Summary
Aim : The gastrointestinal transit of sequentially administered capsules was investigated in relation to the availability of fluid along the intestinal lumen by magnetic resonance imaging.
...Methods : Water‐sensitive magnetic resonance imaging was performed on 12 healthy subjects during fasting and 1 h after a meal. Specifiable non‐disintegrating capsules were administered at 7, 4 and 1 h prior to imaging.
Results : While food intake reduced the mean fluid volumes in the small intestine (105 ± 72 mL vs. 54 ± 41 mL, P < 0.01) it had no significant effect on the mean fluid volumes in the colon (13 ± 12 mL vs. 18 ± 26 mL). The mean number of separated fluid pockets increased in both organs after meal (small intestine: 4 vs. 6, P < 0.05; large intestine: 4 vs. 6, P < 0.05). The distribution of capsules between the small and large intestine was strongly influenced by food (colon: 3 vs. 17 capsules, P < 0.01).
Conclusions : The results show that fluid is not homogeneously distributed along the gut, which likely contributes to the individual variability of drug absorption. Furthermore, transport of fluid and solids through the ileocaecal valve is obviously initiated by a meal‐induced gastro‐ileocaecal reflex.
Stem cell therapy is a promising treatment for neurological disorders such as cerebral ischemia, Parkinson's disease and Huntington's disease. In recent years, many clinical trials with various cell ...types have been performed often showing mixed results. Major problems with cell therapies are the limited cell availability and engraftment and the reduced integration of grafted cells into the host tissue. Stem cell-based therapies can provide a limitless source of cells but survival and differentiation remain a drawback. An improved understanding of the behaviour of stem cells and their interaction with the host tissue, upon implantation, is needed to maximize the therapeutic potential of stem cells in neurological disorders. Organotypic cultures made from brain slices from specific brain regions that can be kept in culture for several weeks after injecting molecules or cells represent a remarkable tool to address these issues. This model allows the researcher to monitor/assess the behaviour and responses of both the endogenous as well as the implanted cells and their interaction with the microenvironment leading to cell engraftment. Moreover, organotypic cultures could be useful to partially model the pathological state of a disease in the brain and to study graft–host interactions prior to testing such grafts for pre-clinical applications. Finally, they can be used to test the therapeutic potential of stem cells when combined with scaffolds, or other therapeutic enhancers, among other aspects, needed to develop novel successful therapeutic strategies or improve on existing ones.
The P2X5 receptor, an ATP-gated cation channel, is believed to be involved in tumor development, inflammatory bone loss and inflammasome activation after bacterial infection. Therefore, it is a ...worthwhile pharmacological target to treat the corresponding diseases, especially in minority populations that have a gene variant coding for functional homotrimeric P2X5 channels. Here, we investigated the effects of dihydropyridines on the human full-length P2X5 receptor (hP2X5
) heterologously expressed in
oocytes using the two-microelectrode voltage clamp method. Agonist dependency, kinetics and permeation behavior, including Cl
permeability, were similar to hP2X5
expressed in HEK293 or 1321N1 cells. Additionally, 1,4-dihydropyridines have been shown to interact with various other purinergic receptors, and we have examined them as potential hP2X5 modulators. Of seven commercially available and four newly synthesized dihydropyridines tested at hP2X5
, only amlodipine exerted an inhibitory effect, but only at a high concentration of 300 µM. Isradipine and-even more-nimodipine stimulated ATP-induced currents in the low micromolar range. We conclude that common dihydropyridines or four new derivatives of amlodipine are not suitable as hP2X5 antagonists, but amlodipine might serve as a lead for future synthesis to increase its affinity. Furthermore, a side effect of nimodipine therapy could be a stimulatory effect on inflammatory processes.
Abstract No long term effective treatments are currently available for brain neurological disorders such as stroke/cerebral ischemia, traumatic brain injury and neurodegenerative disorders. Cell ...therapy is a promising strategy, although alternatives to embryonic/foetal cells are required to overcome ethical, tissue availability and graft rejection concerns. Adult cells may be easily isolated from the patient body, therefore permitting autologous grafts to be performed. Here, we describe the use of adult neural stem cells, adrenal chromaffin cells and retinal pigment epithelium cells for brain therapy, with a special emphasis on mesenchymal stromal cells. However, major problems like cell survival, control of differentiation and engraftment remain and may be overcome using a tissue engineering strategy, which provides a 3D support to grafted cells improving their survival. New developments, such as the biomimetic approach which combines the use of scaffolds with extracellular matrix molecules, may improve the control of cell proliferation, survival, migration, differentiation and engraftment in vivo . Therefore, we later discuss scaffold properties required for brain cell therapy as well as new tissue engineering advances that may be implemented in combination with adult cells for brain therapy. Finally, we describe an approach developed in our laboratory to repair/protect lesioned tissues: the pharmacologically active microcarriers.
Reward system dysfunction is evident across neuropsychiatric conditions. Here we present data from a double-blinded pharmaco-fMRI study investigating the triggering of anhedonia and reward circuit ...activity in women.
The hormonal states of pregnancy and parturition were simulated in euthymic women with a history of postpartum depression (PPD+; n = 15) and those without such a history (PPD−; n = 15) by inducing hypogonadism, adding back estradiol and progesterone for 8 weeks (“addback”), and then withdrawing both steroids (“withdrawal”). Anhedonia was assessed using the Inventory of Depression and Anxiety Symptoms (IDAS) during each hormone phase. Those who reported a 30 % or greater increase in IDAS anhedonia, dysphoria, or ill temper during addback or withdrawal, compared with pre-treatment, were identified as hormone sensitive (HS+) and all others were identified as non-hormone sensitive (HS−). The monetary incentive delay (MID) task was administered during fMRI sessions at pre-treatment and during hormone withdrawal to assess brain activation during reward anticipation and feedback.
On average, anhedonia increased during addback and withdrawal in PPD+ but not PPD−. During reward feedback, both HS+ (n = 10) and HS− (n = 18) showed decreased activation in clusters in the right putamen (p < .031, FWE-corrected) and left postcentral and supramarginal gyri (p < .014, FWE-corrected) at the withdrawal scans, relative to pre-treatment scans.
A modest sample size, stringent exclusion criteria, and relative lack of diversity in study participants limit the generalizability of results.
Although results do not explain differential hormone sensitivity in depression, they demonstrate significant effects of reproductive hormones on reward-related brain function in women.
•Estradiol and progesterone administration triggered depression symptoms in women with a history of postpartum depression.•Estradiol and progesterone administration also decreased activity in brain areas that respond to rewards.•Changes in brain activity in the reward network caused by pregnancy hormones did not explain why some women experience postpartum depression while others do not.
Information on what aerosol particle types are the major sources of ice nucleating particles (INPs) in the atmosphere is needed for climate predictions. To determine which aerosol particles are the ...major sources of immersion-mode INPs at a coastal site in Western Canada, we investigated correlations between INP number concentrations and both concentrations of different atmospheric particles and meteorological conditions. We show that INP number concentrations are strongly correlated with the number concentrations of fluorescent bioparticles between −15 and −25 °C, and that the size distribution of INPs is most consistent with the size distribution of fluorescent bioparticles. We conclude that biological particles were likely the major source of ice nuclei at freezing temperatures between −15 and −25 °C at this site for the time period studied. At −30 °C, INP number concentrations are also well correlated with number concentrations of the total aerosol particles ≥ 0.5 μm, suggesting that non-biological particles may have an important contribution to the population of INPs active at this temperature. As we found that black carbon particles were unlikely to be a major source of ice nuclei during this study, these non-biological INPs may include mineral dust. Furthermore, correlations involving chemical tracers of marine aerosols and marine biological activity, sodium and methanesulfonic acid, indicate that the majority of INPs measured at the coastal site likely originated from terrestrial rather than marine sources. Finally, six existing empirical parameterizations of ice nucleation were tested to determine if they accurately predict the measured INP number concentrations. We found that none of the parameterizations selected are capable of predicting INP number concentrations with high accuracy over the entire temperature range investigated. This finding illustrates that additional measurements are needed to improve parameterizations of INPs and their subsequent climatic impacts.
We recently reported the isolation of a unique subpopulation of human stromal cells from bone marrow (BM) termed marrow-isolated adult multilineage inducible (MIAMI) cells, capable of differentiating ...in vitro into mature-like cells from all three germ layers. The oxygen tension (pO
2) in BM ranges from 1 to 7%, which prompted us to examine the role of pO
2 in regulating the capacity of MIAMI cells both to self-renew and maintain their pluripotentiality (stemness) or to progress toward osteoblastic differentiation. MIAMI cells were grown under low-pO
2 conditions (1, 3, 5, and 10% oxygen) or air (21% oxygen). The proliferation rate of cells exposed to 3% oxygen (3 days) increased, resulting in cell numbers more than threefold higher than those of cells exposed to air (at 7 days). In cells grown under osteoblastic differentiation conditions, the expression of the osteoblastic markers osteocalcin, bone sialoprotein, osterix, and Runx2 and alkaline phosphatase activity was upregulated when incubated in air; however, it was blocked at low (3%) pO
2. Similarly, biomineralization of long-term cell cultures was high under osteoblastic differentiation conditions in air but was undetectable at low (3%) pO
2. In contrast, low pO
2 upregulated mRNAs for OCT-4, REX-1, telomerase reverse transcriptase, and hypoxia-inducible factor-1α, and increased the expression of SSEA-4 compared to air. Moreover, the expression of embryonic stem cell markers was sustained even under osteogenic culture conditions. Similar results were obtained using commercially available marrow stromal cells. We hypothesize a physiological scenario in which primitive MIAMI cells self-renew while localized to areas of low pO
2 in the bone marrow, but tend to differentiate toward osteoblasts when they are located closer to blood vessels and exposed to higher pO
2. Our results strongly suggest that maintaining developmentally primitive human cells in vitro at low pO
2 would be more physiological and favor stemness over differentiation.
Mesenchymal stem cells (MSCs) residing in bone marrow (BM) are the progenitors for osteoblasts and for several other cell types. In humans, the age‐related decrease in bone mass could reflect ...decreased osteoblasts secondary to an age‐related loss of osteoprogenitors. To test this hypothesis, BM cells were isolated from vertebral bodies of thoracic and lumbar spine (T1–L5) from 41 donors (16 women and 25 men) of various ages (3–70 years old) after death from traumatic injury. Primary cultures were grown in alpha modified essential medium with fetal bovine serum for 13 days until adherent cells formed colonies (CFU‐Fs). Colonies that stained positive for alkaline phosphatase activity (CFU‐F/ALP+) were considered to have osteogenic potential. BM nucleated cells were plated (0.5, 1, 2.5, 5, or 10 × 106 cells/10‐cm dish) and grown in dexamethasone (Dex), which promotes osteoblastic differentiation. The optimal plating efficiency using BM‐derived cells from donors of various ages was 5 × 106 cells/10‐cm dish. BM‐derived cells were also grown in the absence of Dex at this plating density. At the optimal plating density, in the presence of Dex, the number of CFU‐F/ALP+ present in the BM of the younger donors (3–36 years old) was 66.2 ± 9.6 per 106 cells (mean ± SEM), but only 14.7 ± 2.6 per 106 cells in the older donors (41–70 years old). With longer‐term culture (4–5 weeks) of these BM cells in medium containing 10 mM β‐glycerophosphate and 100 μg/ml ascorbic acid, the extracellular matrix mineralized, a result consistent with mature osteoblastic function. These results demonstrate that the number of MSCs with osteogenic potential (CFU‐F/ALP+) decreases early during aging in humans and may be responsible for the age‐related reduction in osteoblast number. Our results are particularly important in that the vertebrae are a site of high turnover osteoporosis and, possibly, the earliest site of bone loss in age‐related osteoporosis.
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