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BACKGROUND: Primary progressive aphasia (PPA) is a neurodegenerative syndrome characterized by speech and/or language impairment with relatively spared cognition. Research investigating behavioral speech-language intervention and methods for cognitive-linguistic assessment in PPA has predominantly centered around monolingual speakers. This gap hinders the widespread adoption of evidence-based approaches and exacerbates the inequities faced by culturally and linguistically diverse populations living with PPA. OBJECTIVE: This scoping review synthesizes the current evidence for assessment and treatment practices in bilingual PPA as well as the operationalization of bilingualism in PPA. METHODS: Arksey & O'Malley's scoping review methodology was utilized. Information was extracted from each study and entered into a data-charting template designed to capture information regarding operationalization of bilingualism in PPA and assessment and treatment practices. RESULTS: Of the 16 identified studies, 14 reported the results of assessments conducted in both languages. Three studies reported positive naming treatment outcomes. Thirteen studies included English-speaking participants, revealing linguistic bias. Most studies reported age of acquisition, proficiency, and patterns of language use rather than providing an operational definition for bilingualism. CONCLUSIONS: Neither formal assessment measures nor clear guidelines for assessment of bilingual PPA currently exist; however, language-specific measures are emerging. Speech-language intervention in bilingual PPA has been relatively unexplored, representing a significant gap in the literature. In order to improve diagnostic and treatment options for bilingual PPA, targeted efforts to increase representation of bilinguals from various sociocultural contexts, as well as those who speak a variety of language pairs, is necessary.
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Afasia Progresiva Primaria , Multilingüismo , Humanos , Lenguaje , Lingüística , Habla , Afasia Progresiva Primaria/diagnóstico , Afasia Progresiva Primaria/terapiaRESUMEN
The aim of this study was to comprehensively characterise S. aureus from the Caribbean Islands of Trinidad and Tobago, and Jamaica. A total of 101 S. aureus/argenteus isolates were collected in 2020, mainly from patients with skin and soft tissue infections. They were characterised by DNA microarray allowing the detection of ca. 170 target genes and assignment to clonal complexes (CC)s and strains. In addition, the in vitro production of Panton-Valentine leukocidin (PVL) was examined by an experimental lateral flow assay. Two isolates were identified as S. argenteus, CC2596. The remaining S. aureus isolates were assigned to 21 CCs. The PVL rate among methicillin-susceptible S. aureus (MSSA) isolates was high (38/101), and 37 of the 38 genotypically positive isolates also yielded positive lateral flow results. The isolate that did not produce PVL was genome-sequenced, and it was shown to have a frameshift mutation in agrC. The high rate of PVL genes can be attributed to the presence of a known local CC8-MSSA clone in Trinidad and Tobago (n = 12) and to CC152-MSSA (n = 15). In contrast to earlier surveys, the USA300 clone was not found, although one MSSA isolate carried the ACME element, probably being a mecA-deficient derivative of this strain. Ten isolates, all from Trinidad and Tobago, were identified as MRSA. The pandemic ST239-MRSA-III strain was still common (n = 7), but five isolates showed a composite SCCmec element not observed elsewhere. Three isolates were sequenced. That showed a group of genes (among others, speG, crzC, and ccrA/B-4) to be linked to its SCC element, as previously found in some CC5- and CC8-MRSA, as well as in S. epidermidis. The other three MRSA belonged to CC22, CC72, and CC88, indicating epidemiological connections to Africa and the Middle East.
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We have investigated the prevalence of carbapenemase-producing uropathogens at the University Hospital of the West Indies, Jamaica. From 64 unique urine samples collected between January and March 2020, only 2 closely related Klebsiella pneumoniae (ST11, 14 SNPs of difference; no clear epidemiological links found between patients) were carbapenemase-producers. By whole-genome sequencing (WGS), blaNDM-5 was found on ~46 kb, IncX3 plasmid. These findings highlight the necessity for continuous surveillance of these pathogens in Jamaica. IMPORTANCE As the problem of antibiotic resistance continues to be a global problem, we hope to be able to shed further insight into what is happening within the Caribbean, from which there has been a paucity of data. The ability to appropriately tackle the problem of resistance requires surveillance from all territories, including resource limited settings. In this paper, we look at a mechanism of resistance that renders some critical antibiotics useless, including carbapenems, cephalosporins, and penicillin.
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Introduction: The aim of this study was to investigate the prevalence and distribution of AmpC beta-lactamases (BLs) in uropathogens (E. coli and K. pneumoniae) at the University Hospital of the West Indies Jamaica (UHWI). Method: De-duplicated consecutive urine samples, collected from January to March 2020 at the UHWI, were analyzed. Screening and phenotypic confirmatory tests were conducted using resistance to cefoxitin and the Disc Approximation Test (DAT) respectively, for isolates of interest. Multiplex PCR was performed on cefoxitin resistant (CR) isolates for the detection of bla CIT, bla MOX, bla FOX, bla ACC, and bla DHA genes. Whole genome sequencing (WGS) was used to further detect AmpC BL genes in PCR negative isolates with indeterminate phenotypic results. Results: Sixty-four Gram negative isolates were obtained from 61 patients (55% female), aged 18 months to 88 years old. At least 35% (26) had complicated urinary tract infections. Only 7 out of 64 isolates were E. coli or K. pneumoniae, had antibiograms suggestive of possible AmpC BL production and were CR. DATs confirmed AmpC BL in two of these (1 K. pneumoniae; 1 E. coli), one tested negative (E. coli) and four had inconclusive results (K. pneumoniae). PCR detected bla DHA and bla CIT in two CR isolates. WGS further detected bla CMY-42 in one isolate. The prevalence of screened CR isolates with AmpC BL is 57.14% (4 of 7), representing 6.25% of the sample. AmpC BL producers tested had 100% susceptibility to meropenem and nitrofurantoin. Conclusion: AmpC BL prevalence among E. coli and K. pneumoniae, common urinary pathogens, in the studied isolates is low. Although cefoxitin screening is helpful, phenotypic screening using the DAT can yield indeterminate results best clarified by molecular testing.
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Escherichia coli , Klebsiella pneumoniae , Humanos , Femenino , Masculino , Klebsiella pneumoniae/genética , Escherichia coli/genética , Cefoxitina/farmacología , Prevalencia , Centros de Atención Terciaria , Antibacterianos/farmacología , beta-Lactamasas/genética , Proteínas Bacterianas/genética , Pruebas de Sensibilidad MicrobianaRESUMEN
Endosymbiotic relationship has played a significant role in the evolution of marine species, allowing for the development of biochemical machinery for the synthesis of diverse metabolites. In this work, we explore the chemical space of exogenous compounds from shipworm endosymbionts using LC-MS-based metabolomics. Priority T. turnerae strains (1022X.S.1B.7A, 991H.S.0A.06B, 1675L.S.0A.01) that displayed antimicrobial activity, isolated from shipworms collected from several sites in the Philippines were cultured, and fractionated extracts were subjected for profiling using ultrahigh-performance liquid chromatography with high-resolution mass spectrometry quadrupole time-of-flight mass analyzer (UHPLC-HRMS QTOF). T. turnerae T7901 was used as a reference microorganism for dereplication analysis. Tandem MS data were analyzed through the Global Natural Products Social (GNPS) molecular networking, which resulted to 93 clusters with more than two nodes, leading to four putatively annotated clusters: lipids, lysophosphatidylethanolamines, cyclic dipeptides, and rhamnolipids. Additional clusters were also annotated through molecular networking with cross-reference to previous publications. Tartrolon D cluster with analogues, turnercyclamycins A and B; teredinibactin A, dechloroteredinibactin, and two other possible teredinibactin analogues; and oxylipin (E)-11-oxooctadec-12-enoic acid were putatively identified as described. Molecular networking also revealed two additional metabolite clusters, annotated as lyso-ornithine lipids and polyethers. Manual fragmentation analysis corroborated the putative identification generated from GNPS. However, some of the clusters remained unclassified due to the limited structural information on marine natural products in the public database. The result of this study, nonetheless, showed the diversity in the chemical space occupied by shipworm endosymbionts. This study also affirms the use of bioinformatics, molecular networking, and fragmentation mechanisms analysis as tools for the dereplication of high-throughput data to aid the prioritization of strains for further analysis.
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Shear stress is recognized as a regulator of angiogenesis. However, the shear stress experienced by the endothelial cells of capillary sprouts remains unknown. The objective of this study was to estimate shear stress due to local interstitial flow along endothelial tip cells at the end of the capillary sprout lumen. Computational fluid dynamics were used to model flow within a blind-ended vessel, transendothelial flow across the vessel wall, and flow within the surrounding perivascular/interstitial space. Shear stress along the wall of the tip cells was calculated while varying sprout length, perivascular space channel width, and vessel wall hydraulic conductivity. Increasing sprout length, increasing wall hydraulic conductivity, and decreasing perivascular space width increased shear stress magnitude. Wall shear stress magnitude within the lumen ranged from 0.015 to 0.55 dyne/cm2 at the sprout entrance and linearly decreased to near zero at the base of the tip cells. Tip cell wall shear stress magnitude due to interstitial flow ranged from 0.009 to 4.65 dyne/cm2. In 3 out of 8 cases, shear stress magnitude was above 1 dyne/cm2 and considered physiologically relevant. The results provide a framework for discussing the role of local mechanical cues in regulating endothelial cell dynamics involved in angiogenesis. Mainly, interstitial flows may generate physiologically relevant shear stresses on tip cells in certain scenarios. This source of tip cell shear stress has not been previously considered or modeled.
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Capilares , Células Endoteliales , Capilares/fisiología , Hidrodinámica , Estrés Mecánico , VenasRESUMEN
Altered extracellular matrix (ECM) production is a hallmark of many fibroproliferative diseases, including certain cancers. The high incidence of glycan-rich components within altered ECM makes the use of glycan-binding proteins such as Galectin-3 (G3) a promising therapeutic strategy. The complexity of ECM as a rich 3D network of proteins with varied glycosylation states makes it challenging to determine the retention of glycan-binding proteins in altered ECM environments. Computational models capable of predicting the transport of glycan-binding proteins in altered ECM can benefit the design and testing of such proteins and associated novel therapeutic strategies. However, such computational models require many kinetic parameters that cannot be estimated from traditional 2D pharmacokinetic assays. To validate transport properties of G3 in 3D ECM constructs, we developed a species transport model that includes diffusion and matrix-binding components to predict retention of G3 fusion proteins in glycan-rich ECM. By iteratively comparing our computational model to experimental results, we are able to determine a reasonable range of parameters for a robust computational model of G3 transport. We anticipate this overall approach to building a data-driven model is translatable to other ECM-targeting therapeutic strategies.
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Matriz Extracelular , Galectina 3 , Simulación por Computador , Matriz Extracelular/metabolismo , Galectina 3/metabolismo , Glicosilación , Polisacáridos/metabolismoRESUMEN
OBJECTIVES: To quantitatively determine the antimicrobial susceptibility of clinical Neisseria gonorrhoeae isolates from men with urethral discharge in Jamaica and to describe the syndromic treatment therapies administered. METHODS: Urethral eSwabs (Copan) were collected from 175 men presenting with urethral discharge to the Comprehensive Health Centre STI Clinic, Kingston, Jamaica. Clinical information was collected and MICs of eight antimicrobials were determined for N. gonorrhoeae isolates (n = 96) using Etest and interpreted using CLSI criteria. RESULTS: The median age of the subjects was 28 years (range: 18-73 years) with a median of 2 sexual partners (range: 1-25) per male in the previous 3 months. All examined N. gonorrhoeae isolates were susceptible to ceftriaxone (96/96), azithromycin (91/91), cefixime (91/91) and spectinomycin (91/91). For ciprofloxacin and gentamicin, respectively, 98.9% (91/92) and 91.3% (84/92) of the isolates were susceptible and 1.1% (1/92) and 8.7% (8/92) showed intermediate susceptibility/resistance. For tetracycline and benzylpenicillin, respectively, 38.0% (35/92) and 22.0% (20/91) of the isolates were susceptible, 52.2% (48/92) and 74.7% (68/91) showed intermediate susceptibility/resistance and 9.8% (9/92) and 3.3% (3/91) were resistant. Syndromic treatment was administered as follows: 93.1% received 250 mg of ceftriaxone intramuscularly plus 100 mg of doxycycline orally q12h for 1-2 weeks and 6.9% received 500 mg of ciprofloxacin orally plus 100 mg of doxycycline orally q12h for 1 week. CONCLUSIONS: Ceftriaxone (250 mg) remains appropriate for gonorrhoea treatment in the examined population of men in Kingston, Jamaica. Surveillance of N. gonorrhoeae AMR should be expanded in Jamaica and other Caribbean countries to guide evidence-based treatment guidelines.
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Gonorrea , Neisseria gonorrhoeae , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Ceftriaxona/farmacología , Ceftriaxona/uso terapéutico , Niño , Preescolar , Ciprofloxacina/farmacología , Farmacorresistencia Bacteriana , Gonorrea/tratamiento farmacológico , Gonorrea/epidemiología , Humanos , Lactante , Jamaica/epidemiología , Masculino , Pruebas de Sensibilidad MicrobianaRESUMEN
AIM: Human papillomavirus (HPV) has been reported to be associated with oral and oropharyngeal cancer. However, little information is available about the epidemiology of oral HPV infection in Jamaica. The purpose of the present study was to assess the prevalence of oral HPV strains using the oral rinse method in HIV and non-HIV Jamaican patients, as well as to determine the association of HPV with sexual practices, smoking, and alcohol use. METHODS: A cross-sectional study was conducted on patients attending The University of the West Indies Mona Dental Polyclinic and the Centre for HIV/AIDS Research and Education Services. Salivary samples were tested through molecular analysis for 37 HPV genotypes using the linear array HPV genotyping test. A survey questionnaire was used to obtain demographic details, smoking history, alcohol practice, sexual practice, and history of HPV testing. RESULTS: The HPV prevalence was 8.65% in 18-64 y olds (N = 104), with a slight female predilection (55%). No high-risk HPV types were found. HPV-84 was the most common type in both HIV and non-HIV patients; 66.7% of HPV-positive participants reported that they had six or more lifetime sexual partners. CONCLUSION: The prevalence of oral HPV was similar to that in other countries. No statistically-significant relationship was observed between the prevalence of HPV and either the number of sexual partners, smoking, or alcohol history. A nationwide study on oral HPV detection might be helpful in developing a HPV vaccination policy in Jamaica.
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Genotipo , Infecciones por VIH/complicaciones , Epidemiología Molecular , Antisépticos Bucales , Papillomaviridae/genética , Infecciones por Papillomavirus/complicaciones , Adolescente , Adulto , Estudios Transversales , ADN Viral/análisis , Femenino , Técnicas de Genotipaje , Humanos , Jamaica/epidemiología , Masculino , Persona de Mediana Edad , Enfermedades de la Boca/epidemiología , Enfermedades de la Boca/virología , Neoplasias Orofaríngeas , Prevalencia , Factores de Riesgo , Conducta Sexual , Fumar , Encuestas y Cuestionarios , Adulto JovenRESUMEN
[This corrects the article DOI: 10.1186/s13756-018-0315-3.].
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Background: Antibiotic resistance (ABR) is a serious threat that requires coordinated global intervention to prevent its spread. There is limited data from the English-speaking Caribbean. Methods: As part of a national programme to address antibiotic resistance in Jamaica, a survey of the knowledge, attitudes and antibiotic prescribing practices of Jamaican physicians was conducted using a 32-item self-administered questionnaire. Results: Of the eight hundred physicians targeted, 87% responded. The majority thought the problem of resistance very important globally (82%), less nationally (73%) and even less (53%) in personal practices. Hospital physicians were more likely to consider antibiotic resistance important in their practice compared to those in outpatient practice or both (p < 0.001). Composite knowledge scores were generated and considered good if scored > 80%, average if 60-79% and poor if < 60%. Most had good knowledge of factors preventing resistance (83%) and resistance inducing potential of specific antibiotics (59%), but only average knowledge of factors contributing to resistance (57%). Knowledge of preventative factors was highest in females (p = 0.004), those with postgraduate training (p = 0.001) and those > four years post graduation (p = 0.03). Empiric therapy was often directed by international guidelines and cultures were not routinely done. Limited laboratory and human resources were identified as challenges. Conclusion: Physicians in this study were aware of the problem of ABR, but downplayed its significance nationally and personally. These results will guide a national antibiotic stewardship programme.
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Programas de Optimización del Uso de los Antimicrobianos , Actitud del Personal de Salud , Farmacorresistencia Microbiana , Conocimientos, Actitudes y Práctica en Salud , Médicos/psicología , Antibacterianos/normas , Antibacterianos/uso terapéutico , Programas de Optimización del Uso de los Antimicrobianos/normas , Actitud , Región del Caribe , Estudios Transversales , Prescripciones de Medicamentos , Educación Médica , Femenino , Hospitales , Humanos , Jamaica , Masculino , Pautas de la Práctica en Medicina , Encuestas y CuestionariosRESUMEN
The human oral cavity contains more than 500 different bacterial species. These organisms belong to several phyla including Bacteroidetes, Firmicutes, Tenericutes, Actinobacteria, Proteobacteria, Euryarchaeota, Chlamydiae, and Spirochaetes. Many of these have the ability to colonize the gingival crevices and the outer surface of the tooth forming biofilms often leading to dental plaque formation. These bacteria produce acid that erode teeth causing cavities or infections. The diagnosis of these infections is often clinical and antibiotics are used empirically to treat some infections or as prophylaxis. The characterization, definitive diagnosis, and susceptibility testing of oral bacterial infections are valuable in guiding appropriate therapy and in prevention of disease.
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Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/terapia , Enfermedades de la Boca/diagnóstico , Enfermedades de la Boca/terapia , Caries Dental/diagnóstico , Caries Dental/microbiología , Caries Dental/terapia , Placa Dental/diagnóstico , Placa Dental/microbiología , Placa Dental/terapia , Humanos , Enfermedades de la Boca/microbiologíaRESUMEN
INTRODUCTION: Consistent practice of hand hygiene (HH) has been shown to reduce the incidence and spread of hospital acquired infections. The objectives of this study were to determine the level of compliance and possible factors affecting compliance with HH practices among HCWs at a teaching hospital in Kingston, Jamaica. METHODOLOGY: A prospective observational study was undertaken at the University Hospital of the West Indies (UHWI) over a two weeks period. Trained, validated observers identified opportunities for hand hygiene as defined by the WHO "Five Hand Hygiene Moments" and recorded whether appropriate hand hygiene actions were taken or missed. Observations were covert to prevent the observer's presence influencing the behaviour of the healthcare workers (HCWs) and targeted areas included the intensive care units (ICUs), surgical wards and surgical outpatient departments. A ward infrastructure survey was also done. Data were entered and analysed using SPSS version 16 for Windows. Chi-square analysis using Pearson's formula was used to test associations between 'exposure' factors and the outcome 'compliance'. RESULTS: A total of 270 hand hygiene opportunities were observed and the overall compliance rate was 38.9%. No differences were observed between the various types of HCWs or seniority. HCWs were more likely to perform hand hygiene if the indication was 'after' rather than 'before' patient contact (p = 0.001). CONCLUSION: This study underscores the need for improvement in HH practices among HCWs in a teaching hospital. Health education with particular attention to the need for HH prior to physical contact with patients is indicated.
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Adhesión a Directriz , Higiene de las Manos/métodos , Personal de Salud , Control de Infecciones/métodos , Infección Hospitalaria/prevención & control , Hospitales Universitarios , Humanos , Jamaica , Estudios ProspectivosRESUMEN
INTRODUCTION: The global dissemination of the New Delhi metallo-beta-lactamase (NDM) gene among certain strains of bacteria has serious implications since the infections caused by such organisms pose a therapeutic challenge. Although the NDM gene has been detected in various parts of the world, this is the first report of its detection in the English-speaking Caribbean. The NDM producing Klebsiella pneumoniae was isolated from an Indian patient who had recently relocated to Jamaica. METHODOLOGY: Identification and susceptibility testing of the K. pneumoniae isolate was performed using the Vitek 2 automated system) in keeping with Clinical and Laboratory Standards Institute (CLSI) standards. It was identified as a metallobetalactamase producer using the Rosco KPC+MBL kit. Genotypic screening for common betalactamase (including carbapenemase) genes, was carried out using two multiplex PCRs: one for SHV-, TEM-, CTX-M-, OXA-1-, and CMY-2-types, and one for VIM-, KPC-, IMP-, OXA-48, GES-, and NDM-types. Strain typing was conducted by pulsed-field gel electrophoresis (PFGE) using XbaI and multi-locus sequencing (MLS). Plasmid isolation and analysis was also performed. RESULTS: K. pneumoniae (N11-02395), not previously associated with the dissemination of the NDM in India, Sweden or the UK, was found to harbor the NDM-1 gene on plasmid pNDM112395. CONCLUSION: The identification of the NDM-1 gene underscores the need for effective surveillance and infection control measures to identify and prevent spread of multidrug resistant Gram negative bacilli. Strict infection control measures implemented for this patient helped to prevent the spread of this organism to other patients.
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Infecciones por Klebsiella/microbiología , Klebsiella pneumoniae/enzimología , Klebsiella pneumoniae/aislamiento & purificación , beta-Lactamasas/análisis , beta-Lactamasas/genética , Electroforesis en Gel de Campo Pulsado , Humanos , Lactante , Jamaica , Klebsiella pneumoniae/clasificación , Klebsiella pneumoniae/genética , Masculino , Pruebas de Sensibilidad Microbiana , Tipificación Molecular , Plásmidos/análisisRESUMEN
Selective targeting of diseased cells can increase therapeutic efficacy and limit off-target adverse effects. We developed a new tool to selectively perforate living cells with functionalized gold nanoparticles (AuNPs) and near-infrared (NIR) femtosecond (fs) laser. The receptor CD44 strongly expressed by cancer stem cells was used as a model for selective targeting. Citrate-capped AuNPs (100 nm in diameter) functionalized with 0.01 orthopyridyl-disulfide-poly(ethylene glycol) (5 kDa)-N-hydroxysuccinimide (OPSS-PEG-NHS) conjugated to monoclonal antibodies per nm(2) and 5 µM HS-PEG (5 kDa) were colloidally stable in cell culture medium containing serum proteins. These AuNPs attached mostly as single particles 115 times more to targeted CD44(+) MDA-MB-231 and CD44(+) ARPE-19 cells than to non-targeted CD44(-) 661W cells. Optimally functionalized AuNPs enhanced the fs laser (800 nm, 80-100 mJ cm(-2) at 250 Hz or 60-80 mJ cm(-2) at 500 Hz) to selectively perforate targeted cells without affecting surrounding non-targeted cells in co-culture. This novel highly versatile treatment paradigm can be adapted to target and perforate other cell populations by adapting to desired biomarkers. Since living biological tissues absorb energy very weakly in the NIR range, the developed non-invasive tool may provide a safe, cost-effective clinically relevant approach to ablate pathologically deregulated cells and limit complications associated with surgical interventions.
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Oro/química , Rayos Láser , Nanopartículas del Metal/química , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Línea Celular Tumoral , Ácido Cítrico/química , Citometría de Flujo , Humanos , Receptores de Hialuranos/inmunología , Receptores de Hialuranos/metabolismo , Microscopía Fluorescente , Polietilenglicoles/química , Succinimidas/químicaRESUMEN
Milk proteins are frequently used as supplements in fortified foods. However, processing produces chemical changes which likely affect the nutritional advantage. This study was intended to explore the possible difference in digestibility between extruded and non-extruded caseins and how the dietary N (ε) -carboxymethyllysine (CML) is metabolised. Normal rats were randomized into either an extruded protein diet (EP) or the same with unextruded proteins (UEP), for two periods of 2 weeks at 7 to 9 and 11 to 13 weeks of age. However, no difference in protein digestibility was detected between the two diets, either in young or in adult animals, despite a 9.4-fold higher level of CML and an 8.5-fold higher level of lysinoalanine in the EP than in the UEP. No diet-related changes were observed in plasma CML, either protein bound or free. Amounts of 38 and 48 % of the orally absorbed CML were excreted in urine and faeces, respectively, in UEP-fed rats. Lower rates of excretion were found in the EP-fed rats (23 and 37 %, respectively). A second animal study using a single oral dose of free CML (400 µg/rat) was set up to measure the systemic concentration of CML every hour from 0 to 4 h. It revealed that protein-bound CML was not affected by the oral dose of CML, and the highest free CML level found in the circulation was 600 ng/mL. Extruded proteins, therefore, appear to be well digested, and CML rapidly eliminated. Since its elimination is, however, incomplete, the question of its biodistribution and metabolism remains open.
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Caseínas/metabolismo , Proteínas en la Dieta/metabolismo , Lisina/análogos & derivados , Animales , Caseínas/farmacocinética , Culinaria/métodos , Dieta , Proteínas en la Dieta/farmacocinética , Digestión/fisiología , Heces , Manipulación de Alimentos/métodos , Lisina/sangre , Lisina/metabolismo , Lisina/farmacocinética , Lisinoalanina/metabolismo , Reacción de Maillard , Ratas , Ratas Wistar , Aumento de Peso/efectos de los fármacosRESUMEN
We tested the hypothesis that heart rate (HR) reduction, induced by the selective hyperpolarization-activated current inhibitor ivabradine (Iva), might improve left ventricular (LV) function, structure, and electrical remodeling in severe post-myocardial infarction (MI) chronic heart failure (HF). MI was produced in adult male Wistar rats. After 2 mo, echocardiography was performed before the randomization into MI and MI + Iva (10 mg x kg(-1) x day(-1)) groups. After 3 mo of treatment, echocardiography and 24-h telemetry were recorded. Cardiac collagen, mRNA, and protein expressions of angiotensin-converting enzyme (ACE) and ANG II type 1 (AT(1)) receptor were quantified. As a result, at 2 mo post-MI, all rats displayed severe congestive HF signs (ejection fraction < 30%). At 5 mo post-MI, body and heart weights were similar in the MI and MI + Iva groups. LV ejection fraction and LV end-diastolic pressure were worsened in the MI group, whereas both were improved with Iva. Iva reduced HR by 10.4% (P < 0.03 vs. MI) and ventricular premature complexes by 89% (P < 0.03) and improved HR variability (standard deviation of the RR interval) by 22% (P < 0.05). There were no effects of Iva on PR, QRS, and QT durations. Interstitial fibrosis in the MI-remote LV was markedly reduced by Iva (4.0 +/- 0.1 vs. 1.8 +/- 0.1%, P < 0.005). Increases in ventricular gene and protein expressions of ACE and AT(1) receptor in MI were completely blunted by Iva. In conclusion, these data indicated that HR reduction by Iva prevents the worsening of LV dysfunction and remodeling that may be related to a downregulation of cardiac renin-angiotensin-aldosterone system transcripts. Such beneficial effects of Iva on cardiac remodeling open new clinical perspectives for the treatment of severe HF.
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Antiarrítmicos/administración & dosificación , Benzazepinas/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Frecuencia Cardíaca/efectos de los fármacos , Miocardio/patología , Disfunción Ventricular Izquierda/tratamiento farmacológico , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Animales , Colágeno/metabolismo , Modelos Animales de Enfermedad , Esquema de Medicación , Ecocardiografía Doppler , Electrocardiografía Ambulatoria , Fibrosis , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Ivabradina , Masculino , Infarto del Miocardio/complicaciones , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/fisiopatología , Miocardio/metabolismo , Peptidil-Dipeptidasa A/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptor de Angiotensina Tipo 1/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/genética , Índice de Severidad de la Enfermedad , Volumen Sistólico/efectos de los fármacos , Telemetría , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Izquierda/fisiopatología , Presión Ventricular/efectos de los fármacosRESUMEN
BACKGROUND: Cardiomyocyte-specific overexpression of aldosterone synthase in male (MAS) mice induces a nitric oxide-independent coronary dysfunction. Because calcium-activated potassium (BKCa) channels are essential for vascular smooth muscle cell (VSMC) relaxation, we hypothesized that aldosterone alters their expression and/or function in VSMCs. METHODS AND RESULTS: Left coronary artery segments were isolated from MAS or male wild-type mice and mounted in a wire myograph. Responses to acetylcholine were assessed (in the presence of a nitric oxide synthase inhibitor) without or with the cyclooxygenase inhibitor diclofenac, the KCa inhibitors charybdotoxin plus apamin, or the BKCa inhibitor iberiotoxin. Expression of BKCa was quantified in hearts by real-time quantitative polymerase chain reaction and Western blot and in isolated coronary arteries by polymerase chain reaction. The effect of aldosterone on BKCa expression also was studied in cultured rat aortic VSMCs. Acetylcholine-mediated coronary relaxation was markedly decreased in MAS mice and was prevented by spironolactone. Diclofenac did not affect the MAS-induced impairment in the responses to acetylcholine, whereas charybdotoxin plus apamin virtually abolished the relaxation in both male wild-type and MAS mice. After iberiotoxin, relaxation to acetylcholine was decreased to a larger extent in male wild-type than in MAS, leading to similar levels of relaxation. BKCa-alpha and -beta1 subunit expressions were significantly decreased in MAS heart and coronary arteries. In cultured VSMCs, aldosterone induced a concentration-dependent decrease in BKCa expression, which was prevented by spironolactone. CONCLUSIONS: Aldosterone overexpression altered VSMC BKCa expression and coronary BKCa-dependent relaxation. The resulting alteration of relaxing responses may contribute to the deleterious effects of aldosterone in cardiovascular diseases. BKCa channels may therefore be useful therapeutic targets in cardiovascular diseases.