Drug disposition and targeting: Transport across the blood-brain barrier

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Transport mechanisms for the antidepressant citalopram in brain microvessel endothelium

Blood-brain barrier transport of the selective serotonin reuptake inhibitor and antidepressant, citalopram, was studied using monolayers of bovine brain microvessel endothelial cells (BMECs). This study provides for the first time, evidence of a transport mechanism for a selective serotonin reuptake inhibitor (SSRI). Carrier-mediated transport, efflux mechanisms, as well as inhibition of metabolizing enzymes of citalopram were investigated. Citalopram transport was saturable and temperature-dependent suggesting that passage of the drug across BMECs was mediated by a carrier mechanism. Since the apical to basolateral and basolateral to apical permeability coefficients were similar and cyclosporin A, a P-glycoprotein inhibitor, does not modify the transport of citalopram, it appeared that no active efflux systems were involved in this transport. Citalopram is only available as a racemic drug and its pharmacological effect resides mainly in the S-(+)-enantiomer. However, the passage of citalopram enantiomers across BMEC monolayers was not stereoselective. Finally, inhibition of the metabolizing enzymes of citalopram and monoamine oxidases did not modify the permeation of citalopram across BMECs. Collectively, our results suggested that citalopram crosses the blood-brain barrier via a non-stereoselective, bidirectional and symmetrical carrier-mediated mechanism without influences of active efflux mechanisms or monoamine oxidases

Understanding Trail Runners' Activity on Online Community Forums: An Inductive Analysis of Discussion Topics

Recreational trail runners often participate in online community forums where they can freely read posted messages, join discussions and/or introduce new discussion topics. This tool can enhance learning as runners connect with other trail runners and reflect on how they can better organize their own practice. Studying forum activity would provide greater insight into the relationship between field practice and dedicated forums. The aim of this study was therefore to detect the topics discussed online by trail runners in order to understand how they collectively look for solutions that help them adapt to issues that emerge during actual practice. The discussion topics (n = 171) on the forum hosted by the Raidlight brand were examined using inductive content analysis, which distinguished two general dimensions. The first dimension was training and had four first-order themes (i.e., "specific trail running sessions", "complementary trail running sessions". "training plans" and "specific questions about races") grouped into two second-order themes (i.e., "training session contents" and "structure and schedule"). The second dimension was health and had seven first-order themes (i.e., "tendinitis", "muscle issues", "foot issues", "sprains and fractures", "pain", "physiology" and "substances and practitioners") grouped into two second-order themes (i.e., "pain and injury" and "prevention"). The results indicate that the issues that trail runners discuss on forums are significant and that the successions of questions and solutions are a fruitful means for building, enriching and adjusting their activity as they cope with constraints. As a practical consequence, suggestions for improving such online platforms are made

Selective Vulnerability of Neuronal Subtypes in ALS: A Fertile Ground for the Identification of Therapeutic Targets

It is well defined that subpopulations of motoneurons have different vulnerability to the pathology causing amyotrophic lateral sclerosis (ALS). In the spinal cord, the fast fatigable motoneurons have been shown to be the first to degenerate, followed by fatigue-resistant and slow motoneurons. In contrast motoneurons located in the Onuf’s and oculomotor nuclei appear to be resistant to disease. With a focus on research mainly done on mice overexpressing the mutated human superoxide dismutase (SOD1) protein, we review recent studies exploring the mechanisms that underlie the selective vulnerability of the various motoneuron subtypes. By comparing differences in gene expression between these populations, it has been possible to identify factors, which critically determine the survival of motoneurons and the neuromuscular function in the pathologic context of ALS. Furthermore, we discuss the contribution of non-cell autonomous processes, involving glial cells and the skeletal muscle, in the neurodegenerative process. Exploring the cause of neurodegeneration from the angle of the selective neuronal vulnerability has recently led to the identification of novel targets, which open opportunities for therapeutic intervention against ALS

Ammonia trace measurements at ppb level based on near-IR photoacoustic spectroscopy

A photoacoustic sensor using a laser diode emitting near 1532nm in combination with an erbium-doped fibre amplifier has been developed for ammonia trace gas analysis at atmospheric pressure. NH3 concentration measurements down to 6ppb and a noise-equivalent detection limit below 3ppb in dry air are demonstrated. Two wavelength-modulation schemes with 1f and 2f detection using a lock-in amplifier were investigated and compared to maximise the signal-to-noise ratio. A quantitative analysis of CO2 and H2O interference with NH3 is presented. Typical concentrations present in ambient air of 400ppm CO2 and 1.15% H2O (50% relative humidity at 20°C) result in a NH3 equivalent concentration of 36ppb and 100ppb, respectivel

Age-related anxieties and the effects on successful aging

M.A.This study aimed to explore the perceptions of a sample of senior citizens at the Reuven Senior Centre in order to ascertain their age-related feelings and experience of the aging process. Eighty respondents were systematically selected to complete an age-related questionnaire. Forty-seven questionnaires were completed and returned, which formed the data basis of the study. The nature of the research was exploratory - descriptive as it attempted to investigate and portray the perceptions of the respondents. The research design which was used, was quantitative in nature and a questionnaire was used for the purpose of data collection. Furthermore the study could be described as a correlational research design. This design assumes a cause and effect relationship. Major findings included: The senior citizen respondents expressed that they experience age-related anxieties. Major anxieties included the fear of failing health, physical ability and becoming dependent on others. From the study, it would be inappropriate to suppose a relationship between the absence of age-related anxiety and the phenomenon of successful aging. Further research would be necessary with various population samples across the spectrum of age. Fear of aging and of the aged may be more relevant to younger people who have not yet reached an older age. This may be referred to as a fear of the unknown. Social workers have a role to play in the re-education and positive reframing of age-related issues to allay unnecessary fears. All the respondents seemed to exhibit successful aging. No overt depression or malfunctioning was evident. Findings indicate that the senior citizen sample at the Reuven Senior Centre Complex exhibit qualities of successful aging. Despite old people having fewer resources for happiness than their younger counterparts, they have great adaption capacities. Old people should not be pitied but admired for their strength and wisdom

Risk factors for vulnerable youth in urban townships in South Africa: the potential contribution of reactive attachment disorder

Reactive attachment disorder (RAD) is a psychiatric disorder developing in early or middle childhood as a consequence of significant failures in the caregiving environment. RAD results in children failing to relate socially, either by exhibiting markedly inhibited behaviour or by indiscriminate social behaviour and is associated with significant socio-behavioural problems in the longer term. This study examined RAD in South Africa, a setting with high environmental risks. We recruited a sub-sample of 40 10-year-old children from a cohort enrolled during pregnancy for whom early attachment status was known. Children were purposefully selected to represent the four attachment categories using the data available on the strange situation procedure (SSP) at 18 months. The Manchester Child Attachment Story Task (MCAST) assessed current attachment and RAD was diagnosed using a standardised assessment package. A high proportion of the children (5/40% or 12.5%) fulfilled diagnostic criteria for RAD; all were boys and were displaying the disinhibited type. SSP classification at 18 months was not significantly associated with RAD symptoms at age of 10 years, while current MCAST classifications were. This suggests that children in this sample are at much higher risk of RAD than in high-income populations, and despite a fairly typical attachment distribution in this population at 18 months, RAD was evidenced in later childhood and associated with current attachment disorganisation. The strengths of this research include its longitudinal nature and use of diagnostic assessments. Given increasing evidence that RAD is relatively stable over time and introduces longer term socio-behavioural risks; the high rate of RAD in this sample (12.5%) highlights potential developmental threats to children in low- and middle-income countries (LMICs). Our results should be interpreted with caution given sample size and risk of selection bias. Further research is needed to confirm these findings

Upper and Lower Respiratory Tract Viral Infections and Acute Graft Rejection in Lung Transplant Recipients

Background. Lung transplant recipients are frequently exposed to respiratory viruses and are particularly at risk for severe complications. The aim of this study was to assess the association among the presence of a respiratory virus detected by molecular assays in bronchoalveolar lavage (BAL) fluid, respiratory symptoms, and acute rejection in adult lung transplant recipients. Methods. Upper (nasopharyngeal swab) and lower (BAL) respiratory tract specimens from 77 lung transplant recipients enrolled in a cohort study and undergoing bronchoscopy with BAL and transbronchial biopsies were screened using 17 different polymerase chain reaction—based assays. Results. BAL fluid and biopsy specimens from 343 bronchoscopic procedures performed in 77 patients were analyzed. We also compared paired nasopharyngeal and BAL fluid specimens collected in a subgroup of 283 cases. The overall viral positivity rate was 29.3% in the upper respiratory tract specimens and 17.2% in the BAL samples (P < .001). We observed a significant association between the presence of respiratory symptoms and positive viral detection in the lower respiratory tract (P = .012). Conversely, acute rejection was not associated with the presence of viral infection (odds ratio, 0.41; 95% confidence interval, 0.20-0.88). The recovery of lung function was significantly slower when acute rejection and viral infection were both present. Conclusions. A temporal relationship exists between acute respiratory symptoms and positive viral nucleic acid detection in BAL fluid from lung transplant recipients. We provide evidence suggesting that respiratory viruses are not associated with acute graft rejection during the acute phase of infectio

Comparison of vitality states of finishers and withdrawers in trail running: An enactive and phenomenological perspective.

Studies on ultra-endurance suggest that during the races, athletes typically experience three vitality states (i.e., preservation, loss, and revival) at the phenomenological level. Nevertheless, how these states contribute to the management and outcome of performance remains unclear. The aim of this study was to determine whether and how the vitality states experienced by runners and their evolution during a trail race can be used to distinguish finishers from withdrawers. From an enactive and phenomenological framework, we processed enactive interviews and blog posts of race narratives. We distinguished units of meaning, which were grouped into sequences of experience; each sequence was then categorized as one of the three vitality states: state of vitality preservation (SVP), state of vitality loss (SVL) or state of vitality revival (SVR). We analyzed the distribution of these vitality states and their temporal organization at the beginning, in the second and third quarters, and at the end of the races, and we qualitatively characterized runners' adaptations to SVL. Results showed that finishers completed the race in SVP, with overall significantly more sequences in SVP and significantly fewer sequences in SVL than withdrawers. SVR did not discriminate finishers from withdrawers. The temporal organization of the vitality states showed a significant difference in the emergence of SVP from the second quarter of the race, as well as a significant difference in the emergence of SVL from the third quarter of the race. The analysis of adaptations to SVL confirmed that finishers were more capable of exiting SVL by enacting a preservation world when they felt physical or psychological alerts, whereas withdrawers remained in SVL. Our results showed that finishers and withdrawers did not enact the same phenomenological worlds in the race situation, especially in the organization of vitality adaptations and their relationships to difficulties; the cumulative effect of the succession of experienced vitality states differed, as well