Prediction of plasma sodium changes in the acutely ill patients: the potential role of tissue sodium content.

BACKGROUND Rapid correction of dysnatremias can result in neurological complications. Therefore, various formulas are available to predict changes in plasma sodium concentration ([Na+]) after treatment, but these have been shown to be inaccurate. This could be explained by sodium acumulation in skin and muscle tissue, which is not explicitly considered in these formulas. We assessed the association between clinical and biochemical factors related to tissue sodium accumulation and the discrepancy between predicted and measured plasma [Na+]. METHODS We used data from an intensive care unit (ICU) cohort with complete data on sodium, potassium, and water balance. The predicted plasma [Na+] was calculated using the Barsoum-Levine (BL) and the Nguyen-Kurtz (NK) formula. We calculated the discrepancy between predicted and measured plasma sodium and fitted a linear mixed-effect model to investigate its association with factors related to tissue sodium accumulation. RESULTS We included 594 ICU days of sixty-three patients in our analysis. The mean plasma [Na+] at baseline was 147±6 mmol/L. The median (IQR) discrepancy between predicted and measured plasma [Na+] was 3.14 mmol/L (1.48, 5.55) and 3.53 mmol/L (1.81, 6.44) for the BL and NK formulas, respectively. For both formulas, estimated total body water (p=0.027), initial plasma [Na+] (p<0.001) and plasma [Na+] change (p<0.001) were associated with the discrepancy between predicted and measured plasma [Na+]. CONCLUSION In this ICU cohort, initial plasma [Na+], total body water, and plasma [Na+] changes, all factors that are related to tissue sodium accumulation, were associated with the inaccurateness of plasma [Na+] prediction

Vascular perfusion and hypoxic areas in RIF-1 tumours after photodynamic therapy.

The influence of photodynamic therapy (PDT) on vascular perfusion and the development of hypoxia was investigated in the murine RIF-1 tumour. Image analysis was used to quantify changes in perfusion and hypoxia at 5 min after interstitial Photofrin-mediated PDT. The fluorescent stain Hoechst 33342 was used as an in vivo marker of functional vascular perfusion and the antibody anti-collagen type IV as a marker of the tumour vasculature. The percentage of total tumour vasculature that was perfused decreased to less than 30% of control values after PDT. For the lower light doses this decrease was more pronounced in the centre of the tumour. The observed reduction in vascular perfusion showed a good linear correlation (r = 0.98) with previously published tumour perfusion data obtained with the 86Rb extraction technique. The image analysis technique provides extra information concerning the localisation of (non)-perfused vessels. To detect hypoxic tumour areas in vivo, an immunohistochemical method was used employing NITP [7-(4'-(2-nitroimidazol-1-yl)-butyl)-theophylline]. A large increase in hypoxic areas was found for PDT-treated tumours. More than half the total tumour area was hypoxic after PDT, compared with < 4% for control tumours. Our studies illustrate the potential of image analysis systems for monitoring the functional consequences of PDT-mediated vascular damage early after treatment. This provides direct confirmation that the perfusion changes lead to tissue hypoxia, which has implications for the combined treatment of PDT with bioreductive drugs

Is green space in the living environment associated with people's feelings of social safety?

Abstract. The authors investigate whether the percentage of green space in people's living environ- ment affects their feelings of social safety positively or negatively. More specifically they investigate the extent to which this relationship varies between urban and rural areas, between groups in the community that can be identified as more or less vulnerable, and the extent to which different types of green space exert different influences. The study includes 83736 Dutch citizens who were interviewed about their feelings of social safety. The percentage of green space in the living environment of each respondent was calculated, and data analysed by use of a three-level latent variable model, controlled for individual and environmental background characteristics. The analyses suggest that more green space in people's living environment is associated with enhanced feelings of social safetyöexcept in very strongly urban areas, where enclosed green spaces are associated with reduced feelings of social safety. Contrary to the common image of green space as a dangerous hiding place for criminal activity which causes feelings of insecurity, the results suggest that green space generally enhances feelings of social safety. The results also suggest, however, that green space in the most urban areas is a matter of concern with respect to social safety.

<i>Cntn4</i>, a risk gene for neuropsychiatric disorders, modulates hippocampal synaptic plasticity and behavior

Neurodevelopmental and neuropsychiatric disorders, such as autism spectrum disorders (ASD), anorexia nervosa (AN), Alzheimer’s disease (AD), and schizophrenia (SZ), are heterogeneous brain disorders with unknown etiology. Genome wide studies have revealed a wide variety of risk genes for these disorders, indicating a biological link between genetic signaling pathways and brain pathology. A unique risk gene is Contactin 4 (Cntn4), an Ig cell adhesion molecule (IgCAM) gene, which has been associated with several neuropsychiatric disorders including ASD, AN, AD, and SZ. Here, we investigated the Cntn4 gene knockout (KO) mouse model to determine whether memory dysfunction and altered brain plasticity, common neuropsychiatric symptoms, are affected by Cntn4 genetic disruption. For that purpose, we tested if Cntn4 genetic disruption affects CA1 synaptic transmission and the ability to induce LTP in hippocampal slices. Stimulation in CA1 striatum radiatum significantly decreased synaptic potentiation in slices of Cntn4 KO mice. Neuroanatomical analyses showed abnormal dendritic arborization and spines of hippocampal CA1 neurons. Short- and long-term recognition memory, spatial memory, and fear conditioning responses were also assessed. These behavioral studies showed increased contextual fear conditioning in heterozygous and homozygous KO mice, quantified by a gene-dose dependent increase in freezing response. In comparison to wild-type mice, Cntn4-deficient animals froze significantly longer and groomed more, indicative of increased stress responsiveness under these test conditions. Our electrophysiological, neuro-anatomical, and behavioral results in Cntn4 KO mice suggest that Cntn4 has important functions related to fear memory possibly in association with the neuronal morphological and synaptic plasticity changes in hippocampus CA1 neurons

Behavioral, physiological, and molecular differences in response to dietary restriction in three inbred mouse strains

, physiological, and molecular differences in response to dietary restriction in three inbred mouse strains. Am J Physiol Endocrinol Metab 291: E574 -E581, 2006. First published May 2, 2006; doi:10.1152/ajpendo.00068.2006.-Food restriction paradigms are widely used in animal studies to investigate systems involved in energy regulation. We have observed behavioral, physiological, and molecular differences in response to food restriction in three inbred mouse strains, C57BL/6J, A/J, and DBA/2J. These are the progenitors of chromosome substitution and recombinant inbred mouse strains used for mapping complex traits. DBA/2J and A/J mice increased their locomotor activity during food restriction, and both displayed a decrease in body temperature, but the decrease was significantly larger in DBA/2J compared with A/J mice. C57BL/6J mice did not increase their locomotor activity and displayed a large decrease in their body temperature. The large decline in body temperature during food restriction in DBA/2J and C57BL/6J strains was associated with a robust reduction in plasma leptin levels. DBA/2J mice showed a marked decrease in white and brown adipose tissue masses and an upregulation of the antithermogenic hypothalamic neuropeptide Y Y1 receptor. In contrast, A/J mice showed a reduction in body temperature to a lesser extent that may be explained by downregulation of the thermogenic melanocortin 3 receptor and by behavioral thermoregulation as a consequence of their increased locomotor activity. These data indicate that genetic background is an important parameter in controlling an animal&apos;s adaptation strategy in response to food restriction. Therefore, mouse genetic mapping populations based on these progenitor lines are highly valuable for investigating mechanisms underlying strain-dependent differences in behavioral physiology that are seen during reduced food availability. locomotor activity; body temperature; food intake; neuropeptide Y; melanocortin ENERGY BALANCE is regulated by processes that influence food intake and energy expenditure. The main components of energy expenditure are metabolism and thermogenesis induced by exercise, cold, and diet, and these are regulated by the interaction of behavioral, physiological, and molecular mechanisms. Imbalances in energy state can result in health problems, such as malnutrition, eating disorders, or obesity Food restriction paradigms are widely used in animal studies to investigate mechanisms involved in the regulation of energy balance Behavioral thermoregulation is one of the mechanisms by which endothermic animals achieve and maintain a stable body temperature during times of food shortage In addition to behavioral thermogenesis, endothermic animals use autonomic mechanisms to regulate their core temperature (47). For example, brown adipose tissue (BAT)-mediated nonshivering thermogenesis is involved in heat production when animals are exposed to cold. Mitochondrial uncoupling proteins (UCPs) in the BAT generate heat by uncoupling oxidative phosphorylation, and, in mice, targeted inactivation of the gene coding for UCP1 leads to cold sensitivity (13). Leptin increases the thermogenesis in BAT by increasing UCP1 expression (48); therefore, decreased heat production resulting from hypoleptinemia could be associated with the increased locomotor activity seen in some inbred mice strains and rats in response to restricted feeding. Leptin&apos;s effects on the hypothalamic neuropeptide Y (NPY) and melanocortin systems have been implicated in the regulation of energy balance (56, 59). For example, selective NPY Y 1 and Y 5 receptor agonists increase food consumption and decrease circulating levels of thyroid hormones, showing that both receptors mediate the stimulatory effects of NPY on foo

Forskolin-induced Organoid Swelling is Associated with Long-term CF Disease Progression

RATIONALE: Cystic fibrosis (CF) is a monogenic life-shortening disease associated with highly variable individual disease progression which is difficult to predict. Here we assessed the association of forskolin-induced swelling (FIS) of patient-derived organoids (PDO) with long-term CF disease progression in multiple organs and compared FIS with the golden standard biomarker sweat chloride concentration (SCC). METHODS: We retrieved 9-year longitudinal clinical data from the Dutch CF Registry of 173 people with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Individual CFTR function was defined by FIS, measured as the relative size increase of intestinal organoids after stimulation with 0.8 µM forskolin, quantified as area under the curve (AUC). We used linear mixed effect models and multivariable logistic regression to estimate the association of FIS with long-term FEV1pp decline and development of pancreatic insufficiency, CF-related liver disease and diabetes. Within these models, FIS was compared with SCC. RESULTS: FIS was strongly associated with longitudinal changes of lung function, with an estimated difference in annual FEV1pp decline of 0.32% (95%CI: 0.11%-0.54%; p=0.004) per 1000-points change in AUC. Moreover, increasing FIS levels were associated with lower odds of developing pancreatic insufficiency (adjusted OR: 0.18, 95%CI: 0.07-0.46, p<0.001), CF-related liver disease (adjusted OR: 0.18, 95%CI: 0.06-0.54, p=0.002) and diabetes (adjusted OR: 0.34, 95%CI: 0.12-0.97, p=0.044). These associations were absent for SCC. CONCLUSION: This study exemplifies the prognostic value of a PDO-based biomarker within a clinical setting, which is especially important for people carrying rare CFTR mutations with unclear clinical consequences

Healthcare consumption of patients with left ventricular assist device: real-world data

BACKGROUND: A left ventricular assist device (LVAD) is a life-saving but intensive therapy for patients with end-stage heart failure. We evaluated the healthcare consumption in a cohort of LVAD patients in our centre over 6 years. METHODS: All patients with a primary LVAD implantation at the University Medical Centre Utrecht in Utrecht, the Netherlands from 2016 through 2021 were included in this analysis. Subsequent hospital stay, outpatient clinic visits, emergency department visits and readmissions were recorded. RESULTS: During the investigated period, 226 LVADs were implanted, ranging from 32 in 2016 to 45 in 2020. Most LVADs were implanted in patients aged 40-60 years, while they were supported by or sliding on inotropes (Interagency Registry for Mechanically Assisted Circulatory Support class 2 or 3). Around the time of LVAD implantation, the median total hospital stay was 41 days. As the size of the LVAD cohort increased over time, the total annual number of outpatient clinic visits also increased, from 124 in 2016 to 812 in 2021 (p = 0.003). The numbers of emergency department visits and readmissions significantly increased in the 6‑year period as well, with a total number of 553 emergency department visits and 614 readmissions. Over the years, the annual number of outpatient clinic visits decreased by 1 per patient-year follow-up, while the annual numbers of emergency department visits and readmissions per patient-year remained stable. CONCLUSION: The number of patients supported by an LVAD has grown steadily over the last years, requiring a more specialised healthcare in this particular population