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The widespread use of proton pump inhibitor drugs (PPIs) world wide for almost two decades is gradually increasing concern among physicians and the public that their benefits may be attended by a variety of risks that until recently have received little attention. Based largely on observational studies, a number of adverse drug reactions (ADRs) have emerged as likely or possibly associated with PPI therapy. Such ADRs are either uncommon in incidence, or associated only with prolonged use or high doses of the drugs. Not all these ADRs are class effects, although often erroneously treated as such, and some may occur only in subpopulations, susceptible because of age, genetics, comorbidity or environmental factors such as Helicobacter pylori infection or cotherapy with other agents.
The incidences of minor adverse events, identified in premarketing clinical trials, are typically of the order of 1–5% and include headache, diarrhea, constipation, nausea and rash, with little difference between products and with only minor differences from those seen with H2-receptor antagonists (H2RAs) or placebo. These effects of therapy will not be discussed here except to say that the short-term use of the drugs in recommended doses is generally well tolerated, even in children, the fetus, the pregnant and the elderly, with only rare exceptions. Nonetheless, from studies not designed to determine drug safety systematically, a number of associated ADRs have emerged and are the focus of this brief commentary. Due to limitations of space, this review will not attempt to discuss all relevant studies or provide detailed bibliographic references: for more information on specific points, the interested reader is referred to other recent reviews [1,2•–4•].
The available literature mainly identifies associations of PPI therapy, often weak, and frequently accompanied by unsupported speculations as to the mechanisms that underlie them. However, such observational data, despite the listed imperfections, are often later borne out by the results of randomized controlled trials (RCTs), and prove to have furnished valuable clues to important effects, unrecognized prior to extensive postmarketing use. That these suspected ADRs are unproven in no way justifies the belief that PPI therapy is completely well tolerated. Most prominent among associations of ADRs with long-term PPI therapy are concerns about the risks of bone fractures, increased susceptibility to infections and effects of altered gastric function.
Effects on bone
To date, four studies have shown an association between chronic PPI use and fractures of the hip or other sites, including spine, wrists and forearms [5–8], the risks increasing (in two reports) with dose of drug and duration of exposure. Most of the reported hazard ratios or odds ratios (ORs), for various sites in various groups, were between 1.0 and 2.0, except for an OR of 2.65 [confidence interval (CI) 1.80–3.90] attending the use of more than 1.75 daily doses per day for more than 1 year. These risk increases were applied to low baseline risk rates in untreated controls. Some have used the term ‘osteoporotic fractures’ to describe these events, but as at least three studies have later indicated, PPI therapy is not associated with any appreciable changes in bone density, over periods adequate to reveal the effects of other relevant factors, such as steroids [8,9•]: the term osteoporotic, with implications as to pathogenesis, should now be dropped. Similarly, attempts to link hypochlorhydria with significantly impaired calcium absorption, have failed to show any consistent relationship [4•,9•], although other hypochlorhydric states, such as pernicious anemia or following gastrectomy, have also been associated with increased rates of hip fracture .
Two studies were unable to find an increased risk of hip fracture, unless at least one additional risk factor such as steroid use or preexisting osteoporosis was present [11,12••], suggesting that PPI use may be dangerous mainly in vulnerable subgroups. The authors involved in these studies emphasize their awareness that unrecognized confounding may play a major role in associating fractures with PPI therapy. Although the US FDA have recently issued some cautionary advice about the use of long-term or high-dose PPI therapy, the authors of the report also felt that it was not clear that PPI use accounted for the increases in fractures seen in PPI users in epidemiological studies.
Despite all these reservations and failures to demonstrate either drug-related calcium malabsorption or decreases in bone density, it seems likely that in some vulnerable individuals, PPI use contributes to an increased risk of fractures at various sites, in a manner related to dose of drug and duration of therapy. Although the mechanism(s) underlying their genesis remains unknown, several possibilities are worthy of examination. Osteoclasts in bone contain H+/K+ ATP-ases that acidify vacuoles in bone matrix during vacuolar resorption: two studies have shown that omeprazole inhibits bone resorption in vitro and in vivo in humans [2•,4•], decreasing bone turnover. This should lead to increases in bone density as measured by bone scans but, as pointed out by Targownik et al.[9•], might increase fracture risk by blocking the repair of microfractures, thus weakening bone strength. They observed that in the rare disease osteopetrosis, in which vacuolar osteoclastic proton pumps are congenitally absent, bone remodeling is impaired, bone density is increased and repeated fractures occur [9•].
Another factor might be deficiency of vitamin B12, whose absorption is impaired in some PPI users and which is integral to bone development, especially to osteoblastic function: deficiency of B12 has been associated with increased risk of fractures . In all, but especially in H. pylori-infected patients, PPI use dose dependently leads to hypergastrinemia and in animal models, leads to hyperparathyroidism and increased bone turnover. On the contrary, PPIs appear to reduce the absorption of magnesium, causing hypomagnesemia, which, in turn, inhibits parathyroid function and may cause tetany. There have now been four reports of hypomagnesemia caused by PPIs, due to impaired absorption of magnesium. This could result from actions of PPIs that interfere with the TRPM6 and TRPM7 ion channels that conduct divalent cations into cells [3•]. These channels are regulated strongly by protons in several sites, and PPI-induced alterations in gut pH could thus influence absorption of magnesium or calcium, in turn affecting parathyroid function, bone metabolism and susceptibility to fracture.
There is an urgent need for careful prospective studies of the effects of PPIs on bone metabolism and for, epidemiologic studies carefully designed to minimize confounding by various clinical factors. Meanwhile, the overall increase in fracture risk appears small. Although the increased risk does not require discontinuation of needed PPI therapy, high-dose or long-term use should be confined to situations in which any increase in risk is clearly justified by the need for PPI in the particular case. A similar risk, though of lesser magnitude, probably also applies to the use of H2-receptor antagonists (H2RAs) [5,12••]. Much of the fracture risk may ultimately prove to arise from widespread use of PPIs in very sick people whose comorbid illnesses collectively increase the risk of fracture.
Susceptibility to infection
The principal function of gastric acid in humans is, as a host defense, to sterilize all contents entering the digestive tract. It is effective against sensitive organisms, preventing infection unless the inoculum is large, acid-resistant, highly virulent or host defenses are impaired. Reduction in acidity is associated with increased risks of both enteric and systemic infection. Following the famous admonition of Sir Arthur Hurst to the British Government in 1934, that people with hypochlorhydria should not be sent to the tropics, there have been numerous previous papers on the risks of infection associated with hypochlorhydria caused by disease, surgery or therapeutic agents .
In a recent review, Dial [14••] has analyzed effects of PPIs on gastric host defense against microbes. Acid secretion is believed to be of key importance in killing organisms, but elevations in gastric pH, delayed gastric emptying, increased bacterial translocation, decreased gastric mucus viscosity and changes in flora may all contribute. The only organism uniquely adapted to surviving the acid milieu is H. pylori, and the effects of PPIs in inhibiting gastric acidity/elevating pH are significantly greater in H. pylori-infected individuals than in controls. In the absence of gastritis, gastric acidity does not decrease with age: the increasing prevalence of hypochlorhydria or achlorhydria in elderly individuals is mainly due to chronic gastritis and increasing atrophy and relates to a birth-cohort effect associated with the risk of H. pylori infection in the individual's youth, and not to age per se. H. pylori gastritis is likely to be an important confounding factor in our understanding of an apparent increase in risk and severity of C. difficle infections in the elderly, especially when treated with acid suppressive drugs. In trials, all marketed PPIs cause some diarrhea, but how much of this is of infectious cause has been little studied. Some diarrhea may also be caused by small bowel bacterial overgrowth (SIBO) as discussed later. However, because of the rising incidence, costs and severity of the illness, much scrutiny has been devoted to the risk of Clostridium difficile-associated diarrhea (CDAD).
Clostridium difficile and other enteric infections
As borne out by systematic analysis  and as reviewed by Dial [14••], there is a consistent association between PPI therapy and an increased risk of CDAD, with a pooled OR of 1.94 (95% CI 1.37–2.75) for any antisecretory therapy, of 1.96 (95% CI 1.28–3.0) for PPI therapy and 1.4 (95% CI 0.85–2.29) for H2RA therapy. The OR for Salmonella, Shigella or other enteric infection was 2.55 (95% CI 1.53–2.46). Similar or greater increases in C. difficile colitis have been observed in patients with chronic renal failure, in high-risk and average-risk hospital settings, and in community studies. In a large pharmaco-epidemiologic cohort study, involving 101 796 hospital discharges from a tertiary care center over 5 years , the occurrence of nosocomial CDAD increased from 0.3% (95% CI 0.21–0.31) in patients receiving no acid suppression, to 0.6% in those receiving H2RAs (95% CI 0.49–0.79), to 0.9% (95% CI 0.8–0.98) in those receiving once daily PPI and to 1.4% (95% CI 1.15–1.72) in those receiving more frequent PPI therapy. After adjustments for age, comorbid conditions, antibiotic exposure and other factors, ORs rose from 1.53 (H2RAs), to 1.74 (daily PPI), to 2.36 (>daily PPI). These figures support a dose–response effect and argue for causality. Finally, the risk for recurrent CDAD during 90 days after discharge from hospital was increased 42% by cotherapy with PPIs during attempts to abolish CDAD . These results are impressive but still need to be confirmed in prospective, randomized studies.
In recent times, we have come to realize that C. difficile spores are frequently spread between patients, particularly in hospitals, and cause illness even in the absence of prior antibiotic use: normal enteric flora protect against their activation and greatly diminish the risk of infection. Antibiotic therapy abolishes this protection. In attempts to understand the effects of PPIs on CDAD, attention has focused on the pH-dependent conversion at higher pH of the acid-resistant spores to the more virulent vegetative form of the organism, by delayed gastric emptying prolonging the duration of this process, and possibly by effects of bile salts, potassium and phosphate in gastric juice [14••]. An accentuation of these effects by H. pylori infection has not been studied, but may account for the increased risk in the elderly. The marked increase in CDAD infection in the past two decades has coincided in time with increasing use of PPIs, but other factors such as the emergence of more virulent strains may also play a part.
In conclusion, it appears highly likely that PPI therapy will prove to increase the risk of infection with a number of gastrointestinal pathogens, among which C. difficile is the most important, and most in need of prospective studies. There is increasing need to consider possible risks and benefits before prescribing or continuing PPI therapy, particularly in hospitalized patients on antibiotics or during institutional outbreaks, in the frail, the elderly or the immunosuppressed, and in those embarking on travel to areas of risk.
Although a number of early studies suggested a weak association between community-acquired pneumonia (CAP) and PPI use, a recent survey of 70 RCTs, of which seven met strict criteria for inclusion into meta-analysis, found no association, although about half the studies showed a trend toward significant increases. In two separate studies, there appeared to be a high risk of CAP in the first 5–14 days of therapy, but nothing for longer times or with chronic exposure. There are no convincing data to indicate significant links with nosocomial or ventilator-associated pneumonias . Despite abnormal gastric colonization in PPI users, and theoretical risks of increased micro-aspiration or translocation, no reports have appeared. Reports of increased leakage of the gastric mucosa (probably via tight junctions) caused by several PPIs so far apply only to molecules in the 500–4000 Da weight range and not to larger molecules or particles, but this may change : this phenomenon is unlikely to affect bacteria.
Small intestinal bacterial overgrowth
Despite long-standing suspicions that acid-suppressive therapy increases the risk of SIBO, it has been uncertain whether this risk is uniform in all users or is perhaps restricted to certain subgroups, such as the elderly, the H. pylori-infected or those with irritable bowel syndrome (IBS). There is growing acceptance of the presence of SIBO in 25–40% of patients with IBS-type symptoms, particularly gaseous bloating, excessive flatus and diarrhea, but also to a lesser extent in those in whom constipation or pain are dominant symptoms. Whether PPI use is an independent risk factor for SIBO in individuals free of IBS is not well studied. Furthermore, the type of overgrowth due to PPIs may be caused more by oropharyngeal flora rather than by the usual flora of the more distal gut and give rise to a different clinical picture. Despite such reservations, in a recent study of 450 patients with a positive glucose hydrogen breath test (GHBT), among 200 GERD patients on PPIs, GHBT was positive in 50% compared with 24.5% among 200 PPI nonusers with IBS and 6% among 50 normal controls, all differences between groups being highly significant . Thus, even if there were IBS patients among the PPI users (unstated), the combination of IBS and PPI therapy carries at least twice the risk seen with IBS alone: an accompanying editorial identifies some additional reservations.
Although some other recent studies have not confirmed the observation, their designs [small numbers, use of lactulose breath test (LBT), etc.] do not allow confident rejection of the reported association. Furthermore, the association is strongly supported by a number of other observations, including chronic use of PPIs as an independent risk factor for SIBO in the elderly (OR 7.9), PPI therapy increasing the occurrence of relapses of SIBO after eradication by antibiotic therapy (OR 3.52) and PPI use an independent predictor of positive GHBT in 2000 non-IBS patients with a variety of diseases such as diabetes, cirrhosis, collagen vascular diseases or residua of previous gastric surgery (OR 1.27, P = 0.028). Older studies, culturing small bowel bacterial contents, also found increased risks of SIBO with H2RA therapy, greater for ranitidine than for cimetidine, and that the incidence of SIBO rose in scleroderma patients changed from H2RAs to PPIs.
In conclusion, although there is an undoubted need for randomized prospective studies in this area, it seems likely that chronic use of PPIs increases the risk of SIBO in a sizable number of individuals, the risk increasing with time on drug. This number may be influenced by a number of other factors including the presence of IBS, chronic gastritis, H. pylori infection, other comorbid conditions and exposure to antibiotics or to drugs or diseases that affect gastric emptying.
Spontaneous bacterial peritonitis
Although the pathogenesis of spontaneous bacterial peritonitis (SBP) is incompletely understood, translocation of bacteria across the intestinal wall is believed to be an important causative factor. It follows that alteration in intestinal flora, such as occurs with PPI use, may play an important role in SBP, although additional factors are clearly involved. It has been hypothesized that PPIs, widely used in cirrhotic patients, may favor intestinal bacterial overgrowth and translocation, increasing the risk of SBP. One recent retrospective case–control study of 70 cirrhotic, community-based patients with SBP, on multivariate analysis found that PPI use was associated with SBP with an OR of 4.31 (95% CI 1.34–11.7). Affected patients had advanced cirrhosis, and higher ascitic fluid protein was protective. Of interest was that 47% of patients had no indication for PPI treatment .
Inhibition of gastric secretion of acid, pepsin, intrinsic factor, vitamin C and other substances has given rise to concerns about a number of possibly resulting clinical deficiency states.
Both hydrochloric and ascorbic acids secreted by the stomach are involved in converting ferric to ferrous iron and maintaining it in the reduced state. Ascorbic acid, whether of dietary or gastric origin, also chelates nonheme iron and keeps it in solution until absorbed. PPIs inhibit secretion of both substances. In addition, vitamin C is unstable at high pH and is readily converted to dehydro-ascorbic acid in inflamed H. pylori-infected mucosa. Thus, conditions for iron absorption are significantly suboptimal during PPI therapy, particularly in the presence of H. pylori gastritis. Despite use of PPIs to reduce iron absorption in hemochromatosis and observations that omeprazole inhibited the correction of iron deficiency anemia by oral iron until the PPI was stopped, there has been no prospective study of the association of PPI therapy with iron deficiency anemia and no proper trial of the efficacy of oral iron administration during PPI therapy . PPI use has also been linked with the possible development of painful restless legs syndrome, long associated with iron deficiency and low serum ferritin concentrations. In my opinion, iron deficiency is the most important of the uninvestigated potential adverse effects of PPI therapy, especially in the elderly and the poorly nourished, and is in urgent need of prospective studies.
PPI therapy leads to diminished acid secretion, diminished antral D-cell release of somatostatin, consequent increased G-cell release of gastrin and hypergastrinemia. This causes oxyntic cell hyperplasia, increased parietal cell mass, glandular dilatations and stimulation of enterochromaffin-like (ECL) cells to release chromogranin and histamine, raising their concentrations in serum. Cellular hyperplasias can cause obstructions at the mouths of fundic glands, causing them to balloon, become prominent and polypoid in appearance. Hyperplastic or cystic-type fundic polyps arise in 7–10% of the patients taking PPIs for 12 months or more: these are benign and regress with cessation of therapy. However, in patients with familial adenomatous polyposis, fundic polyps may progress during PPI therapy, becoming dysplastic and harboring adenocarcinoma: these should be excised during surveillance endoscopy [4•]. Other specific consequences of hypergastrinemia are now briefly reviewed.
Rebound acid hypersecretion
This is an effect of acid suppression recognized for many years by basic investigators but largely ignored by clinicians [24••,25••]. Sustained hypergastrinemia due to daily PPI therapy leads to increased gastric acid-secretory capacity that is not apparent during PPI therapy, but that appears promptly when the drug is stopped. In normal volunteers, treated for 8 weeks with esomeprazole 40 mg per day, stopping the drug was followed by the de-novo development of dyspeptic symptoms in more than 40% of previously symptomless patients. Other smaller studies, published as abstracts, had previously reported similar increases in acid-related symptoms after stopping PPI therapy, both in normal volunteers and in symptomatic patients, and are discussed elsewhere. Depending on the dose and duration of exposure, it can take 2–3 months for rebound acid hypersecretion (RAHS) to return to pre-PPI basal levels [24••]. Like nocturnal acid breakthrough, RAHS is not prominent in H. pylori-infected patients.
This phenomenon implies that a post-PPI-therapy period of difficulty should be anticipated. Symptoms can be managed with antacids or H2RA drugs (which cause negligible RAHS and can be discontinued later with little difficulty), or perhaps the PPI dose could be tapered down over a period rather than suddenly discontinued: to date, too few studies of tapering drug cessation have been reported for any conclusion to be drawn. Furthermore, as gastrin acts by releasing histamine, the ultimate mediator of acid secretion, tolerance to histamine and to the effects of H2RAs occurs during PPI therapy, decreasing H2RA efficacy; thus, PPIs should not be used in advance of H2RAs, an argument against ‘step-down’ therapy and other popular practices [24••].
Impaired gastric emptying of solids
This action can be of importance in managing functional dyspepsia and gastroesophageal reflux, particularly in those whose emptying is already delayed due to diabetes, vagotomy or the use of opiate drugs. The volume of gastric contents is important not only for patient comfort but also for triggering transient lower esophageal sphincter relaxations (TLESRs) and for exacerbating reflux in those with low sphincter pressures, particularly at night and in recumbency. A detailed scholarly review of the physiology of gastric emptying and its alteration by PPIs has recently been published by investigators from Japan [26•].
Hypergastrinemia and neoplasia
Gastrin has trophic effects on many tissues and stimulates a number of tumor cell lines in culture, including colon cancer cells. Although there have been suggestions that hypergastrinemia is associated with an increased risk of colon cancer, several recent large studies have found no such increase in patients using PPIs [2•]. Neither does PPI therapy increase the risk of adenocarcinoma of the stomach or cause progression of gastritis or gastric atrophy, except possibly in patients with active H. pylori infection .
More troubling, because of the extensive use of PPIs in patients with GERD, is a possible effect of gastrin on the progression of Barrett's esophagus to cancer. This is the subject of much recent research and controversy: the bulk of the data seem to suggest that in most patients progression of dysplasia is halted or reversed by PPI therapy . However, in a recent study, although there was no significant difference in serum gastrin with increased degrees of neoplasia, in multivariable analysis, the highest quartile of serum gastrins was associated with a significantly increased OR for advanced neoplasia (high-grade dysplasia or adenocarcinoma) with an OR 5.46 (95% CI 1.20–24.8). This finding suggested that some subset of Barrett's esophagus patients may be cancer prone, perhaps responding only to serum gastrin above a certain ‘threshold’ level . The issue remains unresolved, but of considerable interest, in view of the marked rise in the incidence of adenocarcinoma at the cardioesophageal junction over the past two decades, as acid-suppressive therapy for GERD has greatly increased.
PPIs inhibit acid secretion, leading antral G cells to release gastrin, causing hypergastrinemia. Gastrin, in turn, binds to gastric mucosal ECL cells, causing them to release chromogranin, histamine and other substances. The acid-secretory effects of gastrin are inhibited by PPI, but the potential proliferative effects on mucosal cells or cancers are not. In most patients, PPI-induced elevations in serum gastrin are moderate (50–400 pg/ml) and normalize when the drug is stopped. However, in some patients (mostly those with H. pylori infection and atrophic gastritis), plasma levels can rise to between 400 and 4000 pg/ml. The trophic, concentration-dependent effects of gastrin are exerted at much lower concentrations, above 40 pg/ml.
In rodents given PPIs, hypergastrinemia leads to the development of gastric carcinoids; hypergastrinemia also does this in both the genetically prone MEN-1 subset of humans with Zollinger–Ellison syndrome (hyperchlorhydric) and in another genetic disorder pernicious anemia (hypochlorhydric). In GERD patients, long-term PPI use is associated with the development of focal areas of hyperplasia of ECL cells in 10–30% of patients: the genetic contribution to this is unknown. Whether or not PPI therapy leads to the development of gastric or other carcinoids in humans has never been formally studied, despite large recent increases in the incidence of these comparatively rare tumors in many sites. These increases have occurred over the past three decades . The annual population incidence in gastric carcinoids has risen from 0.03% (1969–1971) to 0.12% (1992–1999) in men and from 0.02% (1969–71) to 0.18% (1992–1999) in women, increases of 400 and 900%, respectively, and the percentage of all carcinoids occurring in the stomach has also risen from 2.4 to 8.7% over the same period . Carcinoid tumors of the small intestine, including duodenum, show similar increases: small intestine is now the major site of gastrointestinal carcinoids.
These increases in incidence rates have been observed in several large analyses in western countries. Beginning slowly in the era of H2RA therapy, the greatest increases have paralleled the widespread marketing of PPIs, a trend observed by many experts [32,33]. Unfortunately, the databases from which these observations were drawn did not record the use of medications, precluding case–control studies. Although the statement has often been made that there have been no cases of gastric carcinoids in humans using PPIs, this is not strictly correct : what can be said is that the available reports in all cases lack information essential to confidently assessing their merit. Beyond this, with population carcinoid incidences in the order of one to two per 1000 people (autopsy rate 1%), prospective studies would require huge numbers of individuals in order to perform statistical analyses with power adequate to demonstrate meaningful differences in their incidence rates. The fraction of PPI users who might demonstrate such a change is unknown. However, with the contemporary growth in large data banks, that now record medication use as well as clinical information, well designed case–control studies could prove of great value in exploring this important issue. The scientific basis for expecting long-term PPI use to cause carcinoid tumors is quite strong and merits serious attention. Hypergastrinemia may also stimulate carcinoid development or growth in other sites. At a minimum, it seems reasonable to discontinue PPI therapy in patients with carcinoid tumors.
Food allergies and eosinophilic esophagitis
Experiments show that a number of ingested potential food allergens that are normally degraded by acid-peptic digestion, become antigenic when the gastric pH rises to values seen during PPI therapy . Other investigations have shown that PPIs dose dependently increase mucosal permeability to small molecules that could include peptide antigens . Adults treated with PPIs for 3 months develop a rise in plasma IgE levels, new food-specific IgE antibodies and a mucosal immune response to offending allergens. A recent hypothesis generating much interest proposes that PPIs may play a key etiologic role in causing eosinophilic esophagitis, as both PPI use and the incidence of eosinophilic esophagitis have risen over closely similar periods .
Effects on other medications
Rises in pH and lack of gastric acid have been shown to impair the absorption of various drugs in common use, including ketoconazole, indinavir, midazolam, didanosine and methadone. Following absorption, some but not all PPIs inhibit various components of the cytochrome P-450 (CYP) enzyme system in liver and intestine, notably CYP 2C19 and CYP 3A4. This has varying effects, most of them subclinical, on many other drugs in common use, but the effects have not risen to the level of posing clinically significant problems. PPIs also variably affect the hepatic catabolism of thyroxine by UDP-glucuronyl transferase, increasing TSH slightly and in some cases requiring an increase in the dose of thyroxine . Another interaction, currently causing a flurry of attention because of its possible linkage to adverse clinical outcomes, is the effect of PPI therapy in patients also using clopidogrel.
Clopidogrel is a prodrug used to inhibit platelet aggregation in patients at increased cardiovascular risk. After absorption, it requires activation by CYP 2C19, before becoming active against platelets. Some PPIs, notably omeprazole and esomeprazole, are metabolized to various extents by CYP 2C19 and this diminishes the activation of clopidogrel, but this is not believed to be a class effect of all PPIs. What is at the heart of current controversy is whether or not this effect on platelet activation translates into increased risks of myocardial infarction, arterial stent occlusion or other related thrombotic risks including death. There have been several large studies, all potentially flawed in various ways, which have yielded conflicting and contradictory conclusions. Even among those observational studies that claim that risk is increased, the ORs or hazard ratios are generally low (under 2.0) and not enough to confidently exclude residual confounding by comorbidity, cotherapy, population genetic heterogeneity and other factors. The studies are especially problematic in their lack of accounting for genetic polymorphisms in CYP 2C19. These affect the metabolism of clopidogrel, contributing to clopidogrel resistance in approximately 30% of the patients [36•]. There are also 21 polymorphisms of CYP 2C19, giving rise to the existence of two main PPI patient groups, extensive metabolizers and poor metabolizers, variously responding to different PPIs [37,38•]. The frequencies of occurrence of such polymorphisms are also different in different races and geographical areas, but, so far, not addressed in resolving problems with clopidogrel activation.
Cotherapy with clopidogrel and low-dose PPI therapy is widely used to minimize the risk of serious gastrointestinal bleeding, particularly in high-risk patients, so a balancing of risks in the individual patient is appropriate. Although the FDA has recently promulgated some cautionary statements , these remain controversial, and many feel that the risk of cotherapy with low-dose omeprazole (20 mg per day) may be acceptable, especially in those at high risk of gastrointestinal bleeding, and particularly if the daily doses are given 12 h apart. The agency's acknowledgement that H2RAs like famotidine, ranitidine or nizatidine (but not cimetidine) can be used instead of PPIs in cotherapy until the issue is resolved also seems prudent. Several studies have shown reductions in hospitalization for gastrointestinal bleeding in patients taking both clopidogrel and PPI compared with those taking clopidogrel alone (COGENT trial results at http://www.theheart.org/article/1007145.do) . With pending emergence of newer antiplatelet agents that do not require activation by CYP 2C19 or interact with PPIs, the whole issue may prove short-lived.
PPIs enjoy an enviable record of safety, but like many drugs that experience a huge increase, particularly in long-term users, after initial marketing, subtle side-effects with low incidences but considerable clinical importance may gradually surface. These ADRs are often relevant only to small numbers of cases or cause only minor problems, but nevertheless they demand widespread education of providers as to their occurrence and management. The true importance of these kinds of events can only be estimated from careful prospective and, when possible, randomized, studies designed solely to measure safety, with minimal confounding. The effects of PPIs now demand such studies, especially addressing the ADRs already associated with their use.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 671–672).
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23 McColl KEL. Effect of proton pump inhibitors on vitamins and iron. Am J Gastroenterol 2009; 104:S3–S9.
24•• Waldum HL, Qvigstad G, Fossmark R, et al
. Rebound hypersecretion of acid from a physiological, pathophysiological and clinical point of view. Scand J Gastroenterol 2010; 45:389–394. A critical highly informed review of potential clinical consequences of hypergastrinemia
25•• Reimer C, Sondergard B, Hilsted L, Bytzer P. Proton-pump inhibitor therapy induces acid related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology 2009; 137:80–87. A demonstration that PPI use causes rebound hypersecretion of acid after therapy stops.
26• Sanaka M, Yamamoto T, Kuyama Y. Effects of proton pump inhibitors on gastric emptying: a systematic review. Dig Dis Sci 2010; 55:2431–2440. A review of effects of PPI therapy on gastric emptying of solids and clinical implications.
27 Kuipers EJ. Proton pump inhibitors and gastric neoplasia. Gut 2006; 55:1217–1221.
28 Kuipers EJ. Barrett's esophagus, proton pump inhibitors and gastrin: the fog is clearing. Gut 2010; 59:148–149.
29 Wang JS, Varro A, Lightdale CJ, Lerkowit N, et al
. Elevated serum gastrin is associated with a history of advanced neoplasia in Barrett's esophagus. Am J Gastroenterol 2010; 105:1039–1045.
30 Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid
tumors. Cancer 2003; 97:934–959.
31 Modlin IM, Lye KD, Kidd M. A 50-year analysis of 562 gastric carcinoids: small tumor or larger problem? Am J Gastroenterol 2004; 99:23–32.
32 Hodgson N, Koniaris LG, Livingstone AS, Franceschi D. Gastric carcinoids: a temporal increase with proton pump inhibitor introduction. Surg Endosc 2005; 19:1610–1612.
33 Waldum H, Gustafsson B, Fossmark R, Qvigstad G. Antiulcer drugs and gastric cancer. Dig Dis Sci 2005; 50:S39–S44.
34 Merwat SN, Spechler SJ. Might the use of acid-suppressive medications predispose to the development of eosinophilic esophagitis? Am J Gastroenterol 2009; 104:1897–1902.
35 Sachmechu I, Reich DM, Wibowo AM, et al
. Effect of proton pump inhibitors on serum thyroid-stimulating hormone level in euthyroid patients treated with levothyroxine for hypothyroidism. Endocr Pract 2007; 13:345–349.
36• Mega JL, Close SL, Wiviott SD, Shen L, et al
. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360:354–362. A good discussion of the relevance of genetic polymorphisms in resistance to clopidogrel.
37 Chaudry AS, Kocchar R, Kohli KK. Genetic polymorphism of CYP2C19 and therapeutic response to proton pump inhibitors. Ind J Med Res 2008; 127:521–530.
38• Klotz U. Impact of CYP2C19 polymorphisms on the clinical action of proton pump inhibitors (PPIs). Euro J Clin Pharmacol 2009; 65:1–2. A good discussion of the relevance of genetic polymorphisms to the clinical effects of PPIs.
39 Alkhatib AA, Elkhatib FA, Khatib OF. Gastric acid-reducing medications and clopidogrel: what are the latest FDA recommendations? Am J Gastroenterol 2010; 105:1211.
40 Ray WA, Murray KT, Griffin MR, Chung CP, et al
. Outcomes with concurrent use of clopidogrel and proton pump inhibitors. Ann Int Med 2010; 152:337–345.

domain: biology


text:
Pout and Go from Luna by Lisa. This ultimate lip trio includes a liner, lipgloss and a lipstick in charm holder.
The most perfect nude pink shade - Love - is the best accessory you can bring with you to add drama to your lips, as well as your accessories. Deliver amplified shine and vibrant pigment with this medium coverage luxurious lipstick that effortlessly glides onto lips for a sculpted, multidimensional shimmer. Pair with the lip liner in shade Lust, to expertly define your pout. Finish your look with the Silky Lip Gloss in shade Passion. A silky gloss with conditioning extracts and hyaluronic acid to hydrate and soften your lips. Ultra-comfortable and wearable, this gloss contains sunflower seed oil to condition, raspberry seed oil to soften, rosehip oil to rejuvenate and aloe vera leaf extract to soothe and calm.

domain: beauty


text:
In April, amidst the early days of the economic downturn, we examined the likely effects that the pandemic-induced recession would have on government budgets and the public sector workforce. Now, more than three months into the economic unrest, hard data reveals the severity of the employment, wage, and output losses. The picture is not good, including the effects on public sector jobs.
The initial employment losses in the state and local government sectors are much more severe than the early months of the Great Recession and these declines are much larger than any three-month stretch during the previous downturn. Early indications are that this recession is likely to have a significant and lasting effect on Michigan’s public sector workforce at all levels.
The near shutdown of many parts of the U.S. economy beginning in March and continuing through May swelled the number of unemployed Americans by more than 14 million, from 6.2 million in February to 20.5 million in May. Michigan’s numbers are no less frightening, as the ranks of the unemployed jumped from 180,000 in February to over 1 million in May with some comparing the dramatic job losses to the Great Depression. The state’s unemployment rate rose from 3.6 percent to 21.2 percent over the same period, with 10 of 83 counties registering rates above 25 percent in May.
Both nationally and in Michigan, these numbers are substantially greater than the unemployment situation arising from the Great Recession. Michigan’s high-water mark during that downturn was 725,000 unemployed (June 2009) with an unemployment rate of 14 percent. The path of employment losses during the Great Recession can be seen in the chart below (shaded area represents period of recession).
Change in Monthly Private and Public Sector Employment Since December 2007
Source: Bureau of Labor Statistics
Private sector employment experienced a steep and sustained decline from the end of 2007 through the middle of 2009. During this period, employment losses in the local government sector were much more gradual, while the number of state government jobs actually increased throughout the recession. This job growth was primarily driven by hiring at the state’s 15 public universities.
By the end of the recession in mid-2009, the private sector had lost about 11.5 percent of its jobs. But the combined state and local public sector, driven by the job losses in local government, including K-12 education, had only shed about 1.2 percent of jobs (note: there are nearly two local government jobs for every state government job) through June 2009. While state employment remained steady and private sector employment fully recovered, local governments continued to shed jobs well into mid-2016. Further, the rebound in this sector since has been much weaker than that experienced with either private or state government jobs. By February 2020, the number of local government jobs was 15 percent below the pre-Great Recession level.
Thus far during the current downturn, employment losses across all sectors of the economy have been more severe than any time during the Great Recession.
State and Local Government Job Losses
The May jobs report revealed a bit of good news with the start of a recovery from steep private sector losses. After losing almost 980,000 jobs from February to April, more than 240,000 private sector jobs were added in May. Still, private employment is down nearly 20 percent since February. This positive news was tempered by continued cuts to the public sector in Michigan, including public education at all levels.
Accounting for about one of every seven jobs in Michigan, state and local governments lost a total of 65,000 jobs since February, or about 11 percent of the total workforce. Since the onset of the pandemic in early March, state and local officials have issued hiring freezes, furloughed workers at shuttered facilities, laid off seasonal employees and trimmed full-time payrolls. While the private sector incurred greater losses than the public sector since February, the reopening of the economy and lifting of stay-in-place orders provides some hope for the return of private sector jobs. The prospect of coming state and local budget cuts means that the public sector workforce remains vulnerable to further reductions.
The first three months of the COVID-19 recession have been unlike the experience of the Great Recession ten years ago. During the first three months of the Great Recession, the public sector lost just one percent of its jobs (see chart below), a small fraction of the current decline. These losses were concentrated in the local government workforce. Current job declines have been much more widespread.
At the state level, over 36,000 jobs have been lost since February. The state education workforce has contracted by almost 25 percent in the pandemic recession, which equates to about 33,000 jobs and accounts for 90 percent of the total state decline. Many of these losses are a result of school closures and looming budget cuts at public universities. Like local governments, university officials issued furloughs, cut seasonal workers, and enacted hiring freezes. Many of Michigan’s 15 public universities are facing significant losses of revenue including state aid, and many students are considering postponing their enrollment for the fall semester, both of which compound an already serious problem.
One area of state employment that has avoided major reductions thus far is Michigan state government. Although Governor Whitmer instituted mandatory two-day furloughs for two-thirds of the state workforce, they have not materially changed the overall employment picture. Monthly civil service payroll reports show that the state workforce is only down a tiny fraction since February. This may be short-lived as officials recently announced a budget agreement to address a $2.2 billion shortfall in the current year that requires a state hiring freeze and layoffs.
At the local government level, the workforce shrank by 29,000 jobs in the first three months of the current downturn. Local education jobs, including K-12 schools and community colleges that account for a little more than half of the total sector, are down 7 percent, equating to a loss of about 14,300 jobs since February. With the closure of public and private school buildings in early March and the shift to remote learning, many schools made significant cuts to non-instructional hourly staff (bus drivers, custodians, and para-professionals), maintaining teaching positions to deliver instruction during the shutdown. Non-instructional positions account for one-half of the K-12 workforce. Most of the cuts to date relate to closures, but further reductions are expected in the coming months in response to budget cuts.
Outside of education, municipal employment is down 8 percent. This includes general administrative jobs in city and county government, but notably public safety positions. The data does not specify how many police and/or fire jobs have been lost. Similar to the state sector, local governments responded to stay-at-home orders by cutting seasonal workers and furloughing staff. Further job losses are expected as local government budgets are cut in response to declining state aid and tax revenues.
Public Sector Job Losses During the First Three Months of Recession
Source: Bureau of Labor Statistics
Looking beyond the first three months of the Great Recession, the number of jobs lost pale in comparison to that experienced during the early months of the COVID-19 recession. The worst three-month private sector job loss during the Great Recession was 4 percent (November 2008 to January 2009), a full year after the onset of the downturn. The worst three-month span for state and local government occurred between May and July of 2009 with a decline of 10.0 percent. Both of these three-month changes are less than the initial employment hit of the current downturn. The Pew Research Center suggests that although the number of jobs lost is significantly higher than the Great Recession, the nature of the layoffs in the public sector may be temporary rather than permanent. However, this will not be known until the full effect of the recession can be studied.
Federal Government to the Rescue?
Because deficit spending is prohibited under state law, government job losses are continuing in anticipation of current and future budget shortfalls. State revenue estimators project combined budget deficits in the General Fund and School Aid Fund of $3.5 billion for next fiscal year. At the same time the state and local governments are preparing for budget cuts, the demand for core governmental services remains fairly constant during the pandemic.
The federal government has passed three substantial coronavirus relief bills including the $2.2 trillion CARES Act in March to help individuals and businesses respond to the problems created by the pandemic. So far, federal action has not sufficiently helped state and local governments make up for the revenue they are losing, and many sectors are suffering due to shortfalls. The federal government’s response has been targeted at helping states respond to COVID-19, but is not designed to fill holes in their budgets caused by the pandemic. The just-announced current-year budget agreement uses some of the state’s CARES funding to offset state budget cuts.
While state and local leaders are hoping for further help from the federal government to make up for revenue shortfalls in the short term, it is unlikely that sufficient federal funds will arrive soon enough to stem the massive government employment losses arising from state and local budget adjustments that have to be made. Further, it is unknown whether federal assistance will be available to backfill state and local revenue losses and make public budgets whole or solely to fight COVID-19.
The prospects for the public sector look bleak at the moment. In particular, the local government job-shedding that began with the onset of the Great Recession has re-ignited with the economic disruption caused by the pandemic. As public budgets are slashed, these jobs are going to disappear. Budget cuts will lead to local government layoffs, not only public workers but also those employees working on local contracts and grants. As all these workers are laid off, they will reduce their spending on various consumer goods and services, which will reduce employment further in the already hard-hit retail sector. Further, job losses may hamper the ability of the government to deliver the services taxpayers expect.
Peter McAndrews, our summer intern and a student at Michigan State University James Madison College, assisted with data collection, research and writing.

domain: statistics


text:
Haven't been able to draw any more 2001 Toa, so here's a drawing I did a long time ago.
in b4 he didn't slip.
Mistakes were made.
This is awesome!
Pretty sweet, though the one side of the pauldron is considerably larger than the other.
Brain thinks of Sadie...
Not bad. I tried so hard to think of a JtO joke there but welp I really like your style!
He has spent a little too much time with the rack
Great job! I like that you did away with the gold on his thighs.
Your personal icon says it all.

domain: artistic


text:
Sun, May 01, 2022 06:00 PM - Tue, May 31, 2022 11:00 PM
Enjoy authentic Mediterranean delights, perfectly crafted for sharing, highlights include wood-fired oven pizza and signature pasta dishes.
Alba Terrace transcends day-to-night, offering the finest locally sourced coffee, light lunches and sharing plates to linger over whilst bathing in the natural sunlight that streams into the space.
- AED 155: 2-hours dining experience per person
Alba Terrace - The Abu Dhabi EDITION Hotel
May 01 - May 31, 2022
06:00 PM - 11:00 PM

domain: food


オング ジアン フー
Radiation reaction (RR) force plays an important role in gamma ray production in the interaction of ultraintense laser with relativistic counterpropagating electron at intensity 1022 W/cm2 and beyond. The relationship between emission spectrum and initial kinetic energy of electron at such intensities is yet to be clear experimentally. On the other hand, the energy from both the relativistic electron beam and laser pulse may be converted into the gamma rays. Therefore, the conversion efficiency of energy purely from laser pulse into gamma rays is of great interest. For an electron bunch, the laser field has to be treated self-consistently by solving Maxwell’s equations. A full 3-D particle-in-cell (PIC) simulation has to be carried out in order to obtain accurate description for radiation emission by electron in laser field.
Posted : 2016年03月31日


Posts Tagged ‘4S’
The iOS 5.0.1 update promised to address the battery issues surrounding Apple’s latest smartphone the iPhone 4S. Despite the promise, customers flooded the company’s support pages with complaints of the problem getting worse. Apparently, the Cupertino firm continues to investigate these battery problems.
Apple told AllthingsD, “The recent iOS software update addressed many of the battery issues that some customers experienced on their iOS 5 devices. We continue to investigate a few remaining issues.”
When the iOS 5.0.1 update rolled out last Friday, many thought this would be the end of the iPhone 4S’s battery woes. Some complained that the update gave their smartphone the problem, when they didn’t experience any battery issues in the past. Some complained that the update made the problem much worse. Sadly, Apple is yet to announce when a new update will address the new problems.
Issues surrounding the iPhone 4S do not end here. Apart from the smartphone’s battery woes, it also has an issue with voice calls. Initially, reports started pouring in on an echo affecting voice calls when headphones were plugged in. Later on, customers complained they experienced white noise even when the headsets were not plugged in.
Bottom line, Apple has to sort out these issues pronto before their customers decide to jump ship and get their hands on upgrade to either Nokia’s new Windows Phone Mango-powered Lumia 800 or Samsung’s new Android flagship the Galaxy Nexus.
Are you one of the iPhone 4S owners suffering from these problems? Can’t wait for another update to address these issues, or are you afraid it will just make things worse? Voice out your frustrations through a comment.
Apple’s support forums reveal that more owners of the iPhone 4S are complaining about the phone’s voice calls. It looks like the problem is further intensifying.
The forums are flooded with massive complaints from owners of the iPhone 4’s successor. Customers complain about audio disappearing with both inbound and outbound calls. Pages upon pages worth of complaints are starting to pile up, which suggests that the problem may be even bigger than the iPhone 4’s antenna problems.
Initially, the problem was thought to only affect a small number of iPhone 4Ses. Customers have reported to experience an irritating echo effect when either Apple or third-party headphones were plugged in. However, more of the smartphone’s users have been coming forward claiming that the problem is also experienced without the headphones plugged in. It looks like Apple is facing widespread scrutiny. What good is any phone if it will not allow you to make and take calls?
Aside from the iPhone 4S’s voice call problems, it is known to drain the batteries faster than expected; Siri reveals personal information, and a hacker revealed that an iOS bug allows other people to steal personal data such as contacts, photos, and sending text messages through the phone without its users even knowing.
According to some users, the voice call issues of the iPhone 4S can be resolved by tapping on the handset’s speaker button. Others claim that a system restore also provides a temporary fix.
Are you experiencing voice call issues on your iPhone 4S? Have you discovered a solution to problem? If you have, please share it through a comment.
Is the Apple iPhone 4S coming? According to Engadget, it is most likely that the mooted smartphone will be coming.
There are definitely numerous rumors flying around regarding the iPhone 5 and the iPhone 4S. Initially, we weren’t sure if Apple’s next generation handset would be called the iPhone 5 or the iPhone 4S. Soon after, we started hearing that Apple’s next dual-core powered smartphone would launch alongside an entry-level handset that is said to be the iPhone 4S. Recently, we heard that the iPhone 5 will be delayed, due to design and production problems. However, it is said that millions of units of the iPhone 4S is rolling out of the production line. This means that might see Apple’s entry-level smartphone this October.
Now, Engadget reports that the iPhone 4S will definitely be coming soon. Their source sent them a screenshot showing AT&T’s system showing the “iPhone 4S White” on a dropdown menu. The screenshot shows the said smartphone below a list of already launched iOS-powered handsets.
Are there any legs to this rumor? Will we soon see the iPhone 4S in white? Of course, you should take this information with a grain of salt. We’ll keep you posted once we know more.


Elite residing house, in Vake, located at the round Garden. Built on the rock, 9-story residential building, with modern, sophisticated facade and with special effects glamorous blended to rounded located buildings.
The first floor of residential building will be devoted to commercial areas, from the elevation of land – on the 1th floor will be located the parking. The Common area of project is …….Totally, in the Building will be located 22 flats
GBG –offers to high quality service and original view for establishing your new life style.
- White Frame;
- Was built by brick and B25 Mark Concrete
- Underground parking;
- Natural gas, water, electricity, internet, cable TV;
- 1 (One) entrance;
- The elevator with European standards;
- High-quality aluminum doors and windows.
- Completed facade;
- Ceiling height of 3.1M


text:
The City of Vancouver was hit by a disturbing statistic this month, when figures were released showing a 249-per-cent increase in unsheltered homelessness from figures produced in 2011.
The increase from 2011 took a huge spike this past year when numbers rose from 273 to over 500 individuals living on Vancouver’s streets.
Despite increased efforts by the provincial and municipal governments, more and more people in Vancouver are being denied the simple human right for shelter.
For our city to truly advance, we must increase the care offered to our most vulnerable citizens. Only then can we sit back and enjoy our laurels.
Here are three ways ordinary Vancouverites can help tackle homelessness:
1. Volunteer at a Shelter
Many homeless choose the streets over shelters because of the conditions of social housing. Volunteers are needed to help raise the standards of living at shelters across the Lower Mainland. To find a shelter that needs volunteers in your area, visit the Greater Vancouver Shelter Strategy website.
2. Financial Assistance
The Lookout Emergency Aid Society offers programs for Vancouver citizens to subsidize rent costs for the homeless. Their packages range from $75 to $300 per month. These programs help house individuals who are looking to move out of the Downtown Eastside.
3. Express Your Opinions
Inform your MLA that this is a problem that concerns everyone living in Vancouver, not just the people living without a home. A minimum wage increase and additional social housing projects are two of the ways the government can help. They need to be reminded that the public is behind these initiatives.

domain: sociology


text:
(MENAFN- Asia Times)
The oldest temple in the world has been accorded special protection by the United Nations.
The 11,000-year-old temple site in Turkey's southeastern Anatolia region was granted UNESCO World Heritage status on Sunday, the UN agency announced at a meeting in Manama, the Bahraini capital.
The daily<> Must-reads from across Asia - directly to your inbox
Located in what was once known as Upper Mesopotamia, Gobekli Tepe (Potbelly Hill) is the world's oldest known megalithic structure.
The site in the southeastern province of Sanliurfa was reopened to tourists earlier this year after restoration work was completed.
The site contains "monumental circular and rectangular megalithic structures, interpreted as enclosures, which were erected by hunter-gatherers in the Pre-Pottery Neolithic age between 9,600 and 8,200 BC," UNESCO said in a statement.
"It is likely that these monuments were used in connection with rituals, probably of a funerary nature."
<> <> <> <> Culture archaeology heritage Turkey UNESCO World Heritage Gobekli Tepe Anatolia Sanliurfa tourism Comments
MENAFN provides the information “as is” without warranty of any kind. We do not accept any responsibility or liability for the accuracy, content, images, videos, licenses, completeness, legality, or reliability of the information contained in this article. If you have any complaints or copyright issues related to this article, kindly contact the provider above.

domain: topicality


text:
Extended Abstracts from the Second Meeting of the Federation of European Societies of Neuropsychology, Amsterdan, Netherlands, 22–24 September, 2010View this Special Issue
M. Berlingeri, L. Sacheli, L. Danelli, F. Ferri, D. Traficante, S. Basilico, M. Sberna, R. Sterzi, G. Bottini, E. Paulesu, "Neurofunctional and Neuromorphological Evidence of the Lack of Compensation in Pathological Aging", Behavioural Neurology, vol. 23, Article ID 892373, 3 pages, 2010. https://doi.org/10.3233/BEN-2010-0290
Neurofunctional and Neuromorphological Evidence of the Lack of Compensation in Pathological Aging
This article has no abstract.
Copyright © 2010 Hindawi Publishing Corporation and the authors. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

domain: library


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Established in 1996, Izmir Shipyard is a builder with a focus on high performance vessels of Aluminium or HDPE construction. Stock designs include patrol boats, pilot boats, workboats, and utility crafts for commercial and public customers. Over 50 vessels have already been delivered and SeaBoats are proud to market them all over the world. IZ 1500 AL is a Patrol Boat jointly developed by Izmir Shipyard in cooperation with KND Naval Design (South Africa) , and we have one unit under construction with a delivery time of just 20 weeks from order. This is a very efficient vessel, with speeds abo... read more


(New Book) An account edited by Siegfried Hecker, Doomed to Cooperate tells the story of the collaboration through the words of American and Russian scientists who traveled to each other’s nuclear complexes to work together within the individual bounds of nuclear secrecy. The content reveals not only the scientific endeavors and benefits of strengthened nuclear safety and security in Russia and worldwide, but also the intensity, emotion, friendships, and sometimes humor that resulted. Published in a two-volume set, Doomed to Cooperate is a reading experience.
Known familiarly as lab-to-lab collaboration, the idea germinated with the joint verification experiments that followed the Reagan-Gorbachev summit in Reykjavik in 1986. Soviet and American nuclear scientists came together to monitor a nuclear test at the Nevada Test Site in 1988. This was followed by a second verification test at Semipalatinsk in the Soviet Union. The reciprocal verifications allowed the United States and the Soviet Union to ratify a treaty banning the testing of nuclear weapons of yields greater than 150 kilotons. The Threshold Nuclear Test Ban Treaty had been signed in 1974 but never ratified until joint verification became a reality. While each side was eager to share the other’s scientific and technical knowledge, the personal communication and respect that developed was of equal importance. […]
Read More | Contents of Volume One | Contents of Volume Two
See contributions by PONARS Eurasia member Alla Kassianova.


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Michael showalter on sex and the city in Gloucester
Funny Pantswas published in February The State. Films directed by Michael Showalter. Cahill, best known for his role as Tag, Rachel's assistant-turned-boyfriend on "Friends," is said bisexual boyfriend. Carrie ends up ditching him at a party. Advertisement - Continue Reading Below.
It doesn't get more New York than that.
Cahill, best known for his role as Tag, Rachel's assistant-turned-boyfriend on "Friends," is said bisexual boyfriend. Michael Showalter, famous for his role in "Wet Hot American Summer," had the rough task of defending Berger's infamous breakup Post-it. Matthew McConaughey played a fictionalized version of himself.
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Luca Calvani as O's assistant. Alan Cumming as O. Certified Fresh Pick. Email address. I've brought this up to friends of mine who love the show.
Michael Showalter born June 17, is an American comedian, actor, director, writer, and producer. A member of the sketch comedy trio Stella , he first came to recognition as a cast member on MTV's The State , which aired from to
Michael Showalter is a writer, director and comedian living with his wife and their cats in Brooklyn, NY. He co-wrote and co-starred in the cult film Wet Hot American Summer and is one-third of the comedy trio Stella ,which had a critically….
Check out our list of the month's most anticipated films and shows to stream from home. Watch the video.
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Michael Showalter born June 17, is an American comedian, actor, director, writer, and producer.
During the late '80s, he joined a New York-based comedy troupe which formed the basis for a hilarious sketch-comedy show called The State. Although many episodes were created, only 26 aired on MTV.
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Justin Theroux played two different characters Miranda has a really hard time getting over her breakup with Steve, but when she meets Robert, it seems like she might have found her perfect match. For those staunch SATC defenders out there, who will view any negative criticism as proof of my hater status or some agenda to look cool in front of my "bros," you should know that I unabashedly love Miley's new album and HBO's Girls , and I have watched the "Roar" music video like a dozen times.
It doesn't get more New York than that. My male hipster friend tells me that they don't count as skinny jeans unless they are flush against his thigh. Moments that might make one question the show's female empowerment objectives:.
Michael showalter on sex and the city in Gloucester
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Jason Lewis Jerry 'Smith' Jerrod. Michael Showalter Billy. Brent Crawford Peter. David Wilson Barnes Andrew. Gabe Doran Frankie. La La Anthony. Michael Showalter (playing Berger's best friend) stares blankly as Carrie implodes while attempting to describe how modern women never.
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Michael Showalter, Writer: Wet Hot American Summer. Michael Showalter is a director, writer, and producer who most recently directed the hit The Big Sick. Previously he directed and co-wrote the film Hello, My Name Is Doris starring Sally Field. Michael's first film was the The Baxter () starring Michelle Williams and Justin Theroux. Michael is a co-creator of the critically. Michael Showalter (born June 17, ) is an American comedian, actor, director, writer, and producer. A member of the sketch comedy trio Stella, he first came to recognition as a cast member on MTV's The State, which aired from to He and David Wain created the Wet Hot American Summer franchise, with Showalter co-writing and starring in Wet Hot American Summer (), and the Netflix Born: June 17, (age 50), Princeton, New Jersey, U.S.
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Michael Showalter (born June 17, ) is an American comedian, actor, director, writer, and , Sex and the City, Billy, Episode: "The Post-It Always Sticks Twice". –, The Wrong Coast, Writer. –, Cheap Seats, Ron. Throughout its 94 episodes across six seasons, "Sex and the City" Michael Showalter, famous for his role in "Wet Hot American Summer,".
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It's directed by Michael Showalter, who co-created the “Wet Hot American reality series set in and off the coast of Gloucester before the pandemic shut Thursday at 9 p.m., is hosted by Kristin Davis from “Sex and the City.”. Oil City Confidential is a music film about Dr Feelgood, Wilko Johnson, Lee In this comedy directed by and starring Michael Showalter, Elliot is a man who is The Opposite Sex and How to Live with Them See Movie, Movie Tv.
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Bena, Wa BUBAN, MICHAEL E P - PERTH AMBOY | W | Salisbury, Mass PACKARD HAROLDE Gloucester M. - Gas BUD 5 5, ,0| S Houston, sex – BAYOU CITY BARGE LINES INC no Houston TX - BUD SHOWALTER, W RAYMOND JR washington D Gloucester, UK: Peter Smith, Scott, Gilbert. Showalter, Elaine. Sexual Anarchy: Gender and Culture at the Fin-de-Siècle. “Tradition and Revision: The Classic City Novel and Virginia Woolf's Night and Day. Ed. Michael Holroyd.
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domain: entertainment


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Handling Insurance Disputes And Bad Faith Cases
Insurance companies are long on happy slogans but infamous for denying or short-changing claims when the people they insure actually invoke the policy. If the insurer is relying on technicalities or deceit to refuse coverage, you may have grounds to sue them for bad faith insurance denial.
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domain: law


Necessary pruning should be done as soon as can be managed. When pruning large amounts of foliage or more than one third the crown mass, pruning should be avoided during the dry hot months. Dead and diseased wood can be removed anytime. The best time to prune is when the tree or shrub is dormant, usually in the winter months.
The images above show the proper way to prune. Images provided courtesy of the Virginia Cooperative Extension Service.
TO PRUNE OR NOT TO PRUNE
Is There A Question?
Shedding or self-pruning is a natural process in which trees and shrubs minimize disease and promote vigor. This occurs when leaves, twigs and branches die, decay and detach from the living tree. Trees identify weak and dying branches and begin the shedding process by walling off the diseased limb. Rot inhibiting cells contain and separate diseased wood from healthy wood. Walled off tree parts are deprived of food and eventually wither and die. The “Containment of Disease in Trees,” or CODIT, was first discovered by Alex Shigo and is the principal behind the “New Tree Biology” employed today. Selective pruning compliments the shedding process to promote healing and renewed vigor in trees and shrubs.
How Do I Decide What To Prune?
Understanding arboriculture is helpful, however, simply follow this priority of pruning and your tree will be grateful.
A) Dead and dying limbs
B) Broken limbs
C) Rubbing and diseased limbs
D) In growing, crossing and suppressed branches
E) Congested or crowded branches
Avoid removing more than one third of the crown mass and please do not top off branches leaving unhealthy stubs.
What is A Proper Pruning Cut?
Make pruning cuts like those illustrated above. And remember when reducing tree size or heading back branches always prune back to a healthy lateral branch and avoid pruning back to a branch smaller than one third the size in diameter of the branch being removed.


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domain: painting


Client: Cerionx/IonField Systems
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The Tip Charger uses plasma technology to sterilize pipette tips in the pharmaceutical laboratory. Phase One Design first designed the pump and filter approaches for the cooling and exhaust functions and then created the overall product configuration based on manufacturing, assembly, service, and ergonomic concerns. We developed the apperance design, detailed all molded, machined, and fabricated parts, and managed the prototyping process for Cerionx.


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PG&E safety work causes natural gas odor in Oakley, Antioch
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Younus, Mohammad (1968) The place of agricultural development in the economic development of Pakistan. Masters thesis, Durham University.
The topic studied in this thesis seeks to explain that in Pakistan the over all economic growth rate is very much correlated with the agricultural growth rate. Therefore, integrated development efforts necessarily mean the transformation of the massive sector like agriculture. The first three chapters deal with the basic problems of population growth and per capita supply of food, the problems of capital formation in the agricultural sector and agricultural taxation. The study of these problems reveal that since a check on population is not possible in the short run, the supply of food requires to be boosted to match the population growth rate. To elevate the agricultural sector" from desperate poverty two methods have been suggested: i) use of surplus labour for capital formation; and (ii) increased rate of selective agricultural taxation. In chapter four the problems of labour redundancy are studied and it is found that land-labour ratio is very low in Pakistan, largely due to disguised unemployment. Under these conditions major technological change is not possible as this would mean a partial replacement of agricultural labour by capital. The labour absorptive capacity of all other sectors is low because of the fact that capital intensity for all other sectors is high compared to the agricultural sector. Therefore, the absorptive capacity of the agricultural sector itself will have to be enlarged by more intensive cultivation. In the fifth chapter the dualistic growth model and the impact of agriculture on industrialisation is examined. It is concluded that for an expansion in the industrial sector, the expansion of the agricultural sector is essential. An expanded agricultural sector would not only supply cheap food to the industrial sector, but it may also earn much needed foreign exchange for development imports and increased effective demand would also be forthcoming from this sector. In the sixth chapter the importance of agricultural sector is studied in the context of previous chapters and it is clear that agriculturalists in Pakistan are quite responsive to technical change and even to prices and profitability. The speedy transformation of the agricultural sector not only requires the building of an adequate infrastructure but also an improvement in the supply factors. In this connection, keeping in view the fact that capital is a scarce factor in underdeveloped countries; a single factor development approach has been suggested.
|Item Type:||Thesis (Masters)|
|Award:||Master of Arts|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||14 Mar 2014 16:43|

domain: agronomy


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