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1.
J Clin Exp Neuropsychol ; : 1-15, 2024 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-38704611

RESUMO

Increased schizotypal traits have previously been associated with atypical semantic cognition in community samples. However, no study has yet examined whether adults diagnosed with schizotypal personality disorder (SPD) display atypical semantic fluency and memory. We hypothesized that 24 adults diagnosed with SPD would name more idiosyncratic words on the semantic fluency task and show decreased semantic recall for animal and fruit category words compared with 29 participants with borderline personality disorder (BPD) and a community sample of 96 age-matched controls. We examined whether atypical semantic cognition was specifically associated with disorganized and eccentric speech and thinking, or more broadly with pathological personality traits and personality functioning. Our main hypothesis was confirmed, as the SPD participants named more idiosyncratic words and recalled fewer semantically related words compared with controls. Surprisingly, participants with BPD likewise named more atypical words compared with controls. More idiosyncratic semantic fluency was associated with more eccentric speech and thinking. Increased idiosyncratic semantic fluency and reduced semantic recall were both coupled to increased detachment and lowered personality functioning, while reduced semantic recall further was related to increased interpersonal problems. Our findings suggest that persons with SPD, and to a lesser degree BPD, show atypical semantic cognition, which is associated with eccentric speech and thinking, and more broadly with impaired personality function, social withdrawal, and emotional flatness. The idiosyncratic semantic cognition may worsen difficulties with social reciprocity seen in SPD and BPD.

2.
Br J Nurs ; 32(16): S32-S41, 2023 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-37682765

RESUMO

BACKGROUND: Stoma surgery is a life-changing event and patients must subsequently make significant adjustments to their lives. AIM: The study set out to understand the level of interaction between patients and stoma care nurses (SCNs) in relation to preparing patients for stoma surgery and in adjustment to life with a stoma. METHODS: Retrospective, self-reported questionnaires for patients and SCNs. FINDINGS: Most patients (98%) with planned stoma surgery had pre-operative consultations with health professionals in contrast to 36% of patients with unplanned surgery, who did not. One third of patients with unplanned surgery did not feel prepared for life with a stoma based on the information provided during their hospital stay. Two thirds of the nurses reported having sufficient time to prepare patients for stoma surgery and to life with a stoma. CONCLUSION: SCNs are key in preparing patients for surgery and for life with a stoma. Variations in care were experienced by patients having planned versus unplanned surgeries.


Assuntos
Emoções , Enfermeiros Clínicos , Humanos , Estudos Retrospectivos , Pessoal de Saúde , Tempo de Internação
3.
Children (Basel) ; 10(6)2023 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-37371224

RESUMO

The International Classification of Diseases 11th Revision (ICD-11) introduces fundamentally new diagnostic descriptions for personality disorder and autism spectrum disorder. Instead of the traditional categorical taxonomies, both personality disorder and autism spectrum disorder are described as being on a continuum. Accumulating research has pointed out that, in some cases, adolescents with autism spectrum disorder are at risk of being confused with having a personality disorder, which particularly applies to female adolescents. Case reports describe how adult autistic women struggled with social and identity roles as children and adolescents, using compensatory strategies such as social imitation and other types of camouflaging. Furthermore, some adolescents with autism display emotion dysregulation and self-injury. The ICD-11 recognizes that features of autism spectrum disorder may resemble features of personality disorder, but the two diagnoses have not yet been formally compared to one another. The present article therefore sought to outline and discuss the overlap and boundaries between the ICD-11 definitions of personality disorder and autism spectrum disorder and propose guiding principles that may assist practitioners in differential diagnosis with female adolescents. We specifically highlight how aspects of the self and interpersonal functioning along with emotional, cognitive, and behavioral manifestations may overlap across the two diagnoses. Restricted, repetitive, and inflexible patterns of behavior, interests, and activities are core features of autism spectrum disorder, which may be masked or less pronounced in female adolescents. Collecting a developmental history of the early presence or absence of autistic features is vital for a conclusive diagnosis, including features that are typically camouflaged in females. A number of future directions for research and clinical practice are proposed.

4.
Microbiol Spectr ; 11(4): e0062523, 2023 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-37289074

RESUMO

Polyether ionophores are complex natural products known to transport various cations across biological membranes. While several members of this family are used in agriculture (e.g., as anti-coccidiostats) and have potent antibacterial activity, they are not currently being pursued as antibiotics for human use. Polyether ionophores are typically grouped as having similar functions, despite the fact that they significantly differ in structure; for this reason, how their structure and activity are related remains unclear. To determine whether certain members of the family constitute particularly interesting springboards for in-depth investigations and future synthetic optimization, we conducted a systematic comparative study of eight different polyether ionophores for their potential as antibiotics. This includes clinical isolates from bloodstream infections and studies of the compounds' effects on bacterial biofilms and persister cells. We uncover distinct differences within the compound class and identify the compounds lasalocid, calcimycin, and nanchangmycin as having particularly interesting activity profiles for further development. IMPORTANCE Polyether ionophores are complex natural products used in agriculture as anti-coccidiostats in poultry and as growth promoters in cattle, although their precise mechanism is not understood. They are widely regarded as antimicrobials against Gram-positive bacteria and protozoa, but fear of toxicity has so far prevented their use in humans. We show that ionophores generally have very different effects on Staphylococcus aureus, both in standard assays and in more complex systems such as bacterial biofilms and persister cell populations. This will allow us to focus on the most interesting compounds for future in-depth investigations and synthetic optimizations.


Assuntos
Antibacterianos , Anti-Infecciosos , Humanos , Animais , Bovinos , Ionóforos/farmacologia , Ionóforos/química , Antibacterianos/uso terapêutico , Anti-Infecciosos/farmacologia , Bactérias Gram-Positivas , Biofilmes , Testes de Sensibilidade Microbiana
5.
Br J Nurs ; 32(6): S4-S12, 2023 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-36952372

RESUMO

BACKGROUND: More than 90% of people with an ostomy worry about leakage, with associated high rates of psychological morbidity. AIMS: To assess the performance of a novel digital ostomy leakage notification system in subjects with faecal stomas who experience and worry about leakage. METHOD: A prospective, single-arm, pilot study (ClinicalTrials.gov: NCT04894084) with 25 subjects testing the product for 21 days. Subjects completed questionnaires at baseline and termination of study evaluating leakage episodes, leakage worry and quality of life (QoL). FINDINGS: Mean age was 56 years, 60% had an ileostomy, and 40% were females. Mean episodes of leakage outside the baseplate decreased significantly from 2.8 to 0.5 episodes after 21 days' use of the test product (P<0.001), worry about leakage decreased significantly (P<0.001) and QoL improved. CONCLUSION: The findings indicate strong improvements to emotional health with the test product, driven by reductions in leakage incidents outside baseplate and in users' worry about leakage.


Assuntos
Estomia , Estomas Cirúrgicos , Feminino , Humanos , Pessoa de Meia-Idade , Masculino , Qualidade de Vida/psicologia , Projetos Piloto , Estudos Prospectivos , Estomia/psicologia , Ileostomia , Inquéritos e Questionários
6.
Br J Nurs ; 32(1): 8-19, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36626266

RESUMO

BACKGROUND: Leakage of stomal effluent outside the baseplate that soils clothes or bedsheets is a common problem for many people with a stoma and significantly impacts their quality of life. AIM: To understand behavioural changes for people experiencing faecal leakage outside the baseplate regarding the usage of pouching systems, supporting products and interactions with health professionals. METHODS: Retrospective, self-reported questionnaire. FINDINGS: Respondents on average experienced 1.1 incidents of faecal leakage outside the baseplate per fortnight. In periods with issues of leakage, 21% of respondents had been in contact with health professionals, 40% increased their use of pouching systems, 25% increased their use of existing supporting products, and 21% included additional supporting products to their change routine. The increased use of healthcare resources was estimated to cost £32.47 in the 3 weeks following a leakage incident. CONCLUSION: Incidents of leakage outside the baseplate lead to increased use of healthcare resources.


Assuntos
Qualidade de Vida , Estomas Cirúrgicos , Humanos , Estudos Retrospectivos , Inquéritos e Questionários , Autorrelato
7.
J Autism Dev Disord ; 53(11): 4280-4292, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36001194

RESUMO

It is unclear whether children with autism spectrum disorders have atypical semantic fluency and lower memory for the semantics of words. Therefore, we examined semantic typicality, fluency and recall for the categories of fruits and animals in 60 children with autism aged 7-15 years (boys: 48/girls: 12) compared to 60 typically developing controls. Relative to controls, the autism group had reduced animal fluency, fruit typicality and recall for fruits. Notably, these measures were associated with more autistic-like symptoms and/or lower adaptive functioning across the autism and control groups. In conclusion, atypical semantics of fruits in the autism group may reflect development of idiosyncratic semantic networks while their lower semantic fluency and recall suggest impaired executive language functions.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Masculino , Feminino , Humanos , Adolescente , Criança , Semântica , Idioma , Rememoração Mental , Testes Neuropsicológicos
8.
Br J Nurs ; 31(16): S24-S38, 2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36094040

RESUMO

BACKGROUND: People with a stoma are reported to experience leakage, which negatively impacts patient quality of life (QoL). AIM: To assess the impact of leakage experienced by individuals with a stoma in the UK. METHODS: Data were analysed from 301 patients living in the UK who completed a questionnaire concerning the physical and psychosocial impact of living with a stoma. FINDINGS: Most respondents had had their stoma for more than 5 years. Nine out of 10 worried about leakage to varying degrees and half the respondents accepted that this was a worry they had to live with. Almost 70% experienced leakage onto clothes within the preceding year, and 28% experienced this monthly. Peristomal skin complications were experienced by 82% of respondents, the severity of which correlated with reductions in QoL. CONCLUSION: Despite the consequential negative impact of leakage on QoL, individuals are not seeking advice to resolve leakage-related issues, including from their specialist stoma care nurse.


Assuntos
Qualidade de Vida , Estomas Cirúrgicos , Humanos , Prevalência , Estomas Cirúrgicos/efeitos adversos , Inquéritos e Questionários , Reino Unido/epidemiologia
9.
Front Psychol ; 13: 889245, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35814102

RESUMO

We raise the new possibility that people diagnosed with developmental dyslexia (DD) are specialized in explorative cognitive search, and rather than having a neurocognitive disorder, play an essential role in human adaptation. Most DD research has studied educational difficulties, with theories framing differences in neurocognitive processes as deficits. However, people with DD are also often proposed to have certain strengths - particularly in realms like discovery, invention, and creativity - that deficit-centered theories cannot explain. We investigate whether these strengths reflect an underlying explorative specialization. We re-examine experimental studies in psychology and neuroscience using the framework of cognitive search, whereby many psychological processes involve a trade-off between exploration and exploitation. We report evidence of an explorative bias in DD-associated cognitive strategies. High DD prevalence and an attendant explorative bias across multiple areas of cognition suggest the existence of explorative specialization. An evolutionary perspective explains the combination of findings and challenges the view that individuals with DD have a disorder. In cooperating groups, individual specialization is favored when features that confer fitness benefits are functionally incompatible. Evidence for search specialization suggests that, as with some other social organisms, humans mediate the exploration-exploitation trade-off by specializing in complementary strategies. The existence of a system of collective cognitive search that emerges through collaboration would help to explain our species' exceptional adaptiveness. It also aligns with evidence for substantial variability during our evolutionary history and the notion that humans are adapted not to a particular habitat but to variability itself. Specialization creates interdependence and necessitates balancing complementary strategies. Reframing DD therefore underscores the urgency of changing certain cultural practices to ensure we do not inhibit adaptation. Key improvements would remove cultural barriers to exploration and nurture explorative learning in education, academia, and the workplace, as well as emphasize collaboration over competition. Specialization in complementary search abilities represents a meta-adaptation; through collaboration, this likely enables human groups (as a species and as cultural systems) to successfully adapt. Cultural change to support this system of collaborative search may therefore be essential in confronting the challenges humanity now faces.

10.
Autism Res ; 15(8): 1469-1481, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35545929

RESUMO

Children and adolescents on the autism spectrum display sensory disturbances, rigid and repetitive behavior, social communication problems and a high prevalence of impaired adaptive functioning. Autism is associated with slowed behavioral and neural habituation to repeated sensory input and decreased responses to sensory deviations. Mismatch negativity (MMN) reflects a pre-attentive difference in the neural response to sensory deviations relative to regularities and studies overall suggest that children and adolescents with autism tend to have smaller MMN. However, it remains unclear whether reduced MMN in autism is coupled to severity of specific autistic symptoms or more generally to lower level of adaptive functioning. To address these questions, the present study used electroencephalography (EEG) to assess whether auditory MMN in 59 children and adolescents with autism aged 7-14 years compared to 59 typically developing children and adolescents were related to specific autistic symptoms or level in adaptive functioning. As hypothesized, the autism group had a lower MMN amplitude than controls. Smaller MMN amplitudes were specifically associated with lower adaptive functioning in the autistic subjects but not in controls while no apparent relationships were observed with autistic-like social interaction and communication problems, atypical language, rigidity, stereotypy or sensory sensitivity symptoms. Our findings indicate that a blunted response to changes in sensory input may underlie or contribute to the generalized difficulties with adapting to daily life circumstances seen in children and adolescents with autism. LAY SUMMARY: Children and adolescents on the autism spectrum have a high prevalence of impaired adaptive functioning. Neuroimaging studies have reported that children and adolescents with autism display attenuated brain activity when discriminating sensory input. However, it is unknown whether this attenuation is related to autistic symptoms and/or adaptive functioning. The present study used electroencephalogram (EEG) to show that attenuated brain response in discrimination of novel compared to repetitive sounds in children and adolescents with autism is related to their impaired adaptive functioning.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Estimulação Acústica/métodos , Adolescente , Transtorno do Espectro Autista/complicações , Encéfalo , Criança , Eletroencefalografia/métodos , Humanos
11.
Br J Nurs ; 31(6): S48-S58, 2022 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-35333558

RESUMO

BACKGROUND: Many people with a stoma experience leakage of stomal effluent. AIM: To investigate the impact of leakage on individuals with a stoma. METHODS: The Ostomy Life Study 2019 included a survey concerning experiences with stomal effluent leakage and the validated Ostomy Leak Impact tool. FINDINGS: Respondents with frequent leakage episodes were significantly more affected emotionally and they were feeling less in control than those who rarely or never experienced leakage. The emotional impact of experiencing leakage onto clothes appeared to last up to 1 year after the last leakage incidence. Because of worrying about leakage users increased their product usage and, of those who were in employment, 65% reported that leakage and the related worry influenced their ability to work. CONCLUSION: Most people with a stoma were emotionally impacted by experiencing leakage, especially by leakage outside the baseplate (resulting in soiled clothes). New solutions are warranted that can help reduce the impact of leakage.


Assuntos
Estomia , Estomas Cirúrgicos , Ansiedade , Humanos , Estomia/psicologia , Qualidade de Vida/psicologia , Inquéritos e Questionários
13.
J Glob Antimicrob Resist ; 29: 29-41, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35131507

RESUMO

The ATP synthase is a multicomponent enzyme that is largely conserved across the kingdoms of life. In many species the ATP synthase is central in the synthesis of ATP by using the electrochemical proton gradient generated via the electron transport chain. Bacteria inhabit very diverse ecological niches; hence their metabolism to extract nutrients and generation of ATP varies from species to species. Some species are obligate aerobes (e.g., Mycobacterium tuberculosis), relying on oxidative phosphorylation for ATP synthesis, whereas others are strict anaerobes (e.g., Clostridioides difficile) relying primarily on substrate-level phosphorylation using various fermentative pathways. Yet other species, such as Staphylococcus aureus and Escherichia coli are facultative anaerobes and can convert energy via both respiratory and fermentative pathways. The metabolic propensity and growth conditions experienced by bacterial species have a great impact on the necessity of a functional ATP synthase for viability. The ATP synthase has been validated as a druggable target with the approval of the ATP synthase inhibitor bedaquiline for treatment of M. tuberculosis, an organism in which the ATP synthase is essential for growth. Currently, no ATP synthase inhibitors are in clinical use against non-mycobacterial pathogens. In this review, the physiological functions of the ATP synthase in various bacterial pathogens are discussed in relation to the metabolic pathways utilized for providing energy. The ATP synthase is essential in important pathogenic species that are obligate aerobes, obligate anaerobes and aerotolerant anaerobes, whereas it is dispensable for growth in most facultative anaerobic pathogens. Interference with the ATP synthase in facultative anaerobes has physiological consequences, such as membrane hyperpolarization, which can be exploited for combination therapies. Collectively, the available data indicate that the ATP synthase is an interesting target for development of new antimicrobials beyond M. tuberculosis.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Trifosfato de Adenosina/metabolismo , Inibidores Enzimáticos/metabolismo , Humanos
14.
Microbiol Res ; 257: 126974, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35091344

RESUMO

Emergence of antibiotic resistant bacteria is evolving at an alarming pace; therefore, we must start turning to alternative approaches. One of these, could be the use of antibiotic adjuvants that enhances the effect of antibiotics towards resistant bacteria. A novel antibiotic adjuvant is cannabidiol (CBD), which we have previously shown can enhance the effect of bacitracin (BAC). BAC targets cell wall synthesis by inhibiting dephosphorylation of the lipid carrier undecaprenyl pyrophosphate prior to recycling across the membrane. However, the mechanism underlying this CBD mediated potentiation of BAC has remained unknown. To explore this, we examined resistance to CBD in Staphylococcus aureus through daily exposures to CBD. By subsequent whole genome sequencing, we observed multiple genes to be mutated, including the farE/farR system encoding a fatty acid efflux pump (FarE) and its regulator (FarR). Importantly, recreation of mutations in these genes showed decreased susceptibility towards the combination of CBD and BAC. Furthermore, we searched the Nebraska Transposon Mutant Library for CBD susceptible strains and identified menH encoding a protein participating in menaquinone biosynthesis. Strains containing deletions in this and other menaquinone related genes showed increased susceptibility towards CBD, while addition of exogenous menaquinone reversed the effect and reduced susceptible towards CBD. These results suggest that CBD potentiates BAC by redirecting the isoprenoid precursor isopentenyl pyrophosphate towards production of menaquinone rather than the lipid carrier undecaprenyl pyrophosphate, which dephosphorylation is inhibited by BAC. This in turn might decrease the level of undecaprenyl pyrophosphate thus enhancing the effect of BAC. Our study illustrates how antibiotic adjuvants may apply to enhance efficacy of antimicrobial compounds.


Assuntos
Canabidiol , Staphylococcus aureus , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana , Vitamina K 2
15.
Pediatr Res ; 91(4): 879-887, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-33790412

RESUMO

BACKGROUND: Evidence suggests that fronto-limbic brain regions and connecting white matter fibre tracts in the left hemisphere are more sensitive to glucocorticoids than in the right hemisphere. It is unknown whether treatment with glucocorticoids in childhood is associated with microstructural differences of the uncinate fasciculus and cingulum bundle, which connect fronto-limbic brain regions. Here, we tested the hypothesis that prior glucocorticoid treatment would be associated with differences in fractional anisotropy (FA) of the left relative to right uncinate fasciculus and cingulum bundle. METHODS: We performed diffusion-weighted imaging in 28 children and adolescents aged 7-16 years previously treated with glucocorticoids for nephrotic syndrome or rheumatic disease and 28 healthy controls. RESULTS: Patients displayed significantly different asymmetry in the microstructure of uncinate fasciculus with higher left but similar right uncinate fasciculus FA and axial diffusivity compared to controls. No apparent differences were observed for the cingulum. Notably, higher cumulative glucocorticoid doses were significantly associated with higher uncinate fasciculus FA and axial diffusivity bilaterally. CONCLUSIONS: Our findings indicate that previous glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with long-term changes in the microstructure of the uncinate fasciculi, and that higher cumulative glucocorticoid doses have a proportional impact on the microstructure. IMPACT: It is unknown if treatment with glucocorticoids in childhood have long-term effects on fronto-limbic white matter microstructure. The study examined if children and adolescents previously treated with glucocorticoids for nephrotic syndrome or rheumatic disorder differed in fronto-limbic white matter microstructure compared to healthy controls. The nephrotic and rheumatic patients had higher left but similar right uncinate fasciculus FA and axial diffusivity. Higher bilateral uncinate fasciculus FA and axial diffusivity was associated with higher cumulative glucocorticoid doses. We revealed new evidence suggesting that previous glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with long-term changes in uncinate fasciculi microstructure.


Assuntos
Síndrome Nefrótica , Substância Branca , Adolescente , Anisotropia , Encéfalo , Criança , Imagem de Tensor de Difusão/métodos , Feminino , Glucocorticoides/uso terapêutico , Humanos , Masculino , Síndrome Nefrótica/diagnóstico por imagem , Síndrome Nefrótica/tratamento farmacológico , Fascículo Uncinado , Substância Branca/diagnóstico por imagem
16.
Br J Nurs ; 30(22): S4-S12, 2021 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-34889680

RESUMO

BACKGROUND: Leakage is a common problem for people with a stoma. AIM: To investigate how people with a stoma and stoma care nurses perceive different patterns of effluent under the baseplate. METHODS: The Ostomy Life Study 2019 included a user survey and a nurse survey covering experiences of leakage and the perception of leakage. FINDINGS: Most people with a stoma perceived effluent reaching outside the baseplate as leakage (88-90%), whereas effluent close to the stoma only was not perceived as leakage by the majority (81-91%). Effluent covering major parts of the baseplate was perceived as leakage by most respondents with a colostomy or ileostomy (83%), whereas fewer respondents with a urostomy perceived this as leakage (57%). Most of the nurses (70%) did not perceive effluent close to the stoma as leakage. CONCLUSION: This study revealed that effluent confined to the area next to the stoma is generally not perceived as leakage.


Assuntos
Estomia , Estomas Cirúrgicos , Colostomia , Humanos , Ileostomia , Percepção
17.
Artigo em Inglês | MEDLINE | ID: mdl-34099064

RESUMO

BACKGROUND: People suffering from Borderline Personality Disorder (BPD) seem to have incoherent autobiographical narratives. Tentative evidence suggests that reduced narrative coherence of autobiographical memories is associated with insecure attachment. However, it remains unknown whether incoherent autobiographical narratives in people with BPD are coupled to experiences of childhood trauma, which is highly prevalent in BPD. METHOD: We examined if written autobiographical memories in 26 female participants with BPD had reduced narrative coherence relative to 28 healthy female controls and whether more incoherent narratives were associated with childhood trauma. RESULTS: As hypothesized, results showed that compared to controls, the autobiographical memories in participants with BPD had reduced narrative coherence, specifically inadequate orientation about the narrative and lack of narrative structure. More self-reported childhood adversity was coupled to lower orientation across groups whereas increased childhood adversity showed a specific relationship to lowered narrative structure in BPD participants. CONCLUSION: Women with BPD had incoherent autobiographical narratives, and reduced narrative coherence was associated with more self-reported childhood adversity, which appeared to explain the group differences.

18.
Dev Cogn Neurosci ; 50: 100982, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34171560

RESUMO

Verbal fluency is the ability to retrieve lexical knowledge quickly and efficiently and develops during childhood and adolescence. Few studies have investigated associations between verbal fluency performance and brain structural variation in children. Here we examined associations of verbal fluency performance with structural measures of frontal and temporal language-related brain regions and their connections in 73 typically-developing children aged 7-13 years. Tract-based spatial statistics was used to extract fractional anisotropy (FA) from the superior longitudinal fasciculus/arcuate fasciculus (SLF/AF), and the white matter underlying frontal and temporal language-related regions. FreeSurfer was used to extract cortical thickness and surface area. Better semantic and phonemic fluency performance was associated with higher right SLF/AF FA, and phonemic fluency was also modestly associated with lower left SLF/AF FA. Explorative voxelwise analyses for semantic fluency suggested associations with FA in other fiber tracts, including corpus callosum and right inferior fronto-occipital fasciculus. Overall, our results suggest that verbal fluency performance in children may rely on right hemisphere structures, possibly involving both language and executive function networks, and less on solely left hemisphere structures as often is observed in adults. Longitudinal studies are needed to clarify whether these associations are mediated by maturational processes, stable characteristics and/or experience.


Assuntos
Encéfalo , Semântica , Adolescente , Anisotropia , Encéfalo/diagnóstico por imagem , Criança , Humanos , Substância Branca/diagnóstico por imagem
19.
Front Mol Biosci ; 8: 691569, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34150853

RESUMO

Staphylococcus aureus is a leading cause of bacterial infections world-wide. Staphylococcal infections are preferentially treated with ß-lactam antibiotics, however, methicillin-resistant S. aureus (MRSA) strains have acquired resistance to this superior class of antibiotics. We have developed a growth-based, high-throughput screening approach that directly identifies cell wall synthesis inhibitors capable of reversing ß-lactam resistance in MRSA. The screen is based on the finding that S. aureus mutants lacking the ClpX chaperone grow very poorly at 30°C unless specific steps in teichoic acid synthesis or penicillin binding protein (PBP) activity are inhibited. This property allowed us to exploit the S. aureus clpX mutant as a unique screening tool to rapidly identify biologically active compounds that target cell wall synthesis. We tested a library of ∼50,000 small chemical compounds and searched for compounds that inhibited growth of the wild type while stimulating growth of the clpX mutant. Fifty-eight compounds met these screening criteria, and preliminary tests of 10 compounds identified seven compounds that reverse ß-lactam resistance of MRSA as expected for inhibitors of teichoic acid synthesis. The hit compounds are therefore promising candidates for further development as novel combination agents to restore ß-lactam efficacy against MRSA.

20.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070683

RESUMO

Infections with enterococci are challenging to treat due to intrinsic resistance to several antibiotics. Especially vancomycin-resistant Enterococcus faecium and Enterococcus faecalis are of considerable concern with a limited number of efficacious therapeutics available. From an initial screening of 20 peptidomimetics, 11 stable peptide/ß-peptoid hybrids were found to have antibacterial activity against eight E. faecium and E. faecalis isolates. Microbiological characterization comprised determination of minimal inhibitory concentrations (MICs), probing of synergy with antibiotics in a checkerboard assay, time-kill studies, as well as assessment of membrane integrity. E. faecium isolates proved more susceptible than E. faecalis isolates, and no differences in susceptibility between the vancomycin-resistant (VRE) and -susceptible E. faecium isolates were observed. A test of three peptidomimetics (Ac-[hArg-ßNsce]6-NH2, Ac-[hArg-ßNsce-Lys-ßNspe]3-NH2 and Oct-[Lys-ßNspe]6-NH2) in combination with conventional antibiotics (vancomycin, gentamicin, ciprofloxacin, linezolid, rifampicin or azithromycin) revealed no synergy. The same three potent analogues were found to have a bactericidal effect with a membrane-disruptive mode of action. Peptidomimetics Ac-[hArg-ßNsce-Lys-ßNspe]3-NH2 and Oct-[Lys-ßNspe]6-NH2 with low MIC values (in the ranges 2-8 µg/mL and 4-16 µg/mL against E. faecium and E. faecalis, respectively) and displaying weak cytotoxic properties (i.e., <10% hemolysis at a ~100-fold higher concentration than their MICs; IC50 values of 73 and 41 µg/mL, respectively, against HepG2 cells) were identified as promising starting points for further optimization studies.


Assuntos
Antibacterianos , Enterococcus faecalis/crescimento & desenvolvimento , Enterococcus faecium/crescimento & desenvolvimento , Peptoides , Resistência a Vancomicina/efeitos dos fármacos , Enterococos Resistentes à Vancomicina/crescimento & desenvolvimento , Antibacterianos/química , Antibacterianos/farmacologia , Peptoides/química , Peptoides/farmacologia
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