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Alterations in intestinal permeability
Recent advances in clinical practice
M C Arrieta,
L Bistritz,
J B Meddings
Department of Medicine, University of Alberta, Alberta Canada
Dr J B Meddings
Department of Medicine, 2F1.30 Walter C Mackenzie, Health Sciences Center, 8440-112 St, Edmonton, Alberta Canada; jon.meddings{at}ualberta.ca
http://dx.doi.org/10.1136/gut.2005.085373
The goal of this review is to describe barrier function of the intestine, the structure of the tight junction, methods to evaluate intestinal permeability, and most importantly the relevance of abnormal permeability to disease. In this context, we will also present an emerging paradigm regarding the genesis of autoimmune diseases and describe the data that supports this from the perspective of both human disease and animal models. While this is a complicated area there are several points worth remembering:
epithelial permeability of the gastrointestinal tract can be evaluated in a site specific manner;
increased intestinal permeability is observed in association with several autoimmune diseases. It is observed prior to disease and appears to be involved in disease pathogenesis;
there are new and novel therapies directed at altering abnormally increased intestinal permeability and these may play a role in treating or preventing these diseases.
BARRIER FUNCTION
From the lower oesophageal sphincter to the anus, the gastrointestinal tract has a single contiguous layer of cells that separates the inside of the body from the external environment. Separation is important as there are a wide variety of environmental agents in the lumen of the bowel that can initiate or perpetuate mucosal inflammation if they cross the epithelial barrier. While the epithelial lining of the intestine plays a critical role in preventing access of these agents, it is not the only component of what is termed barrier function. Also important are secreted products such as immunoglobulin, mucous, defensins, and other antimicrobial products.
The importance of epithelial barrier function in normal homeostasis can be appreciated from experiments performed in the early 1990s where cell wall extracts from luminal bacteria were injected into the colonic wall of rats.1 This simple manoeuvre of bypassing the epithelial barrier and placing luminal compounds directly into the colonic wall initiated an inflammatory disease that was characterised by granulomatous reactions both in the bowel and, importantly, as a systemic inflammatory process. Similar results were also observed by variably expressing a dominant negative N-cadherin mutant in epithelial cells along the crypt-villus axis. This induced abnormal function of intercellular junctions and initiated a mucosal inflammatory disorder that resembled Crohn's disease.2 The important concept that emerges from these experiments is that by simply abrogating epithelial barrier function, inflammatory disease can be induced in a susceptible host with features that are expressed both locally and systemically.
ANATOMICAL STRUCTURE OF THE EPITHELIAL BARRIER
Much of the epithelial barrier is formed by the rigid lipid bilayer of the enterocyte brush border. As in most cell membranes, this structure has appreciable solubility to lipid compounds but offers a strong barrier to water soluble constituents. The enterocyte balances its dual function as both an absorptive and barrier cell by embedding transport systems within this membrane for the water soluble compounds that it wishes to transport. However, at the junction between epithelial cells there is a potential route for solute traffic that is not regulated by brush border membrane transporters or channels. In order to regulate traffic through this paracellular pathway, mammalian epithelial cells form a series of intercellular junctions along their lateral margins. Closest to the luminal surface lies the tight junction and underneath is the adherens junction.
These structures are enormously complex in both their lipid and protein constituents. An ever expanding family of proteins are found in the vicinity of these junctions, forming fibrils that cross the plasma membrane to interact with proteins from the adjoining cell. These proteins also interact intracellularly with the actomyosin ring that encircles the enterocyte at the level of the tight junction through numerous smaller proteins. The fibrils between cells consist of at least two types of tetraspanning membrane proteins, occludin and members of the claudin family. The latter is comprised of at least 19 different but related proteins, their name coming from the Latin "to close". It is of interest that defects in claudins have already been associated with human disease: a genetic mutation in claudin 16 appears to be involved in renal hypomagnesaemia, characterised by massive renal loss of magnesium.3 Furthermore, claudins 3 and 4 are targets for the bacterially produced toxin, Clostridia perfringens enterotoxin which dramatically increases tight junctional permeability in tissue culture systems.4
On the intracellular side of the membrane, the carboxy terminal end of these proteins interacts with the tight junction proteins ZO-1, ZO-2, and ZO-3 (see fig 1⇓). These proteins belong to the membrane associated guanylate kinase superfamily and possess an enzymatically inactive guanylate kinase-like domain. Underneath the junctional complex lies a ring of actin microfilaments and contraction of this has been proposed to regulate paracellular permeability. Connecting this ring to the junctional complex (ZO family members) are a series of actin filaments, as schematically outlined in fig 1⇓. In addition to these protein constituents, there are numerous other junctional proteins that have been described and a tremendous effort is underway to elucidate the physiological interactions of these proteins in terms of cellular and junctional function. Excellent reviews of tight junctional structure and the protein composition of these fascinating organelles are available.5–,8 One emerging concept is that the relative abundance of the different claudin family members is important in determining the physiological properties of the junction. Along normal developmental axes (such as along the crypt-villus axis) or during disease expression, the relative abundance of the claudins can change by up to 1000-fold while other more structural protein components seem to change relatively little.9
Tight junction structure. Homotypic association of claudin and occludin is illustrated. Numerous other proteins have been described and for a detailed description of their function and localisation, the reader is referred to the reviews given in the text.
It is also important to consider what factors alter permeability of the junction. We now recognise that the functional state of the tight junction, once considered a static parameter, is in reality incredibly dynamic. Epithelial tight junctions open and close all the time in response to a variety of stimuli. These include dietary state, humoral or neuronal signals, inflammatory mediators, mast cell products, and a variety of cellular pathways that can be usurped by microbial or viral pathogens.10–,19 A complete discussion of all of these mechanisms is beyond the scope of this article but a few deserve closer attention as they are important in our understanding of disease pathogenesis.
The first are dietary factors. It is now generally appreciated that the permeability of the paracellular pathway can be modulated by transcellular absorptive processes. During activation of the sodium dependent glucose transporter (SGLT1), there is a physiological opening of tight junctions that allows for the movement of small molecules and peptides.20–,23 This pathway will accommodate particulate sizes of the order of 2000 molecular weight (MW) but still exclude large particles such as horseradish peroxidase (MW ∼40 000).24 Although this is a normal physiological event, the purpose it subserves remains unclear. However, as discussed in the next section, this observation is important in our understanding of how to understand permeability measurements.
A physiological pathway, relevant to disease, is the zonulin pathway. Many bacteria alter tight junction state, presumably to enhance their own growth requirements. Vibrio cholerae secretes a variety of toxins and one of these, zonula occludens toxin, was recognised as increasing paracellular permeability. The mechanism by which this occurred was novel and involved binding to an apical membrane receptor on the enterocyte with subsequent activation of an intracellular pathway resulting in actomyosin contraction and increased paracellular permeability. The investigators speculated that it was unlikely that this pathway was present for the sole benefit of the bacteria and that a more likely scenario was that the pathway was a physiological one that bacteria had evolved to take advantage of. This proved to be true and in an elegant piece of work this bacterial toxin was used to identify the human homologue for this pathway now termed zonulin.25 It appears that in many scenarios where permeability is increased, a common pathophysiological event is upregulation of zonulin secretion from a lamina propria source into the lumen26–,28 with inappropriate activation of this pathway. The end result is increased paracellular permeability. This is illustrated in fig 2⇓.
Zonulin pathway. Depicted is a schematic view of what is known about the regulation of zonulin. Multiple steps are illustrated. (1) A luminal trigger for zonulin release arises and interacts with receptors, presumably on the epithelial cell. Triggers can be bacterial or food products such as gluten. (2) The trigger is sensed and a signal is passed to a lamina propria cell (3) where zonulin is released, diffuses to the luminal compartment, and thereafter binds to an apical receptor (4). This initiates a complex series of intracellular events that ultimately involves phosphorylation of tight junction proteins and opening of the paracellular space (5–6).
Measurement of permeability
Over the past several decades there has been a concerted effort to develop simple non-invasive means to evaluate the permeability properties of the paracellular pathway. In order to rationally evaluate methods to quantitatively evaluate the paracellular pathway in vivo, it is important to keep in mind a few simple principles. Movement across this pathway occurs by a non-carrier mediated process and as such depends on several features.
The concentration gradient across the barrier.
The surface area of the epithelium.
The time available for permeation.
The intrinsic permeability properties of the barrier.
As the last item is the characteristic of interest for measurement, it is important to try and avoid differences in the first three variables during the measurement process by carefully selecting the probes used and the method of their employment. Historically, a wide variety of probes have been utilised to determine paracellular permeability properties. Typically, they have several features in common; they are usually small, water soluble, non-charged compounds that are not destroyed in the gut, are non-toxic, not metabolised or sequestered once absorbed, and quantitatively cleared by the kidney into the urine. Finally, they should be easily detectable in urine and easily separated from similar endogenous or dietary compounds. This area has been extensively reviewed recently.29,30
Despite the proliferation of available probes, the majority of work in humans and experimental animals has employed a variety of small saccharide probes and/or Cr-EDTA. This is simply because these probes satisfy the criteria above, are cheap, and easily detectable. However, it is important to recognise that several of these probes are destroyed by processes that take place in the lumen of the gut and this limits their exposure to the epithelium in a manner that can be advantageously used to evaluate permeability characteristics in a regional manner.
As an example, sucrose is a useful probe for determining permeability characteristics of the gastroduodenal region.31 Distal to the gastroduodenal region, sucrose is rapidly hydrolysed by sucrase-isomaltase and therefore permeation of intact sucrose across the gastrointestinal mucosa must occur in the most proximal regions of the gut. In a similar manner, the traditional small intestinal permeability probes, lactulose, mannitol, rhamnose, or cellobiose, are degraded by the bacterial flora of the large intestine and yield no information regarding colonic permeability characteristics. Furthermore, under conditions of small intestinal bacterial overgrowth, loss of lactulose and mannitol is impossible to quantify and calls into question determination of permeability. In order to evaluate colonic permeability properties, probes must be selected that are stable in this environment. These include either Cr-EDTA or sucralose.32 Although these probes are stable throughout the gastrointestinal tract, they preferentially provide information regarding colonic permeability because, under normal conditions of intestinal transit, they reside within the colon for the majority of their time in the gut. The principles and techniques of probe selection for regional permeability determinations are discussed more extensively elsewhere32 but the basic features of these probes are schematically depicted in fig 3⇓.
Region specific permeability measurements. By carefully choosing probes that have only a limited exposure to the gastrointestinal epithelium site, selective permeability determinations can be made. Sucrose is destroyed once it leaves the stomach and so sucrose permeability is a reflection of gastroduodenal disease. In a similar manner, lactulose and mannitol are destroyed in the caecum and provide information regarding the small intestinal epithelium. Finally, probes such as sucralose and Cr-EDTA are stable throughout the gut. They provide preferential information regarding the colonic epithelium as they spend most of a 24 hour exposure period in that organ.
Perhaps the most important issue to consider is what the permeation rate of the various probes actually means. The most concise hypothesis regarding the routes various probes take across the epithelium has been provided by Fihn and colleagues.33 These investigators provided data to suggest that there are a series of "aqueous pores" distributed along the crypt-villus axis of the small intestine. At the tips of the villus are relatively abundant small channels (radius <6 A) while in the crypts there exist much larger channels (50–60 A) in low abundance. At the base of the villus are intermediate sized (10–15 A) channels. The channels at the tips of the villus are increased in number by addition of glucose22 and susceptible to solvent drag effects while those in the crypt are unaffected by these alterations. The intermediate sized channels seem to be unaffected by solvent drag effects, perhaps as under physiological conditions this part of the villus is not exposed to luminal contents. With these data it would appear that, under normal conditions, molecules the size of disaccharides (for example, lactulose) are restricted from moving across the villus tip whereas mannitol can do so with relative freedom. This hypothesis is illustrated schematically in fig 4⇓ and provides one possible explanation for the marked difference in permeation rates for probes with small differences in physical size.
Small intestinal permeation pathways. Depicted is a schematic representation of the crypt-villus axis. The broken line is an estimated depth of "luminal exposure"—the limit to which solvent drag effects are noticeable. This limit is loosely based on the known distribution of the sodium dependent glucose transporter 1 along this axis. Within this region glucose stimulated water flux is evident and can also drag particles that can fit through the same pathways as water is using. On the left is a qualitative estimate of increasing pore size along the crypt-villus axis with a horizontal bar providing a qualitative estimate of the number of each sized pore. The location of uptake for the various sized probes is shown on the right with the number in parentheses referring to the hydrodynamic radius of each probe in angstroms.
Traditionally, small intestinal permeability is expressed as the ratio of the fractional excretion of a larger molecule to that of a smaller one (for example, lactulose:mannitol). Using the paradigm from the preceding paragraph, this would represent the number of intermediate sized pathways as a proportion of the total number of aqueous channels. As the smaller channels are concentrated at the villus tips, permeation rates of compounds across this pathway become a rough assessment of mature small intestinal surface area. This is well established from a clinical perspective. In diseases where there is a marked reduction in mature small intestinal surface area, such as coeliac disease, there is a substantial reduction in the fractional excretion of small probes such as mannitol. Coupled with this there is an increase in the fractional excretion rates of larger probes such as lactulose. This would suggest either an increased number of intermediate sized channels per unit surface area or the appearance of an alternate pathway, accessible to lactulose, that is not evident under normal physiological circumstances. As intermediate sized channels appear to be present in the immature parts of the crypt-villus axis, relative expansion of this crypt-villus fraction (as observed in coeliac disease) is a possible explanation. However, there are also data demonstrating that the presence of either epithelial damage or increased rates of apoptosis provide alternate routes for the permeation of larger molecules such as lactulose.34–,36
The net result of a reduction in the fractional excretion of mannitol and an increase in that of lactulose is a dramatic increase in the lactulose:mannitol ratio. The converse is seen during the healing process of the coeliac lesion. During treatment with a gluten free diet, the first sign of recovery is seen as an increase in the fractional excretion of mannitol, suggesting that recovery of mature surface epithelium precedes the reduction in apoptosis and damage.37 This interpretation fits well with the known pathophysiology of coeliac disease.
Therefore, a reasonable interpretation of permeability data, expressed as a lactulose:mannitol ratio, is the amount of epithelial damage as a proportion of mature small intestinal surface area. It is important to remember that this parameter provides no information about either colonic or gastric permeability. The former is due to the fact that both probes are destroyed in the colon and the latter since the surface area of the small intestine is so much greater than that of the stomach. In order to obtain this type of information, additional probes such as sucrose and sucralose are necessary and provide the necessary data without detracting from the measurement of small intestinal permeability. Additional probes to assess absorptive function can also be added to extend the usefulness of such testing.38,39
NEW PARADIGM FOR AUTOIMMUNE DISEASE
As discussed previously, there are data available suggesting that abrogation of epithelial barrier function can induce inflammatory disease, either locally or remotely. We will offer a hypothesis to explain this observation and then provide experimental data to support this. In order to do this we will consider type 1 diabetes as a model disease and then extend these observations to several other diseases that we believe have similar aetiologies.
We hypothesise that many diseases have a pathogenesis that consists of three main features, represented diagrammatically in fig 5⇓.
Disease initiation pathway. Depicted is a proposed model of the initiation of autoimmune disease. In this model, an initiating factor is found in the environment (lumen of the gut) that is kept separate from the mucosal immune system by a competent epithelial barrier. Abrogation of this barrier by any mechanism allows for initiation of the disease process.
A genetically susceptible immune system (the mucosal immune system), that allows the host to react abnormally to an environmental antigen.
An environmental product that triggers the disease process.
The ability for the environmental agent to interact with the mucosal immune system. Since the purpose of the epithelial barrier is to keep these two factors separate, and we measure this function of the barrier by permeability, the corollary of this is that an increase in permeability is a requirement for disease expression.
Within this model the specificity for disease location (target tissue) is provided by both the antigen and the genetic abnormality of the immune system. For instance, the target may be the beta cells of the pancreatic islets (diabetes), the epithelial cells of the gut (coeliac disease), or the myelin sheaths surrounding nerve (multiple sclerosis). In some cases the antigen is known, such as gluten for coeliac disease, but for most it is not and may represent a dietary antigen, an antigen from the host flora, or a transient infectious antigen. The antigen may cross the epithelial barrier at any level of the gut and this may provide some clues to the type of antigen involved. As we will demonstrate, permeability alterations can be observed at several levels of the gut and at each of these the type of prevalent antigen differs. For instance, in the proximal gut, intact dietary antigens will be common but in the distal gut, antigens from the microflora will be more abundant. This model also does not place any requirements on how the increase in permeability arises. This can occur during an infectious process, by activation of endogenous humoral pathways, or by microbial manipulation of the host's epithelial cell pathways. It may also be a transient event and this may be an explanation for the lack of detectable permeability abnormalities in some patients.
So, what is the evidence to support this paradigm? Probably the best example is that of type 1 diabetes in the BB rat. In this model of autoimmune diabetes an inbred line of rat develops classical autoimmune diabetes when weaned onto a normal diet.40 However, if the animal is instead weaned onto a hydrolysed diet, a much lower incidence of diabetes results. This is an inbred line of animals and so a genetic susceptibility of the mucosal immune system is not an unreasonable proposition. However, the observation that simply altering the diet can dramatically change the risk of disease suggests a dietary trigger that can be removed by protein hydrolysis. In view of the paradigm outlined above, we would also predict that these animals should have increased intestinal permeability. When measured, there is a marked increase in permeability of both the small intestine (lactulose/mannitol ratio) and of the stomach (sucrose).41 The increase in permeability was not due to diet as animals receiving the hydrolysed diet had the same increase as those on the regular diet.
The increase in permeability is not present at all ages and so the question arises as to what is the mechanism of the increased permeability. As discussed previously, one potentially abnormal pathway is the zonulin system to open the paracellular pathway. Recent work has demonstrated that in the BB rat, coincident with the increase in permeability, there is increased zonulin secretion into the lumen.42 Therefore, in this model of autoimmune disease we now have evidence for a dietary antigen and an abnormality of the zonulin pathway that leads to increased permeability. The disease can be prevented by removing the antigen, but most exciting of all, it can also be prevented by abolishing the increased permeability. This was recently demonstrated by Watts et al using a zonulin receptor antagonist which prevented the increase in small intestinal permeability and expression of diabetes.42 The message inherent in these experiments is that expression of diabetes requires the genetic predisposition of the rat strain, the dietary provocative agent, and abnormal permeability. Removal of either the luminal antigen or the permeability defect prevents disease, despite retaining the genetic predisposition.
There are a variety of human diseases in which it has been suggested that abnormal permeability is important. These include: diabetes, Crohn's disease, coeliac disease, multiple sclerosis, irritable bowel syndrome, and a pot pourri of others. Each will be discussed in the following sections.
Given that the BB rat model of type 1 diabetes provides strong support for increased permeability playing a key role in disease pathogenesis, it is perhaps not surprising that this has been further investigated. In the non-obese diabetic mouse there have not been any studies evaluating alterations in permeability but there is evidence of a coeliac-like enteropathy with an increased number of intraepithelial lymphocytes.43 In other situations with these findings, increased permeability is typically present and it would not be a surprise if it were present in this mouse model of type 1 diabetes.
In humans, increases in intestinal permeability in type 1 diabetics were first reported 20 years ago.44 These early studies did not exclude patients with concomitant coeliac disease nor did they use some of the more modern detection methods for the probes. However, more recent studies, that have taken these into account, continue to find that type 1 diabetic patients have increased small intestinal permeability.45,46 This is not simply related to hyperglycaemia or poor glycaemic control as patients with type 2 diabetes have normal permeability.47
Of great interest is a recent publication48 that examined 339 type 1 diabetic patients and 89 of their first degree relatives. In this work it was demonstrated that diabetic patients had significantly higher serum zonulin levels than either controls or their relatives. Furthermore, by examining serum stored for HLA testing, these authors also demonstrated that "pre-diabetics" (positive for IA2 autoantibodies but before the onset of diabetes) had elevated zonulin levels in seven of 10 specimens. Patients with increased zonulin, not unexpectedly, also had increased permeability.
Therefore, the data seem fairly convincing that in both animal models and human type 1 diabetes, a substantial percentage of individuals have increased permeability that appears to precede the disease state and may play a role in pathogenesis.
The aetiology of Crohn's disease remains unknown. However, the three features discussed above appear important. Environmental factors are critical; the disease is unlikely to develop in susceptible animal models under germ free conditions49 or in humans where luminal contents are diverted. From these data it would appear that luminal antigens or other factors are critical. A genetic component is also apparent and several gene mutations have been identified, including those in NOD2/CARD1550 as well as in the organic cation transporter (OCTN or IBD5).51,52
In animal models of Crohn's disease, the interleukin 10−/− mouse, the SAMP mouse, and the mdra deficient mouse, it has now been convincingly demonstrated that abnormal permeability is present prior to expression of the inflammatory disease.53–,55 It is unclear whether preventing the increase in permeability will prevent disease as these experiments have not yet been done but the observation of increased permeability prior to development of disease is now well established. In some models, the permeability increase is present months before disease expression.54
In the human condition it is also evident that increased small intestinal permeability is commonly observed in populations at high risk of developing Crohn's disease.56–,61 Increased permeability is observed in the absence of symptoms of disease, suggesting that it is not merely an early manifestation of Crohn's disease. There is now one case report of a young woman found to have abnormal permeability during a family study who subsequently developed Crohn's disease.62 At the time when her permeability was increased, extensive investigations revealed no evidence of bowel disease. It took years for Crohn's disease to develop. There are also data to suggest that patients with increased permeability are also likely to have evidence of subclinical inflammation, as assessed by calprotectin excretion.63
There is also an apparent link between increased permeability and the recently described mutation in the NOD2/CARD15 gene. In a recent study, Buhner et al demonstrated that not only is the risk of having abnormal permeability and a NOD2 mutation increased among first degree relatives of those with Crohn's disease, but these are related. Relatives with a NOD2 mutation had a 75% chance of having increased permeability,64 suggesting that this mutation may influence epithelial permeability. The mechanism by which this might occur is unclear. The NOD2 gene product does not appear to be present in enterocytes where the permeability abnormality is expressed. However, the gene product is present in Paneth cells and there the mutation is associated with a reduction in secretion of defensins,65 an observation previously reported to be associated with Crohn's disease.66 This may represent an important link as reduced defensin secretion would be expected to alter the luminal microflora which in turn can have profound effects on epithelial permeability by many different mechanisms.67–,69
While an altered microflora, either induced by altered Paneth cell secretion or other mechanism, can directly increase permeability, there are other potential aetiologies. Altered expression of tight junction proteins may also increase paracellular permeability. In fact, increased expression of claudin-2 has been demonstrated to increase permeability,70 presumably as homodimers of this protein form associations that are not as "tight" as heterodimers with other claudins. In this regard, it is of interest to note that upregulation of claudin 2 expression has been reported in patients with Crohn's disease and ulcerative colitis.71 Whether this is an effect of the inflammation itself or a pre-existing abnormality could not be determined. However, other authors have reported that the abnormality in expression of junctional proteins is specific to biopsies taken from inflamed regions of ulcerative colitis and Crohn's disease patients; those portions of the gut that were not inflamed appeared to be similar to the control biopsies in terms of junctional proteins.72
In terms of function, Soderholm and colleagues73 reported that baseline permeability in non-inflamed portions of gut taken from patients with Crohn's disease is similar to controls, but following exposure of the tissues to a mildly damaging agent (sodium caprate) the non-inflamed tissue demonstrated a marked increase in paracellular permeability. This would suggest that there is a subtle alteration of function, independent of inflammation, which can be manifest as an increase in paracellular permeability. Similar findings are observed in vivo manifesting as hyperresponsiveness of the small intestine to the damaging effects of non-steroidal anti-inflammatory compounds such as aspirin or ibuprofen.74,75
Taken together, these data support the hypothesis that there is a permeability abnormality in Crohn's disease and that this abnormality is important in the genesis of disease. At least some of the reported genetic associations of Crohn's disease appear to involve these pathways.
Coeliac disease also appears to follow the paradigm. It is an exceedingly common disease that may affect up to 1% of the population and has clear genetic and environmental components. From a genetic perspective, almost all coeliac patients (95%) are HLA-DQ2 positive while the remainder carry HLA-DQ8.76 There is also evidence of other important genetic linkages.77 With this disease we have the good fortune to have identified the inciting environmental antigen—gluten. Removal of this agent prompts complete remission of all attributes of the disease, including a return of abnormal intestinal permeability to almost the normal range in the majority of subjects.78 In fact, an increase in permeability is a sensitive test for the presence of even small amounts of gluten in the diet.78 However, if intestinal permeability normalises during disease remission, how can there be any evidence that increased permeability plays a role in the aetiology of this disease?
In fact, there is increasing evidence that this is the case. The first line of evidence comes from animal studies. An inbred Irish Setter dog line develops a gluten sensitive enteropathy that mimics human coeliac disease. In these animals the disease can be completely prevented by weaning the animal onto a gluten free diet. However, subsequent exposure to the antigen immediately prompts development of the disease. Importantly, animals that have never been exposed to dietary gluten have increased small intestinal permeability.79 This strongly suggests that in this animal model abnormal permeability precedes disease.
In humans the data are more difficult to interpret as we do not have good data in individuals prior to the onset of disease. However, with careful analysis it is apparent that tight junctional structure is abnormal in children with coeliac disease.80,81 In some studies gluten removal does not totally resolve the defect, suggesting that either some portion of the damage is irreversible or that there is a prior alteration in the tight junction.81
From a functional viewpoint, intestinal permeability has not been well assessed in relatives of patients with coeliac disease. In one study about one third of first degree relatives had abnormal permeability.82 Approximately 8% of these had a positive endomysial antibody test, underwent biopsy, and were demonstrated to have asymptomatic coeliac disease but the reason for the abnormal permeability in the remainder was not reported.
Patients with dermatitis herpetiformis (DH) provide an interesting perspective in this regard. Subjects with this condition exhibit an enormous range of associated bowel pathology from frank coeliac disease to a completely normal intestinal biopsy and no evidence of bowel disease. In a recent study of 18 such patients28 it was noted that all DH patients had increased intestinal permeability, including those patients without evidence of intestinal disease. Furthermore, these patients also had elevated serum zonulin levels, suggesting that the abnormal permeability was associated with, and perhaps caused by, an abnormality of the zonulin pathway. As some of these patients may go on to develop coeliac disease, it would appear that in these cases increased permeability would precede development of disease and a potential mechanism of this is upregulation of the zonulin pathway.
The association of abnormal permeability and increased zonulin secretion in a gluten sensitive disease (DH) is intriguing. Recent work suggests that in coeliac disease, gluten functions as a trigger for zonulin release which subsequently increases paracellular permeability.83 These events were found to be MyD88 dependent suggesting the involvement of a TLR pathway that did not appear to be either TLR2 or TLR4. The authors suggest a model of coeliac disease in which gluten first interacts with the innate immune system through a TLR pathway. This subsequently induces release of zonulin from a lamina propria source, increased paracellular movement of gluten, and enhanced interaction of gluten with the mucosal immune system initiating the inflammatory disease process. This model is a minor variation on the paradigm presented.
There are a variety of other diseases in which a similar disease paradigm may be at work. Atopic dermatitis has been suggested to involve dietary antigens and many patients describe a dietary association to disease flares. However, convincing evidence of abnormal permeability in this patient group is hard to find. Many studies that have examined relatively small numbers of patients found no evidence of altered permeability84–,86 while several others have found abnormalities in a subgroup of patients.87–,89 In at least some of these patients relief of symptoms has accompanied probiotic treatment90 and in one study probiotics not only reduced the skin disease but also decreased elevated small intestinal permeability.91 It is unclear from this study whether the increased permeability was a cause of the atopic dermatitis or an associated area of inflammation. From the data available it is difficult to conclude whether atopic dermatitis fits the proposed disease paradigm.
Rheumatological conditions have long been associated with abnormalities of intestinal function and the concept of abnormal reactivity to a luminal antigen in these conditions is prevalent. Perhaps the best evidence for this comes from the literature on ankylosing spondylitis. Increased gastrointestinal permeability has been recognised to be present in these patients for decades but it was unclear whether this was due to the disease or its treatment with non-steroidal anti-inflammatory drugs (NSAIDs).92 With more recent work, the effect of NSAIDs has been isolated and it is apparent that these patients appear to have a primary defect in intestinal permeability that is also shared by a subgroup of relatives.93 In this study, the permeability defect was limited to the small intestine and not expressed in the stomach. However, in contrast, a recent study has suggested that patients with ankylosing spondylitis and Helicobacter pylori infection not surprisingly have increased gastric permeability.94 When the bacteria was eradicated, increased gastric permeability to sucrose fell in non-arthritic patients but remained elevated in those suffering from spondylitis. The authors suggest that this represents a pre-existing increase in gastric permeability, perhaps important in disease pathogenesis.
Irritable bowel syndrome (IBS) is also interesting to consider in this regard. In the paediatric population there is a recognised association between the symptoms of IBS, food hypersensitivity, and in some cases true food allergy. When intestinal permeability was measured pre and post provocation with suspect foods, it was demonstrated that these patients developed abnormal permeability.95 However, the concept of IBS developing as a consequence of, or in concert with, a functional derangement of gut function is best exemplified by the observation that this condition is commonly observed following acute infectious gastroenteritis. The strongest association is with Campylobacter infections and in this condition increased permeability can be observed up to a year following infection.96 In another large study involving IBS following a waterborne outbreak of gastroenteritis, increased permeability was more commonly observed in patients with IBS than controls.97 These studies provide intriguing data that abnormal permeability may be involved in disease pathogenesis, although they cannot exclude an alternative explanation that mild gut damage (measured by increased permeability) is associated with the development of IBS by another mechanism. Hopefully, the ability to interfere therapeutically with pathways that regulate intestinal permeability will allow us to establish whether increased permeability is a necessary prerequisite for the development of these diseases.
The paracellular pathway between intestinal epithelial cells has become important in our understanding of gastrointestinal and systemic disease. Long thought to be a static non-regulated barrier to the passage of luminal material, it is now recognised to be a dynamic constantly changing structure with a functional state that is carefully regulated. Luminal organisms can modulate the state of the tight junction through multiple mechanisms and while opening tight junctions may be of benefit for the microflora, it may be deleterious to the host. Abnormal function of this pathway can also be observed in conditions where the structure of the proteins comprising the junction is abnormal.
The functional state of the junction can be assessed by measuring the rate of movement of probes across the junction. This is what is referred to as gastrointestinal permeability testing and there are a variety of means to accomplish this either in vivo or in vitro. By carefully selecting the method used, it is possible to measure the permeability of various sites within the gastrointestinal tract.
For decades a variety of pathological states have been associated with abnormal permeability. Many of these are a consequence of intestinal epithelial damage that is associated with disease but not involved in a causal manner in the genesis of disease. However, in several autoimmune conditions it appears that increased permeability is a constant and early feature of the disease process. Furthermore, it is becoming increasingly apparent that in some conditions increased permeability is critical to the development of disease as if it is abrogated the disease does not develop. This is particularly true in type 1 diabetes. In other diseases such as Crohn's disease or coeliac disease, a similar pattern of findings are apparent but the experiment to try and prevent disease by preventing the increase in permeability has not been performed.
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Competing interest: JBM is a member of the scientific advisory board of ALBA Pharmaceuticals. There are no other competing interests.
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Mr. Kirby Fitzpatrick, of Oklahoma City, Okl., for plaintiff in error.
Mr. W. C. Duncan, of Ada, Okl., for defendants in error.
This is a suit by the defendant in error J. C. Chapman to recover possession of certain land and to have his title quieted against the claims of Lottie Carney, the plaintiff in error, and of the Albersons, the other defendants in error. The right of possession is immaterial now, but there was a judgment quieting the title of the plaintiff against the above named parties which was affirmed by the Supreme Court of the State and in which error is alleged by Lottie Carney. The land was allotted to John Alberson, a Chickasaw Indian, who was averred by the plaintiff to [247 U.S. 102, 103] be the lawful son of Charles Puiler, a Chickasaw, and Louisa James, an Indian woman. She died and later Alberson died leaving Puller his sole heir, if Puller was married as alleged. Puller conveyed to the plaintiff. The defendants denied the marriage and if they were right Lottie Carney is Alberson's heir.
If any federal question is presented in the case it arises under the Act of Congress of May 2, 1890, c. 182, 38, 26 Stat. 81, 98, by which all marriages theretofore 'contracted under the laws or tribal customs of any Indian nation' located in the Indian Territory are declared valid. The date of the supposed marriage was in 1887 and therefore if it complied with the terms of the act it was validated if not valid before. The plaintiff in error, after asking instructions as to what constituted a common law marriage that were given in substance, asked for another that a common law marriage was not recognized by the Chickasaws and that a marriage of Chickasaws without a compliance with their laws was void. Taking all the requests for rulings and the rulings together we are inclined to agree with the Court below that common law marriage and marriage under the customs of the tribe were used as equivalent phrases and to assume in favor of the plaintiff in error that the request means that a marriage of Chickasaws although in accord with their customs was invalid under a Chickasaw Act of October 12, 1876, unless solemnized by a judge or ordained preacher of the Gospel. This assumption would seem to carry with it the implication that the Act of Congress did not validate a marriage in accordance with still prevailing custom if no judge or preacher added his sanction, and so to ask a constr ction of that Act that, again by implication, was refused.
In this somewhat remote way a federal question is opened, but it cannot profit the plaintiff in error. There was some evidence that Charles Puller and Louisa James held themselves out as man and wife and were reputed [247 U.S. 102, 104] MARRIED. THERE WAS EVIDENCE ALSO THAT IT was customARy to disregard solemnization before a judge or preacher. It would be going somewhat far to construe the Chickasaw statute as purporting to invalidate marriages not so solemnized. The Act of Congress made valid marriages under either custom or law. Whatever may be the requisites to satisfy that Act the above mentioned evidence warranted a finding that they had been complied with, as is expressly provided by statute for the case of a marriage of a white man with an Indian woman. Act of August 9, 1888, c. 818, 3, 25 Stat. 392 (Comp. St. 1916, 4105). The reason for the rule is stronger here.


text:
Sweden's top court rejects extradition request for journalist wanted by Turkey
Sweden's top court on Monday rejected an extradition request for a man wanted by Turkey, saying the Scandinavian country does not criminalize the act he is accused of committing.
In a statement, the Swedish Supreme Court said there were "obstacles to extradition because it is a matter of so-called political crimes, i.e. crimes that are directed against the state and that are political in nature."
The court in Stockholm said there was "a risk of persecution based on the person's political views" if he were returned to Turkey.
The court did not name the man who was the subject of Turkey's request. Swedish news agency TT identified him as Bulent Kenes and said the Turkish government wants him in connection with a 2016 coup attempt.
4 CHIMPANZEES EUTHANIZED AFTER ESCAPING FROM SWEDISH ZOO
Kenes, 55, who has asylum in Sweden, was the editor of the English-language Today's Zaman newspaper, which was owned by a network linked to U.S.-based Muslim cleric Fethullah Gulen. It was closed down as part of a government crackdown on the group. Turkey blames Gulen for the failed coup and lists his network as a terror organization.
Turkey has held up Sweden and Finland's requests to join NATO over what it claimed was their inadequate response to groups it considers terrorist organizations, including an alleged lack of cooperation on extraditions.
When Sweden and Finland dropped their longstanding policies of military nonalignment and applied to join the Western military alliance in May, Turkish President Recep Tayyip Erdogan said his country would not approve them. He accused the two Nordic countries of turning a blind eye to terrorism.
Any decision on NATO enlargement requires the unanimous approval of alliance members.
Turkish exiled journalist Bulent Kenes is seen in Stockholm, on Dec. 19, 2022. Sweden's top court has rejected an extradition request for Kenes, who is wanted by Turkey, saying the Scandinavian country does not criminalize the act he is accused of committing. (Fredrik Sandberg/TT News Agency via AP)
Erdogan singled Kenes out last month during a joint news conference with the Swedish prime minister in Ankara.
SWEDEN FINDS TRACES OF EXPLOSIVES NEAR DAMAGED NORD STREAM PIPELINE: 'GROSS SABOTAGE'
"There is one member of the (Gulen) terrorist organization in Sweden, whose name I will give: Bulent Kenes," Erdogan said. "For example, the deportation of this terrorist to Turkey is of great importance to us, and we of course want Sweden to act with more sensitivity (on the issue)."
Kenes welcomed Monday's court decision but insisted he shouldn't be considered a suspect.
"I'm happy of course. But the decision was expected," Kenes told Swedish broadcaster SVT. "I am not completely satisfied because they say that I am suspected of crimes in Turkey. I have committed no crime at all. These accusations are completely fabricated by Erdogan's regime."
"Unfortunately, I expect bad things from Erdogan and his regime. They will continue to try to abuse the legal system," SVT quoted Kenes as saying.
There was no immediate reaction from Turkish officials.
Earlier this month, Sweden deported an unnamed man who fled there after being convicted by a Turkish court of membership in an armed organization in 2015. Turkey's state-run Anadolu Agency identified the man as Mahmut Tat who had been sentenced to more than six years in prison.
https://www.foxnews.com/world/swedens-top-court-rejects-extradition-request-for-journalist-wanted-by-turkey
kenes
bulent
committing
Crash-Warning Device Might Not Have Saved Kobe Bryant Helicopter, Experts Say
Breathtaking Painting Depicts President Trump & Co. 'Crossing the Swamp'
Jennifer Coolidge danced away being played off the Emmy Awards
CNN December 20, 2022

redpajama_set_name: RedPajamaCommonCrawl


Food Bank: Totals for last month = Parish Church 16.75kg. Holy Trinity 25.4kg.
Evening Prayer: at the Parish Church will be changing from 4:00pm to 5:00pm from Monday 15th April onwards.
Phoenix Gardeners invite you to a coffee morning at Bingham House, Dyer Street on Tuesday April 2nd from 10.30am.
Foodbank totals for February: Here are the totals for the three churches. St. Lawrence 33.4 kg. Holy Trinity 52.6 kg and Parish Church 14.45 kg. Many thanks for all contributions.
House Group: please note change of date to Monday 7th January at 7.30pm at 85 Chesterton Park.
Parish Office: will be closed from Friday 21st December 2018 until Thursday 3rd January 2019.
Foodbank totals for November: Parish Church 23.7 kg and Holy Trinity Church 50.15 kg. Many thanks for all contributions.
Canon Graham will be holding open office for anyone who wishes to meet with him, every Monday evening at The Parish Office between 5:00pm and 7:00pm.
The Parish Office will be closed all day on Tuesday 20th November.
Restore@4: You are welcome to Restore@4 in HTW on Sunday 18th Nov at 4pm. A time of relaxed worship, teaching and prayer to restore our souls!
Mothers' Union members are holding a coffee morning in the Parish Church on Friday 16th November from 10 o'clock to 12 o'clock. Everyone is welcome.
Food bank: Thank you for all the collections for last month. Parish church 31.95 kg, Holy Trinity church 29.8 kg and St. Lawrence 16.1 kg.
Canon Graham will be holding open office for anyone who wishes to meet with him, every Monday evening at 1 Coxwell street between 5:00pm and 7:00pm.
Mothers' Union members are holding a coffee morning in the Parish Church on Friday 21st September from 10 o'clock to 12 o'clock. Everyone is welcome.
Mothers' Union members are holding a coffee morning in the Parish Church on Friday 17th August from 10 o'clock to 12 o'clock. Everyone is welcome.
The Parish Church Flower Group are holding a fundraising Coffee Morning and Cake Stall in the Church on Saturday August 25th 10.30–12 noon.
Peter Bontoft: We are pleased to announce Peter has been elected as new head server and Sacriston at the Parish Church.
Rev. Canon Graham Morris. The licensing service for our new vicar, the Reverend Canon Graham Morris, will be held in the Parish Church on Saturday 22nd September at 4pm.
Mothers' Union members are holding a coffee morning in the Parish church on Friday 18th May from 10.00am to 12 noon. Everyone is welcome.
The Revd Michael St John Chanel. A Thanksgiving Eucharist will be held at St Nicholas Church, Longparish, Hampshire on Sunday 8th April at 6.00pm.
Do Nothing to Change your Life!
Mothers' Union members are holding a coffee morning in the Parish church on Friday 26th January from 10.00am until 12 noon. Everyopne is welcome.
Foodbank News – The total collected within the Parish for October was 139.1kg of food. Thank you for all your ongoing support.
Doors open at 7pm, concert starts 7.30pm. Refreshments available. Tickets £12.50 adult; £6.00 under 16 and are available from Poulton Village Shop.
Bereavement Service – will be held at Holy Trinity Church on Sunday 29th October at 3.00pm. All are welcome.
Thank you to everyone who attended our July curry night. We were pleased to see such a great turnout and hope everyone who came along enjoyed the evening.
Father Marks Sermon - for Revd Katie's 1st Mass is available to read on our website. Please note that many of the sermons given throughout the year can be viewed here.
Pewsheet - Dont forget to look at the pew sheet for events coming up in the Parish. These are available to look at online - look under Worship and Services.
Mothers Union Coffee Morning - Please come and join us for coffee and chat at 10am in the Parish Church on Friday 15th April.
Canon Andrew Bowden's sermon given at the Plough Sunday Service on 24th January 2016 can now be viewed and read online under 'talks/sermons'.
Crafts, worship and refreshments on an Easter theme.
Come and have fun and hear the Easter Message too.
The Holocaust Memorial Day Service will be held at the Parish Church at 1:00pm on Wednesday 27th January.
The Songs of Praise service will be held at the Parish Church on January 17th at 6pm.
Our Christmas tree festival starts this weekend. Do pop in for a bit of Christmas magic!!!!
The Parish Autum Fayre took place on Saturday 12th September in the grounds of Holy Trinity Church.
Blaze will be car washing on the Parsonage Drive during the Parish Fayre on Saturday 12th September and again in the afternoon on Sunday 13th September. Please bring along your car and support them.
Parish Fayre - Holy Trinity grounds on September 12th 2015. Raffle tickets on sale now.
Our next Messy Mass takes place on Sunday 12th July at 4pm in the Parish Church. Come and join us.
Please come and join us on Sunday 12th July at 6pm in the Parish Church for our first Blaze/Sing It! service.
Please take a look under our Worship and Service's section for the sermons that Father Leonard gave out in Cameroon.
WEDNESDAY 25TH MARCH - after the Corporate Communion, the Mothers' Union are holding a bring and share lunch in the North Aisle. All are very welcome.
Lent Seminar with Revd H Dickinson - Indigestible Doctrines. There are two spaces still available for the groups with Hugh Dickinson.
We will welcome applications for the two posts of Children's worker and Youth worker. Details can be found on our jobs page.
Please come and visit the shop which now has a selection of wonderful Christmas Gifts, Advent Calendars and Candles and cards for sale.
The last Social event was on Saturday 22nd November.  Over sixty people attended and were entertained by MJ-UK and samples various wines.
Many congratulations to Olly and Francesca upon the safe arrival of their baby daughter Tessa Ruth, born 4.48am on Tues 26/08/14 weighing 7lbs, 3oz.
ALL ARE VERY WELCOME TO JOIN US AT ST LAWRENCE ON SUNDAY 10TH AUGUST AT 3PM FOR TEA AND CAKE.
WW1 COMMEMORATIVE CONCERT - 7.30PM FRIDAY 8TH AUGUST IN THE PARISH CHURCH. ALL WELCOME TO ATTEND.
Corner Stone Premises - are now available for hire. Please contact Katie at the Parish Office to discuss rates and availability.
Outing to Lydiard Park and House on Sunday 15th June. Details in the pew leaflet. Meet at Lydiard Park at 12.30pm for a picnic. Minibus spaces are available.
A further reminder that the APCM is being held on Tuesday 29th April at St Lawrence Church at 7.15pm. All welcome to attend.
We have many different activities going on throughout the Parish for Lent and leading up to Easter.
The programme of Social Events are now available on the Social Events page under Community & What's On.
December/January Parish Life, the monthly magazine for the Parish of Cirencester, is now available in the churches or one line.
The Sing4Sue concert planned for Friday 6th December has been cancelled.
On 20th October at 6pm a choir from Koln (Cologne) will be singing Evensong in the Parish Church.
Saturday 5th October at 7.30pm in the Parish Church.
The Parish review led by Joanna Noles is now available on line or as a hard copy from the Parish office.
Here are the details of our next pilgrimage walk, on July 13th, from Great Rissington to Southrop - just over 10 miles in total.
Come and enjoy a relaxing afternoon in the parsonage garden. Cream teas will be available, along with a treasure hunt, garden games and hopefully plenty of sunshine!
This is in aid of the Holy Trinity Heating fund.
7pm for a 7.30pm start at the Parish Hall, Watermoor.
The Annual Report to the PCC for 2012/13 is now available in the churches.
School of Faith - book now!
Details of Christmas services are listed in the monthly calendar and show who is presiding and preaching at each.


text:
Investigating language use, shift and change across generations in Nigeria: The case of Ijáw
Ayomoto, Bomiegha Ofeni. 2019. Investigating language use, shift and change across generations in Nigeria: The case of Ijáw. Doctoral thesis, Goldsmiths, University of London [Thesis]
Text (Investigating language use, shift and change across generations in Nigeria: The case of Ijáw)
EDU_thesis_AyomotoB_2019.pdf - Accepted Version
This sociolinguistic study examines the life stories of a selected group of Nigerians spanning four generations. Their socio-economic backgrounds are varied, but they share the bond of the Ijáw language, which is key to their ethnic identity, Izón. The thesis investigates why the Ijáw language appears to be in decline and examines the way language use has changed across generations and why the language is apparently not being passed down from one generation to the next. In addition, it highlights the participants' own perspectives on this decline and their efforts to reverse it.
Methodologically, the study adopts a qualitative approach by examining the life stories of the participants as recorded during interviews via the application of thematic analysis exploring the participants' experiences, beliefs, emotions, attitudes and practices pertaining to Ijáw. The data reveal several themes, including the emotional attachment of love and pride versus the sense of loss in terms of the language, the shift from Ijáw to English, Nigerian Pidgin English and Yoruba, and the issue of blame for its decline. Key findings include the identification of a shift in the use of Ijáw and the manifestation of new trends in language use which one participant describes as "funkyfied". This new trend reflects a tendency for the younger generation of educated, urban speakers to alter the Ijáw language by dynamically mixing it with other languages and viewing language, along with dress and music, not as a fence but as a cultural bridge.
This thesis focuses on language use, language shift and language change over time and across generations, providing useful insights for the exploration of other declining indigenous languages in Africa and around the world.
Thesis (Doctoral)
Language, culture, identity, shift, translanguaging, code-switching, hybridity, intergeneration
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Moved by Representative Bernier, seconded by Representative Ott that Assembly Amendment 1 be recommended for adoption.
Moved by Representative Novak, seconded by Representative Jacque that Assembly Bill 98 be recommended for passage.
Ayes: (11) Representative Spiros; Representatives Kremer, Ott, Jacque, Horlacher, Novak, Bernier, Krug, Goyke, Kessler and Crowley.


Latest OJAS Gujarat Bharti 2019 : Online Jaherat & Maru Gujarat Bharti ojas.gujarat.gov.in: Gujarat is a place where no lake of jobs. Wheather is Sarkari jobs or Private Jobs. And if you think I am wrong, then search these terms ojas Gujarat and maru Gujarat in google. Now let me explain to you in simple what is ojas in Gujarat. Ojas Bharti is the Online Job Application System is an online government job in Gujarat website which is developed by the central government of Gujarat. It's a unique website for young people who are searching for government jobs online.
Govt. of Gujarat taken a good step by creating this website because every year thousands of candidates are applying online for Rojgar in this website according to their eligibility. If you are searching for the Gujarat rojgar, then Ojas is the best place to get. Here all types of government jobs are available like gpsc, gwssb, Police and other online job application.
I think every state government has to learn from the Ojas and should release the website for their state that every person who is looking for the job will get job notification easily from home and can apply easily online like facilities provided by the ojas.gujarat.gov.in.
Now here I am going to share with you a table which consists the all upcoming Gujarat rojgar, Government jobs notification. Check the schedule and get the information about the job you are searching for.
If you want to apply for any of the vacancies that given above, then you must go to the OTR, i.e. One Time Registration. OTR is a process where you have to register only once to get the details about all upcoming Ojas Bharti Recruitment.
The process of One Time Registration in ojas is straightforward. Follow the given steps and do the registration easily.
Here you can see the registration link in the header.
Click on the link and then click on the apply button.
After applying you can print your registration form if you want.
Also, there is an edit option if you want to change details or filled wrong information.
This question is undoubtedly coming in your mind if you are looking for the Ojas One Time Registration. So here are the benefits that you will get after doing the OTR.
You don't have to apply again and again for new government jobs.
You will get the information about every govt jobs that will be updating on the website.
You can apply for any job application that suits you or you eligible for.
You will be aware of all upcoming govt maru Gujarat jobs and Online Jaherat in the Gujarati language.
In this website, you will get every single detail that you are searching for like Latest Ojas Bharti 2019, Gujarat Rojgar Recruitment & Samachar, Online Jaherat & Maru Gujarat Bharti 2019. Hope you have got the Ojas Bharti details that you are looking for. Stay tuned to us for more upcoming govt. jobs update in 2019. And for more query leave your questions in the comment box and we will solve it asap.


Wild Dog Raw Veal Mix." BARF"
A great mix of freshly minced veal, ground marrow bone, fruit, vegetables, fish oils, calcium, vitamins & minerals. No presservatives added & snap frozen & cryovaced to seal in all the goodness.This is a totally natural balanced meal for your best friend.
Our puppies are 4 months old fed raw since 8 weeks they are tiny weight in now at 1kg and 1.5kg they love this food. Their coats are shiny stools are perfect and their energy levels high.


text:
United States China Beijing United States Olympic Team Erin Pac Women's skeleton Skeleton Winter Olympic games Sports Women's sports Olympic games Summer Olympic games
Curtis, the 1st US Black skeleton Olympian, blazes new trail
By TIM REYNOLDS - Feb. 12, 2022 10:40 AM EST
Kelly Curtis, of United States, slides during the women's skeleton run 2 at the 2022 Winter Olympics, Friday, Feb. 11, 2022, in the Yanqing district of Beijing. (AP Photo/Pavel Golovkin)
BEIJING (AP) — For Kelly Curtis, representation absolutely matters.
And in her first Olympic appearance, she became a trailblazer.
Curtis finished 21st in the women's skeleton event, her run at the Beijing Games ending Saturday. The result isn't why she'll be remembered. Curtis was the first Black athlete to represent USA Skeleton at the Winter Olympics — and she hopes her presence at the Games will open more doors to her sport.
"It's pretty important. It's part of my identity, but it's not the only thing that I lean on," Curtis said. "I would like to be known as one of the best sliders. It's nice with a cherry on top to be known as the first Black Olympian for USA Skeleton, but I would also like to be one of the best. So that that's really what I'm trying to progress toward every time I go out there and slide."
There are plenty of fascinating elements to Curtis' story. She has an intense dislike for cold weather, which isn't a great thing for someone who competes in a sport where she slides at 80 mph with only a thin sled separating her body from an icy chute. She had six wisdom teeth. She once tried to jump over a fence and broke both her arms. She needed a miracle finish just to qualify for this year's Olympics.
In Beijing, though, most of the questions she's fielding are about race.
"Whether I wanted it or not, we're here now," Curtis said. "I think there'll be a lot more questions just because of my skin tone regarding that. And I didn't expect to be in this position right now. But I'm just trying to embrace it all. ... This is the space I've always been in. It's just more people are taking notice."
Curtis is no accidental success. She was a big-time heptathlete at Division III's Springfield College, a winner of that event at the 2011 Penn Relays and a three-time All-American at the same school that produced 2010 U.S. Olympic women's bobsled medalist Erin Pac.
Her father, longtime and now retired athletic administrator John Curtis, was drafted by the New York Jets in 1971. A family road trip to Atlanta in 1996, after the city played host to that summer's Olympics, opened her eyes to the Games. ("I still remember Izzy the mascot," she said.)
And now she's here.
"I've been very blessed to be able to be in a family that has put athletics in such a high regard and understands that it's a vehicle that can bring us to places that we never thought would be possible," Curtis said. "I've always been known as John Curtis' daughter, and now that I'm on Team USA he's starting to be known as Kelly Curtis' father. I like that."
She was one of three women of color in the skeleton competition at the Beijing Games. The others: Valentina Margaglio of Italy, and Brogan Crowley of Britain.
They echo Curtis' sentiment on race within their sport: Being on the Olympic stage is perhaps the best way for skeleton to grow.
"I'm really proud. I'm really proud," Crowley said. "I know it's different. I don't really see it as different. But when people ask me the question, I guess I reflect a little bit. I am proud and I hope to inspire kind of a new generation of younger children and just make them believe that they can do whatever they want to. Really, there should be no restraints on what you think you can do."
Curtis looks at it the same way. She knows skeleton doesn't get talked about much, and certainly even less in non-Olympic years.
And if anyone heard her story this week and drew inspiration from it, that's what Curtis would call a win.
"I'm standing on the shoulders of giants," Curtis said, "trying to inspire the next generation."
More AP Olympics: https://apnews.com/hub/winter-olympics and https://twitter.com/AP_Sports


In little over a week, the festivities of the Kumbh Mela, the pilgrimage spot for the Hindus located at the confluence of the rivers Ganga, Yamuna and the mythical Saraswati in Prayagraj (formerly Allahabad), will begin. On the peak day, Mauni Amavasya, an estimated 30 million people are expected to converge—probably the single biggest assembly anywhere in the world; it is twice the size of the population residing in the National Capital Region defined around New Delhi. The cumulative attendance is upwards of 70 million; given that it is concentrated over 2,000 hectares, the sheer density of population at the site is staggering.
Managing these devotees so far, without any major mishap, is a remarkable tribute to the state government of Uttar Pradesh—regardless of their political lineage, no government has been found wanting. Spread over 55 days, the site—located on the flood banks of the rivers, which emerge once the monsoon waters recede by November—is more than just a spiritual congregation that has been converging for the last 1,400 years. It is actually a terrific study of so many things. And given that its success is derived using an Indian public delivery system replete with all its warts, the lessons this pilgrimage event holds up are that much more compelling.
First off, Kumbh Nagar (as the place has been christened) is probably India's first smart city. It comes up in about six weeks, once the flood waters recede, and dismantled when the religious congregation concludes. The patch of land, which keeps shifting depending on the contour of the river flow, is split up into grids—probably the best way to organize any urban set-up.
Thereafter, this space is earmarked into little settlements run by religious trusts or akharas managed under the aegis of a spiritual guru. Within this tenement, the entire management of the pilgrims—including feeding three meals a day—is the responsibility of the akhara. This autonomy empowers and at the same time tacitly acknowledges the diversity of the practitioners, each of whom pursue their own version of religious rituals. In fact, this facility—which provides for basic civic amenities, boarding and lodging and hygienic disposal of waste for a transitory population of this scale—has already attracted research as a model to house refugees. Five years ago, Harvard University sent an inter-disciplinary team, including one from urban studies, and concluded as much (bit.ly/2Ttm8D5).
This year, according to the state government, building the city entailed, in a span of few weeks, laying 300km of roads; constructing 1,795 pontoons to be used for developing 22 floating bridges; 1,030km of power lines; 800km of water pipelines; 850km of drains; construction of 122,000 toilets; and, provision of public accommodation with a capacity of 20,000 beds. It is a model India's National Disaster Management Authority should adopt to deal with the fallout of rising extreme weather events such as the floods in Kashmir.
Second, the entire event's success is premised on pilgrims subscribing to the crowd management rules—implemented by volunteers. Those who have witnessed this are struck by the ability of the populace to accept the rule of law—a very important takeaway for a country seeking to get beyond its seven-decade legacy of a discretions-based regime.
Third, flowing from the above, the big takeaway is that the successful organization of the Kumbh Mela proves that as a country "Yes, We Can". It is very similar to the successful implementation of the goods and services tax (GST), which ushered in the era of "one commodity, one tax" regime, replacing 17 taxes and multiple cesses, and the transformation of the country into an economic unity for the first time. Essentially, it shows us that India can successfully implement complex projects of scale by using the very same broken public delivery system.
Finally, the congregation is a terrific repository of big data. Various arms of the government can piggy-back on the infrastructure, including the cellphone footprint of visiting pilgrims, to research issues like health, demography, communication and migration patterns.
Clearly, the lessons from the geography of faith are promising.
Anil Padmanabhan is managing editor of Mint and writes every week on the intersection of politics and economics. His Twitter handle is @capitalcalculus.


text:
Q: How to get alt of each gallery attachment to use it for another data attribute? I searched here a lot, but the decisions are for post attachments.
I have gallery on each product page.
I want to make custom data attribute for each thumbnail, that has to be equal to alt or caption value.
There's the code, a standard attachments loop, and the script what I want to do

        <?php
            $attachment_ids = $product->get_gallery_attachment_ids();
           if ( ! empty( $attachment_ids ) ) { ?>
         <?php
            foreach( $attachment_ids as $attachment_id ) {
//There I try to get alt of each image
                  $image_alt = get_post_meta( $attachment_id, '_wp_attachment_image_alt', true);?>

               <a href="<?php echo wp_get_attachment_image_url( $attachment_id, 'full' ); ?>">
                <?php
                  echo wp_get_attachment_image( $attachment_id, 'full' );?>

                    <?php
                     echo $image_alt;
                      ?>

            <?php
            }
       }
        ?>

Instead of var value I see data-name="[object Object]". Like it's empty.
How to get this attribute correctly, to use its value in my custom data-name attribute?

A: "[object Object]" doesn't mean it's empty. It means it's an object, try to console.log it.
Either way, I think this line should be:
var caption = <?php echo json_encode($image_alt); ?>;

A: It can be done using the hook. here is an example code, modify it as per your need/use.
add_filter(
    'woocommerce_gallery_image_html_attachment_image_params',
    function( $params, $attachment_id ) {
        // Get the alt text from attachment ID.
        $alt_text = trim( wp_strip_all_tags( get_post_meta( $attachment_id, '_wp_attachment_image_alt', true ) ) );

        // Get the attachment caption.
        $caption = _wp_specialchars( get_post_field( 'post_excerpt', $attachment_id ), ENT_QUOTES, 'UTF-8', true );

        // Get the attachment title.
        $title = _wp_specialchars( get_post_field( 'post_title', $attachment_id ), ENT_QUOTES, 'UTF-8', true );

        // Add custom data attributes in parameters.
        $params['data-custom-attr-1'] = $alt_text;
        $params['data-custom-attr-2'] = $caption;
        $params['data-custom-attr-1'] = $title;

        return $params;
    },
    10,
    2
);

redpajama_set_name: RedPajamaStackExchange


I made more progress on my drawing today. I was able to finish it early enough in the day where I was able to use natural sunlight to help take a better photograph. However, the photo still doesn't look quite as it does in real life. I'm sure when Spring is here, it'll get easier to take decent photos.
I'm going to leave it at that as I've said all there is to say about what I've been working on. I'm going to say that I expect to be finished with this piece in two more days. Tomorrow, I have company coming by, and I don't expect to get too much drawing time in. Probably enough to finish the tendrils there and maybe the trunk of the tree. As always, we'll just have to see how it goes.
Hope everyone's having a fantastic Saturday!


And if someone asks me like that, my answer also is my mother. With me, my mother is the best woman in the world. No one can replace her in my heart. I admire my mother, I dont know why she is always busy with daily chores, taking care of my family but she never say she is tired. Just the memory of the foods that my mother prepared for us makes me salivate to this present day. Tips on writing a descriptive essay about mother: Since this is a description essay, one is expected to write about the unique attributes that makes the individual or object being described special, which, in this case, is the speakers mother.
The memory of my mother will follow me wherever I go, and however far tinting my dreams with a gentle scent of rosemary and the shimmering silver of her laugh. My mother had a serene charisma and a soothing aura around her. see more: short essay on my mother. My earliest memories of my mother was her pretty face, beautiful smile, and small frame. To me she was the most beautiful woman on earth and nothing compared to her. Even though she was unlike the celebrity moms who wore designer clothes and ate in fancy restaurants, my mother was very real.
My mother My Childhood Memories of Grandmother Essay 930 Words 4 Pages. Scientists tell us that our sense of smell is the sense most closely related to memory. Some of my most cherished memories of my childhood were created there. The minute I would walk in the door and see Grandma and Grandpa sitting in their matching brown corduroy recliners, any worries or problems would go from my mind. All that mattered from that point on was that I was at Grandmas.
The memories of my childhood haunt me like a passion. Whenever I am sick of the present, I try to get relief in the past days of my childhood. A man can not remember everything that happened in his childhood. My Hero: My Mother Essay 496 Words 2 Pages. The one person that I could never live without, the reason I am standing till this day, is my mother.
My mother is who I thank and admire most of all. As a mother, they dedicated their lives to provide compassion and relevance with their sacrifices to ensure that our needs are always met. Mothers are the primary protectors of every child within the basic unit of the society.


Determining where you would like to purchase a home is never an easy task, whether you are buying your primary residence or looking for a vacation home. However the experience can be much easier when you work with the right Colorado real estate agent. Choosing the right location, quantity of rooms, views and so many other factors need to be considered.
At RealEstateInGolden.com, we enjoy sharing with you the ins and outs of buying Colorado real estate. You'll find my site has all the tools you need to begin your search for a Colorado home and I will help you from your first search until the day you pick up the keys to your new home. I can even help you find the best mortgage rates and local service providers.
Make Your Colorado Home Buying Easy!
The process can be quite simple.
Tour local Colorado homes with me.
Give me a call to start the process and see how easily I can help you find your next home!


text:
const winston = require('winston');

const formatDevelopmentParams = (info) => {
  const { timestamp, level, message, ...args } = info;
  const ts = timestamp.slice(11);

  return `${ts} [${level}] ${message} ${
    Object.keys(args).length ? JSON.stringify(args, '', '') : ''
  }`;
};

const formatProductionParams = (info) => {
  const { level, message, ...args } = info;

  return `[${level}] ${message} ${Object.keys(args).length ? JSON.stringify(args, '', '') : ''}`;
};

const formats = {
  development: winston.format.combine(
    winston.format.colorize(),
    winston.format.timestamp(),
    winston.format.printf(formatDevelopmentParams)
  ),
  production: winston.format.combine(winston.format.printf(formatProductionParams)),
  test: winston.format.combine(winston.format.printf(formatProductionParams)),
};

const env = process.env.NODE_ENV || 'development';

const logger = winston.createLogger({
  level: process.env.LOG_LEVEL || 'debug',
  format: formats[env],
  transports: [new winston.transports.Console()],
});

module.exports = logger;

redpajama_set_name: RedPajamaGithub