Category Archives: Oklahoma Stem Cells

Curr Gastroenterol Rep. Author manuscript; available in PMC 2011 Oct 1.

Published in final edited form as:

PMCID: PMC2965634

NIHMSID: NIHMS233209

Department of Internal Medicine, Division of Digestive Diseases, University of Oklahoma Health Sciences Center, 975 NE 10th Street, SL Young BRC West 1268B, Oklahoma City, OK 73104, USA

Shahid Umar, Department of Internal Medicine, Division of Digestive Diseases, University of Oklahoma Health Sciences Center, 975 NE 10th Street, SL Young BRC West 1268B, Oklahoma City, OK 73104, USA;

Self-renewal in the intestinal epithelia is fueled by a population of undifferentiated intestinal stem cells (ISCs) that give rise to daughter or progenitor cells, which can subsequently differentiate into the mature cell types required for normal gut function. The cellular signals that regulate self-renewal are poorly understood and the factors that mediate the transition from a stem cell to a progenitor cell in the gut are unknown. Recent studies have suggested that ISCs are located either at the crypt base interspersed between the Paneth cells (eg, Lgr-5+ve cells) or at or near position 4 within the intestinal crypt (eg, DCAMKL-1 or Bmi-1+ve cells). This raises the possibility that distinct stem cell regions exist in the crypts and that ISC's state of activation will determine how the self-renewal is regulated in the intestinal tract.

Keywords: Intestinal stem cell (ISC), Self-renewal, Transit amplifying (TA) cell, Enterocytes, Paneth cells, Enteroendocrine cells, Goblet cells, Intestinal crypts, Inflammation, Radiation

The absorptive and protective functions of the gut are dependent on an intact and functional intestinal epithelium. Homeostasis of the normal adult intestinal epithelium is maintained by continuous and rapid replacement of differentiated cells by replication of undifferentiated epithelial or transit cells located within the crypts and subsequent differentiation of their progeny during migration away from the zone of replication. This renewal process involves rapid and continuous proliferation of epithelial cells in the crypt base with subsequent migration of these cells along the crypt-villus axis. The process of epithelial cell renewal within the intestine appears to be entirely dependent upon a limited number of long-lived multipotent intestinal stem or progenitor cells. An intestinal stem cell (ISC), similar to stem cells of the mouse hematopoietic system and the hair follicle, may be broadly defined by at least two properties: the ability to maintain itself throughout long periods of time (ie, self-renewal) and the potential to generate all differentiated cell types including enterocytes, goblet cells, entero-endocrine cells, and Paneth cells (ie, multipotency). When stem cells divide, they are believed to undergo an asymmetric cell division into a new stem cell plus a committed daughter cell. The rapidly cycling daughter cells, also called transit amplifying (TA) cells, then undergo a limited number of cell divisions before terminally differentiating into a tissue mass. The regulatory mechanisms that control stem cell proliferation at baseline and in response to injury are just beginning to be explored. This review highlights recent discoveries and implications the ISC field may have on the regenerative processes in the digestive tract involved in health and disease.

The intestinal epithelium is the most vigorously self-renewing tissue of adult mammals [1]. It is specified from endoderm formed during gastrulation and remains as a stratified cuboidal epithelium until mid-gestation in most vertebrates [2]. During middle to late gestation, the basic tissue architecture of the intestine is established through epithelial-mesenchymal interactions. Induced by signals from mesoderm-derived mesenchyme, the endoderm-derived epithelium evaginates to form villi and intervillus regions. The intervillus regions consist of undifferentiated and actively dividing cells that eventually invaginate into the mucosa to form the crypt of Lieberkhn in the first few days after birth and continue to develop during the next several weeks in the rodent [3].

The small intestinal architecture consists of continuous villi and crypts (). The functional compartment of the epithelium contains differentiated cells no longer capable of dividing that have the features of mature epithelial cells. These differentiated epithelial cells populate the villi and can be categorized based on their function: enterocytes that function to absorb nutrients, goblet cells that secrete a protective mucus barrier and enteroendocrine cells that release gastrointestinal hormones (). Paneth cells that secrete antibacterial peptides on the other hand, reside at the base of the proliferative compartment [4]. The proliferative compartment contains undifferentiated and rapidly cycling cells that populate the crypts of Lieberkhn. The epithelium in this region is responsible for providing the tremendous cell turnover and the protective niche for the epithelial stem cell. As cells begin to differentiate, they migrate toward the lumen and are eventually shed, either from the tip of the intestinal villi or from the surface of the colonic epithelium. Therefore, the crypt is mainly a proliferative compartment, is monoclonal, and is maintained by multipotent stem cells whereas the villus represents the differentiated compartment and is polyclonal as it receives cells from multiple crypts [5].

Intestinal stem cell (ISC) compartments in the mammalian intestine. a The intestinal crypt-villus unit. ISCs reside at the base of the crypt, either in the +4 position counting from the bottom of the crypt (brown) directly above the Paneth cells (gray), or as crypt base columnar (CBC) cells (red) located between the Paneth cells, whereas transit-amplifying (TA) progenitor cells (yellow) can arise from self-renewing CBCs. Goblet cells and enterocytes are labeled purple and green, respectively. b Chemical and immunohistochemical detection of the four principal cell lineages of the small intestine: villus-associated absorptive cells (Fatty acid binding protein, stains the villi), Goblet cells (stained by periodic acid/Schiff), enteroendocrine cells (stained for synaptophysin, arrows), and Paneth cells (stained for lysozyme). c An enlarged view of a small intestinal crypt depicting two different stem cell regions; a quiescent stem cell zone (+4 position), and an active stem cell zone (+1 to +4 positions) scattered between the Paneth cells. The +4 label-retaining cells (LRCs) are normally maintained in a quiescent state through direct interaction with and signals generated from the niche, such as pericryptal fibroblast/myofibroblasts and adjacent enteroendocrine cells within the +4 region. CBCs, continuously activated by signals generated from stromal cells at the crypt base, are responsible for most of the regenerative capacity of the intestine under homeostatic conditions. A gradient of BMP signaling, known to inhibit proliferation, is established along the crypt-villus axis, with relatively high activity throughout the villus and correspondingly less activity within the crypt. An opposite gradient of Wnt signaling, providing an important proliferative stimulus, is highest at the crypt base and decreases toward the crypt-villus junction. (A, reproduced with permission from Dr. Hans Clevers, Hubrecht Institute-Royal Netherlands Academy of Arts and Sciences and the University Medical Center Utrecht, Utrecht, The Netherlands)

The well-compartmentalized structure of the small intestine is advantageous for analysis of developmental processes; however, study within this tissue has been limited by lack of a robust in vitro culture system for primary intestinal epithelial cells. Recently, studies with transgenic and knockout mice have shed light on molecular mechanisms underlying the fetal development of intestine as well as homeostatic epithelial regeneration in the adult. Through these studies, several signaling pathways such as the Wnt, bone morphogenic protein (BMP), phosphatidyl inositol (3,4,5) kinase (PI3K), and Notch cascades have been revealed to play critical roles in regulating proliferation and controlling ISC self-renewal and differentiation in normal tissue.

Stem cells are defined by their ability to self-renew and to give rise to mature cell types to maintain the integrity of the intestinal epithelium. Given the importance of stem cells to body tissues, it has long been postulated that stem cells should divide infrequently to prevent the acquisition of errors during DNA replication and to preserve their long-term proliferation potential. In humans, however, billions of cells are lost on a daily basis and therefore must be replenished for survival. Moreover, human tissues occasionally face traumatic injuries. The injured tissues have to be repaired quickly through rapid stem cell division and differentiation to maintain a proper balance. Thus, an extraordinary mechanism of regulation at the stem cell level apparently exists to allow stem cells to divide sparingly, to maintain their long-term potency, and rapidly, to maintain tissue homeostasis and repair injured tissues. Small intestinal epithelial lining is regenerated every 4 to 5 days. Either four to six [6] or one ISC [7] are present in small intestinal crypts, which cycle slowly (2430 h) and give rise to rapidly cycling TA cells by asymmetric division [8]. The TA cells move up the crypt and undergo differentiation into either absorptive (enterocytes) or secretory lineages (mucous, enteroendocrine, Paneth cells), which then move upward into the villus [9] (). Paneth cells, however, migrate downward to the base of the crypts [4]. Enterocytes are the dominant lineage (90% of total cells), goblet cells comprise 8% to 10% and enteroendocrine cells comprise about 1% of the epithelium. Stem cells in animal tissues are often located and controlled by special tissue microenvironments known as niches. A stem cell niche can be defined as a specific location in a tissue where stem cells can reside for an indefinite period of time and produce progeny cells while self-renewing. This niche is made up of and influenced by nearby proliferating and differentiating epithelial cells as well as by surrounding mesenchymal cells. Although separated from the epithelial cells by the basement membrane, these mesenchymal cells (ie, blood vessels, intraepithelial lymphocytes, and fibroblasts/myofibroblasts) together with the extracellular matrix, promote the epithelial-mesenchymal crosstalk required to maintain the stem cell niche. Epithelial-mesenchymal interactions enable specification of epithelial stem cells during development [10], but the requirement and nature of these communications in adult stem cells remain to be characterized. Excessive stem cell production can result in cancer; thus, maintaining a balance of stem cell quiescence and activity is a hallmark of a functional niche [11]. We have just begun to understand which niche signals regulate self-renewal and maintain the balance between self-renewal and differentiation of ISCs. An increasing number of signaling pathways, including Wnt, BMP, Hedgehog, and Notch, may play important roles in this regard, as discussed in the following section.

Wnt proteins form a family of highly conserved secreted signaling molecules that are capable of signaling both in an autocrine and paracrine fashion. Wnt induces its biologic effects by binding to either the seven-span transmembrane protein Frizzled (Fz) or the single-span low-density lipoprotein receptor-related protein (LRP). Wnt-mediated signaling results in increased stability of -catenin in the cytoplasm, and its interaction with the T-cell factor 4 (Tcf-4) transcription factor within the nucleus. Under normal conditions, -catenin forms a complex of proteins containing adenomatosis polyposis coli (APC), axin, and glycogen synthase kinase-3 (GSK-3) and its levels are tightly controlled through ubiquitin-mediated proteasomal degradation. Wnt factors inhibit the -catenin-APC complex. Hence, -catenin is stabilized and interacts with nuclear Tcf-4 to drive the transcription of specific target genes. Initial studies demonstrated that active Wnt signaling was found in intervillus regions and was thought to inhibit differentiation and stimulate proliferation, as indicated by experiments in which inhibition of Wnt signaling by Tcf-4 disruption halted the proliferation of endoderm and depleted endodermal stem/progenitor cells [12]. These experiments also showed that proliferative cells in the intervillus region were replaced by mature enterocytes usually seen in the villus [12]. However, recent findings indicate that Wnt signaling within the developing intestine may be more complex. In fact, Wnt activity was found exclusively within the villus epithelium from embryonic day 16 (E16) to postnatal day 2 (P2) and was not seen within the intervillus region until P2. However, by E14, villus and intervillus regions displayed unique genetic signatures and by E17.5, proliferative cells were restricted to intervillus regions. In addition, although nuclear -catenin and c-MYC expression corresponded to the villus cells with Wnt activity, other known Wnt target genes and pathway components such as CD44, CyclinD1, and Tcf-4 were present within the intervillus region [13]. These results suggest that Wnt signaling and proliferation may be uncoupled during early development and that perhaps Wnt-independent mechanisms drive early epithelial proliferation. Furthermore, Wnt signaling may play an important role in initial villus formation. Wnt signaling components are expressed by crypt epithelial cells and surrounding mesenchymal cells, which play an extremely important role in normal homeostasis [11, 14, 15] (). Wnt inhibitors, such as Dkk3, may be expressed in a graded manner along the crypt-villus axis, providing the balance between positive and negative regulators of this pathway [16].

Indian hedgehog (Ihh) is also expressed in the intervillus region, whereas its receptor, Patched, is expressed in the adjacent mesoderm [17]. Because Hedgehog inhibition compromises villus formation, this signal is thought to work as a morphogen within the intestine as in other tissues [18]. It remains unclear whether Ihh signaling is dependent on Wnt activation or is completely independent. More recently, Ihh was shown to regulate ISC self-renewal and differentiation [19]. Intestinal epithelial Ihh signals to the mesenchymal compartment to regulate formation and proliferation of mesenchymal cells, which in turn affects the epithelial proliferation and differentiation. These findings provide a basis for analyses of the role of the muscularis mucosae in ISC regulation. Indeed, expression of BMPs mainly in mesoderm-derived mesenchymal cells is regulated by Hedgehog signaling, and BMP signaling also plays a role in regulating morphogenesis during intestinal development [20]. Inhibition of BMP signaling by over-expression of its inhibitor, Noggin, or conditional inactivation of its receptor, BMPR1A, causes ectopic crypt formation, suggesting a role for BMP signaling in restricting crypt numbers [21].

A high level of Notch is expressed in the intestinal stem cells [11]. Four isoforms of the Notch receptor have been identified in mammals (Notch14) [22]. Notch activation is achieved through direct interaction with specific transmembrane ligands of the DSL (Delta/Serrate/Caenorhabditis elegans Lag-2) family, such as Delta-like (DLL) 1, 3, and 4 and Jagged 1-2 in mammals [23]. Notch-DSL ligand binding initiates proteolytic cleavage at both the extracellular and intracellular regions of the Notch receptor, leading to the release of Notch intracellular domain (NICD) [24]. Nuclear localization signals within the NICD direct its translocation, where it binds to and displaces a CSL transcriptional corepressor complex [25, 26]. Basic helix-loop-helix transcription factors of the Hairy/E(spl) (HES) and HES-related genes in vertebrates class are the best-characterized Notch targets [27]. Importantly, Notch transcriptional output depends greatly upon specific cell and tissue types because various events such as pathway crosstalk can affect the transcriptional regulation of tissue-specific differentiation, development, and cell-cycle regulation [28].

The Notch signal controls daughter cells differentiating into absorptive rather than secretory cells. Like Wnt signaling, the Notch pathway also plays a role in stem cell maintenance [28]. Components of the Notch pathway are chiefly expressed in the epithelium at the crypt base, in the stem cell region. Increasing Notch signaling through forced expression of NICD in newborn mouse results in increased cell proliferation in the stem cell compartment and also shows a severe reduction of all three secretory cell types [28]. Conversely, inhibition of the Notch signaling in the intestinal epithelium, either by deletion of the Hes1 gene, the CSL gene, the Notch1 and Notch2 genes, or through pharmacologic -secretase inhibitors, results in an excessive number of secretory cells [1, 29]. Although Notch signaling plays an important role in stem cell proliferation, the experimental results suggest that Notch signaling functions in the TA compartment controlling absorptive rather than secretory cell fate decisions in the intestinal epithelium.

In summary, among the four major signals characterized so far (Wnt, Notch, Hh, and BMP), Wnt signaling mainly functions in the crypt base to maintain stem cell proliferation and self-renewal; Notch signaling mainly functions in the TA compartment to control daughter cell fate determination; and the Hh-BMP signaling from the crypt or intervillus pocket delivers a long-range signal to inhibit the formation of crypts and promote the formation of villi.

The location, number, and behavior of ISCs within the base of the crypt have been characterized by numerous investigators using murine models [4], following chemoradiation [30], somatic mutation [31], chimeric breeding [32], and transgenic overexpression or ablation of specific regulatory genes [12, 20, 21, 33]. Interpretation of these data with respect to the precise position and behavior of ISC within the intestinal crypt continues to be debated [34, 35]. In the mouse small intestine, two types of stem cells have been identified [35]. One type is located below the +4 position in the stem cell zone and the other type is located at the +4 position from the crypt bottom. Cheng and Leblond [4] identified small cycling epithelial cells interspersed between the Paneth cells, or the so-called crypt base columnar (CBC) cells, using morphologic methods in mammalian intestine. Later, Bjerknes and Cheng [36] provided additional information on these specialized cells using elegant clonal marking techniques. These investigators postulated that the CBCs located within the stem cell zone of the crypt base might represent the actual ISC and that all the differentiated intestinal epithelial cell types develop from these CBCs [36]. An alternative hypothesis also suggested that the ISCs were actually located elsewhere at a position that averaged +4 from the bottom of the crypts, with the lowest three positions generally relegated to the terminally differentiated Paneth cells. Evidence supporting this hypothesis of the +4 stem cell model was provided by Potten [30]. These investigators, using the DNA-labeling reagents, bromodeoxyuridine or (3H)-thymidine, on radiation-sensitive, label-retaining cells (LRC) showed that the LRCs were located specifically at the +4 position in the intestinal crypt region, precisely at the origin of the migratory epithelial cell column.

One major obstacle in ISC biology has been the lack of definitive markers that identify ISCs. Reliable markers would allow for definitive identification of the stem cell population and would facilitate the ability to isolate and manipulate these cells in vitro. Numerous proteins are expressed in the crypt compartment but not in the villus, such as EphB2 [37], CD44 [38], and Hes1 [39]. Immunohistochemistry and in situ hybridization studies suggested that RNA binding protein Musashi-1 (Msi-1), involved in Notch signaling, is also expressed in the supra-Paneth cells as well as in CBC cells () [39, 40]. Members of BMP and Wnt signaling pathways (p-PTEN and p-AKT) localize to ISCs [20, 41]. In recent years, fluorescence-activated cell sorting has been used to identify side population (SP) cells in murine small intestine as a source of putative ISCs [42]. These SP cells were distinct from the hematopoietic stem cells and their progeny, based on the absence of surface markers for CD45, c-kit, and CD34. RNA prepared from CD45-negative intestinal SP cells were found to be enriched with Msi-1 [42]. The molecular features of the potential stem cell populations in SP faction were recently characterized [43]. Protein markers such as EphB2 [37], CD44 [38], Fgfr3 [44] and Sox9 [45] have a crypt-base expression pattern, but are not specific to ISCs. Analyses of various Wnt pathway components and their target genes have identified Sfrp5 [46] and Ascl2 [46] as possible ISC markers. Besides these, it was recently shown that telomerase reverse transcriptase (mTert), as identified in GFP transgenic mice, stains a few cells at cell position 4 [47]. None of these genes, however, encode for proteins that are amenable to cell-sorting procedures. Laser-capture microdissection method found numerous transcripts involved in c-myc signaling to be significantly expressed in putative ISC cells [48]. Immunohistochemistry studies showed that doublecortin and Ca2+/calmodulin-dependent kinase-like-1 (DCAMKL-1) and Mapk14 are expressed within the stem cell zones [49].

Proposed intestinal stem cell markers

Long-term DNA-label retention tentatively located stem cells at position +4 directly above Paneth cells [50]. Leucine-rich-repeat-containing G-protein-coupled receptor-5 (LGR5) expression was demonstrated in crypts of small intestines, but not in the villi by in situ hybridization [51]. LGR5 gene marked the slender cycling crypt base columnar (CBC) cells (), interspersed between Paneth cells [51]. LGR5 encodes an orphan G-protein-coupled receptor, characterized by a large leucine-rich extracellular domain [51], and is expressed in colorectal, ovarian, and hepatocellular carcinomas [51]. The CBC cells were positive for proliferation marker Ki67 and occasionally expressed M-phase marker phospho-histone H3 [51]. Adult mice irradiated with 1 to 10 Gy were analyzed for apoptosis after 6 h. Apoptosis was determined in +4 CBC cells and TA cells (located at position 515) [50]. Maximal apoptosis at +4 position was reached at 1 Gy, whereas 10 Gy was needed to measure apoptosis in CBC and TA cells, suggesting that LGR5 may be a marker for stem cells in small and large intestines [51]. Moreover, using genetic approaches, it was demonstrated that LGR5-positive CBCs are multipotent for all mature intestinal epithelial cell types, cycle every 24 h, and persist for 60 days [51]. Thus, even though questions remain regarding the functional role of LGR5 in the intestinal epithelia [52], loss of LGR5 may affect both crypt regeneration and neoplastic transformation.

In 2009, lineage-tracing studies of adult prominin-1 (also called CD133; a pentaspan transmembrane glycoprotein that localizes to membrane protrusions) showed that some prominin-1positive cells are located at the base of crypts in the small intestine, co-express LGR5, and can generate the entire intestinal epithelium, and therefore seem to be small intestinal stem cells as well [53]. Moreover, olfacto medin 4 (OLFM4), which was identified in a gene expression profile for LGR5-positive cells, was shown to be highly expressed in CBCs in the human small intestine and colon, and may therefore be a marker for human intestinal and colon stem cells [54]. Sangiorgi and Capecchi [55] characterized the progeny of crypt Bmi1-positive cells (; ) and argued in support of the +4 LRCs as a population of stem cells within the small intestine. Bmi1 encodes a chromatin remodeling protein of the polycomb group that has essential roles in self-renewal of hematopoietic and neural stem cells. Bmi1 seems to consistently mark long-lived cell clones (>12 months) populated by all intestinal lineages and serves as a specific marker of a cell population located at the +4 position of the crypt. Furthermore, ablation of Bmi1-positive cells by targeted expression of the diphtheria toxin depletes the epithelium of the genetically marked crypts (known as whole crypt units) [55]. Thus, expression of Bmi1 also identifies ISC candidates. In addition to LGR5 and prominin-1, other potential stem cell markers have been identified for which lineage tracing is not yet complete.

It was reported recently that DCAMKL-1, a microtubule-associated kinase expressed in post-mitotic neurons, is a novel putative ISC marker (; ) [56]. DCAMKL-1 was identified as a Gene Ontogeny-enriched transcript expressed in comparison with gastric epithelial progenitor and whole stomach libraries [49] and more recently in gastric stem cells [57]. Immunoreactive DCAMKL-1 cells were found at or near position +4, at a frequency of one cell per five crypts [56]. DCAMKL-1-positive CBC cells were also observed, but at much lower frequency [56]. More recently it was shown that the novel putative ISC marker DCAMKL-1 is predominantly expressed in quiescent cells in the lower two thirds of the small intestinal crypt epithelium and in occasional CBC cells [58]. In contrast, novel putative stem cell marker LGR5 is observed in rapidly cycling CBCs and in occasional crypt epithelial cells [58]. Functionally quiescent DCAMKL-1positive crypt epithelial cells retained BrdU label in a modified label-retention assay [58]. Importantly, it was demonstrated that DCAMKL-1 is a cell surface expression protein, and a specific antibody against the extracellular domain of DCAMKL-1 was used to isolate DCAMKL-1 positive cells from adult mouse small intestine by fluorescence-activated cell sorting [58]. DCAMKL-1positive cells were found to self-renew and form spheroids in suspension culture [58]. These spheroids formed glandular epithelial structures in the flanks of athymic nude mice, which expressed multiple markers of gut epithelial lineage [58]. Thus, DCAMKL-1 is a marker of quiescent ISCs and can be distinguished from the cycling stem/progenitor cells that are LGR5 positive. DCAMKL-1 did not co-localize with other key markers such as chromogranin A, pPTEN, pAKT, somatostatin, or secretin [58]. LGR5 identifies proliferative CBC and TA cells in the gut as evidenced by co-labeling with proliferating cell nuclear antigen. Thus, the original hypothesis of a +4 ISC [50] is likely accurate, and DCAMKL-1positive cells likely represent the elusive quiescent ISCs.

Restoration of normal epithelial architecture and function after intestinal injury induced by a variety of noxious agents (chemical, infectious, radiation, and inflammatory) is a multistep process that involves tight regulatory control of epithelial stem cell dynamics [59]. First, migration of adjacent epithelial cells over the wound reestablishes continuity of the epithelium. Stem cells divide to increase their numbers and to give rise to the more rapidly proliferating TA cells. The transit cell population then expands rapidly to form a regenerative crypt. A single surviving clonogenic crypt stem cell is sufficient to facilitate crypt regeneration. If the injury has completely destroyed some crypts, the surviving crypt stem cells can divide to increase their numbers, and subsequently restore sufficient numbers of crypts by crypt fission, to maintain epithelial homeostasis [59]. Whether this process involves recruitment of a quiescent stem cell population from within the crypt-villus axis or requires replenishment from the bone marrow remains to be determined. Moreover, because the epithelial stem cells within a crypt segregate to daughter crypts when crypt fission occurs, an expansion of the stem cell number must accompany this reparative response. However, the factors that coordinate this complex process in diseases such as human inflammatory bowel disease have not been fully elucidated, and much remains unknown about the biologic consequences of chronic intestinal inflammation on the fate or proliferation of the stem cell population.

Inflammatory bowel disease is characterized by cycles of mucosal injury and ulceration, followed by epithelial regeneration and restoration of normal epithelial architecture and function. In several mouse models of inflammatory bowel disease, alterations of epithelial function have been implicated in the pathogenesis of chronic inflammation [60]. In general, intestinal inflammation is associated with significant upregulation of pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-8, IL-12 and tumor necrosis factor (TNF)-, along with other mediators and growth factors, such as cyclo-oxygenase (COX)-2, basic fibroblast growth factor (bFGF), hepatocyte growth factor, and vascular endothelial growth factor [60]. Expression of these inflammatory mediators is regulated by activation of nuclear factor-B (NF-B). NF-B is a key coordinator of innate immunity and inflammation and has emerged as an important endogenous tumor promoter [61, 62]. Crohn's ileitis is also associated with a reduced expression of Tcf-4, which regulates Paneth cell differentiation, leading to defects in innate immunity [63].

Expansion of the proliferative zone, increased crypt branching, and changes in the normal patterns of cellular differentiation have been documented in human inflammatory bowel disease [60], suggesting that the pathways regulating the relationship between cellular replication and epithelial differentiation have been altered in these diseases. Although it is clear that the intestinal epithelium responds to inflammation and mucosal injury by initiating a regenerative response, the specific effects inflammation may have on the in vivo turnover of epithelial stem cells or progenitor cells, or the way in which the inflammatory milieu may perturb normal epithelial differentiation and/or function remain obscure. Similarly, a number of cytokines, growth factors and other mediators including TNF-, transforming growth factor (TGF)3, trefoil factor-3 (TFF3), IL-1, IL-11, COX1/2, bFGF, FGF-7, and FGF-10 associated with intestinal inflammation or injury can induce increase in crypt epithelial stem cell survival when exogenously administered before radiation [64, 65]. However, more work is needed to understand how enhanced expression of one or more of these peptides, as a consequence of ileal inflammation, directly affects epithelial stem cells or differentiation of progenitor cells.

The radiosensitivity of the small intestine is primarily a function of rapidly dividing progenitor cells derived from epithelial stem cells near the base of intestinal crypts. Although crypt epithelial cells are extremely sensitive to radiation-induced apoptosis, there is little to no apoptosis in the villi. Doses as low as 0.01 to 1.0 Gy induce apoptosis within the lower crypt. Peak apoptosis is observed between 3 and 6 h post-irradiation [6567]. However, at higher doses (>8 Gy), a second apoptotic wave occurs 24 h post-irradiation. After severe irradiation, epithelial cell loss at the villus tips creates an imbalance between epithelial production and turnover, resulting in villi shortening and disruption of the mucosal barrier if all or most of the crypt stem cells die. However, if a single stem cell survives in the crypt region, regenerative crypts will appear within 3 to 4 days, and crypt-villi architecture will be restored within 6 to 8 days. The balance between the rate and extent of crypt-villi regeneration, which depends on the stem cell and the pathologic consequences of denuding the epithelial covering from the small intestine, is a major determinant of survival in the early period after acute radiation exposure.

The possible relationship between the quiescent and the actively cycling nature of the ISCs needs to be further explored. Moreover, it is critical to understand the genetic elements that determine stem cell fate and the basis by which regeneration occurs in order to better understand stem cell plasticity and the contribution made by the stem cell compartment to malignant disease. It is hoped that future studies in this area will provide a better platform to develop therapies to regenerate damaged intestinal epithelia as seen after radiation injuries or inflammatory bowel disease (eg, Crohn's disease).

This work was partially supported by National Institutes of Health Grant R01 CA131413 (to SU) from the NCI.

Disclosure No potential conflict of interest relevant to this article was reported.

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Intestinal Stem Cells - PMC

He played Jesus in The Passion of Christ. But it was another Mel Gibson film that Jim Caviezel referred to when he attended a meeting of the QAnon conspiracy movement last weekend in Las Vegas. In front of the crowd, the actor of 53 years has indeed taken again the famous tirade of William Wallace, the hero of Braveheart, when he addressed the Scottish soldiers before facing the English invader at the risk of their lives.

Fight back and you might die. Run away and you will live, at least for a while. And one day, on your deathbeds, many years will have passed and maybe you will regret that you cannot exchange all your sad spared lives for a chance, a little chance to come back here and kill our enemies, because they can help us. take away life, but they will never take away our freedom!, launches the one who, in September 2020, estimated that American Catholics were persecuted, because the confinement prevented them from going to mass.

During this speech, we also hear him say: We are going to meet the storm of all storms. Yes the storm is among us. According to the American media, the storm refers, in QAnon jargon, to a hypothetical return of Donald Trump to oust the satanic sect that would now control America.

The video, which loops on social networks, arouses many comments across the Atlantic. Actor Kirk Acevedo, who starred with Jim Caviezel in The Red line, posted this message to the attention of his former colleague:

Can we be so different after all these years? We ran together, we played basketball together, we worked together in film and television. Am I now a henchman in Lucifers army? Your words are dangerous and full of hate.

Coming from a conservative Catholic family, Jim Caviezel started out in My Own Private Idaho by Gus Van Sant, in 1991. We then see him in Wyatt Earp de Lawrence Kasdan, The Rock by Michael Bay or The Red line by Terrence Malick. In 2004, he landed the role of his life, that of Jesus in The passion of Christ by Mel Gibson. A borderline experience in which he suffered from pneumonia, dislocated a shoulder, and was even struck by lightning.

Despite its violence, which will cause much discomfort in theaters, the film will generate more than $ 600 million in box office revenue. Jim Caviezel will not be nominated for an Oscar. But he will be received by Pope John Paul II at the Vatican, impressed by his performance.

Subsequently he will be, from 2011 to 2016, in the series Person of Interest, broadcast in France on TF1. But his CV seems to suffer from his personal commitments. A fierce opponent of abortion, he also militates against any form of research on embryonic stem cells. Too bad if being pro-life harms my career, he said at a conference in Boston in 2016.I cant keep silent about the death of so many children.

The pandemic visibly uninhibited the actor. Last April, he participated for the first time in a demonstration of the QAnon movement, a conference entitled Health and Freedom in Tulsa, Oklahoma where protective masks against Covid-19 were burned to the cheers of the crowd.

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They will never take away our freedom! : actor Jim Caviezel quotes Braveheart ... - Paris Beacon News

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More than a year after starting a pandemic that incomparably ravaged communities of color, the predominantly African-American patients of sickle cell disease see a ray of hope with the release of another new treatment.

A new gene-editing therapy called CRISPR has been shown to eliminate all symptoms in at least one study among a small list of FDA-approved treatments for the rare and chronic disease.

The one-time treatment works by altering the DNA in the blood cells and reprogramming the body to stop producing the sickle-shaped cells that obstruct oxygen flow and cause extreme pain or severe fatigue to young and old patients. The body instead goes back to making the type of healthy blood cells produced in the womb.

It works by removing stem cells from the patients body and using CRISPR technology to alter the gene before putting them back in the body.

For Velvet Brown-Watts, more options mean more hope for the community of families affected by sickle cell disease and other related anemias. But she also acknowledged that the science behind the new curative treatment would be a tough sell for some black folks.

I dont ever tell people what to try or what not to try. We tell them to make sure youre getting all the information, Brown-Watts said. Shes the Executive Director of Supporters of Families with Sickle Cell Disease, an Oklahoma support group based in Tulsa. She also has a son who lives with the disease.

Would the person still have the DNA of their family down the line? If my son did that, would he still be carrying the same bloodline, Brown-Watts said, listing questions community members have asked her about the new CRISPR treatment.

Brown-Watts said its exciting whenever theres a new treatment but that some in the black community, mostly faith leaders, may see the gene-editing therapy as playing God.

Im excited about all the new different therapies coming down the pipeline because now it does give patients living with sickle cell options, Brown-Watts said.

Twenty years ago, it was a different story. Throughout the 80s and 90s the only FDA-approved treatment for sickle cell disease, which affects roughly 100,000 Americans and 1 in every 365 African American births, was a repurposed cancer drug called Hydroxyurea.

When you look at diabetes and cancer, they had how many options, Brown-Watts said. And at the time, sickle cell only had one. And it wasnt even a drug for sickle cell.

Brown Watts said she feels that since sickle cell primarily affects African Americans, the FDA, historically, hasnt spent much time investing in research or treatments toward it.

That has changed in recent years as more treatments have been approved and continue to be studied.

Theres now Envari, a powder, and Adakzeo, an infusion drug.

Theres also Oxbryta, a pill that Brown-Watts said has been working for her 16-year-old son, Jeremiah Jr.

Its been a rollercoaster, Brown-Watts said. For our family, the diagnosis changed the core of who we became. You learn to create a synergy for your family so you can build with the tools you have. For us, it was helping him learn how it impacted his body and what it is, what it does, and how he has to learn how to manage.

Thanks to Oxbryta, Brown-Watts has noticed her son has more energy and better oxygen flow, though he still requires oxygen support.

At a time when the Center for Disease Control estimates that 7 percent of black sickle patients with Covid-19 have died compared to less than 1 percent of the general population, emotional and financial support means everything.

The recent study of the gene-editing therapy, published in the New England Journal of Medicine, revealed that months after the treatment, patients who had sickle cell disease remain pain-free and without a need for blood transfusions.

And as more treatments become available, Brown-Watts hopes the community will stand up to address these racial health disparities.

Its almost like when youve been living on an island all alone, and all you had was coconuts coconuts coconuts, and somebody else comes along, and maybe they bring an orange. And you get really excited because now you have options, Brown-Watts said.

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By Michael Le Page, Clare Wilson, Jessica Hamzelou, Adam Vaughan, Conrad Quilty-Harperand Layal Liverpool

A worker covers a pool table at Cafe Louvre ahead of the introduction of new coronavirus restrictions in Prague, Czech Republic

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Tighter restrictions introduced in the UK and across Europe to tackle rising infections

A new three-tier system of restrictions came into force in England today, and Northern Ireland announced that schools there will be closed for two weeks from 19 October, as the UK attempts to curb the spread of the coronavirus. Other European countries are also introducing tighter restrictions in response to sharp rises in cases. The Netherlands yesterday announced a partial nationwide lockdown, which will come into force at 10 pm today. The country recorded almost 7400 cases in 24 hours yesterday in a record daily rise, and currently has a case rate of 412.2 per 100,000 people, according to the latest figures from the European Centre for Disease Prevention and Control (ECDC). The equivalent figure for the UK is currently 283.2 cases per 100,000 people. Under the new rules in the Netherlands, bars, restaurants and cafes will be required to close for four weeks and the sale of alcohol will be banned after 8pm each evening. The Czech Republic, which currently has the highest infection rate in Europe at 581.3 cases per 100,000 people, started a three-week partial lockdown yesterday. Schools, university accommodation, bars and clubs were all told to close. New restrictions are also expected to be announced in Spain and France, where infection rates are currently 293.8 and 307.1 cases per 100,000 people, respectively.

In England, Labour leader Keir Starmer has called for tougher measures, specifically the implementation of a two-week circuit breaker lockdown to try and bring cases under control. At a press conference yesterday, Starmer suggested that schools could stay open but that all pubs and restaurants should close for two weeks, with only essential work and travel allowed. Starmers proposal echoes recommendations made by government scientific advisers more than three weeks ago, which included the implementation of a two-week lockdown, banning of contact between people from different households, closing pubs, restaurants and other venues, and moving all university and college teaching online.

Other coronavirus news

Advice for people in England who are extremely vulnerable to the coronavirus those who have conditions affecting their immune systems, some people with cancer and organ transplant recipients will now be tailored according to the alert level in the area where they live. These 2.2 million people will be advised to take precautions and practice social distancing as cases rise, but most will not be advised to stay at home as they were during the first wave of the virus in spring, the government announced yesterday. The exception to this will include some people in tier three areas, where infection rates are highest. Patient groups, including Blood Cancer UK and Kidney Care UK, criticised the new advice for being insufficient to support those most at risk.

The World Bank has approved $12 billion (9 billion) of funding for buying and distributing coronavirus tests, treatments and any future vaccines in developing countries.

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The worldwide death toll has passed 1.08 million. The number of confirmed cases is more than 38.2 million, according to Johns Hopkins University, though the true number of cases will be much higher.

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Race Against the Virus: Hunt for a Vaccine is a Channel 4 documentary which tells the story of the coronavirus pandemic through the eyes of the scientists on the frontline.

The New York Times is assessing the progress of different vaccine candidates and potential drug treatments for covid-19, and ranking them for effectiveness and safety.

Humans of COVID-19 is a project highlighting the experiences of key workers on the frontline in the fight against coronavirus in the UK, through social media.

Coronavirus, Explained on Netflix is a short documentary series examining the on-going coronavirus pandemic, the efforts to fight it and ways to manage its mental health toll.

New Scientist Weekly features updates and analysis on the latest developments in the covid-19 pandemic. Our podcast sees expert journalists from the magazine discuss the biggest science stories to hit the headlines each week from technology and space, to health and the environment.

COVID-19: The Pandemic that Never Should Have Happened, and How to Stop the Next One by Debora Mackenzie is about how the pandemic happened and why it will happen again if we dont do things differently in future.

The Rules of Contagion is about the new science of contagion and the surprising ways it shapes our lives and behaviour. The author, Adam Kucharski, is an epidemiologist at the London School of Hygiene and Tropical Medicine, UK, and in the book he examines how diseases spread and why they stop.

A man uses a misting and fogging machine to clean and disinfect the Grand Central venue in Liverpool, UK

Danny Lawson/PA Images

UK scientific advisors recommended a short lockdown in England three weeks ago

The UKs Scientific Advisory Group for Emergencies (SAGE) warned ministers three weeks ago that a failure to implement tighter coronavirus restrictions in England would have catastrophic consequences. Documents from SAGE dated 21 September, which were released yesterday, included a recommendation that the government impose a two-week circuit-breaker lockdown to curb the spread of infections. The advisory group cautioned that not acting now to reduce cases will result in a very large epidemic with catastrophic consequences in terms of direct COVID related deaths and the ability of the health service to meet needs. Other recommendations from the group, which were not implemented by the government at the time, included banning all contact between people from different households, closing all bars, restaurants, cafes, indoor gyms and personal services such as hairdressers, and moving all university and college teaching online unless absolutely essential.

At a press conference yesterday, Englands chief medical officer Chris Whitty said he was not confident that new measures, namely a three-tier alert level system announced by UK prime minister Boris Johnson, would be enough to get on top of the coronavirus. Whitty said local authorities in areas put on very high alert would likely have to introduce further restrictions.

Other coronavirus news

A man in the US has become the fifth person recorded to have caught the coronavirus twice, following similar cases in Hong Kong, Belgium, the Netherlands and Ecuador. The 25-year old first tested positive for the virus on 18 April after experiencing several weeks of symptoms but then recovered and tested negative for the virus on both 9 and 26 May, according to a study published in The Lancet Infectious Diseases. However, a few days after testing negative for the second time, he developed more severe symptoms, eventually requiring hospitalisation, and he tested positive for the virus again on 5 June. The man has since recovered. Although cases of coronavirus reinfection with severe illness do not appear to be common, these findings reinforce the point that we still do not know enough about the immune response to this infection, said Paul Hunter at the University of East Anglia, UK, in a statement. Understanding immune responses to the virus and how long any immunity might last is important for vaccine development.

Pharmaceutical company Johnson & Johnson has voluntarily paused clinical trials of its coronavirus vaccine candidate because of an unexplained illness in a study participant. This is standard procedure in vaccine development, and allows time for researchers to determine the cause of the illness and ensure the safety of participants in the trial. In September, trials of a coronavirus vaccine candidate being developed by AstraZeneca in partnership with the University of Oxford were also paused, after a participant fell ill in the UK. Trials of the Oxford-AstraZeneca candidate have since resumed in the UK, Brazil, South Africa and India, but the US trial is still on hold, pending a regulatory review. Both the Johnson & Johnson and Oxford-AstraZeneca vaccine candidates are based on adenoviral vectors modified viruses that can instruct cells to produce coronavirus proteins.

Senior US government health advisor Anthony Fauci has criticised US president Donald Trumps decision to resume campaign rallies without adequate social distancing. The president returned to the campaign trail yesterday to attend a rally in Florida less than two weeks after he tested positive for the coronavirus. That is asking for trouble, Fauci told CNN in an interview. He cited rising virus positivity rates in a number of US states, adding: now is even more so a worse time to do that, because when you look at whats going on in the United States, its really very troublesome.

Coronavirus deaths

The worldwide death toll has passed 1.08 million. The number of confirmed cases is more than 37.8 million, according to Johns Hopkins University, though the true number of cases will be much higher.

Can vitamin D help beat coronavirus?: In this weeks Science with Sam, we take a look at the evidence for the health benefits of sunlight, its importance for your mood and some simple tips to maximise your exposure.

A television shows Britains Prime Minister Boris Johnson speaking in the House of Commons in London, as customers sit at tables inside the Richmond Pub in Liverpool, UK

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Restrictions tighten in parts of England as new three-tier system introduced

UK prime minister Boris Johnson today announced a new three-tier system for setting coronavirus rules in England, due to come into force on Wednesday subject to a debate and vote in parliament tomorrow. Under the new system, different sets of restrictions of increasing severity will apply to different regions. They will be classified as being on medium, high or very high alert based on their case rates per 100,000 people as well as the rate at which infections are rising. The Liverpool city region, which recorded 600 cases per 100,000 people in the week ending 6 October will face the tightest restrictions, classified as tier three. This will mean that those living in Liverpool and surrounding areas will not be allowed to meet people from different households indoors, while gyms and pubs will be required to shut until the measures are reviewed in a month, Johnson told parliament.

Most areas that already have some form of additional restrictions will be classed as high alert level and put under tier two restrictions, meaning that people will not be allowed to mix with those from other households indoors. Nottinghamshire and east and west Cheshire will also be put under tier two rules, said Johnson. The medium alert level will cover most of England and will feature tier one restrictions, including the rule of six and the 10 pm closing time for pubs. Johnson said the goal of the three-tier system was to simplify and standardise local rules.

This is not how we want to live our lives, he said. But is the narrow path we have to tread between social and economic costs of a full lockdown and the massive human and indeed economic cost of an uncontained epidemic, he added. We cannot let the NHS fall over when lives are at stake.

The introduction of a three-tier system does provide greater clarity on what will happen in parts of England to try and address the current rise in covid-19 cases, said Linda Bauld at the University of Edinburgh in a statement. Bauld said the new guidelines are in line with recent evidence linking infections to contact between different households and visits to hospitality venues.

Johnson also outlined financial support measures for people affected by the new measures, including the covering of wages for employees of businesses forced to close due to coronavirus restrictions as well as funding for improved contact tracing for areas on very high alert.

Other coronavirus news

The coronavirus may remain infectious for up to 28 days on surfaces such as mobile phone screens, according to a study by researchers at the Australian Centre for Disease Preparedness published in Virology Journal. The researchers studied coronavirus particles on several common surface types across a range of temperatures, in complete darkness. They found that the virus had a half-life of between 1.7 and 2.7 days at 20C and that viable virus particles could be isolated for up to 28 days on smooth surfaces such as mobile phone screen glass as well as banknotes made of paper and plastic. However, this is probably an overestimate because outside of these laboratory conditions, factors such as exposure to ultraviolet light could increase the chance of virus particles being destroyed.

More people in England are in hospital with covid-19 than before the UK first went into lockdown in March, NHS medical director Stephen Powis told a Downing Street press conference today. If we do not take measures to control the spread of the virus, the death toll will be too great to bear, said Powis. All hospital staff in high risk areas will now be tested for the virus regularly irrespective of symptoms, he added, and Nightingale Hospitals in Manchester, Sunderland and Harrogate have already been asked to prepare for increased numbers of patients in the coming months.

Coronavirus deaths

The worldwide death toll has passed 1.07 million. The number of confirmed cases is more than 37.60 million, according to Johns Hopkins University, though the true number of cases will be much higher.

A woman wearing a face covering walks past a public information poster in Hackney, north London

Dinendra Haria/LNP/Shutterstock

Community infections continue to rise in England, swab testing survey finds

Coronavirus infections in communities in England are continuing to rise, according to the latest results from Imperial College Londons REACT-1 study. Using random swab testing, researchers monitored coronavirus levels and found that about one in 170 people had the virus between 18 September and 5 October, an increase from one in 769 between 22 August and 7 September. The most recent results are based on an analysis of swabs from 175,000 people.

The UKs R number the number of people each coronavirus case infects has gone down slightly for the first time in the last five weeks, from between 1.3 and 1.6 the previous week to between 1.2 and 1.5 in the most recent week, according to official figures. This is most likely to represent the situation two or three weeks ago due to a time lag in the data used to model the R. An R number above 1.0 indicates infections are rising.

While the R value remains above 1.0, infections will continue to grow at an exponential rate, Scientific Advisory Group for Emergencies said in documents published on Friday. This is currently the case for every region in England and all have positive growth rates, reflecting increases in the number of new infections across the country.

Other coronavirus news

There was a record 24-hour increase in global new coronavirus cases on Thursday, with 338,779 cases confirmed around the world according to the World Health Organization. The spike was largely driven by a surge of infections in European countries, including the UK, which on Thursday reported a record daily increase of more than 17,000 new cases. On Friday, the UK reported 13,864 daily new cases. Some hospitals in the north of England will run out of beds within a week, health officials said on Thursday. Cases are also continuing to rise in Spain, France, Italy and Germany. Spains government on Friday declared a state of emergency for 15 days to deal with surging coronavirus cases in Madrid. Almost 25 per cent of intensive care unit beds in France are occupied by covid-19 patients, with the figure rising to 40 per cent in Paris and surrounding areas. France recorded more than 18,000 new cases on Thursday. Daily new cases in Italy jumped from more than 4000 on Thursday to more than 5000 on Friday, with hotspots in the south of the country. On Friday, Germany reported more than 4000 daily new cases for the second consecutive day, with Berlin emerging as one of the hotspots in the countrys second wave.

US president Donald Trump is planning a political rally in Florida this Saturday and may hold a separate rally in Pennsylvania on Sunday night. The White House has not released any information about whether or not he still has coronavirus, or whether he has been tested at all since he tested positive for the virus on 2 October. In June, a rally held by the president in Tulsa, Oklahoma was linked to a spike in coronavirus cases by a local health official.

The Washington, DC Department of Health appealed to all White House staff and anyone who attended an event in the Rose Garden on 26 September to get tested for the coronavirus and seek medical advice, in an open letter released yesterday. The letter says the appeal was prompted by the limited contact tracing performed to date in the White House, adding there may be other staff and residents at risk for exposure to COVID positive individuals.

Coronavirus deaths

The worldwide death toll has passed 1.06 million. The number of confirmed cases is more than 36.62 million, according to Johns Hopkins University, though the true number of cases will be much higher.

CRISPR and covid-19: CRISPR gene editing is already treating disease. But theres far more it might do, from fighting cancer and covid-19 to putting the brakes on climate change, says Feng Zhang, a pioneer of the technique.

Health workers speak with a woman before conducting a test for the coronavirus in Stoke-on-Trent, UK

REUTERS/Carl Recine

Daily coronavirus cases rise to 17,540, up 3300 from the previous day

The UK has recorded 17,540 coronavirus cases in the last 24 hours, an increase of 3300 from yesterday. Deaths also rose slightly, with 77 deaths recorded within 28 days of a positive test, up from the 70 reported on Wednesday. The number of coronavirus patients in hospitals in England has also risen slightly to 3044, up from 2944 yesterday.

Other coronavirus news

Englands contact tracing system only reached 68.6 per cent of those who tested positive for coronavirus, the lowest proportion yet since the system launched in May. The figure is down from 72.5 per cent the previous week. It is also below the target of 80 per cent or more recommended by government scientific advisors to limit infections from spreading. In total, 51,475 people tested positive for the coronavirus in England in the week ending 30 September, a 56 per cent increase compared to the previous week.

In England and Wales, covid-19 was the underlying cause of death in more than three times as many people as influenza and pneumonia combined during 2020, according to analysis by the Office for National Statistics (ONS). The substantially greater number of deaths attributed to covid-19 does tell us that at the moment, covid-19 is a greater risk to people than influenza, Rowland Kao at the University of Edinburgh said in a statement. Kao said this is unsurprising as we have a vaccine against flu but not against covid-19, and because the coronavirus is new to us, whereas some people may have acquired immunity to seasonal flu. The ONS analysis included data between January and August this year.

Coronavirus restrictions in parts of England could be tightened further early next week, with possible closures of pubs and restaurants in the worst-affected areas, according to the BBC. These areas may also see bans on overnight stays away from home. An official government announcement is expected on Monday.

US president Donald Trump today said he would not participate in a virtual presidential debate with Democratic candidate Joe Biden. The debate format was changed because of safety concerns after Trump tested positive for the coronavirus. Im not going to do a virtual debate, Trump said during an interview with the Fox Business Network. Thats not what debating is all about.

Coronavirus deaths

The worldwide death toll has passed 1.05 million. The number of confirmed cases is more than 36.2 million, according to Johns Hopkins University, though the true number of cases will be much higher.

Socially distant future: Coronavirus has put a rocket under plans for more automation, roboticisation and use of AI. Should we fear for our jobs or will we just get better ones?

A restaurant employee removes chairs on a terrace in Brussels

HATIM KAGHAT/BELGA/AFP via Getty Images

New rules introduced in Belgium, France and Germany amid rising cases

Belgium, France and Germany are among European countries that have introduced new restrictions to try and stem surging coronavirus cases. In Belgium, all bars, cafes and event halls will be required to close completely for at least a month, starting at 7 am on Thursday. One in seven people in Brussels are testing positive for the virus, according to officials. In Paris and its surrounding inner suburbs, more than 40 per cent of hospital beds are currently occupied by covid-19 patients, according to the regional health agency. It warned that the proportion could rise to 50 per cent within two weeks without intervention. Bars, gyms and swimming pools in Paris were closed completely on Tuesday for at least two weeks. On Saturday, new rules and curfews will come into force in Germanys capital Berlin, where authorities have recorded 44.2 new cases per 100,000 people over the past seven days. Bars, restaurants and off-licenses in the city will be required to shut between 11 pm and 6 am. Restrictions have been introduced limiting the number of people allowed at private and public gatherings.

In Scotland, which recorded 1054 new coronavirus cases today, first minister Nicola Sturgeon has announced new restrictions on serving alcohol, which come into force at 6 pm on Friday. Bars, pubs and restaurants will not be allowed to serve alcohol indoors for 16 days. Sturgeon described the new measures as a short, sharp action to arrest a worrying increase in infection.

Other coronavirus news

Diagnostic tests in the UK could be delayed due to a supply chain failure affecting Swiss pharmaceutical company Roche, which supplies diagnostic testing equipment and materials to the NHS. Roche said that issues, which are related to a move to a new warehouse, had resulted in a significant drop in its processing capacity, adding that it is prioritising the dispatch of covid-19 diagnostic and antibody tests. However, there are concerns that this strategy could delay other tests, such as those for kidney, liver and thyroid function, as well as for sepsis and other infections. Tom Lewis, a doctor at North Devon District Hospital, told the BBC his hospitals trust had already asked staff to stop all non-urgent blood tests in the community. The problem could take up to two weeks to resolve, a Roche spokesperson told the BBC.

US Democratic presidential candidate Joe Biden has said the next presidential debate on 15 October should not take place if US president Donald Trump still has covid-19. Biden told journalists that the debate, scheduled to take place in Miami, should only be staged in accordance with strict health guidelines, adding if (Trump) still has covid, we shouldnt have a debate.

Coronavirus deaths

The worldwide death toll has passed 1.05 million. The number of confirmed cases is more than 35.9 million, according to Johns Hopkins University, though the true number of cases will be much higher.

Covid-19 symptoms: As the list of covid-19 symptoms recognised by health authorities evolves, we are starting to learn that people seem to fall into one of several symptom clusters, and that we might be missing the most important signs of the disease in children.

Doctors diary: Inadequate coronavirus testing and uncertainty over the success and supply of flu vaccines will leave doctors in England poorly prepared to cope this winter.

Shoppers pass beneath an electronic sign reminding pedestrians to act now to avoid a local lockdown in Manchester, UK

PAUL ELLIS/AFP via Getty Images

UK sees 14,452 cases in a single day, as covid-19 deaths rise for third week in a row

Today, the UK recorded 14,542 daily new coronavirus cases, almost 2000 more than on Monday. This is a record number of new daily cases, with the exception of last Sunday when the number was artificially raised to 22,961 to compensate for thousands of cases that were missed between 25 September and 2 October due to a technical mistake. The number of deaths mentioning covid-19 on the death certificate has risen in the UK for the third consecutive week, according to the Office for National Statistics. There were 234 deaths involving the coronavirus registered in the week ending 25 September, up from 158 from the week before.

Other coronavirus news

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OKLAHOMA CITY (KFOR) An innovative treatment that is harnessing the bodys own immune cells to fight cancer is now being offered at the Jimmy Everest Center for Cancer and Blood Disorders in Children for young people diagnosed with a type of leukemia.

The Jimmy Everest Center, a clinic within OU Childrens Physicians, treats many young people with leukemia.

In the pediatric population, the treatment CAR-T is specifically for young people up to age 25 who have precursor B-cell acute lymphoblastic leukemia (ALL), an aggressive form of blood cancer. To receive CAR-T, their cancer must have returned or become resistant to treatment.

CAR-T is a process in which the patients own cells are redirected to attack the leukemia cells, said David Crawford, M.D., Ph.D., who sees patients in the Jimmy Everest Center. This is a great opportunity because our patients can now be treated with CAR-T at home instead of us sending them to other institutions for the treatment.

CAR-T stands for Chimeric Antigen Receptor T-cell therapy. Patients being treated with CAR-T first have their blood collected in a process similar to a typical blood donation. White blood cells (which include T cells) are filtered out, and the plasma and red cells are returned to the patient. The cells are then sent to a company that inserts the gene for a chimeric antigen receptor into the T cells, which binds to cancer cells and activates the T cells.

This process allows the newly engineered T cells to recognize and attack cancer with remarkable efficiency. Once the CAR-T cells are generated, they are shipped back to the Jimmy Everest Center and given to the patient through an IV, much like a blood transfusion.

Precursor B-cell ALL is the most common childhood malignancy affecting kids from childhood through young adulthood, peaking in diagnoses between ages 3 and 6. Many are cured with chemotherapy and other treatments, but some are not.

Children who relapse are in the greatest danger, Crawford said. For patients who relapse after a stem cell transplant, for example, we previously didnt have any more options. CAR-T is really a game-changer for them.

Unlike other types of cancer therapies, CAR-T therapy is a one-time treatment. The T cells remain in the body, prepared to attack the cancer at any time. The therapy carries a risk of complications, such as cytokine release syndrome and neurotoxicity, but patients are closely monitored and seen daily by their physician, Crawford said.

CAR-T is also being offered at Stephenson Cancer Center for adults diagnosed with advanced lymphomas who are not responding to other treatments. Clinical trials are underway to determine if CAR-T can be used to treat other types of cancer in both adults and children.

For Crawford, it is gratifying to offer his patients and families new hope through CAR-T. Even when his young patients respond well to standard treatment, their quality of life is significantly affected. For those who dont, CAR-T can be a lifesaver.

I wanted to be in a field of medicine where I thought what I was doing made a big difference, and no place can you feel more like that when the patient faces a certainty of dying without the treatment you give them, he said. CAR-T is a breakthrough for our patients.

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Innovative treatments that harnesses bodys own immune cells to fight cancer now offered at Jimmy Everest Center - KFOR Oklahoma City

WASHINGTON, D.C. The chairmen of four U.S. bishops committees, joined by the leaders of several health care, bioethics and pro-life organizations, urgently and respectfully implored the commissioner of the U.S. Food and Drug Administration to ensure any vaccines developed for the coronavirus are free from any connection to abortion.

To be clear, we strongly support efforts to develop an effective, safe, and widely available vaccine as quickly as possible, the leaders said in an April 17 letter to Dr. Stephen M. Hahn, the FDA commissioner.

However, we also strongly urge our federal government to ensure that fundamental moral principles are followed in the development of such vaccines, most importantly, the principle that human life is sacred and should never be exploited, they said.

Copies of the letter were sent to President Donald Trump, Vice President Mike Pence and Health and Humans Services Secretary Alex M. Azar. The text of the letter was released late April 17 by the U.S. Conference of Catholic Bishops.

The chairman who signed it and their respective USCCB committees were: Archbishop Joseph F. Naumann of Kansas City, Kansas, Committee on Pro-Life Activities; Archbishop Paul S. Coakley of Oklahoma City, Domestic Justice and Human Development; Bishop Kevin C. Rhoades of Fort Wayne-South Bend, Indiana, Committee on Doctrine; and Bishop John F. Doerfler of Marquette, Michigan, the Subcommittee on Health Care Issues, which is a subcommittee of the doctrine committee.

Other signatories were the heads of 20 organizations such as the Catholic Medical Association, National Catholic Bioethics Center, American Association of Pro-Life Obstetricians and Gynecologists, National Association of Catholic Nurses, Southern Baptist Ethics &Religious Liberty Commission, Children of God for Life, March for Life Education & Defense Fund, Family Research Council and Students for Life of America.

We are aware that, among the dozens of vaccines currently in development, some are being produced using old cell lines that were created from the cells of aborted babies, they said.

They noted that, for example, Janssen Pharmaceuticals, Inc. has a substantial contract from HHS and is working on a vaccine that is being produced using one of these ethically problematic cell lines.

Other vaccines such as those being developed by Sanofi Pasteur, Inovio and the John Paul II Medical Research Institute utilize cell lines not connected to unethical procedures and methods.

It is critically important that Americans have access to a vaccine that is produced ethically: No American should be forced to choose between being vaccinated against this potentially deadly virus and violating his or her conscience, the group said.

Fortunately, there is no need to use ethically problematic cell lines to produce a COVID vaccine, or any vaccine, as other cell lines or processes that do not involve cells from abortions are available and are regularly being used to produce other vaccines, they said.

The group told Hahn: We urgently and respectfully implore you to not only ensure that Americans will have access to a COVID vaccine that is free of ethical concerns, but to encourage and incentivize pharmaceutical companies to use only ethical cell lines or processes for producing vaccines.

On April 6, a group of about a dozen Democrats in Congress sent a letter to Azar urging the Trump administration to lift restrictions on research that uses human fetal tissue for potential treatment for COVID-19. They argued that allowing fetal tissue in such studies could lead more quickly to a treatment.

On June 5, 2019, The U.S. Department of Health and Human Services banned the National Institutes of Health from using human fetal stem cells from electively aborted babies for government funded research. The department also issued a $20 million grant for research to develop models that do not rely on human fetal tissue.

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Head of FDA urged to ensure any COVID vaccine be free of abortion connection - Crux: Covering all things Catholic

Here at Stem Cell Therapies of Oklahoma, were firmly committed to the belief that regenerative therapy is highly beneficial. Were convinced its the answer to many soft tissue and orthopedic issues experienced by patients today. This is why weve created our cutting-edge practice to help those in pain to find relief. By adopting the latest advances in medicine, were here to help patients live their lives to the fullest.

Around 100 million people in the United States today suffer from a chronic pain condition. Sadly, many cannot find the relief they seek, even when they undergo invasive surgery. The reason for this is that treatments available today dont address the cause of the pain. This may be down to damage or dysfunction because of overuse, aging, traumatic injury or a congenital condition. Whatever the cause, traditional treatments cannot resolve it.

How Does Stem Cell Medicine Work?

The discipline of regenerative medicine covers many methods and procedures. Recently, there have been many impressive advances in the field of stem cell research. We use regenerative treatments that focus on the use of stem cells. These help the body to heal from the inside. A stem cell injection allows your body to use the cells to counteract the inflammation that damages tissues.

Regenerative medicine uses stem cells as its key component, and we have found our patients are impressed by the results. From ligament injuries and joint pain to neuropathy and autoimmune conditions, stem cell treatment could be the answer.

Who Can Benefit from Regenerative Medicine?

Stem cells and natural healing can improve the quality of life for many of our patients. However, not everyone can benefit. Every individual has his or her own healing response, and we cannot guarantee anything in the field of medicine. We will always evaluate your goals and health carefully to ensure you have the best chance of a successful outcome.

If youre keen to dramatically reduce or even eliminate your pain with no need for surgery, regenerative medicine may help. Our treatments require no downtime and there are no side effects. Our treatments also wont mask the symptoms of your condition. Instead, the stem cells will help to heal you from within so you can achieve a full recovery whenever possible. If you want to get back to a normal daily life with no pain or reduced mobility, we can help.

Contact Stem Cell Therapies of Oklahoma Today

If youre ready to find out more about our regenerative medicine treatments, contact our team today. We can offer you expert advice and answer all your questions. We help you make an informed decision about whether regenerative medicine could be the alternative pain relief solution you seek. Whatever the cause of your condition, we can advise you about whether our stem cell therapies could be beneficial. Its our mission to help you live a happier, healthier, and pain-free life.

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Stem Cell Treatments | Stem Cell Therapies of Oklahoma ...

Regenerative medicine involves isolating regenerative cells from a healthy source, and introducing them into the body. Localized treatments utilizing growth factors, cytokines, proteins and mesenchymal stem cells may help with shoulder, knee, wrist and many other joint pain or injuries by amplifying the bodys self-healing nature, which may help repair damaged tissue caused by injury, age or disease.

As experts in regenerative medicine, the Oklahoma Institute of Regenerative Health team has helped thousands of patients like you using the worlds most advanced minimally invasive treatments. Our therapies are used for treating degenerative medical conditions and common injuries, such as osteoarthritis, torn ligaments, muscular tears and sprains. Through extensive experience, our medical staff believe regenerative therapy can improve patient outcomes, and restore a higher quality of life. While every patient is different, one of our therapies may help you, as many of our patients see results within a couple of months of receiving treatment.

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Oklahoma Institute of Regenerative Health in Oklahoma City, OK

Stafford Township, NJ Stem cell therapy is an incredible process for healing damaged tissue, so it seems remarkable that it is availablefor petsright here in Manahawkin. Stafford Veterinary Hospital, at 211 North Main St., began offering the advanced treatment in 2019, under the direction of Michael Pride, medical director at the facility.

There, stem cell therapy is most commonly applied to osteoarthritis, but can also be used in dogs suffering from hip dysplasia and ligament and cartilage injuries, as well as mobility ailments and some chronic inflammatory issues such as inflammatory bowel disease and chronic kidney disease, which is common in cats.

Stem cell therapy is actually the only thing that can help to reverse the process of arthritis, Pride said. Everything else is a Band-Aid.

This process can actually help to rebuild cartilage and really reduce inflammation without the need of using aspirin-type medications, Pride said. Its a newer technology that we can use to avoid chronic use of medications, which might actually be detrimental in the long term for the liver or kidneys.

Stem cell therapy treats the source of the problem by offering the ability to replace damaged cells with new ones, instructs the website staffordvet.com.

Stem cells are powerful healing cells in the pets body that can become other types of cells. For example, in the case of arthritis, stem cells can become new cartilage cells and have natural anti-inflammatory properties, thus reducing pain and increasing mobility.

The stem cells are your primary structural cell for all other cells in the body; they can differentiate into almost any other cell, explained Pride. Were processing it down into that primordial stem cell; were activating it, and were injecting it into where it needs to be, and it just starts taking on the characteristics of the cells around it.

Table-top machines from MediVet Biologics are the first Adipose Stem Cell therapy kits for in-clinic use, a major advancement. Stem cell therapy for animals has been commercially available since 2004. MediVet pioneered in-clinic treatment options around 2010.

Pride believes Stafford Veterinary Hospital offers the only such treatment in the immediate area; another is in Egg Harbor Township, Atlantic County.

Were always trying to figure out different ways to help the patient without hurting them, he said while petting a kitten that had been a patient for another type of treatment.

As stem cell therapy is more in the news regarding humans, a pet owners first question might be where the stem cells come from that are used in the process. The answer: from fat tissue of the pet itself, extracted and processed the same day.

As the therapy has been refined in the last decade, it has actually started to become a lot easier, more cost-effective more recently, said Pride, since weve been able to process fat tissue instead of actually getting bone marrow.

Fat tissue actually has a much higher concentration of adult stem cells than bone marrow does, so its less painful for the patient, they heal a lot easier, and we dont have to process it in a different facility.

Everything comes from the animal, and we give it back to the animal. Nothing comes from another animal. We dont have to worry about them rejecting the sample; its their own tissue, and were giving it back to them.

The pet typically goes home the same day after about eight hours. First, X-rays and a consultation with the veterinarian can determine whether the pet is a candidate for the treatment.

A pet owner may not even know that their animal has arthritis.

Cats have a lot of inflammatory issues that they tend to be very good at hiding, said Pride. A lot of people dont realize that they have arthritis. They think, oh, my cats just getting older; hes not jumping as much; hes not as strong; hes just sleeping most of the day, but actually he has arthritis. Its very difficult to diagnose in cats. A lot of times you end up having to do X-rays to find where the arthritic joints happen to be.

An inch-and-a-half incision is the minor surgery that harvests the fat tissue from the belly while the pet is anesthetized. For a cat, about 20 gramsare extracted. For a large dog, about 40 gramsare needed. While the pet is recovering from the incision surgery, the veterinary hospital is processing the sample. When the sample is ready, the pet is sedated because we then have to give them the joint injections. Then we can reverse the sedation, and they go home.

We asked the doctor if the process always works. He gave the example that on average, a dog such as a boxer that was hobbled is now able to walk without seeming like its painful. In an extreme positive case, a dog that had been barely walking might be bouncing all over the place in two months.

It doesnt always work to the extent that we would love it to, but we usually notice that there is a positive effect from it, Pride remarked. Every patient will be different in what they experience.

For the same reason that everyones situation is going to be different, cost of treatment was not given for this story.

It generally takes about 30 to 60 days for relief to show, the veterinarian said, and the animals progress will be monitored.

On average, results last about 18 months to two years before more stem cells might have to be injected. The procedure takes about an hour.

The nice thing is once we collect those stem cells (from the first procedure), we can bank the leftovers they are cryogenically stored at MediVet corporate headquarters in Kentucky and we dont have to go through the initial anesthetic surgery, said Pride.

Stem cell therapy is one of several innovative modalities available at Stafford Veterinary Hospital. Laser therapy, acupuncture and holistic medicine are others. Care for exotic pets is available, as is emergency pet care.

Visit the website staffordvet.com or call 609-597-7571 for more information on general and specialized services, including: vaccinations, microchipping, spayingand neutering, dental care, wellness exams, dermatology, gastrology, oncology, opthalmology, cardiology, soft-tissue surgery, ultrasound, radiography, nutrition, parasite control, boarding, laborand delivery, end-of-life care, and cremation.

Stafford Veterinary Hospital has been in business since 1965, founded by Dr. John Hauge. Today, five highly skilled veterinarians are on staff, and a satellite, Tuckerton Veterinary Clinic, is at 500 North Green St. in Tuckerton.

Pride has been medical director at Stafford Veterinary Hospital since 2008. He attended Rutgers University, then earned his Veterinary of Medicine degree at Oklahoma State University.

The mild-mannered doctor feels a great rewardfrom treating animals that cant speak for themselves when they feel bad.

These guys, theyre always thankful; you can see what they think, he said of treated pets. The turnaround in their attitude, the turnaround in their ability to be more comfortable, you can see it in their faces; you can see it in their actions. You learn to read animals over time.

Its knowing that were helping those who cant help themselves, he added, and you can see it in them; thats the most gratifying.

mariascandale@thesandpaper.net

See the article here:
Stem Cell Therapy for Dogs and Cats Is Innovative at Stafford Veterinary Hospital - By MARIA SCANDALE - The SandPaper

Nathaniel Beales ten-year-old son, Noah, took his place at his University of Oklahoma graduation on Saturday.

Nathaniel Beale was diagnosed with leukemia in July but completed his degree during treatment. Unfortunately, he was physically unable to attend the graduation celebration of his hard-won academic victory due to an upcoming surgery.

In his place, ten-year-old Noah Beale stepped up to support his father by taking his place at the graduation ceremony. Beale watched a livestream of his son accepting the diploma.

Leukemia affects roughly 1.6 percent of men and women, with 414,773 suffering from the deadly blood cancer in the United States. 61,780 new cases have been reported, and 22,840 have died in 2019 alone. As described by the National Cancer Institute:

Leukemia is cancer that starts in the tissue that forms blood. Most blood cells develop from cells in the bone marrow called stem cells. In a person with leukemia, the bone marrow makes abnormal white blood cells. The abnormal cells are leukemia cells. Unlike normal blood cells, leukemia cells dont die when they should. They may crowd out normal white blood cells, red blood cells, and platelets. This makes it hard for normal blood cells to do their work.

While there is no cure, over 62 percent of patients survive five or more years after diagnosis. With the support of his son and family, Beales fight for life continues.

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10-Year-Old Walks Graduation Stage for Father with Leukemia - Breitbart