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The rise and fall of insulin secretion in type 1 diabetes mellitus
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An understanding of the natural history of beta cell responses is an essential prerequisite for interventional studies designed to prevent or treat type 1 diabetes. Here we review published data on changes in insulin responses in humans with type 1 diabetes. We also describe a new analysis of C-peptide responses in subjects who are at risk of type 1 diabetes and enrolled in the Diabetes Prevention Trial-1 (DPT-1). C-peptide responses to a mixed meal increase during childhood and through adolescence, but show no significant change during adult life; responses are lower in adults who progress to diabetes than in those who do not. The age-related increase in C-peptide responses may account for the higher levels of C-peptide observed in adults with newly diagnosed type 1 diabetes compared withhose in children and adolescents. Based on these findings, we propose a revised model of the natural history of the disease, in which an age-related increase in functional beta cell responses before the onset of autoimmune beta cell damage is an important determinant of the clinical features of the disease.
KeywordsAutoimmunity C-peptide Insulin secretion Natural history Type 1 diabetes
Diabetes Control and Complications Trial
Diabetes Prevention Trial-1
islet cell antibodies
insulin secretory rate
latent autoimmune diabetes of adults
mixed meal tolerance test
Type 1 diabetes occurs when autoimmune destruction of beta cells has reached a stage at which metabolic stability is no longer maintained. At present it is not well understood when this autoimmune destruction begins in relation to the clinical presentation, or whether it follows a gradual or steep course. With the development of new immune modulatory therapies that may be able to arrest the autoimmune destructive process, understanding the details of this progression assumes great importance [1, 2, 3, 4]. Knowledge of the state of beta cell function at each stage of the disease process allows the risks of therapy in terms of adverse events to be weighed against the benefit of recovering residual beta cell function. In this review, we discuss a new analysis of data from the Diabetes Prevention Trial-1 (DPT-1) on insulin secretion in individuals before and after the onset of type 1 diabetes. We also review existing information on insulin secretion in type 1 diabetes, and explore our understanding of the natural history of the disease and the merits of intervention at each stage [5, 6].
Beta cell mass in humans: technical considerations
There are few data concerning changes in beta cell mass in humans. One of the principal limitations of human studies is that it is not currently possible to measure beta cell mass in vivo. Instead, indirect methods based on secretory responses are used to approximate beta cell mass. These approaches have been validated in subjects undergoing syngeneic islet transplants, in whom measured insulin secretion was found to correlate well with the islet mass transplanted [7]. One limitation is that the mass that was viable after transplant was estimated rather than measured in these studies. Most investigations have used C-peptide responses to secretagogues as a measure of insulin secretion, but these measurements have experimental pitfalls that limit their precision under non-steady-state conditions [8]. There is, however, a method of calculating the insulin secretory rate (ISR) which takes the volume of distribution and half-life of C-peptide into account, and provides a better estimate of rapid changes in insulin secretion [9, 10]. This technique has been validated in normal individuals and studied in patients with type 2 diabetes [8, 11]. However, it has been little used to study insulin secretion in type 1 diabetes, and existing validation studies have generally involved young adults, who represent the majority of patients with type 1 diabetes [12], rather than young children. For this reason, evaluation of the C-peptide response to a secretagogue remains the most widely used surrogate measure of functional beta cell mass in children with type 1 diabetes. Since ISR is derived from serum C-peptide levels, there is a very close correlation between the two measures, with the caveat that during non-steady-state conditions, when secretory rates change rapidly, C-peptide levels may under- or overestimate insulin secretion [8].
Insulin secretion increases with growth and metabolic demands
Beta cell mass is not constant. In rodents, beta cell mass increases during normal growth, and is tightly controlled through replication of pre-existing beta cells, differentiation of precursor cells and cell death [13, 14]. In rodents, beta cell mass is stable from 2 to 20 days of life but increases six- to seven-fold between 1 and 7 months of age [15, 16]. After the neonatal period, beta cell replication and mass increase and apoptosis decreases in proportion to body weight and age [13]. Beta cell mass continues to increase well into adult life, eventually reaching a plateau [16].
The peak incidence of type 1 diabetes in humans is between the ages of 6 and 15 years, the time of rapid growth. An increase in insulin secretion during adolescence has been well documented, and is thought to occur in response to increased insulin resistance [17]. Insulin resistance in adolescents was first described by Amiel et al. in 1986 [18] and has since been confirmed by both the minimal model and glucose clamp techniques. An 18–35% reduction in insulin sensitivity occurs with adolescence [19, 20, 21, 22, 23]. In a large cross-sectional study of insulin action in normal adolescents between 10 and 14 years of age, insulin sensitivity decreased in early puberty (Tanner 2) with a nadir at mid-puberty (Tanner 3) and an almost complete return to prepubertal levels by the end of puberty (Tanner 5) [24]. Although the mechanism of insulin resistance is not well understood, it cannot be accounted for by adiposity, and changes in insulin secretion during puberty correlate with similar changes in components of the growth hormone axis [17, 18], but not with changes in gonadal sex steroids (oestradiol, testosterone and dihydrotestosterone); a correlation with changes in adrenal androgens (dehydroepiandrosterone sulphate and androstenedione) has also been reported [19, 20, 21, 25, 26].
A progressive increase in insulin secretion has been described in individuals at risk of type 1 diabetes. Schatz et al. reported results of stimulated insulin secretion in 26 subjects aged 3 to 57 years, all of whom had islet cell antibodies (ICA) and a decreased first-phase insulin response to intravenous glucose [27]. C-peptide increased with age, and an increase in insulin secretion was evident in both the peak and total area under the curve C-peptide response to an OGTT and a mixed meal tolerance test (MMTT). When subjects were divided into those who did and those who did not develop type 1 diabetes during 5.5 years of follow-up, the latter exhibited an increase in C-peptide with time, and the former did not.
Metabolic demand stimulates an increase in beta cell mass in animal models and in humans. Both beta cell hypertrophy and hyperplasia have been shown to account for increases in beta cell mass during conditions of increased demand, for example due to ablation of one insulin receptor allele or in Zucker Diabetic Fatty rats [28, 29]. Beta cell mass also expands with mild and transient hyperglycemia, and hyperglycemia may be the stimulus responsible for expansion of islets that are transplanted into rats following partial pancreatectomy [30, 31]. Replication, neogenesis, and transdifferentiation together with apoptosis have all been suggested to account for the development of new beta cells in these rodent models [14, 32]. Moreover, it has been suggested that glucagon-like peptide-1, which has been shown to stimulate beta cell replication and decrease beta cell apoptosis in rodents, plays a role in islet regeneration after partial pancreatectomy [33, 34]. In obese humans, insulin secretion is increased compared with lean individuals [10], and beta cell mass also increases during pregnancy. Women with longstanding type 1 diabetes, in whom C-peptide levels were not detectable before pregnancy, sometimes produces detectable levels of C-peptide during the third trimester [35, 36]. It has been postulated that an expansion of beta cell mass accounts for the hypoglycaemia that sometimes occurs during this period of gestation. After pregnancy, rodent studies have shown an involution of beta cells through apoptosis [13, 14].
Analysis of insulin secretion before and at diagnosis of type 1 diabetes: data from the DPT-1
In an attempt to improve understanding of changes in insulin production during the prediabetic period and at the time of diagnosis of type 1 diabetes, we analysed data from DPT-1 subjects who were at risk of developing type 1 diabetes. This trial recruited first- and second-degree relatives of patients with type 1 diabetes and tested whether treatment with oral or parenteral insulin would prevent the onset of diabetes [5, 6]. Here we report a secondary analysis of insulin secretion in this population. A total of 2,103 subjects were placed in four categories for risk of type 1 diabetes, based on levels of ICA, insulin autoantibodies, HLA type, and insulin and glucose responses to intravenous and oral glucose tolerance tests. The high-risk category consisted of 372 patients with at least a 50% probability of developing type 1 diabetes within 5 years. Subjects in this category received either subcutaneous insulin or no treatment. Another 338 patients, judged to have a 26 to 50% 5-year risk of developing diabetes, were defined as intermediate-risk, and received either oral insulin or placebo. For our analysis we included data from the untreated control groups (i.e. not treated with parenteral or oral insulin) in both the high-risk and intermediate-risk studies (n=340).
The enrolled subjects underwent a 2-h MMTT every 2 years (high-risk) or every 3 years (intermediate-risk). Of the 340 subjects assessed, 121 progressed to type 1 diabetes. The average age of onset of diabetes was 13.5±0.58 years. Progressors to type 1 diabetes were followed for an average of 2.54±0.14 years and underwent an average of 2.2 MMTTs (range 1 to 5). The non-progressors were followed for an average of 3.2±0.11 years and underwent an average of 2.2 MMTTs (range 1 to 5).
Insulin responses during the MMTTs were analysed both in cross-section and longitudinally, and differentiated according to whether the subjects progressed to diabetes or not over the follow-up periods. The AUC, reflective of the maximal C-peptide response to the mixed meal, was determined for each MMTT. In order to determine the relationship between age and the C-peptide response, a regression was performed separating children and adolescents (age 0–17 years) from adults (age >17 years). The data were also analysed by dividing the C-peptide AUC by the subjects' BMIs to adjust for alterations in insulin secretion that occur in response to changes in insulin resistance secondary to changes in body composition [37].
Is the increased insulin secretion during adolescence unique to this period?
Our analysis of the DPT-1 data shows that insulin secretion increases in childhood in individuals at risk of diabetes. This increase appears to occur before and during puberty, and then decreases during adulthood. The increase in the C-peptide response during childhood is similar in persons who do and do not progress to diabetes and, even in progressors, the slope in children and adolescents is increased in comparison with adults. We used a linear regression model to perform our analysis. Other models could be used to analyse the cross-sectional data, but the use of slopes describing the changes in each individual is the more accurate approach to determine changes over time because of the variability of the cross-sectional data on the C-peptide:BMI ratio at each time point.
It is not clear whether the changes in insulin secretion described by us would be similar in healthy individuals, but they are indicative of changes during progression to type 1 diabetes. It is possible that the islet inflammatory process affects beta cell mass and/or function in a positive or negative manner. Previous studies have shown an increase in beta cell proliferation as well as a loss of beta cell mass in NOD mice during the prediabetic period [40]. All the subjects we studied have evidence of active autoimmunity in the form of islet cell autoantibodies, but individual differences in the extent of the inflammatory process could affect the insulin secretory response as well as beta cell dynamics.
The approaches we used for analysis have some limitations. Our analysis involved measurement of the C-peptide response to an MMTT, which is an indirect reflection of beta cell mass. As noted above, C-peptide responses may not accurately reflect insulin secretion under non-steady-state conditions. Nonetheless, the responses are likely to reflect the peak response to the physiological stimulus over time. It is possible that a more robust stimulus for insulin secretion may uncover greater impairment in individuals who go on to develop type 1 diabetes. This is evident from comparison of insulin secretory responses at the time of diagnosis of type 1 diabetes in response to a mixed meal (52% of normal control subjects) with results for glucagon stimulation after a hyperglycaemic clamp (25% of normal control subjects) [1, 12]. We corrected the C-peptide AUC for the BMI in order to minimise the contribution of obesity and body size, which increase insulin resistance, to our analysis of insulin secretion [10, 41]. We made this correction since these changes during growth might have masked a trend in insulin secretion related to the development of type 1 diabetes, or might also have suggested that insulin secretion was increasing over a period of growth when it was constant in relation to body size. Instead, our studies indicate that, even when corrected for body mass, insulin secretion increases during growth in subjects at risk of type 1 diabetes. These findings are consistent with an expansion of beta cell mass during this period, but direct measurement would be needed to confirm this suggestion.
Can changes in insulin secretion over time in individuals at risk predict the development of type 1 diabetes?
It has been suggested that a relative decrease in insulin secretion occurs over time in high-risk individuals who progress to type 1 diabetes compared with those who do not progress, and that this may be a useful additional marker of risk [27]. We found such a correlation in adult patients, but not in young subjects. In children and adolescents who did and did not progress to type 1 diabetes there were no significant differences in patterns of insulin secretion over time, although the increase in C-peptide responses was slightly higher in non-progressors. The relatively small number of subjects in certain subgroups (e.g. prepubertal progressors, n=9) may account for our failure to detect a difference between progressors and non-progressors. It should also be appreciated that our division into progressors or non-progressors reflects a relatively brief observation period. Since the rate of progression to diabetes does not fall over time [5], some of the designated non-progressors will in time develop diabetes.
Insulin secretion at the time of diagnosis of type 1 diabetes
Age of onset is an important determinant of the absolute initial C-peptide response at diagnosis, but the loss of C-peptide response with further progression of type 1 diabetes is similar across ages. In a previous study, we found a significant relationship between age and the ISR to a 4-h MMTT in subjects with type 1 diabetes at the time of presentation. However, age was not a determinant of the decline in ISR over time after diagnosis [12]. A report from an ADA workshop panel on the use of C-peptide as an endpoint for studies of type 1 diabetes also indicated that levels of C-peptide were lower at diagnosis in younger individuals, but that the difference in the rates of decline after diagnosis in younger and older individuals was not clear [43]. Similar findings have been reported by others: Clarson et al. reported that stimulated C-peptide was associated with age of diagnosis in a group of 20 children with type 1 diabetes [44]. Ludvigsson et al. studied a group of subjects aged 6 to 17 years with a disease duration of 3 to 14 years, and also reported a positive correlation between age of diagnosis and residual C-peptide. Other studies reported that there was a similar decline in C-peptide in 204 consecutive cases followed for 7.4 years, but age at diagnosis and male sex were positively correlated with residual C-peptide at 5 years [45, 46, 47]. Another study reported that 25% of latent autoimmune diabetes for adults (LADA) subjects had a >50% decrease in fasting C-peptide 18 months after diagnosis, which was significantly greater than in subjects with type 2 diabetes, but children with type 1 diabetes were not included for comparison in the same analysis [48]. Thus, differences in the rate of progression (loss of beta cell responses) in younger vs older individuals with type 1 diabetes have not been found consistently.
Insulin secretion after prolonged duration of type 1 diabetes
Collectively, findings from a wide range of prospective studies of adults and children with autoimmune diabetes indicate that there is a persistent decline in insulin production over time to undetectable or near undetectable levels in subjects with type 1 diabetes [12, 42, 43, 49, 50]. Anatomical and functional studies have described the finding of insulin-containing cells in subjects with long disease duration, but the physiological significance of this finding is not known [51, 52]. In subjects in the DCCT with disease duration of between 5 and 15 years, 8% of adults and 3% of children had stimulated C-peptide levels >0.2 pmol/ml, and disease duration was less than 10 years in the majority of those who did [43]. Clinically useful insulin production persisting more than 5 years after diagnosis of type 1 diabetes is thus the exception rather than the rule. The fact that a higher percentage of older subjects have detectable C-peptide levels may be explained by a higher level of C-peptide at the time of diagnosis.
Given that age is an important determinant of C-peptide responses, we need to enquire whether 'latent' autoimmune diabetes in adults is different from autoimmune diabetes of children, or represents the same pathological process with greater insulin production at its outset. Schiffrin and coworkers found that lower age was associated with a more rapid rate of loss of C-peptide in a group of 151 patients with a mean age of 10.2±4.6 years, followed for 2 years [53]. Only few studies have prospectively measured insulin production in subjects with LADA. The UKPDS found that, among patients who were younger than 35 years old at diagnosis, 94% of those with ICA and 84% of those with anti-GAD65 antibodies required insulin therapy by 6 years, compared with 44% of subjects with ICA and 34% with anti-GAD65 antibodies when older than 55 years at diagnosis, clearly suggesting a more rapid progression of beta cell failure in younger versus older LADA patients [54]. In other studies, approximately 80% of ICA-positive subjects with adult onset type 2 diabetes developed complete beta cell failure after 12 years. Other data on the rates of loss of C-peptide suggest that it is similar throughout childhood and in ICA-positive adults compared with children [46, 55, 56]. However, one study suggested a more rapid rate of loss of C-peptide in adults with type 1 diabetes (mean age 45 years) than in LADA patients (mean age 59 years) after 10 years from diagnosis. However, the analysis of this study was limited to fasting C-peptide levels [57]. The available data therefore suggest that LADA may reflect the same pathological process as childhood type 1 diabetes, but starting with greater insulin production.
A revised model of the natural history of type 1 diabetes
The loss of insulin secretion in a mixed meal response at the time of diagnosis is surprisingly small, but similar in younger and older individuals. With more intense provocation, such as a hyperglycaemic clamp followed by glucagon stimulation, a greater impairment can be shown. The limited published information on the rate of loss of C-peptide responses over time suggests that it may be similar at different ages. Because the absolute level of C-peptide is an important determinant of the quality and ease of metabolic control, the clinical differences between younger and older patients with type 1 diabetes may be related to the maturation of a full beta cell response in adults, which is cut short when children and adolescents develop diabetes before this maturation is complete. Because C-peptide response levels at the time patients develop diabetes are higher in older individuals than in children and adolescents, a longer period of time is needed before C-peptide levels become undetectable in adults.
This work was supported by grants R01DK57846, M01 RR00645, U19AI46132, M01RR01271 and P60DK20595 from the National Institutes of Health, and Special Grant 4-1999-711 and Center Grant 4-1999-841 from the Juvenile Diabetes Research Foundation. The DPT-1 was supported through cooperative agreements by the Division of Diabetes, Endocrinology, and Metabolic Diseases, NIDDK, NIH, and by NIAID, NICHD, and the National Center for Research Resources, NIH, as well as by the American Diabetes Association, the Juvenile Diabetes Foundation International, and various corporate sponsors.
Supplementary material
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text:
A groundbreaking feminist graphic novel from Chelsea Cain, Lia Miternique & Kate Niemczyk. From the creative team that brought you the groundbreaking Eisner-nominated series Mockingbird, this trade paperback collects the first story arc (#s 1-4) of the unconventional comingof-age tale-including the informative survival handbook, "CAT FIGHT! A BOYS' GUIDE TO DANGEROUS CATS" and all-new never-beforepublished extras!
About the author: Chelsea Cain is the author of 12 books, including six NYT bestselling Gretchen Lowell thrillers. Cain's novel, One Kick, was turned into the 12-episode television series, Gone, starring Chris Noth and Leven Rambin, debuting in the US this fall. Chelsea's first comic book series, Mockingbird, was nominated for an Eisner for Best Writing and Best New Series.
About the illustrators: Kate Niemczyk is a Polish comic book artist and illustrator with experience in the video game and advertisement industries. Her first comic publication was Marvel's Mockingbird, which was nominated for an Eisner Award for Best Writing (Chelsea Cain) and Best New Series. Lia Miternique is an illustrator and graphic designer. She has illustrated books and designed book jackets for Chronicle and Bloomsbury. She owns Avive Design in Portland, Oregon and her clients include a wide variety from arts organizations to health care to Nike. This is her first comic series.

subset: commoncrawl


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February 27th, 2013, 12:12 PM
Another day of crappy snowy weather. Hope it quits by tomorrow morning, my daughter and I have to drive 90 miles to DesMoines to pick my 19 year old grandaughter up at the airport. She moved there last November and is coming home for the weekend and then flying back Monday. We are so excited to see her and shes really homesick. Thought I'd share some pics. The last one isn't very good because I took it thru our screen door. Hope you enjoy!


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10 cities that survived the last housing crash
The housing bubble and subprime crisis at the root of the 2008 recession-battered homeowners with plunging prices, dumped gluts of unsellable inventory on once-booming markets and sent countless mortgages underwater. But for homeowners in a few select cities, the last decade has meant money in the bank.
GOBankingRates used data from Zillow to examine home values in 2007 compared to home values in 2017 for 100 cities across America. Exactly 10 of those cities saw an increase of 50 percent or more.
Click through to see where home values have increased the most during and after the Great Recession.
See Gallery
This article originally appeared on GOBankingRates.com: 10 Cities That Survived the Last Housing Crash


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The 'Spider-Man: Far From Home' trailer is Marvel admitting that what happens in its movies doesn't matter
Avengers: Infinity War was the highest grossing movie of last year, but it wasn't only adept at generating box office numbers — along with A Star Is Born, it led the year in memes. The Thanos snapping memes were decent, but my personal favorites came from the moment where we discover Peter Parker's fate.
The scale of the casualties at the end of Infinity War made it seem likely that many of these characters wouldn't be gone for long, but Peter Parker's supposed death was the one that managed to make an emotional impact. It was the perfect combination of heartfelt and ridiculous, and produced gems like this:
And this:
Part of the reason people were able to make light of the death scene was Marvel's upcoming release schedule: just after the release of Avengers: Endgame this April, Spider-Man: Far From Home was slated for this July. There was no doubt that Spider-Man would be back. Still, it was a bit jarring to see Mr. Parker alive and well when the trailer for Far From Home dropped this week.
The 'teaser' trailer, which stands at just under three minutes (will the actual trailer last longer than that???), makes no mention of Parker's fate in Infinity War. Instead it picks up right where Spider-Man: Homecoming left off. Your friendly neighborhood superhero (Tom Holland) leaves Manhattan behind for a school trip with his classmates, only to find himself dealing with Nick Fury (Samuel L. Jackson) and a briefly glimpsed villain named Mysterio (Jake Gyllenhaal). (Almost as shocking as seeing Spidey alive and well was seeing Gyllenhaal using his real voice as Mysterio).
This omission isn't necessarily a bad thing; aside from my complaints about the MCU timeline, this movie looks really good. But it is notable, because the trailer was released before Endgame came out. Marvel is flat-out admitting that what happens in its movies does not matter. Character deaths are the most jarring moments in movies because they create a sense of finality, and actual tension. When a character dies there's no going back, and it changes the trajectory of the plot for good. But Parker's self-evident revival is an admission that Marvel never intended for their movies to mean anything on their own, but merely to serve as forward momentum for you to go and buy tickets to the next one (which, admittedly, I will). It's a pretty big shift for the movie industry, one that moves it closer to alignment with television.
This might render the rest of the Avengers films meaningless, but I hope it doesn't do the same to the Spider-Man stand-alone movies. Homecoming was the best Marvel movie since Iron Man, due not only to stellar performances and pacing but to the fact that the story was able to live on its own, outside of the Avengers' universe-saving nonsense.
The Far From Home trailer makes me a little worried that the sequel will lose some of that local charm; we are departing from Spidey's home turf, after all, and there's a lot of Nick Fury for my taste. But I'll keep some hope. Far From Home will have one thing that Homecoming lacked: a fully fleshed-out Zendaya character. And it doesn't hurt to feature one the best actors around as the villain, either. He may not be the friendly neighborhood Spider-Man this time around, but hopefully he can stay away from those pesky globe-trotting Avengers.


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text:
Norwalk policeman injured in motorcycle accident
NORWALK -- A supervisor from the motorcycle patrol unit of the Norwalk Police Department was injured in an accident Friday morning on the Merritt Parkway, police said.
Sgt. Joe Moquin was riding a Norwalk Police motorcycle -- a Harley Davidson Road King -- to the police academy in Meriden, and he broke his ankle or leg during the accident, according to Norwalk Police Sgt. Lisa Cotto.
Cotto said the accident occurred near exit 59 sometime around 8 a.m.
He is currently being evaluated for injuries, and State Police are investigating the accident, Cotto said.


text: Version 2.6 posted. XmlNode now has a Clone method that returns a deep or shallow clone of itself. There's no point mentioning them as I have no control over them. Unfortunately my convention for in or out is opposite to the IDE. My which is Input to the application is equivalent to its' [O] which is Output from the library. I think the IDE convention may be a Microsoft one whereas mine is common-sense .


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Christian Devotional – July 8, 2019
"Do you know who I am and what I have done?" So often we don't feel like people really know us. Obadiah wasn't sure that Elijah really knew him. Read 1 Kings 18:13-14.
Has it not been told to my master what I did when Jezebel killed the prophets of the Lord , that I hid a hundred prophets of the Lord by fifties in a cave, and provided them with bread and water? And now you are saying, 'Go, say to your master, "Behold, Elijah is here "'; he will then kill me."
To be fair, Obadiah was living a secret life as a Christian in king Ahab's court. He realized that Elijah may not know some of the things that he has done and he wanted to make sure that Elijah knew that he was not an enemy of God, but in fact followed and worshiped God. Remember yesterday, Obadiah was 100% convinced that Elijah would be saved and he would be killed as a result of following these actions.
Whether or not Elijah knew all about the things that Obadiah had done, God knew all the things that Obadiah had done. At the end of the day Obadiah had to come to the place where he trusted that Elijah was giving him direction from God and did he trust God, not does he trust Elijah?
We may wonder what God is doing or how God is using other people, but ultimately the question is really about do we trust God and what he is doing. God as the one who is in control and has these situations well in hand. Are we willing to place our faith in him because he does truly know who we are and how he can best use us to bring about his glory..


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Use the bolts already on your back fender.
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But let's explore why you should send a thank you note for each interview. Undoubtedly, there are associates who interview and get the job with nary an interview thank you card sent. But ask yourself this, "Is not sending a thank you note after your interview the classy thing to do? Is it a sincere and kind act? And, could sending a thank you note for my interview help my chances in getting this job?"
Will sending thank you notes after your interview help your chances in securing the position? According to CareerBuilder, "Nearly 15% of hiring managers say they would not hire someone who failed to send a thank-you letter after the interview. Thirty-two percent say they would still consider the candidate, but would think less of him or her." Think of interview thank you notes as part of your "campaign" to get the job. A failure to send them could actually hurt your chances!
A thank you note for your interview can set you apart from other candidates. Let's say you're the head of the corporate practice group at a large law firm and you just interviewed two really stellar candidates. Both had simply terrific interviews, but you only have one offer to give. The next day you receive a sincere handwritten job interview thank you note written on beautiful stationery from one of the candidates. This candidate, in her note, in essence has asked for the job and expressed her extreme interest in the position. In this partner's experience, highly interested candidates end up working very hard and doing tremendous work. At this point, the partner begins to lean toward this candidate and gives her the offer.
A thank you note can remind the firm of your candidacy. If you are one of ten candidates who interviews for a position, then it will become difficult for the interviewers to clearly remember you and the answers you gave during the interview. Sending a thank you note is a good opportunity to remind the firm of your candidacy and to make a stronger impression in their minds.
Interview thank you notes give you an opportunity to ask for the job. Now I'm not saying that you need to be highly aggressive or pushy in your thank you notes. But you should mention that you would really like the position and why. When I help my candidates with interview preparation, I often tell them to make sure that, as a closing note, they express their interest in actually receiving an offer. Firms like to hear that you are interested, as well. It's a two-way street! And a thank you note is another venue for you to get this point across. Furthermore, it is also the very last chance you have to make an impression.
- See Top Ten Interview Questions for more information
The email vs. handwritten note conundrum. I probably get this question the most these days. Is sending an email thank you note appropriate in this day and age? Various opinions abound, leading many candidates to be confused. In short, either is fine.
I happen to think handwritten notes make a great impression and also show that the candidate spent more time on the note's composition. But while a handwritten note will gain you serious style points a la Jacqueline Kennedy Onassis, it does lack speed. There is no doubt that emails are a much faster alternative. And if a firm indicates that they will be making a quick decision, I actually suggest emailing thank you notes in this instance. Furthermore, not everyone has a big box of Crane's personalized stationery sitting in their desk. If you don't have thank you notes on hand, do NOT wait to send them until you've bought a box. Just send an interview thank you email.
- See Interviewing Tips for more information
Further, if writing out the handwritten notes is so daunting that you think it might actually prohibit you from doing it, then you've got to go with emails. Also, ask yourself this, do people often compare your handwriting to a prescribing physician's? Then do the reader a favor and email your note.
Even if you don't receive the offer or even want one, sending a thank you note after your interview can be a good networking opportunity. It's very possible you may not end up working for the firm where you interviewed for whatever reason, but an interview is a great way to make contacts and expand your network. You never know where people will ultimately end up, and it's possible that a partner could transition to your current firm and you could end up working for them anyway. You would want that person to have a favorable opinion of you, right? Friendly relationships can get you a long way in the law. Furthermore, it just makes good business sense to have strong contacts in a variety of firms and corporations. A thank you note helps continue and strengthen that relationship.
So, what are the rules on how to write a thank you note after an interview and send it? What is best to say in an interview thank you card?
- Do not send the same note to every person. Vary it. I have heard many attorneys say that they compare notes with their colleagues to see if the candidate wrote the same one to every person.
- Try to send your interview thank you notes as soon as possible.
- Thank the recruiting coordinator. A lot of attorneys forget this and a good recruiting coordinator can have a lot of power in hiring decisions. This is very important to remember when writing a thank you note after an interview.
- If you are only going to send one thank you note, then thank the hiring partner or the partner with whom you spent the most time.
- Don't say you're a "perfect fit" after a screening interview. You don't have enough information at this point and you will look foolish or naïve.
- Be formal, but keep it brief.
- If sending a handwritten note, use good paper. If you don't have good monogrammed paper at this point in your career, then add this purchase to your to do list. Style points can go a long way when interviewing.
- Spell check. Spell check. Spell check. If you are handwriting your notes, then you need to be doubly sure that you aren't misspelling something. Consider typing out what you want to say in Microsoft Word before transcribing to your note. If you don't show attention to detail in your thank you notes, then how might your work product look?
- Focus on content and avoid too many adjectives. Tell the reader what you gained from the interview instead and what appeals to you about their practice.
- Write up some thank you notes after interview samples to keep on file, always remembering to switch them up and make them meaningful and personalized for each interview.
See the following articles for more information:
- Top 23 Law Firm Interview Tips: How to Excel in Law Firm Interviews
- 21 Major Interview Mistakes to Avoid at All Costs
- The Best Way to Prepare for a Job Search and Interviews
- How to Talk About Other Interviews in Your Interviews
- How to Answer the Tell Me About Yourself Interview Question
- How to Answer the Do You Have Any Questions for Me Interview Question
- Had a Great Interview But Have Got No Response to My Thank-You Emails
- What Does It Mean if I Haven't Heard Anything Back from an Application/Interview in a Couple Weeks?
- What to Wear to a Lunch Interview?
- How to Effectively Interview Lateral Candidates: Pointers for Law Firms
- The Secret to Effectively Sharing Concerns about Your Current Employer without Committing the Most Common Interview Blunder
- How to Conduct Yourself During a Lunch Interview


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Gates will be open on Tuesday at Fenway for the Red Sox home opener, but how do you feel the team is doing so far this season? Vote in the poll above and tune in tonight after the 11 p.m. news on NBC10 Boston for results.
VOTE: What's Your Take on the Red Sox Right Now?
Published Apr 7, 2019 at 5:08 PM
Find NBC Boston in your area
Channel 10 on most providers
Channel 15, 60 and 8 Over the Air


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Bigger map options?
emr131 last edited by
I love this game and play it weekly, but would love to see a larger scaled version of this map so pieces actually fit on it comfortably (ideally large enough to have A&A minis used… especially the War at Sea minis). What options are out there? Is there a high resolution downloadable map of this that I can take to a printer and have it made? Is there an aftermarket map already on sale out there? Does anyone have the ability to do this for me and I need to contact them outside of this forum for copyright reasons?
The only option I really have is to take digital pictures of the map and have the images printed and a collage done to make it bigger. Alternately I guess I could take the pictures and digitally join them and then take them to a printer to have the larger map printed.
captainjack last edited by
Imperious Leader made a REALLY nice large map. I believe he has it posted on mediafire for download. I don't have the link though…
emr131 last edited by
Thanks to his bump, I think I have my answer.


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Best Free MP3 Audio File Splitters
08 Oct 2018 12:33
Mp3 Cutter & Merger is a device for modifying Mp3 information in your Android machine, and the app focus is on creating ringtones, notification tones, alarms and so forth. mp3wrap would be preferrred for this - it is designed to affix collectively MP3 files, without having to decode + re-encode the information (which might result in a loss of audio quality) and will also take care of the ID3 tags intelligently. Select the tracks in the merge mp3 online listing you'd like to insert silence with, then click on 'Silence' to launch a setting home windows as proven at the proper aspect. Step 2. On the first interface, click choose an area file" so as to add a file from your laptop. Alternatively, you may drag and drop the respective files to the field provided. In case your file is positioned on a sure site, simply copy the mp3 url and paste it on the url field in this system and click on Add recordsdata". Wait until the upload process is complete.Moreover, you can too listen to the merged audio whereas enhancing to examine the effects. Then try MP3 Joiner Expert which is an audio joiner that has many options and is straightforward to make use of and can also handle different formats corresponding to FLAC, AAC, WAV, WMA and extra. MP3 Audio Recorder - Report excessive-high quality music or low-bitrate audio streams immediately into compressed sound recordsdata.Your look forward to a life without interruptions has ended. With the help of the audio joiner, listening to songs becomes easier and seamless. On-line mp3 joiner lets you hearken to all types of songs belonging to any format. This joiner works in a manner of combination. All it's a must to do is find this joiner on-line and then take heed to different format of songs by means of it. With the assistance of a joiner, one playlist will look like an incredible monitor of song. Experience entertainment at a whole new stage.Also, you'll be able to batch merge MP3 information by utilizing Text file lists, Excel file lists, CSV file lists, or by coming into the lists of audio files to hitch directly. MP3 Cutter Joiner Free offers an essential functionality for somebody with a big collection of information or tapes, who data these in absence, then needs to chop the resultant recordings into tracks to preserve on CDs or be part of them into an enormous file.1.Merge a number of chapters of an audio e-book. Typically, it is tough for listeners to find the correct chapter to proceed to get pleasure from their audio, due to this fact, a mp3 combiner can actually improve this example. 1. Click on "Choose File" button to pick a file on your computer. You can also click on the dropdown button to decide on on-line file from URL, Google Drive or Dropbox. The audio format may be WAV , WMA , MP3 , OGG , AAC , AU , FLAC , M4A , MKA , AIFF , OPUS or RA Audio file dimension may be as much as 200M.Free Online Editor is specialized in merging and becoming a member of a number of MP3 recordsdata into a new one. It makes ringtone and music creation easier. Simply head to your browser to go to this online site quite than cost time to put in software program in your COMPUTER. 1. Compatible with a lot of the audio formats. Just as mentioned, when you want to use it to mix the WAV from CD, download MP3 online or capture Dolby AC3, you want a strong audio combiner to support all codecs.2. Click on "Submit" button to start out processing. The audio files you added to merge will need to have the identical format and bit fee and many others. The brand new audio file can be appended to the most recent audio file created. For instance: You submit audio files A, B and C one after the other, the most recent output audio file will be file A+B+C combined together.If you're not keen on above-mentioned online MP3 cutters and want to select a extra professional MP3 splitter, you can try to make the most of Joyoshare Media Cutter This dependable clipping device can be utilized to cut off any unwanted elements out of your MP3 information at up to 60X fast velocity. Alternatively, Joyoshare MP3 Cutter is able to outputting files into any obtainable format and preserving unique high quality utterly. Crucially, to satisfy your satisfaction, it will probably assist you to merge any video and audio into one as nicely.Moreover, you can take pleasure in the perfect using expertise on the brand new HTML5 commonplace (not flash). Similar to different audio cutters in market, it is not going to re-encode the MP3 monitor so that the output high quality will be identical as the supply. Nevertheless, what you need to notice is that there isn't any timeline provided to adjust reducing area accurately. Additionally it is not obtainable to select vacation spot format.
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As long as I can remember, I've lived with a persistent and insatiable compulsion to explore as many aspects of the human condition as possible. In fact, I believe most humans share this same curiosity. It was my commitment to this constant urge that eventually led me to become a therapist.
But, before professionally supporting others as they dove into the depths of their psyche, I set out to write about it while earning my bachelors degree at New York University's dramatic writing program. It was there that I met countless others who shared in the obsession to translate the world in a craft of their own choosing. However, one particular craft I seemed to always land near was comedy.
Between sharing an apartment (and rehearsal space) with the co-founder of The Wicked Wicked Hammerkatz, NYU's revered sketch comedy group, and working at the satirical newspaper The Onion, I observed some of today's most gifted and successful writers/performers, both on and off stage.
So, when actor/comedian Kevin Pollak's recent documentary Misery Loves Comedy appeared on my Amazon movie recommendations, I was naturally intrigued. The film, which is dedicated to the late Robin Williams, explores the commonly accepted stereotype that all comedians must be miserable in order to succeed at his or her own craft. Pollak examines the subject through insightful conversations with over 60 famous comics including Tom Hanks, Jimmy Fallon, Amy Schumer, Judd Apatow, Lisa Kudrow, Larry David and Christopher Guest. The interviews dig into everything from career motivations and narcissism to profound pain and suicide.
Though each interview brings a different piece of the puzzle, they all shared in the universal theme that we are driven to belong, especially if we feel different from the norm. The movie highlighted what I find so compelling about the performing arts. Collectively, we all long for connection, and it's in watching another perform that we catch glimpses of ourselves and feel that sense of belonging. What comedy does is provide us those glimpses into our very human truths in a way that enables us to laugh at them. Comedians literally lighten the emotional loads they hold within themselves through their vulnerable jokes, and we breathe the same relief through learning we are not alone in those feelings.
Being on stage makes it instantly permissible to expose the deeply personal and painful experiences and feelings that make many of us feel so "screwed up". We may see this as an entertaining way to momentarily escape our life, but in escaping we are missing the pure beauty of this exchange: we all share in the same spectrum of human emotion. What separates us is our willingness to honestly share our experiences of those emotions with ourselves and others without judgement. Over time, society categorizes these feelings into acceptable and unacceptable, and the mask of performance creates a more accepted form in which to express them.
We each have a tendency to relentlessly judge ourselves against the standard of "normal", but what creates the norm is merely the repression of the undesirable aspects of the human condition. So, we've viewed those who willingly share their most uncomfortable moments in front of an audience as the most troubled souls.
Penn Jillette of the duo Penn & Teller exclaims, "Yes, there are really fucked up people in show business... The people that talk about how fucked up people are in show business -- have they met anyone that's not in show business? The same pain, the same suffering, the same angst, the same tortures, the same doubts, the same misery are all there. In show-business, you show what you're feeling. So yes, they show the angst, but they're showing the angst of humanity. The angst that we all share. If you have a comic that truly had experiences that were outside of the realm of the general humanity, no one would go see them."
If more of us acknowledged this truth within the spotlight of our everyday lives, we'd all learn very quickly that our experiences aren't as separate as we thought. As a therapist, and general lover of humanity, I'm both hopeful and excited to see us all head in the direction of our shared acceptance of one another because we are all born out of the same darkness. It's from this dark place that comedians teach us to find the lightness of our being.
Jamie Rautenberg is a holistic life coach & Licensed Clinical Social Worker. After a lifetime of medical misdiagnoses, she discovered that she was living with late-stage neurological Lyme Disease in March 2013. While receiving intense daily IV infusions, Jamie reframed her healing experience by creating TheDailyInfusion.com, a wellness blog where people can learn how to reclaim their lives through chronic illness & pain. Her passion is to empower others wherever they may be along their path through virtual private coaching sessions. Connect with Jamie at twitter.com/JamieRautenberg


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Coke Holiday Ad Depicting Russia Map Stumbles Into Geopolitical Row
Map inflamed first Russians, then Ukrainians, over hotly disputed region of Crimea
Coca-Cola Co. KO 1.84% 's holiday marketing backfired in Eastern Europe when a New Year's advertisement depicting a map of Russia inflamed first Russians, and then Ukrainians, over the hotly disputed region of Crimea.
The Crimea spat has also tripped up, to a lesser extent, rival PepsiCo Inc., PEP -0.52% which had posted a controversial map of Russia on its website. Both U.S. beverage companies are scrambling this week to pacify angry consumers, bloggers and even the Ukrainian government.
Coke posted a map of Russia decorated with Christmas trees, snowflakes and wrapped presents on the Russian social media network Vkontakte last week. Under the map was the message: "Ring in the New Year together with Coca-Cola."
Initially, the map didn't include Crimea, which Russia annexed in 2014 from neighboring Ukraine, or the Kuril Islands, parts of which are claimed by both Russia and Japan. The map also didn't include the Russian exclave of Kaliningrad.
The U.S. and European Union sanctioned Russia in response to Crimea's annexation and still recognize the territory as part of Ukraine.
" We, as a company, do not take political positions unrelated to our business. "
After the exclusion of Crimea drew criticism from Russians, a new version of the greeting was posted early this week with a map including all three territories. "We sincerely apologize for the situation. The map is fixed!" said a post on VKontakte.
The new map set off a firestorm in neighboring Ukraine, where some lawmakers called for a boycott of Coke for recognizing Crimea as Russian.
On Tuesday, Coke removed the post entirely. It has apologized, saying the ad agency that created the original map later made changes without Coke's knowledge or approval.
"We, as a company, do not take political positions unrelated to our business,'' Coke said. A spokeswoman wouldn't name the ad agency.
PepsiCo also has been pulled into the controversy. A map on PepsiCo's Russian website showed Crimea as part of Russia, according to screen shots of the image published by Russian and Ukrainian media in recent days. But that map drew far less attention in social media and political circles.
A PepsiCo spokesman said Wednesday that the map has been removed from the website but didn't comment further.
The dustup is an example of just one of the difficulties foreign companies have faced as a result of the political rancor between Russia and Ukraine. American companies have long viewed the two countries as something of a single market, in part a holdover from the Soviet days when they were both part of the USSR.
It is also not the first holiday tempest for Coke, which posted an online Christmas video in Mexico in late November showing white people bringing a Coke-decorated Christmas tree to a remote indigenous community. After some critics slammed the ad as racist, Coke took the video down in early December and apologized, saying the ad was meant to convey a message of unity and joy.
Ukraine's embassy in Washington expressed its concerns Tuesday to Coke and the U.S. State Department after Coke showed "illegally occupied'' Crimea as part of Russia. It noted the U.S. has condemned Russia's annexation of Crimea.
A spokeswoman for the U.S. State Department, Pooja Jhunjhunwala, said: "We do not, nor will we, recognize Russia's attempted annexation of Crimea and call on President [Vladimir] Putin to end his country's occupation of this sovereign, Ukrainian territory."
Mustafa Nayyem, a Ukrainian member of parliament from President Petro Poroshenko's party, urged consumers on Facebook to boycott Coke products and take up the hashtag #BanCocaCola. Mr. Nayyem later wrote PepsiCo also had published a map recognizing Crimea as part of Russia and urged Ukrainians to find other examples.
Russia is PepsiCo's largest foreign market, contributing about 7% of companywide revenue in recent years. The country represents a smaller slice of Coke's overseas business. Both companies have operations in Ukraine, which is a smaller market.
Write to Mike Esterl at email@example.com and Paul Sonne at email@example.com
Copyright ©2019 Dow Jones & Company, Inc. All Rights Reserved. 87990cbe856818d5eddac44c7b1cdeb8
Appeared in the January 7, 2016, print edition as 'Coke Ad Sparks Kerfuffle Abroad.'


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Artist Statement
Over the years I have been inspired by residencies and travel in various overseas countries; namely America, Morocco, Japan, Thailand and France. I am also influenced by the unique environment of North Stradbroke Island situated on the eastern side of Moreton Bay near Brisbane, Queensland. Not unlike art, traveling and residing in these various locations offers an experience that is out of the ordinary. There is the challenge of taking on new pathways and the discovery of unknown entities. The accumulation, collation and reinterpretation of visual images from these various ventures provide the inspiration for many of my artworks. The arrangements are random, placing a high value on serendipitous events, intuitive decisions where the laws of chance and serendipity have been given primacy over logic and reason.
Moving back and forth through different modes of expression is usual in my art practice. The best way I can describe these impulsive shifts is that I am merely responding to the experiences that are unfolding in my life; and hooking onto something deep-running in my nature. Of course, this is often shaped by travel, relationships, nature, collective history and current affairs.
Each stylistic shift has its own place in my repertoire and each requires the physical act of marking and rigorously changing the surface tensions. Deep and rich blacks, bulbous forms, silky transitions from black to white, scraped and rigorously altered surfaces, calligraphic fluency, changing scale and seductive accidental surfaces, plus bold colour combinations are all a part of the mix.
My relationship with the sea, through surfing and swimming in waters off Stradbroke Island, has shaped the concept of my recent work. Sea forms and elliptical shapes dominate the imagery and the themes often address the subconscious through hybrid marine forms designed to trigger the viewer's imagination.
Through numerous trips to Japan over the past 2 decades, have built a solid appreciation of the Japanese culture. These travels to Japan have resulted in concepts of rhythm, motion and natural erosion being utilised in many of my visual sojourns.
Russell Craig
November, 2019


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By Dr. Oliver Morgan,Dr. Merle Jordan
Read Online or Download Addiction and Spirituality: A Multidisciplinary Approach PDF
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Addiction and Spirituality: A Multidisciplinary Approach by Dr. Oliver Morgan,Dr. Merle Jordan
by Christopher