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BACKGROUND: Asymptomatic bacteriuria (ASB) - the presence of bacteria in urine without urinary tract infection (UTI) related signs & symptoms (S&S) - is common in the elderly bladder and is not considered pathogenic for UTI. We hypothesise that colonisation with non-uropathogenic bacteria could protect the bladder from invasion of more harmful bacteria. The exact role and dynamics of bacteriuria in the relation to the development of a UTI is still unknown. We aim to provide insight into the course of bacteriuria in the elderly bladder and its relation to UTI in frail older adults. METHODS AND ANALYSIS: A prospective observational cohort study is being conducted in Dutch nursing homes (NHs) between February 2024 and December 2025. Urine samples and case report forms (CRF) on UTI-related S&S will be collected from each consenting NH resident every 3 months for a follow-up period of 18 months. Whenever a UTI-suspicion occurs in between the 3 monthly time points, additional data and a urine sample will be collected. Urine samples undergo several urinalyses (e.g. dipstick and bacterial culture). Additional molecular analysis will be conducted on a selection of cultured Escherichia coli (E. coli) for virulence genes. Primary analyses will be conducted between residents with and without ASB at each time point. The primary outcome is UTI incidence during follow-up. In secondary analyses we will also take into account the low versus high presence of virulence genes of the E. coli. DISCUSSION: The combination of high ASB prevalence and a reduced ability of frail older adults to express UTI-related S&S may lead to UTI misdiagnosis and inappropriate antibiotic use. To our knowledge, this is the first study to investigate the dynamics and role of bacteriuria in the elderly bladder and their potential protective effect on the development of UTI. The study findings with comprehensive analysis of epidemiological, clinical and molecular data could set the fundamental base for future guidelines and studies, and contribute to improving prevention, diagnosis and treatment of UTI in frail older adults, in addition to contributing to antibiotic stewardship in NHs.
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Bacteriuria , Vejiga Urinaria , Infecciones Urinarias , Humanos , Estudios Prospectivos , Anciano , Bacteriuria/microbiología , Bacteriuria/epidemiología , Infecciones Urinarias/microbiología , Infecciones Urinarias/epidemiología , Vejiga Urinaria/microbiología , Países Bajos/epidemiología , Femenino , Masculino , Casas de Salud , Escherichia coli/aislamiento & purificación , Escherichia coli/genética , Anciano de 80 o más Años , Bacterias/aislamiento & purificación , Bacterias/genética , Bacterias/clasificación , Anciano Frágil , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/epidemiologíaRESUMEN
Preclinical studies suggest that the GABAB receptor is a potential target for treatment of substance use disorders. Baclofen (BLF), a prototypical GABAB receptor agonist, is the only specific GABAB receptor agonist available for application in clinical addiction treatment. The nucleus accumbens shell (AcbSh) is a key node in the circuit that controls reward-directed behavior. However, the relationship between GABAB receptors in the AcbSh and memory reconsolidation was unclear. The aim of this study was to investigate the effect of intra-AcbSh injection of BLF on the reconsolidation of morphine reward memory. Male C57BL/6J mice were used to establish morphine conditioned place preference (CPP) model and carry out morphine reward memory retrieval and activation experiment. The effects of intra-AcbSh injection of BLF on morphine-induced CPP, reinstatement of CPP and locomotor activity were observed after environmental cues activating morphine reward memory. The results showed that intra-AcbSh injection of BLF (0.06 nmol/0.2 µL/side or 0.12 nmol/0.2 µL/side), rather than vehicle or BLF (0.01 nmol/0.2 µL/side), following morphine reward memory retrieval abolished morphine-induced CPP by disrupting its reconsolidation in mice. Moreover, this effect persisted for more than 14 days, which was not reversed by a morphine priming injection. Furthermore, intra-AcbSh injection of BLF without morphine reward memory retrieval had no effect on morphine-associated reward memory. Interestingly, administration of BLF into the AcbSh had no effect on the locomotor activity of mice during testing phase. Based on these results, we concluded that intra-AcbSh injection of BLF following morphine reward memory could erase morphine-induced CPP by disrupting its reconsolidation. Activating GABAB receptor in AcbSh during drug memory reconsolidation may be a potential approach to prevent drug relapse.
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Baclofeno/administración & dosificación , Condicionamiento Clásico , Morfina , Núcleo Accumbens/efectos de los fármacos , Trastornos Relacionados con Opioides , Animales , Agonistas de Receptores GABA-B/administración & dosificación , Locomoción , Masculino , Memoria , Ratones , Ratones Endogámicos C57BL , RecompensaRESUMEN
Allogeneic stem cell transplantation (allo-SCT) can be a curative treatment for patients with a hematologic malignancy due to alloreactive T cell responses recognizing minor histocompatibility antigens (MiHA). Yet tumor immune escape mechanisms can cause failure of T cell immunity, leading to relapse. Tumor cells display low expression of costimulatory molecules and can up-regulate coinhibitory molecules that inhibit T cell functionality on ligation with their counter-receptors on the tumor-reactive T cells. The aim of this explorative study was to evaluate immune checkpoint expression profiles on T cell subsets and on cytomegalovirus (CMV)- and/or MiHA-reactive CD8+ T cells of allo-SCT recipients using a 13-color flow cytometry panel, and to correlate these expression patterns to clinical outcomes. MiHA-reactive CD8+ T cells exhibited an early differentiated CD27++/CD28++ phenotype with low KLRG-1 and CD57 expression. These T cells also displayed increased expression of PD-1, TIM-3, and TIGIT compared with total effector memory T cells and CMV-specific CD8+ T cells in healthy donors and allo-SCT recipients. Remarkably, high coexpression of PD-1, TIGIT, and KLRG-1 on MiHA-reactive CD8+ T cells was associated with relapse after allo-SCT. Taken together, these findings indicate that MiHA-specific CD8+ T cells of relapsed patients have a distinctive coinhibitory expression signature compared with patients who stay in remission. This phenotype may serve as a potential monitoring tool in patients. Moreover, these findings suggest that PD-1 and TIGIT play important roles in regulating T cell-mediated tumor control, providing a rationale for immunotherapy with blocking antibodies to treat relapse after allo-SCT.
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Linfocitos T CD8-positivos/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Neoplasias Hematológicas/inmunología , Lectinas Tipo C/inmunología , Proteínas de Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Receptores Inmunológicos/inmunología , Trasplante de Células Madre , Transactivadores/inmunología , Aloinjertos , Linfocitos T CD8-positivos/patología , Femenino , Neoplasias Hematológicas/patología , Neoplasias Hematológicas/terapia , Humanos , Memoria Inmunológica , Masculino , RecurrenciaRESUMEN
BACKGROUND: Tachypnoea in acutely ill patients can be an early sign of a life-threatening condition such as sepsis. Routine measurement of the respiratory rate by GPs might improve the recognition of sepsis. AIM: To assess the accuracy and feasibility of respiratory rate measurements by GPs. DESIGN & SETTING: Observational cross-sectional mixed-methods study in the setting of out-of-hours (OOH) home visits at three GP cooperatives in The Netherlands. METHOD: GPs were observed during the assessment of acutely ill patients, and semi-structured interviews were performed. The GP-assessed respiratory rate was compared with a reference measurement. In the event that the respiratory rate was not counted, GPs were asked to estimate the rate (dichotomised as ≥22 breaths per minute or <22 breaths per minute). RESULTS: Observations of 130 acutely ill patients were included, and 14 GPs were interviewed. In 33 patients (25%), the GP counted the respiratory rate. A mean difference of 0.27 breaths per minute (95% confidence interval [CI] = -5.7 to 6.3) with the reference measurement was found. At a cut-off point of ≥22 breaths per minute, a sensitivity of 86% (95% CI = 57% to 98%) was found when the GP counted the rate, and a sensitivity of 43% (95% CI = 22% to 66%) when GPs estimated respiratory rates. GPs reported both medical and practical reasons for not routinely measuring the respiratory rate. CONCLUSION: GPs are aware of the importance of assessing the respiratory rate of acutely ill adult patients, and counted measurements are accurate. However, in most patients the respiratory rate was not counted, and the rate was often underestimated when estimated.
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Atrial septal defect (ASD) is a common acyanotic congenital cardiac disorder associated with genetic mutations. The objective of this study was to identify the genetic factors in a Chinese family with ASD patients by a whole exome sequencing approach. Causative ASD gene mutations were examined in 16 members from a three-generation family, among which 6 individuals were diagnosed as having ASD. One hundred and eighty-three unrelated healthy Chinese were recruited as a normal control group. Peripheral venous blood was collected from every subject for genetic analysis. Exome sequencing was performed in the ASD patients. Potential causal mutations were detected in non-ASD family members and normal controls by polymerase chain reaction and sequencing analysis. The results showed that all affected family members carried two novel compound mutations, c.1187delT of PCDHGA4 and c.2557insC of SLFN14, and these two mutations were considered to have synergetic function on ASD. In conclusion, the mutations of c.1187delT of PCDHGA4 and c.2557insC of SLFN14 may be pathogenic factors contributing to the development of ASD.
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Endorribonucleasas/genética , Defectos del Tabique Interatrial/genética , Mutación/genética , Adulto , Secuencia de Aminoácidos , Pueblo Asiatico/genética , Exoma/genética , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Adulto JovenRESUMEN
Ras-associated protein-1 (Rap1), a small GTPase in the Ras-related protein family, is an important regulator of basic cellular functions (e.g., formation and control of cell adhesions and junctions), cellular migration, and polarization. Through its interaction with other proteins, Rap1 plays many roles during cell invasion and metastasis in different cancers. The basic function of Rap1 is straightforward; it acts as a switch during cellular signaling transduction and regulated by its binding to either guanosine triphosphate (GTP) or guanosine diphosphate (GDP). However, its remarkably diverse function is rendered by its interplay with a large number of distinct Rap guanine nucleotide exchange factors and Rap GTPase activating proteins. This review summarizes the mechanisms by which Rap1 signaling can regulate cell invasion and metastasis, focusing on its roles in integrin and cadherin regulation, Rho GTPase control, and matrix metalloproteinase expression.
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The onset of local invasion and lymphatic metastasis in pancreatic cancer limits survival following surgical intervention and additional therapies. Reduced expression of KiSS1 in pancreatic cancer is associated with cancer metastasis. Previous studies have indicated that kisspeptin, the KiSS1 peptide, is able to bind to its receptorGPR54 (hOT7T175) and suppress the migration of PANC1 pancreatic cancer cells. Whether the metastatic suppression of KiSS1 is dependent on the levels of GPR54 in pancreatic cancer cell lines remains unclear. Human BxPC3 pancreatic carcinoma cells are highly differentiated without exhibiting metastasis, however PANC1 pancreatic carcinoma cells are poorly differentiated and exhibit local and lymph node metastasis. Compared with primary cultured trophoblasts, BxPc3 and PANC1 cells were observed to express low levels of KiSS1 mRNA and protein, measured using reverse transcriptionquantitative polymerase chain reaction and western blotting, respectively. However, greater mRNA and protein expression levels of GPR54 were observed in PANC1 cells compared with BxPc3 cells. An MTT assay was used to investigate the effect of KiSS1 on BxPc3 and PANC1 cell proliferation. There were no significant differences in proliferation following transfection with KiSS1 in BxPc3 and PANC1 cells compared with the controls (P>0.05). A Transwell assay with chambers coated with Matrigel was used to evaluate the in vitro invasive ability of BxPc3 and PANC1 cells, with the invasion index of BxPc3 and PANC1 cells significantly reduced following 48 h of KiSS1 overexpression (P<0.05). The mRNA and protein expression levels of KiSS1 were significantly increased in BxPc3 and PANC1 cells 48 h subsequent to transfection with KiSS1 (P<0.05), while GPR54 expression was not altered (P>0.05). KiSS1 is a metastasis suppressor gene of pancreatic cancer, and this suppression is not dependent on the expression levels of GPR54. Therefore, KiSS1 is potentially a novel target for gene therapy.
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Kisspeptinas/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Receptores Acoplados a Proteínas G/metabolismo , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Invasividad Neoplásica , Neoplasias Pancreáticas/genética , Receptores Acoplados a Proteínas G/genética , Receptores de Kisspeptina-1 , Transfección , Neoplasias PancreáticasRESUMEN
Evidence on the association between dietary fiber intake and pancreatic cancer risk has been controversial. Therefore, we carried out this meta-analysis to summarize available evidence from epidemiologic studies on this point. Relevant studies were identified by searching PubMed, Embase and Web of Science databases as well as by reviewing the rence lists of relevant articles. Random or fixed-effects model was used to calculate the summary risk estimates and 95% confidence intervals (CIs). This meta-analysis included one cohort and thirteen case-control studies which involving a total of 3287 subjects with pancreatic cancer. After summarizing the risk estimates of these studies, we yielded a significant association between dietary fiber intake and pancreatic cancer risk among case-control studies (odds ratio = 0.54; 95%CI = 0.44-0.67; I(2) = 41.4%; P = 0.043) but a non-significant result in cohort study (hazard ratio = 1.01; 95%CI = 0.59-1.74). Additionally, significant inverse associations were observed when we carried out the stratify analyses by the study characteristics and adjustment for potential confounders among case-control studies. Given only one cohort study included in the present meta-analysis, further prospective-designed studies should validate our findings and report more detail results, including those for subtypes of fiber, the risk estimates which corrected the impact of measurement errors and fully adjust for the potential confounders.