidence interval, 0.47-0.93). HMR patients scored higher PIM3, were not discharged home until 28 days, counted fewer ventilation-free days and needed renal replacement therapy more often. CONCLUSION: Elevated lactate levels at admission, as well as applying the optimal cutoff for ΔL, allowed to predict short-term mortality: if an increase or minimal decrease in lactate maximum levels occurred from D1 to D2, death was almost eight times more probable. In critically ill children, delta-lactate predicts short-term outcome.

Screening the dermatological potential of plectranthus species components: antioxidant and inhibitory capacities over elastase, collagenase and tyrosinase.

A series of Plectranthus spp. plant extracts (aqueous, acetonic, methanolic and ethyl acetic) obtained from eight different species, and previously isolated compounds (ranging from polyphenols, diterpenes and triterpenes), were assayed for in vitro inhibition of the skin-related enzymes tyrosinase, collagenase and elastase, and for studying their antioxidant properties. The ethyl acetic extracts of P. grandidentatus and P. ecklonii registered the highest antioxidant activity, whereas acetonic, methanolic and ethyl acetic extracts of P. ecklonii, P. grandidentatus, P. madagascariensis and P. saccatus concerning the enzymatic inhibition assays revealed high anti-tyrosinase and anti-collagenase activities. From the isolated compounds tested, abietane diterpenes and triterpenes were highly active against tyrosinase and elastase activity. Overall, the experimental results showed the powerful antioxidant and inhibitory action on skin-related enzymes tyrosinase, collagenase and elastase of Plectranthus spp. extracts and/or isolated compounds, supporting their further research as bioactive metabolites against skin sagging and hyperpigmentation in cosmetic and pharmaceutical formulations.

In Vitro Antimicrobial Activity of Isopimarane-Type Diterpenoids.

The antimicrobial evaluation of twelve natural and hemisynthetic isopimarane diterpenes are reported. The compounds were evaluated against a panel of Gram-positive bacteria, including two methicillin-resistant Staphylococcus aureus (MRSA) strains and one vancomycin-resistant Enterococcus (VRE) strain. Only natural compounds 7,15-isopimaradien-19-ol (1) and 19-acetoxy-7,15-isopimaradien-3ß-ol (6) showed promising results. Isopimarane (1) was the most active, showing MIC values between 6.76 µM against S. aureus (ATCC 43866) and 216.62 µM against E. faecalis (FFHB 427483) and E. flavescens (ATCC 49996). Compound (6) showed moderated activity against all tested microorganisms (MIC between value 22.54 and 45.07 µM). These compounds were found to be active against the methicillin-sensitive strains of S. aureus (CIP 106760 and FFHB 29593), showing MIC values of 13.55 (1) and 22.54 (6) µM. Both compounds were also active against vancomycin-resistant E. faecalis (ATCC 51299) (MIC values of 54.14 and 45.07 µM, respectively). In addition, the cytotoxicity of nine compounds 7,15-isopimaradien-3ß,19-diol (2); mixture: 15-isopimarene-8ß-isobutyryloxy-19-ol and 15-isopimarene-8ß-butyryloxy-19-ol (3); 3ß-acetoxy-7,15-isopimaradiene-19-ol (5); 19-acetoxy-7,15-isopimaradiene-3ß-ol (6); 3ß,19-diacetoxy-7,15-isopimaradiene (8); 15-isopimarene-8ß,19-diol (9); 19-O-ß-d-glucopyranoside-7,15-isopimaradiene (10); lagascatriol-16-O-ß-d-glucopyranoside (11) and lagascatriol-16-O-α-d-mannopyranoside (12) was evaluated in the human breast cancer cell line MDA-MB-231. Isopimarane (2) was the only compound showing some cytotoxicity. The IC50 value of compound (2) was 15 µM, suggesting a mild antiproliferative activity against these breast cancer cells.

Plasma and platelet clusterin ratio is altered in Alzheimer's disease patients with distinct neuropsychiatric symptoms: findings from a pilot study.

BACKGROUND: Clusterin protein in plasma has been found to differentiate between people with and without cognitive changes. However, these findings are not conclusive, despite the clusterin gene variations repeatedly being linked to increased risk for dementia, in particular Alzheimer's disease (AD). METHOD: We analysed the level of clusterin in platelet and plasma in 25 subjects with a clinical diagnosis of AD and 26 subjects with no cognitive impairment. RESULTS: In the current study, we report that the levels of both plasma and platelet clusterin are similar between AD and cognitively intact individuals. Clusterin plasma and platelet levels, as well as the plasma/platelet clusterin ratio, were not affected by age, gender, cognitive impairment and/or overt behavioural symptomatology, including presence of hallucinations and delusions, as well as depression. However, the plasma/platelet clusterin ratio was positively associated in with the Neuropsychiatric Inventory measures of agitation, apathy, irritability and motor aberrant behaviour in AD subjects. CONCLUSION: Previous inconsistencies in reported blood clusterin levels may be a result of underlying non-cognitive symptoms in people with AD. Our findings need now to be replicated in larger group of dementia subjects.

Early stage design decisions: the way to achieve sustainable buildings at lower costs.

The construction industry attempts to produce buildings with as lower environmental impact as possible. However, construction activities still greatly affect environment; therefore, it is necessary to consider a sustainable project approach based on its performance. Sustainability is an important issue to consider in design, not only due to environmental concerns but also due to economic and social matters, promoting architectural quality and economic advantages. This paper aims to identify the phases through which a design project should be developed, emphasising the importance and ability of earlier stages to influence sustainability, performance, and life cycle cost. Then, a selection of sustainability key indicators, able to be used at the design conceptual phase and able to start predicting environmental sustainability performance of buildings is presented. The output of this paper aimed to enable designers to compare and evaluate the consequences of different design solutions, based on preliminary data, and facilitate the collaboration between stakeholders and clients and eventually yield a sustainable and high performance building throughout its life cycle.

The Effectiveness of Intervention Programs for Perpetrators of Intimate Partner Violence with Substance Abuse and/or Mental Disorders: A Systematic Review.

Despite the high prevalence and severity of intimate partner violence (IPV) perpetration among men with mental health (MH) problems and substance use (SU), there is limited evidence on the most effective ways to reduce IPV within these groups. Hence, the present systematic review aims to evaluate the effectiveness of psychological interventions for male IPV perpetrators with MH issues and SU problems. Five databases (B-On, Pubmed PsycInfo, Science Direct, and Scopus) were searched for studies examining the effectiveness of IPV interventions. Twenty-three studies met the inclusion criteria, with 13 interventions described. Interventions were grouped into (1) specific interventions for SU among IPV perpetrators (k = 8), (2) nonspecific interventions for SU among IPV perpetrators (K = 3), and (3) specific interventions targeting MH among IPV perpetrators (k = 2). Cognitive behavioral therapy and motivational interviewing techniques were the most common approaches. Both specific and nonspecific programs addressing SU problems showed some positive effects on perpetrators' behavior and attitudes. However, data from the two intervention programs focusing on MH showed reduced symptoms and re-assaults but without significant differences between the conditions. Despite methodological shortcomings in the studies, the specific and nonspecific interventions targeting SU and IPV show promise, which hinders drawing firmer conclusions. Nonetheless, further research is necessary to deepen our understanding of the MH impact interventions on IPV perpetrators.

Babies in the Corporeal Turn: The Cognitive Embodiment of Early Motor Development and Exploration in the Brazilian Context of Early Childhood Education.

The corporeal turn in developmental psychology has rekindled interest regarding how early motor development contributes to and enhances cognitive development across the first years of life. By highlighting embodied perceptual-motor engagement with the world, embodied cognitive learning emphasizes the importance of experience and perceptual-motor mechanisms in modulating the development of person-environment systems. The field currently calls for research that combines such conceptual frameworks with the complex everyday material and sociocultural landscapes that resource infants' developmental trajectories. We, therefore, aim to connect the conceptual refinement of bodily-anchored exploration to the contextual reality of everyday settings of early childhood education (ECE)-here situated in the Brazilian context-as relevant social and cultural suppliers and modulators of the developmental trajectories of babies. Secondarily, we ponder on the premises of national pedagogical curricula and their role in mediating the quality of experiences and systems of person-environment relations more closely. Cultural-historical psychology, in dialogue with the principles of Ecological Psychology, constitutes the theoretical framework that underpins the microgenetic analyses conducted. By analyzing episodes of exploratory actions of a focal baby situated in the ECE context, we seek to apprehend motor-perceptual indicators of embodied cognitive processing by considering the modes of appropriation entailed in episodes of embodied exploration. We reflect on pedagogical implications considering official national documents of early childhood education. This work contributes by providing complementary insights into the nature of infants' everyday sociocultural embodied experiences and their development in pedagogically oriented settings.

KCL TEST: an open-source inspired asymptomatic SARS-CoV-2 surveillance programme in an academic institution.

Rapid and accessible testing was paramount in the management of the COVID-19 pandemic. Our university established KCL TEST: a SARS-CoV-2 asymptomatic testing programme that enabled sensitive and accessible PCR testing of SARS-CoV-2 RNA in saliva. Here, we describe our learnings and provide our blueprint for launching diagnostic laboratories, particularly in low-resource settings. Between December 2020 and July 2022, we performed 158277 PCRs for our staff, students, and their household contacts, free of charge. Our average turnaround time was 16 h and 37 min from user registration to result delivery. KCL TEST combined open-source automation and in-house non-commercial reagents, which allows for rapid implementation and repurposing. Importantly, our data parallel those of the UK Office for National Statistics, though we detected a lower positive rate and virtually no delta wave. Our observations strongly support regular asymptomatic community testing as an important measure for decreasing outbreaks and providing safe working spaces. Universities can therefore provide agile, resilient, and accurate testing that reflects the infection rate and trend of the general population. Our findings call for the early integration of academic institutions in pandemic preparedness, with capabilities to rapidly deploy highly skilled staff, as well as develop, test, and accommodate efficient low-cost pipelines.

The Psychological Impact of Restorative Justice Practices on Victims of Crimes-a Systematic Review.

BACKGROUND: Restorative justice emerges as a theoretical-practical approach to the criminal legal system, in which the reparation of damage of the victim is a central point. However, the growing empirical production referring to the effects of this approach on victims is sometimes shown to be weakened or dispersed, focusing mainly on their satisfaction. OBJECTIVE: The present work intended to systematically evaluate the empirical production of the restorative justice field, to aggregate and examine information in the literature regarding the psychological impacts on victims who participated in restorative practices. METHODS: A search was made using electronic databases to identify quantitative, qualitative, and mixed-method studies, published between January 2000 and December 2020 that reported psychological impacts on real victims of crimes, who participated in mediations/conferences victim-offender. RESULTS: 35 studies were identified as focusing on the psychological impacts on victims resulting from restorative practices. These studies have shown effects on post-traumatic symptomatology, on the emotions and emotional needs resulted from victimization, as well as on the victims' perceptions of their offenders. CONCLUSIONS: The present research showed that restorative justice practices have a positive psychological impact on victims, who are frequently forgotten in conventional justice, and that some of these impacts persist over time.

The Effectiveness of Psychological Treatment in Adult Male Convicted for Sexual Offenses Against Children: A Systematic Review.

Child sexual abuse is a public health problem of global magnitude with profound and negative consequences for the victims and society. Thus, psychological intervention with individuals who sexually offended against children is crucial for reducing recidivism. Numerous reviews and meta-analyses have shown the effectiveness of psychological interventions in individuals who sexually offended, but few reviews have been done on this subtype of offenders. This article reviews evaluation studies of intervention programs designed to treat individuals who sexually offended against children, providing a more detailed account of treatment procedures. Articles were identified from peer-reviewed databases, bibliographies, and experts. Following full-text review, 12 studies were selected for inclusion by meeting the following criteria: quantitative or qualitative research studies published in English from 2000 to 2020 with titles or abstracts that indicated a focus on treatment effectiveness, detailing the psychological treatment procedures on adult, male individuals convicted for child sexual abuse. Cognitive-behavioral therapy with a relapse prevention approach was the most frequent modality found in child sexual offending treatment. Besides, different criminogenic and non-criminogenic factors emerge as targets for intervention. Study design, study quality, and intervention procedures shortened the accumulation of evidence in treatment effectiveness.

Using the algorithm of the Fetal Medicine Foundation to determine the cutoff point for prediction of pre-eclampsia in a Brazilian population.

BACKGROUND: To use the algorithm of the Fetal Medicine Foundation (FMF) to determine the cutoff point for prediction of preeclampsia (PE) in a Brazilian population. METHODS: Randomized clinical trial with 274 nulliparous patients at gestational age between 11 and 13 weeks and 6 days. To calculate the risk of PE, the algorithm available at the website of the FMF (http://fetalmedicine.org/research/assess/preeclampsia/first-trimester) was used. Among the patients, 138 did not use preventive measures (100 mg/day aspirin [ASA]). Youden's criteria were used to calculate the cutoff point. To test the effectiveness of 100 mg/day ASA in preventing PE, the patients were divided into two groups - at risk above and below the cutoff point. RESULTS: In the group comprising the 135 patients that did not take ASA, the median age was 22 years, the Body Mass Index (BMI) was 59.3 kg/m2, the mean arterial pressure (MAP) was 73.3 mmHg, and the mean pulsatility index of uterine artery Doppler was 1.71. The median gestational age at delivery was 39.3 (38.1-40.3) weeks. The prevalence of PE was 11.1%. In our sample, the use of 100 mg/day ASA reduced total PE by 36.3% (prevalence of PE in the group above the cutoff point was 19% and 12.1% when ASA and placebo were used, respectively). CONCLUSIONS: The cutoff point defined for prediction of PE was 1:155 with sensitivity of 80%, specificity of 57.5%, positive predictive value of 19.1%, and negative predictive value of 95%, which should help to select patients that will benefit from prophylactic ASA.

Can healthy lifestyle modify risk factors for dementia? Findings from a pilot community-based survey in Chennai (India) and Newcastle (UK).

BACKGROUND: Currently there are no effective treatments available for dementia. Attention has turned to defining preventive strategies and identifying modifying effects of lifestyle, including physical activity, diet, alcohol intake and smoking, in reducing cognitive decline and overt memory problems in the elderly. METHODS: In this study, we addressed the modifying aspects of various components of lifestyle in two ageing samples and explored the possible effects that exercise, diet and spiritual and religious beliefs have upon physical and mental health. A total of 251 subjects (128 in Chennai, India, and 123 in Newcastle, UK) filled in a questionnaire regarding their lifestyle habits. Data were analysed with χ² analysis. RESULTS: Our findings highlight that spiritual and religious beliefs promoted good physical and mental health and were negatively associated with risk factors for dementia, such as high blood pressure, high cholesterol level and diabetes. Lifelong diet and physical activity also contributed to better overall well-being in both samples. CONCLUSIONS: Our study suggests substantial lifestyle variations between two urban populations in Chennai, India, and Newcastle-upon-Tyne, UK. Further detailed work is required to identify the lifestyle components that have the greatest impact on modifying the known risk factors for dementia.

Platelet immunoglobulin and amyloid precursor protein as potential peripheral biomarkers for Alzheimer's disease: findings from a pilot study.

BACKGROUND: the diagnosis of dementia, in particular Alzheimer's disease (AD), is enhanced with the use of molecular biomarkers. Since cerebrospinal fluid analysis and molecular neuroimaging are not routinely used in many countries, blood biomarker molecules may be more readily applicable in a routine clinical setting. METHODS: twenty-five subjects with a clinical diagnosis of AD and 26 control participants were assessed for cognitive and behavioural functioning. Platelet measures of amyloid protein precursor (APP), tau protein, clusterin, α-synuclein and immunoglobulin (Ig) were measured. Linear regression analysis for platelet proteins and cognitive and behavioural status were determined, and receiver operating characteristic (ROC) curves created to assess the discriminating power of each biochemical parameter between AD and control groups. RESULTS: both AD and control subjects had similar platelet levels of measures platelet proteins, with the exception of slightly elevated Ig levels in AD subjects (P = 0.052). The latter were not related to increasing age, or extent of cognitive impairment. APP-N measures were negatively correlated with cognitive scores. CONCLUSION: these preliminary findings suggest that platelet measures of the traditional biomarkers for AD are feasible in the periphery. The measures of platelet APP-N and Ig, in particular, merit further study in a larger cohort of AD and control subjects.

Measuring Self-Serving Cognitive Distortions with Special Reference to Juvenile Delinquency: A Validation of the "How I Think" Questionnaire in a Sample of Portuguese Adolescents.

The present study aims to test the psychometric properties of the Portuguese version of the "How I Think" (HIT) questionnaire. The HIT questionnaire is a self-report measure of self-serving cognitive distortions. Our sample was comprised of 442 Portuguese-speaking adolescents and young adults (254 males and 188 females), aged between 12 and 20 years. Of the total 442 participants, 351 were recruited from a Portuguese school and 91 from four Portuguese detention centers for juvenile delinquents. Data analysis provided evidence supporting the original six-factor model solution, composed of a four-category typology of self-serving cognitive distortions (i.e., Selfcentered, Blaming Others, Minimizing/Mislabeling, and Assuming the Worst), an Anomalous responding, and one Positive filler factor. Further, results showed satisfactory internal consistency, convergent validity, and discriminant validity. In conclusion, this article provides Portuguese researchers and practitioners with a valid measure of self-serving cognitive distortions.

Trophic niche changes associated with the eradication of invasive mammals in an insular lizard: an assessment using isotopes.

Invasive species are a major threat to island biodiversity, and their eradications have substantially contributed to the conservation of island endemics. However, the consequences of eradications on the trophic ecology of native taxa are largely unexplored. Here, we used the eradication of invasive black rats Rattus rattus and European rabbits Oryctolagus cuniculus from the Berlenga Island, in the western coast of Portugal, as a whole-ecosystem experiment to investigate the effects of the eradication of invasive mammals on the trophic niche and body dimensions of the island-restricted Berlenga wall lizard Podarcis carbonelli berlengensis over a 2-year period. Our results suggest an expansion of the isotopic niche and an intensification of the sexual dimorphism of the lizard following mammal eradication. Additionally, we found considerable variability in isotopic niche across the island and detected evidence of sex-specific and season-modulated nutritional requirements of this threatened reptile. Our findings support that the eradication of 2 of the planet's most problematic invasive vertebrates led to changes in the lizard trophic niche and sexual dimorphism in just 2 years. This suggests that the ecological pressures-for example, prey availability and habitat structure-to which lizards are exposed have substantially changed post-eradication. Our study emphasizes the scientific value of island eradications as experiments to address a wide range of ecological questions and adds to the increasing body of evidence supporting substantial conservation gains associated with these restoration interventions.

Low-dose acetylsalicylic acid does not modify maternal vascular reactivity in nulliparas.

OBJECTIVE: To assess if the low-dose acetylsalicylic acid (ASA) would be capable of modifying endothelial function throughout pregnancy in nulliparous patients. METHODS: A double-blind, randomized clinical trial with 277 were included. A total of 139 were orally administered 100 mg/day of ASA, and 138 received placebo. Endothelial function was assessed by flow-mediated dilation (FMD) in the brachial artery before the start of medication (11-14 weeks) and 20-24 and 30-34 weeks of gestation. The intervention was maintained until 34 weeks. The Mann-Whitney U test was used to compare the placebo and ASA groups. The comparison of FMD during pregnancy was performed using the Friedman test. RESULTS: The groups (ASA and placebo) were similar regarding to age, weight, height, and body mass index (BMI) (p > .005). The comparison of values of FMD (%) between placebo vs. ASA at 11 and 14 weeks (8.9 vs. 9.7%, p: .253), 20 and 24 weeks (8.8 vs. 10.7%, p: .152), and 30 and 34 weeks (10.7 vs. 9.8%, p: .314) did not show significant changes throughout pregnancy. We observed a significant prevalence of PE in the placebo regarding to ASA group [14 (10.2%) vs. 8 (5.8%), p: .171]. CONCLUSION: Acetylsalicylic acid did not modify the endothelial function assessed by FMD of the brachial artery during pregnancy in nulliparous women.

Population wide testing pooling strategy for SARS-CoV-2 detection using saliva.

SARS-CoV-2 pandemic has forced frequent testing of populations. It is necessary to identify the most cost-effective strategies for the detection of COVID-19 outbreaks. Nasopharyngeal samples have been used for SARS-CoV-2 detection but require a healthcare professional to collect the sample and cause discomfort and pain to the individual. Saliva has been suggested as an appropriate fluid for the diagnosis of COVID-19. We have investigated the possibility of using pools of saliva samples to detect SARS-CoV-2 in symptomatic and asymptomatic patients. Two hundred and seventy-nine saliva samples were analyzed through RT-PCR of Envelope, Nucleocapsid and Open Reading Frame 1ab genes. Reproducibility assays showed an almost perfect agreement as well as high sensitivity (96.6%), specificity (96.8%), positive predicted value (96.6%), and negative predicted value (96.8%). The average Cycle Threshold of the genes detected was 29.7. No significant differences (p > 0.05) were detected when comparing the cycle threshold average of two consecutive reactions on the same positive saliva samples. Saliva samples have a higher median viral load (32.6) than in nasopharyngeal samples (28.9), although no significant differences were detected (p > 0.05). Saliva-pool samples allowed effective SARS-CoV-2 screening, with a higher sensibility (96.9%) on 10-sample pools than in 20-sample pools (87.5%). Regardless of pools size specificity was high (99.9%) and an almost perfect agreement was observed. Our strategy was successfully applied in population wide testing of more than 2000 individuals, showing that it is possible to use pooled saliva as diagnostic fluid for SARS-CoV-2 infection.

Acute heart failure: on the track of a rare disease.

Eosinophilic granulomatosis with polyangiitis is an antineutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis with cardiac involvement in more than 60% of cases. Authors describe the case of a 48-year-old woman who presented with progressively worsening asthenia, dyspnoea and macular, non-painful, non-itchy cutaneous lesions. She had signs of congestion on clinical examination and a history of asthma and nasal polyps. Blood tests showed eosinophilia (11.2%), positive troponin I (9698 µg/L), elevated B-type natriuretic peptide (2047 pg/mL) and positive C reactive protein (6.68 mg/dL). Echocardiogram displayed moderate left ventricular enlargement, left ventricular ejection fraction of 28% and mild pericardial effusion. Levosimendan relieved the congestion. Additional testing confirmed positive antinuclear antibodies with ANCA-negative autoimmune pattern. Cardiac magnetic resonance showed severely depressed systolic function due to diffuse hypokinesia. Cardiac biopsy had intercellular oedema and eosinophilic infiltrate. Treatment with prednisolone and cyclophosphamide was started. This is a case of a rare disease presenting with life-threatening cardiac involvement.

Increased antibacterial properties of indoline-derived phenolic Mannich bases.

The search for antibacterial agents for the combat of nosocomial infections is a timely problem, as antibiotic-resistant bacteria continue to thrive. The effect of indoline substituents on the antibacterial properties of aminoalkylphenols was studied, leading to the development of a library of compounds with minimum inhibitory concentrations (MICs) as low as 1.18 µM. Two novel aminoalkylphenols were identified as particularly promising, after MIC and minimum bactericidal concentrations (MBC) determination against a panel of reference strain Gram-positive bacteria, and further confirmed against 40 clinical isolates (Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, and Listeria monocytogenes). The same two aminoalkylphenols displayed low toxicity against two in vivo models (Artemia salina brine shrimp and Saccharomyces cerevisiae). The in vitro cytotoxicity evaluation (on human keratinocytes and human embryonic lung fibroblast cell lines) of the same compounds was also carried out. They demonstrated a particularly toxic effect on the fibroblast cell lines, with IC50 in the 1.7-5.1 µM range, thus narrowing their clinical use. The desired increase in the antibacterial properties of the aminoalkylphenols, particularly indoline-derived phenolic Mannich bases, was reached by introducing an additional nitro group in the indolinyl substituent or by the replacement of a methyl by a bioisosteric trifluoromethyl substituent in the benzyl group introduced through use of boronic acids in the Petasis borono-Mannich reaction. Notably, the introduction of an additional nitro moiety did not confer added toxicity to the aminoalkylphenols.