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The maintenance of glucose homeostasis during pregnancy is critical to the health and well-being of both the mother and the developing fetus. Strikingly, approximately 7% of human pregnancies are characterized by insufficient insulin production or signaling, resulting in gestational diabetes mellitus (GDM). In addition to the acute health concerns of hyperglycemia, women diagnosed with GDM during pregnancy have an increased incidence of complications during pregnancy as well as an increased risk of developing type 2 diabetes (T2D) later in life. Furthermore, children born to mothers diagnosed with GDM have increased incidence of perinatal complications, including hypoglycemia, respiratory distress syndrome, and macrosomia, as well as an increased risk of being obese or developing T2D as adults. No single environmental or genetic factor is solely responsible for the disease; instead, a variety of risk factors, including weight, ethnicity, genetics, and family history, contribute to the likelihood of developing GDM, making the generation of animal models that fully recapitulate the disease difficult. Here, we discuss and critique the various animal models that have been generated to better understand the etiology of diabetes during pregnancy and its physiological impacts on both the mother and the fetus. Strategies utilized are diverse in nature and include the use of surgical manipulation, pharmacological treatment, nutritional manipulation, and genetic approaches in a variety of animal models. Continued development of animal models of GDM is essential for understanding the consequences of this disease as well as providing insights into potential treatments and preventative measures.
- gestational diabetes mellitus
- pregnancy
- β-cell
- hyperplasia
- hypertrophy
- glucose-stimulated insulin secretion
the failure of sufficient insulin production or signaling during pregnancy results in gestational diabetes mellitus (GDM), a condition affecting approximately 7% of all pregnancies in the United States (3). GDM is defined as diabetes appearing specifically during pregnancy, typically during the second trimester, as women diagnosed with GDM show no signs of diabetes prior to the pregnancy (80). While 3–5% of GDM patients remain diabetic post-pregnancy, most women regain euglycemia following parturition (29). Risk factors for GDM include a family history of type 2 diabetes (T2D), obesity, and certain ethnic backgrounds, including Asian and Hispanic (13, 89). While abnormal glucose homeostasis has immediate health concerns for a pregnant woman, it is the long-term health consequences that often prove the most deleterious. Women diagnosed with GDM are six times more likely to develop T2D later in life than women who maintain normal blood glucose levels during pregnancy (10). Other maternal health concerns have also been associated with GDM, including preeclampsia and increased probability of cesarean section (80). Children born to mothers with GDM have an increased risk of developing perinatal hypoglycemia, hypocalcemia, polycythemia, jaundice, respiratory distress syndrome, and macrosomia and have an increased risk of obesity and T2D as adults (23, 80).
The transitory nature of GDM makes the study of its physiology in humans difficult, since by definition the disease exists only during pregnancy. Study of pancreatic tissue from pregnant women with and without GDM would advance our understanding of the islet defects that contribute to the disease. However, the scarcity of post mortem tissue samples and the lack of imaging modalities to noninvasively measure β-cell mass in vivo hinder this process. For these reasons, animal models provide an attractive alternative to studying the mechanisms behind, and possible therapeutics for, GDM. In this review, we explore the various techniques and animal models that are currently available for the study of this disease, highlight their respective strengths and weaknesses, and discuss what these models reveal about the β-cell in GDM.
As is true with most biomedical research, many of the animal models for GDM utilize either mice or rats; thus, rodent models will be the primary focus of this review. However, other vertebrates, including dogs, pigs, sheep, and nonhuman primates, have been used in the study of GDM, and these models will also be discussed when appropriate.
Finally, many models of diabetes during pregnancy are often more appropriate for studying the health consequences of hyperglycemia on the offspring of mothers with GDM rather than the physiology of GDM itself. In this review, we emphasize the utility of animal models that focus on the maternal aspects of GDM, in order to better understand the etiology and effects of the disease in human patients.
Relevance of Animal models to Human GDM
In humans, pregnancy is accompanied by a variety of maternal hormonal and metabolic changes that allow for optimal fetal growth. Global hormonal changes, including increased production of prolactin and placental lactogen, decrease maternal insulin sensitivity, thus ensuring sufficient amounts of glucose crossing the placenta to nourish the developing fetus. Maternal glucose production is also increased via gluconeogenesis and glycogenolysis in order to increase available energy stores. Likewise, late pregnancy is characterized by increased plasma concentrations of free fatty acids (FFA) (81). While increased FFA serve as a supplemental energy source, they also contribute to the increase in insulin resistance associated with pregnancy (99).
Alterations in glucose production and insulin sensitivity during pregnancy necessitate compensatory actions in order to maintain maternal euglycemia. Research using a variety of animal models indicates that one of the most important determinants of euglycemia during pregnancy is achieved through physiological changes in the maternal pancreatic β-cell. Notably, these changes include increased β-cell mass via proliferation and hypertrophy, increased insulin production, and enhanced glucose-stimulated insulin secretion (GSIS) (Fig. 1) (77, 78, 108). These adaptations are not uniform throughout pregnancy, however, as increased β-cell replication, β-cell size, and GSIS peak midway through gestation and return to pregestational levels close to parturition. Although these events are firmly established in rodents, the compensatory changes that occur in the human β-cell during pregnancy remain much more controversial. An early report concluded that pregnancy was accompanied by a more than twofold increase in the fraction of pancreas occupied by β-cells (103). This finding makes it tempting to speculate that rodents and humans have similar mechanisms to maintain glucose homeostasis during pregnancy. In contrast, a more recent study found a more modest increase in β-cell mass expansion during human pregnancy, with only an approximately 1.4-fold increase in volume density of β-cells, and no evidence of the increased β-cell replication and size that has been documented in pregnant rodents (6). Due to the scarcity of subjects, both studies included samples from women of varying age and at different stages of pregnancy. In addition, the cause of death for the pregnant women in these studies varied and included accidental death and death from diseases, some of which were inflammatory in nature. These confounding variables make direct measurements of changes in β-cell mass during human pregnancy difficult, as age, gestational stage, and disease all affect β-cell mass and function.
Admittedly, factors not directly related to the β-cell may influence the development of GDM in humans, but current animal models and genome-wide association studies indicate that loss of proper β-cell function is the single largest determinant in pathogenesis of the disease.
Diagnosing GDM
Currently, the diagnostic criterion for GDM is somewhat controversial. Using classic diagnostic standards, abnormally high blood glucose levels on a 1-h 50-g oral glucose tolerance test (OGTT) would be followed by a 2-h 75-g or a 3-h 100-g OGTT test (Table 1) (65, 74, 80). Two or more abnormal values on the follow-up test would be indicative of GDM. In contrast, guidelines laid forth in 2010 by the International Association of Diabetes and Pregnancy Study Groups (IADPSG) recommend a diagnosis of GDM if any one of three blood glucose levels is abnormally high on a 2-h 75-g OGTT (Table 2) (66). The American Diabetes Association (ADA) has already adopted this diagnostic standard, and if adopted by physicians nationwide, the IADPSG guidelines will create a dramatic rise in GDM diagnoses, with some estimates placing it as high as one in five pregnancies (60). While it is beyond the scope of this article to comment on which diagnostic criteria should be used in human patients, anyone interested in studying GDM using animal models should carefully decide on diagnostic criteria that are appropriate for their selected model before initiating any studies.
Surgical Models to Study Diabetes During Pregnancy
As endocrine pancreas function is the single most important determinant of glucose homeostasis, it is unsurprising that surgical reduction (partial pancreatectomy; Ppx) of this organ is arguably the most direct way to induce diabetes during pregnancy in animal models. Ppx results in dramatic reduction in the insulin-producing β-cells (as well as all other pancreatic cell types) and, as a consequence, impairs the ability of the body to regulate glucose homeostasis. In the early 20th Century, total pancreatectomy was employed in dogs both before and during various stages of pregnancy (9 wk gestation) to induce diabetic symptoms. While these early reports pioneered research in diabetes and pregnancy, they often proved contradictory. For example, Markowitz and Soskin (62) reported that total pancreatectomy in the dog during advanced stages of pregnancy resulted in hyperglycemia and glycosuria within days, while Carlson and Drennan noted an absence of glycosuria after performing a similar operation (8). Others performed Ppx prior to pregnancy and reported the presence of glycosuria during early gestation, which lessened as the pregnancy progressed (12). However, as is true for similar studies at that time, glucose homeostasis in pancreatectomized nonpregnant controls was not reported, making uncertain whether pregnancy exacerbated, ameliorated, or had no effect on the diabetic phenotypes. Other caveats to these studies include the very small sample sizes (typically 1–3 dogs) used in these experiments as well as administration of exogenous insulin to varying degrees to keep the dogs healthy and allow the pregnancy to come to term, complicating analysis of diabetic phenotypes. These early experiments were less than ideal for other reasons, since maternal death and spontaneous abortion proved a common occurrence within days after the procedure.
Although Ppx is not commonly used in rodent models of GDM, one report used a 95% Ppx technique to induce diabetes in rats prior to pregnancy (42). Once diabetes was confirmed with measurement of elevated blood glucose, Ppx female rats were mated to control males to induce pregnancy. This strategy was used to determine whether the uterus of pregnant rats was affected by diabetes. In those studies, production of secreted pro- and anti-vasoconstrictive signaling molecules was significantly altered compared with controls, as demonstrated by an increase in thromboxane and a corresponding decrease in prostacyclin. These findings support the notion that the intrauterine environment is altered in pregnant diabetic women, potentially affecting fetal development and contributing to the increased health risks of children born to mothers with GDM. However, the utility of this model is unclear, as diabetes took up to three months to develop, in contrast to other published studies, where 90% Ppx resulted in overt diabetes within two weeks of the procedure (98).
Although Ppx can successfully result in diabetes during pregnancy, the procedure is nonspecific in its actions, removing both endocrine and exocrine tissue. Surgery also results in inflammation, and other changes in the pancreatic microenvironment not necessarily related to diabetes, including upregulation of growth factors such as EGF, that facilitate mild pancreatic regeneration following the procedure (36, 71). Furthermore, human GDM is a spontaneous event that is caused by a combination of both genetic and environmental factors, not a disease that occurs due to a sudden insult to the pancreas. As such, Ppx is not a true model of GDM and does not accurately reflect the etiology of the disease. Rather, it is more useful for studying fetal outcomes of diabetic mothers and changes in the uterine environment that accompanies diabetes during pregnancy.
Although rarely employed in the context of pregnancy, Ppx does induce diabetes in a variety of other animals, including pigs, sheep, and nonhuman primates (28, 41, 55). Despite the drawbacks mentioned previously, for model organisms in which genetic or drug-induced GDM are either not practical or possible, Ppx remains a viable option for study of the effects of diabetes during pregnancy on maternal health and the subsequent health of the offspring.
Chemical Models To Study Diabetes During Pregnancy
A variety of chemicals are currently available that either result in the death of insulin-producing β-cells or otherwise impair β-cell function. As a result, these drugs can be used to disrupt glucose homeostasis in a time-dependent manner, including during pregnancy. In this section, we will discuss some of the more common drugs that have been used to generate animal models to study diabetes during pregnancy.
One of the most widely used diabetogenic drugs is streptozotocin (STZ), a glucosamine-nitrosurea compound that selectively kills β-cells after being transported into the cells through the GLUT2 transporter (92). As an alkylating agent, it causes cell death largely through DNA damage, ultimately leading to necrosis and/or apoptosis (2, 72, 91). Susceptibility to STZ and the amount of time required to induce diabetes are subject to a variety of factors, including species, strain, age, sex, and dose (7, 61, 87, 106). As such, no universally agreed-upon protocol and dosing strategy exists for its use. Thus, a protocol for STZ-mediated induction of diabetes needs to be determined empirically after a consultation of the published literature.
In rodents, the timing of STZ administration to induce diabetes during pregnancy varies, with some researchers administering the drug before pregnancy, some treating with STZ immediately after successful mating, and others treating in the last week of gestation (1, 63, 94). While induction before pregnancy may be preferred so as to avoid potential toxic effects on the embryos, STZ administration before pregnancy adversely affects mating behavior, at least in part due to the diabetic phenotypes it produces (104). STZ can cross the placenta, but its short half-life of less than five minutes makes it unlikely to affect the earliest stages of embryonic development (84, 90). Furthermore, by the last week of pregnancy in rats and mice, maternal β-cell size and replication are already beginning to return to pre-pregnancy status; thus, STZ administration at this late time point does not really interrogate the β-cell compensatory mechanisms and physiology that underlie GDM (78, 85). STZ treatment late in gestation also risks harming the developing fetal β-cells, since GLUT2 expression increases during late gestation in preparation for birth (76). For these reasons, STZ administration on the day of successful mating is often the preferred time point.
Rats and mice remain the most common models for STZ-based studies of diabetes during pregnancy, but larger animals have been successfully used as well. Pigs, sheep, and nonhuman primates are each susceptible to STZ-induced diabetes and have been used to study how diabetes during pregnancy affects growth and metabolism of the mother and fetus (17, 18, 21, 50). Not surprisingly, studies in larger animals, although potentially more relevant to human physiology, are more limited due to the increased cost of studying large cohorts.
Alloxan, a pyrimidine derivative, is used with similar success to STZ to induce diabetes in pregnant animals (58). Originally derived in the first half of the 19th Century during an investigation into the chemical nature of uric acid, alloxan was not widely known to be diabetogenic until 1943 when it was reported to cause β-cell death after injection into rabbits (20). Like STZ, alloxan is transported into β-cells through the GLUT2 transporter (31). Once in the cytosol, alloxan induces reactive oxygen species (ROS) formation, resulting in β-cell necrosis and consequent disruption of normal glucose homeostasis (11). The dosage of alloxan necessary to induce diabetes, as well as the physiological outcomes, is affected by extraneous factors, including species, age, diet, and gestational time point of administration (16, 47, 57, 100). Even the method of delivery can affect alloxan's diabetogenic properties in certain species, as alloxan injection directly into the pancreas of the guinea pig causes β-cell death, whereas systemic administration had less effect on β-cell viability (32).
Chemical destruction of β-cells confers the advantage of rapidly inducing diabetes, with elevated blood glucose evident within two days of STZ administration in rodents (101). Although alloxan was established as a diabetogenic drug before STZ, the latter remains the method of choice for many laboratories. This is at least in part due to the higher mortality rate and nephrotoxicity attributed to alloxan (5, 37). Likewise, alloxan has a circulating half-life of less than three minutes after intravenous injection, almost half that of STZ, making proper dosing more challenging (105). Despite these caveats, alloxan has also proved effective in generating models of diabetes during pregnancy in a wide variety of species, including mice, rats, rabbits, pigs, and sheep (27, 67, 83, 102, 112).
Similarly to Ppx, STZ or alloxan administration in adult animals creates a permanent state of diabetes through widespread destruction of β-cells. This results in a different physiological state than GDM, where the disease is a result of maternal insulin resistance and/or deficiency. The permanent nature of the STZ/alloxan treatment, and the lack of extensive pancreatic regeneration in treated adults, also means that the animal will remain diabetic after parturition, in contrast to GDM patients, where glucose homeostasis typically returns to pregestational levels. It is most likely for these reasons that STZ/alloxan-based models often do not recapitulate many of the clinical outcomes of GDM, including macrosomia (26). For these reasons, STZ- and alloxan-based GDM models are useful for studying how diabetes during pregnancy affects fetal development but less so in studying the pathogenesis of GDM itself.
Additionally, STZ/alloxan-induced models of diabetes during pregnancy often result in severe elevation of blood glucose, whereas GDM is characterized by more mild glucose intolerance (61). While islet transplants into STZ-treated mice can ameliorate the extreme elevation in blood glucose, the procedure naturally increases the difficulty and cost of the model (88). Thus, both surgical and chemical induction can be used to assess the consequences of hyperglycemia on mother and offspring but do not truly mimic human GDM.
Nutritional Manipulation to Induce GDM
Obesity and high-fat diet (HFD) are known risk factors for GDM among pregnant women across various ethnic backgrounds. As the ability of HFD to disrupt β-cell function and confer insulin resistance and diabetes is also a well-established phenomenon in animal models, several models of GDM have been created using high-fat feeding in pregnant animals. Holemans et al. (38) demonstrated that virgin female rats maintained on a HFD became obese after four weeks but displayed normal glucose clearance in response to a glucose challenge. In contrast, after successful mating and maintenance on the HFD, an overt GDM phenotype was present by the end of gestation (gestational day 20), as demonstrated by significantly elevated glucose levels in an intravenous glucose tolerance test (IVGTT). Seemingly, HFD before pregnancy primed the females for a diabetic state during gestation. It is unclear how long it takes GDM to develop in this model, since glucose challenges earlier in gestation were not reported. Maternal overnutrition in rats has also been achieved through glucose infusions directly into pregnant dams. Gauguier et al. (25)induced hyperglycemia and hyperinsulinemia through continuous glucose infusions during the last week of pregnancy and observed that the offspring born to these mothers displayed impaired insulin secretion and glucose intolerance as adults, replicating the finding that human children born to GDM mothers are more likely to develop T2D.
HFD treatment has also been carried out in mice to examine maternal pathologies during GDM that may affect fetal outcomes. Liang et al. (59) placed mice on a HFD initiated one month before pregnancy and continued throughout gestation. In agreement with other HFD models, the treatment resulted in elevated blood glucose and insulin levels during pregnancy. Significantly, HFD also caused placental pathologies, including endothelial cell damage due to oxidative stress, and loss of embryo-nourishing trophoblast cells. While fetal outcomes were not reported in this publication, it highlights the changes in the placenta that occur during GDM that have the potential to affect offspring health. However, in this model, elevated blood glucose and insulin levels were observed before onset of pregnancy, and thus this model does not accurately represent most cases of the human disease.
While rodents are widely used in the study of GDM, HFD has also been used to induce GDM in larger model organisms. One such study placed ewes on an obesogenic diet from 60 days prior to mating until gestational day 75, the time point halfway through the approximately 147-day pregnancy of sheep (22). At gestational day 75, pregnant ewes fed the obesogenic diet displayed insulin resistance and increased circulating glucose. Fetuses showed an increase in pancreatic weight as a percentage of fetal weight, a significant increase in β-cell area, and a significant increase in proliferating β-cells. The authors speculated that physiological changes during development could contribute to premature β-cell dysfunction later in the life of the offspring, ultimately resulting in increased disposition to obesity and diabetes.
HFD has also proven successful in generating GDM models in dogs (70). Pregnant dogs placed on a high-fat, high-fructose diet starting approximately halfway through their nine-week pregnancy displayed impaired glucose clearance by the seventh week of pregnancy as determined by an OGTT. Despite these advantages, a HFD model of GDM does not take into account the strong impact genetic background plays in disease. Furthermore, all HFD-based models of GDM create a condition similar to T2D, where peripheral insulin resistance and increased adiposity are strong drives of disease. While some patients may present with GDM due to preexisting obesity, many manifest with the disease despite being lean prior to pregnancy. For example, one study found that the fraction of GDM cases attributable to obesity was only 15.1% among Asians/Pacific Islanders (53).
Notably, diet-based GDM models confer several advantages over other models of the disease. Most importantly, obesity is a known contributor to the development of GDM in human patients. Furthermore, HFD-based models have been successfully used to study both the etiology and the pathology of GDM in maternal tissue as well as the health consequences on fetal offspring of diabetic mothers. In larger models such as sheep, they also allow the study of GDM in an animal with a more comparable body mass to humans than rodents and also share the human trait of being generally monotocous. Additionally, like surgically induced models of diabetes during pregnancy, they allow the study of GDM in animals where genetic manipulation is not available and/or practical but have a significant advantage over surgical models by not requiring expertise in difficult surgical procedures or causing significant mortality issues.
Genetic Models of GDM
Genetic susceptibility is a critical factor in the development of diabetes, and numerous mutant rodent lines are available that display diabetic phenotypes during pregnancy (Table 3). While many of these models have contributed to our understanding of how diabetes affects both maternal and fetal health, the overwhelming majority of these mutants display severe glucose intolerance even in a nonpregnant state, thus limiting their use as an accurate model of human GDM. In this section, we discuss several mutant and transgenic mouse models where pronounced diabetic phenotypes develop as a result of pregnancy and are thus excellent models for studying the maternal pathogenesis and etiology of GDM.
Genetic manipulation of cellular receptors to induce GDM.
The db/db mouse is a classic model for the study of obesity and diabetes (40). These mice are mutant for the leptin receptor (ObR), a member of the cytokine receptor family, and are characterized by an inability to adequately suppress feeding behavior (9). As a result, they become morbidly obese and develop T2D. db/db females are sterile (44). In contrast, females heterozygous for the mutant allele (db/+) are fertile, do not display perturbed glucose homeostasis in the nonpregnant state, and show normal fasting serum glucose and insulin levels (48). However, during pregnancy, db/+ females display hyperphagic feeding behavior and increased adiposity, contributing to the development of insulin resistance and a GDM phenotype characterized by moderate glucose intolerance (48, 110, 111). Offspring of db/+ mothers also show characteristics commonly reported for infants of GDM mothers, including macrosomia, regardless of fetal genotype (48). ObR has a direct role in islet growth in addition to its important role in satiety. Conditional loss of the leptin receptor from β-cells resulted in impaired glucose homeostasis in mice fed a HFD compared with weight-matched controls despite no change in food intake. This finding raises the possibility that ObR also has a direct role in β-cell development or growth during pregnancy, but this possibility has yet to be thoroughly explored, and it is complicated by the fact that in this model ObR was also deleted from parts of the hypothalamus. The GDM phenotype of the db/+ mouse makes it one of the first truly accurate genetic mimics of human GDM in which the diabetic phenotype is not present in healthy nonpregnant animals. Additionally, this model is useful for studying both the pathogenesis of GDM and the health consequences of children born to GDM mothers.
Genetic mouse models of GDM can also be generated as a direct result of defects in the β-cell to appropriately respond to pregnancy hormones. A notable example of this includes mice deficient for the prolactin receptor (PrlR), another member of the cytokine receptor family (49). Increased production of prolactin is one of many physiological changes that occur maternally during pregnancy in both rodents and humans. A key consequence of elevated prolactin is increased β-cell proliferation through PrlR signaling mediated by Jak2/Stat5 activation (24, 39). While homozygous PrlR mutants (PrlR−/−) are unable to carry pregnancy to term, heterozygous PrlR (PrlR+/−) females are fertile. In a nonpregnant state, PrlR+/− females display a decrease in islet mass (possibly reflecting developmental abnormalities) compared with controls but maintain euglycemia. During pregnancy, PrlR+/− females display moderate glucose intolerance and fail to upregulate β-cell proliferation. This mouse model provides in vivo evidence for the importance of prolactin signaling in β-cell adaptation to pregnancy, and suggests that failure of maternal prolactin signaling could be a contributing factor to the development of GDM. Such speculation was validated when an association between polymorphisms in the 5′-UTR and promoter region of the human PRLR gene and GDM was found in a population of Chilean patients (56).
Other cellular receptors have also been implicated in β-cell adaptation during pregnancy and as such can be manipulated to create GDM models. Among these factors are c-Met, a tyrosine kinase receptor that promotes β-cell proliferation and survivability when stimulated by hepatocyte growth factor (HGF) (15). During pregnancy, expression of HGF and c-Met is upregulated in the maternal pancreatic endothelial cells of the blood vessels and the β-cells, respectively (15, 43). In conditional knockout mice lacking c-Met in the pancreas (PancMet KO), normal glucose homeostasis and normal islet architecture is observed in virgin females, indicating that c-Met is not necessary for β-cell development during embryogenesis (15). However, by gestational day 15, PancMet KO females have a significant decrease in β-cell mass compared with controls, and the mice display mild glucose intolerance, as determined by intraperitoneal glucose tolerance test (IPGTT). These phenotypes were accompanied by a decrease in PrlR expression and a decrease in Stat5 localization to the nuclei of β-cells. As PrlR-induced Stat5 dimerization and nuclear localization is a critical event in β-cell expansion during pregnancy, the authors speculate that this process may be regulated by HGF/c-Met signaling (4).
Genetic manipulation of serotonin signaling to induce GDM.
In addition to prolactin and HGF, other secreted factors are associated with β-cell expansion during pregnancy. Circulating maternal prolactin and placental lactogen during pregnancy induce expression of the enzymes tryptophan hydroxylase-1 (Tph1) and tryptophan hydroxylase-2 (Tph2), and the 5-hydroxytryptamine (serotonin) receptor 2B (5Htr2b) in β-cells by signaling through phosphorylated Stat5 (52, 93). Tph1 drives serotonin synthesis in β-cells, which signals in an autocrine/paracrine fashion to increase β-cell mass expansion through 5Htr2b. Interruption of this pathway can result in insufficient β-cell mass expansion during pregnancy and GDM. In mice, Kim et al. (52) showed that female Htr2b KO mice (Htr2b−/−) are euglycemic as virgins but develop moderate glucose intolerance by gestational day 13 as well as having a significant reduction in β-cell mass compared with pregnant controls. Pharmacological methods were also used to substantiate these genetic findings, including inhibition of serotonin signaling using p-chlorophenylalanine (PCPA), an inhibitor of Tph1, and the Htr2b antagonists SB-204741 and methysergide. The authors also used diet manipulation to inhibit serotonin signaling. Serotonin is generated from tryptophan in a multistep enzymatic process, and since tryptophan is an essential amino acid, rodents, humans, and many other animals must acquire it from their diet (69). Kim et al. took advantage of this fact to disrupt serotonin signaling by feeding pregnant mice a tryptophan-free diet from gestational days 6 to 12 (52). An IPGTT at gestational day 13 revealed severe glucose intolerance. Significantly, tryptophan deprivation did not have an effect on glucose homeostasis in virgin females.
While disruption of the serotonin signaling pathway has pronounced detrimental effects on maternal euglycemia, limitations with these models exist. A significant number of Htr2b−/− mice die embryonically due to defects in heart development, creating practical issues in generating the mice and demonstrating that loss of Htr2b results in a pleiotropic phenotype, limiting the utility of Htr2b−/− mice as a model for GDM (73). A conditional allele of Htr2b would circumvent these problems and potentially yield a more accurate model of human GDM, but it has yet to be reported. Although tryptophan deprivation induces GDM in rodents, it is not a suggested cause of the disease in humans. Tryptophan deficiency also produces a more extreme glucose intolerance phenotype than what is typically seen in human GDM patients.
Regardless of these limitations, it is clear that serotonin signaling is important in β-cells during pregnancy. Intriguingly, the use of selective serotonin reuptake inhibitors (SSRI) is linked to increased incidence of T2D in humans, arguing that disruptions of serotonin signaling can contribute to human diabetes (54, 75). The long-term consequences of such treatments to maternal and fetal health are currently unclear. One can speculate that such treatment would cause an increase in long-term GDM-associated phenotypes in treated females and their offspring; however, no such study has yet been conducted.
Genetic manipulation of nuclear factors to induce GDM.
Nuclear factors have also been manipulated to generate models of GDM. Menin is a tumor suppressor that forms a complex with myeloid/lymphoid or mixed-lineage leukemia 2 (MLL2) to regulate the latter's histone methyltransferase activity (46). This in turn inhibits cell proliferation through regulation of the cyclin-dependent kinase inhibitor p27. Karnik et al. (45) have shown that menin expression decreases in maternal β-cells during pregnancy, likely due to placental lactogen-induced inhibition of menin transcription by B-cell lymphoma 6 protein (Bcl-6). To determine whether menin downregulaton is essential for β-cell mass expansion during gestation, transgenic mice were generated that conditionally overexpressed menin in β-cells. These mice, referred to as βMen1 mice, displayed no changes in fasting glucose levels or glucose clearance in response to a glucose challenge as virgins. In contrast, pregnant βMen1 females developed hyperglycemia by gestational day 9, which continually worsened throughout gestation; however, even control females in that study displayed elevated blood glucose. After parturition, blood glucose returned to prepregnancy levels. BrdU labeling to mark proliferating cells indicated that βMen1 females have a deficiency in β-cell proliferation during pregnancy. Furthermore, β-cell mass was significantly reduced in pregnant βMen1 females compared with pregnant controls and was indistinguishable from β-cell mass in virgin βMen1 females.
There are also several transcription factors that affect β-cell proliferation during pregnancy. Hepatocyte nuclear factor 4α (HNF-4α) is expressed in α-cells and β-cells as well as nonpancreatic tissues. In β-cells, it induces expression of the Kir6.2 subunit of the ATP-sensitive potassium channel critical for GSIS (34, 68). Virgin female mice with a β-cell-specific knockout of HNF-4α (HNF-4αloxP/loxP; Ins.Cre) display mild glucose intolerance, with normal islet architecture and β-cell mass (33). However, during pregnancy, HNF-4αloxP/loxP; Ins.Cre females display a significant reduction in β-cell mass and proliferation compared with pregnant controls, indicating that HNF-4α is essential for pregnancy-induced hyperplasia, a critical adaptation for maintaining euglycemia during pregnancy. Pregnant HNF-4αloxP/loxP; Ins.Cre females also displayed reduced pancreatic insulin content and pronounced glucose intolerance. While the mild glucose intolerance prior to pregnancy may reflect a role for HNF-4α during normal β-cell development, it is clear from the lack of β-cell expansion during pregnancy that the gene is also necessary for the compensatory mechanisms in mice necessary to prevent GDM phenotypes. Among human patients, polymorphisms in HNF-4α are a known cause of maturity onset of diabetes of the young (MODY); however, a conclusive link to GDM has yet to be reported (96, 109).
Like HNF-4α, Forkhead box D3 (FoxD3) is a transcription factor expressed in the pancreatic islets in adult rodents (79). During pregnancy, placental lactogen signaling decreases FoxD3 expression in β-cells. Mice specifically lacking FoxD3 in β-cells (Foxd3fl/−; Pdx1-Cre) have decreased β-cell mass as virgins, indicative of a role of FoxD3 in normal β-cell development or growth. Despite this, virgin Foxd3fl/−; Pdx1-Cre females maintain euglycemia (82). In contrast, by gestational day 15.5, pregnant Foxd3fl/−; Pdx1-Cre dams have severe glucose intolerance and decreased serum insulin levels. Additionally, β-cell mass, proliferation, and size were all significantly decreased. Genes required for β-cell proliferation displayed misregulated expression in the islets of pregnant Foxd3fl/−; Pdx1-Cre females, including enhancer of zeste homolog 2 (Ezh2), which was significantly downregulated, and S-phase kinase-associated protein-2 (Skp2), which was significantly upregulated. Thus, despite the fact that FoxD3 expression is extinguished in β-cells during pregnancy, its function is required for normal β-cell compensation in pregnancy. These seemingly contradictory results suggest that FoxD3 expression in quiescent β-cells establishes a state in which genes necessary for β-cell compensation can be induced by other factors during pregnancy.
Forkhead box M1 (FoxM1) is another transcription factor involved in β-cell proliferation (113). During pregnancy, FoxM1 is induced by both PrlR- and c-Met-mediated signaling (15, 113). Our group has previously shown that mice with pancreas-specific inactivation of FoxM1 (FoxM1Δpanc) display increased menin and p27, which impairs postnatal β-cell proliferation and β-cell mass expansion (114). Despite this phenotype, FoxM1Δpanc females maintain glucose homeostasis as virgins, although males become diabetic by nine weeks of age. By gestational day 12.5, females show mild glucose intolerance that worsens as gestation progress. FoxM1Δpanc females show no induction of maternal β-cell proliferation and no increase in β-cell mass during pregnancy, contributing to the GDM phenotype.
The list of genetic models available for the study of GDM continues to grow. Each of these animals provides valuable insights into the mechanisms of maternal β-cell adaptation during pregnancy and suggests genetic pathways that may influence the disease in humans (Fig. 2). Unfortunately, the techniques used to create genetic mutations in mice are not possible or practical for many other animals. Additionally, single-gene mutants often create simplistic models of GDM. This stands in stark contrast to GDM in humans, in whom disease susceptibility is most commonly due to complex interactions between polygenetic and environmental factors.
Genetic factors for GDM in humans.
It is becoming increasingly clear that GDM in humans is a heterogeneous disorder strongly influenced by genetic predispositions. Cases of GDM cluster in families, and Asians and Hispanics have an increased risk for the disease compared with Caucasians (19, 89). In further support of a genetic contribution, a strong association between GDM and genetic variants in potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11), mannose-binding lectin (protein C) 2 (MBL2), and transcription factor 7-like 2 (TCF7L2) have been made (64, 95, 97, 107). KCNJ11 is a β-cell potassium channel necessary for the proper control of insulin secretion; thus, mutations in this gene could have profound effects on glucose homeostasis (30). MBL2 is a critical component of pathogen recognition in the innate immune system, and its current physiological link to diabetes remains elusive (51). In contrast, TCF7L2 is a transcription factor whose loss from the pancreas in conditional knockout mice results in perturbed GSIS, providing a potential rationale behind association of polymorphisms in the gene to GDM (14).
Significantly, KCNJ11, MBL2, and TCF7L2 have also been linked to T2D (86). It thus remains possible that GDM may not have any exclusive genetic predisposition but rather shares in those that are found in other forms of diabetes. Despite this evidence strongly suggesting a genetic component to GDM, no definitive heritability of GDM has been established, indicating that genetic predisposition is not enough to cause the disease, and other environmental stressors that occur during pregnancy are also required to trigger disease onset. Furthermore, many of the animal models we have discussed demonstrate that changes in the in utero environment complicate the study of GDM inheritance, and studies tracing inheritance of diabetes in human patients indicate that the same is true in humans (35). As such, further studies are needed to clarify the impact of genetics on the inheritance of GDM.
Concluding Remarks
Since the first experimental model of GDM using pregnant Ppx dogs, many alternative animals and techniques have been proposed to continue the study of this disease (Table 4). While each model has advanced our understanding of how maternal diabetes during pregnancy can affect fetal outcomes and long-term maternal health, a thorough understanding of its causes and consequences in humans remains elusive. Undoubtedly, genetics and environmental factors contribute to the pathogenesis of GDM, since both genetic defects affecting β-cell expansion and diet-induced obesity can lead to the disease. As such, a single ideal GDM model may not be possible. A realistic alternative may include using animal models with differing etiologies for developing GDM, including a genetic background that predisposes the animal to environmental modulations in physiology under the right conditions.
R. C. Pasek was supported by the Vanderbilt Molecular Endocrinology Training Program (Grant 5 T32 DK-07563). M. Gannon was supported by a grant from the Veterans Administration (1BX000990-01A1) and the Juvenile Diabetes Research Foundation (1-2011-592).
No conflicts of interest, financial or otherwise, are declared by the author(s).
Author contributions: R.C.P. and M.G. prepared figures; R.C.P. and M.G. drafted manuscript; R.C.P. and M.G. edited and revised manuscript; R.C.P. and M.G. approved final version of manuscript; M.G. conception and design of research.
We thank Dr. Maria Golson for critical reading of the manuscript.
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text:
I host several SQL Server databases using a remote ISP and am interested in finding when the remote SQL Server was restarted. ( I dont have 'sa' privileges on this remote database.) I wrote this query to check this information, but am not sure if this stored procedure is correct. Any feedback will be appreciated. (I have assumed adding @@CPU_BUSY to @@IDLE will give the time since the SQL Server was last re-started.)

My current ISP's SQL Server has typical values of
3,500,000 connections and 7% @@CPU_BUSY to @@IDLE time. Is this normal?

Thanks,
Rohan

create proc UpTime as
begin
declare @Hrs int, @Min int, @Sec int
select @Sec = @@IDLE / 32
select @Min = @Sec / 60
select @Hrs = @Min / 60
select @Min = @Min % 60
select @Sec = @Sec % 60
select @@Version
select @@CPU_BUSY/32.0 CPU_BUSY,convert(varchar(10),@Hrs) + ' Hours ' + convert(varchar(10),@Min) + ' Minutes ' + convert(varchar(10),@Sec) + ' Seconds.' CPU_IDLE,@@Connections Connections,(100.0*@@CPU_BUSY)/@@IDLE
end

subset: commoncrawl


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text:
Pepe gets far too much attention, how about we give Wojak a little love here. he is so much more relocatable than pepe but pepe gets all the attention
>wojak is my spirit meme
idk man i can relate much better to pepe
wojak looks like his soul has already died and there is no expression in his face except sadness and anger sometimes
How do you relate to pepe more anon?
More wojak
>start browsing 4chan as an angsty 13yo
>got on /r9k/ as soon as it was made the first time
>grew up with 4chan as a big part of my life
>now I'm 22 and, thanks to genes, I am a Chad
>6'2 with a great jawline and fit from not being lazy
>have a loving girlfriend, great friends and a great life
>can't for the love of god leave this place
Comment too long. Click here to view the full text.
I 'unno, maybe just close the tab and move on with your life
Fuck off to experience project
Friend. There is no end to Mr. Bones wild ride. You cannot leave
How is this guy still a virgin faggots?
uh ew
You look like your still in a quote on quote fuck the world phase
For more pictures of this 22 year old robot.
This board is for the winter-born.
Anyone born in the warm months is normal scum.
The opposite, actually. Winter-born people were conceived in summer, are products of sluts and Chads fucking during the holidays. I know; I am one.
Posting some pics I've taken recently because I threw up 12 times last night and the pain in my back is agonizing and I need something to distract me
This faggot
Why do you care what some loser on tumblr wrote?
3 and 4 are pretty on point
The others for more into other categories though
Besides, who really cares? Big shit some guy thinks anxiety attacks are blah blah blah. Ok? I mean really why do you care?
i don't see what the problem is here
and i'm usually really good at seeing problems
When I win the powerball tomorrow I'm going to buy 4chan from china moot and make it so users have to verify employment and having a gf to post here
your days are fucking numbered, robots
Eugh, as much as I know this is a joke, bait, blah blah blah, it's just a really bad idea overall
I mean you'd lose about 75% of 4chan's population, essentially turning this place into a ghost town
Not to mention "verifying employment" will take out another 20%
So basically, you'll waste your money, only to have the site die
When I win powerball I'll give most of it to Charity, children in orphanages probably.
And how much would you give to your wife's son, you fucking kuck
/blackbot feels/ thread
ITT: post blackbot feels
>i played childish gambino at a party
>everyone laughed me out and called me a lame
>they roast me to this day
>Go to mostly white party school
>white folks play country music while we play cards against humanity
>play drinking game to acdc thunderstruck
Asian pussy is nice
>tfw no white gf
i was hoping 2015 would bring me a white gf
not even hispanic or asian women are playing ball
Not sure where the Asians came from in your story but okay
If you wear gym shoes with jeans, you are letting everyone know you're autistic.
Jeans are cheap and durable.
Gym shoes are comfortable.
pic related, shoes i wear all the time.
fucking normalfag
If I castrate myself, will I stop wanting to have a gf? Will I stop feeling the feels?
I really can't take it anymore tbqch (to be quite certainly honest) honest lads
No, you will stop wanting to have sex. There is no cure for wanting to feel loved.
There's one though.
That's not a cure for problems in life, that's just ignoring them.
Why haven't you tried getting laid at a juggalo gathering /r9k/? Go to an ICP concert and you'll get laid.
Look mom, it's the white underclass! :D
Too much soda, rather have beer and water.
No, even those girls wouldn't want to have sex with me
It's been a year since POO POO PEE PEE
Post the best
Oh god I've missed poopoopeepee.
it's been longer than that you failed normie
No it hasn't ( unless you mean 13-14 months isn't 1 year) op is correct. we were here. It was hilariously unforgettable.
Why don't you wax your balls, robots?
Why would I
No one else will ever see them
The girl waxing it would
stop being negaitve
What is the fastest you have ever driven robots?
115mph on the M40 in England for me, though I was a passenger doing 125mph on the autobahn once
120 mph in car, 155 on motorcycle
It's fun
you think you are being cool by driving eradically and endangering other peoples lives? real life isn't like your video games no one is going to applaud you for being a maniac on the road. Driving is a privilege not a right
28 years per life.
Any europeans here?
I had like a hole in one of my molars for over a year but it didnt hurt.
Now i was just eating something and half the teeth broke of.
Yes i know im an idiot. My question is: How much will it cost me to get this fixed?
Also did anyone have similar things happening to them?
help me out oh mighty robot
im too autistic to go to my dentist and then not having the money ;_;
Check to see if there are any dental schools near you, a lot of dental schools will do the work for a cheaper price.
There's a law in a couple of countries now, where you have to pay full price for any visit to the dentist, if you didn't go there at least once a year. So you're pretty much fucked, you will have to pay around, i don't know, 80 euros maybe to get the tooth removed.
Where do I find women with no standards who'll fuck an overweight shut-in neet like me?
A prostitute
Nowhere, women like that don't exist, even the ugly ones have ridiculous standards.
Massage parlors


text: USS Constitution sails under her own power Posted at 7:48 am on September 11, 2012 by Neil McCabe Share on Facebook Share on Twitter Share on Facebook Share on Twitter Tags: Author's Bio: Neil McCabe Neil W. McCabe is the editor of HE's "Guns & Patriots" e-letter and was a senior reporter at the Human Events newspaper. McCabe deployed with the Army Reserve to Iraq for 15 months as a combat historian. For many years, he was a reporter and photographer for "The Pilot," Boston's Catholic paper. He was also the editor of the free community papers "The Somerville (Mass.) News and "The Alewife (North Cambridge, Mass.)." Email him: [email protected] Recent Stories How Crazy Are Black Lives Matter Cultists? This Crazy. October 27, 2016 - No Comments Rap Star With Stupid Hair Really Sorry He Got Busted With A Gun. Again. October 27, 2016 - No Comments Food Delivery Driver Delivers To Robbers At 1,100 Feet-Per-Second October 27, 2016 - No Comments


text:
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2 Bed, 1 Bath Apartment for $1,215/mo
2 Bed, 1 Bath Apartment
4469 North Ave, San Diego, CA
Hillcrestuniv. Hts 2br 2ba
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Where you'd be living
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text:
This part will fit the following vehicles:
|2007 - 2008
Other identifiers for this part: TYC #: 11-6210-01.
Fits years: 07 2007, 08 2008
This part fits the following Honda Fit trims: Sport Tail Lights & Bulbs
- Each product conforms to US Motor Vehicle Safety Standards
- All products are brand new, NOT used or refurbished
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- Industry's Top Brands
- Limited Lifetime Warranty
- Most Orders Shipped Priority Mail
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- 2048-Bit SSL Encrypted
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My order was fine. I liked the easiness of purchasing from your website and got the part I needed at a fair price. All in all a very satisfying experience and I will recommend your website to my friends. Thank you.
With our ASE certified staff guiding the ordering process, you can be sure that you'll be getting the right part for the job. Because we do our best to give you everything necessary to order and install the parts, most of our replacement tail lights include installation instructions, providing a step-by-step process. You'll know exactly how to put the tail light in, and which parts are necessary for the project!
Price Quality Average: 5 / 5 starsWe searched on line for a replacement part for my truck. We found Go-Part. The site was as described. The parts were well described. The parts were well pictured. The price was EXCELLENT!! Upon talking to a representive from Go-Part I knew we had picked the right place. He was easy to understand, helpful and clear on what the part was and his description matched what was on the site. Very easy transaction. The part was here in 3 days. Would definetly order from them if need be.by DennisBare
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text:
Farm Service Agency
100 E 8th Ave Rm 2603, Pine Bluff, AR 71601
(870) 534-3200
Compliment this business
Street address:
100 E 8th Ave Rm 2603
City / suburb:
Pine Bluff
ZIP code:
(870) 534-3200
Contact name:
Bill Groce
GPS Longitude:
GPS Latitude:
Places nearby
0 miles away
U.S. Postal Service
0 miles away
Building Maintenance Services, Nec
General information
- Public Administration Administration Of Economic Programs Regulation Of Agricultural Marketing
Business data
|Standard industrial classification code:
|City / suburb:
|Pine Bluff, AR
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According to our records, this business is located at 100 E 8th Ave Rm 2603 in Pine Bluff (in Jefferson County), Arkansas 71601, the location GPS coordinates are: 34.2211241 (latitude), -92.0025977 (longitude). Farm Service Agency is categorized under Regulation Of Agricultural Marketing (SIC code 9641). Known organization associate is Bill Groce. You can contact the company by phone at (870) 534-3200.
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Business Services, Nec
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Rio Olympics might be a mess, but Tokyo 2020 has some cool high-tech plans
Driverless taxis for athletes and holograms for info.
Thu, Jul 07 2016
Clinton takes big step toward easing tensions with Sanders
With new college affordability plan, the presumptive Democratic nominee won praise from rival.
Thu, Jul 07 2016
US urges aerial spraying amid jump in Puerto Rico Zika cases
The U.S. territory is debating whether to fumigate with the insecticide Naled.
Wed, Jul 06 2016


text:
May 10, 2016 7:31 PM by News Staff
Police are searching for the person responsible for robbing a Redding bank this afternoon.
Police say the robber waited till the majority of customers left and handed a note to the clerk demanding an undisclosed amount of money.
It all went down at the sierra central credit union off the thousand block of Yuba Street around 2:48 p.m. this afternoon.
No one was hurt.
Police say the man didn't have a gun and he's described as a Hispanic male about six feet tall and think built wearing black clothing and eye glasses.
If you have any information on this robbery call Redding Police.
14 hours ago


text:
Joined: 02 June 2011
Posts: 60
I think d following are d songs that may work on them...
batein kuch ankahee se - Life in a Metro
Saibo - Shor in the City
Saawrey- Shor in the City
Jeene Ke Isarey Mil Gaye- Phir Milenge
You may post Your Suggestions.
Thank You,
All was well, until the leap did them apart!
The 'other woman's entry in the show will surely spice things up.
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text:
India's federal crime bureau has arrested three senior executives at Satyam,
the outsouring provider that was formerly audited by PricewaterhouseCoopers.
According to a statement, Satyam's vice president, as well as a senior
manager and an assistant manager in the company's finance department were
arrested on Sunday in connection with the accounting fraud investigation.
Satyam's founder and former chairman Ramalinga Raju and two other senior
managers were arrested in January after Raju confessed to falsifying the
accounts and overstating profits.
Related reading
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Does Darwin's theory apply to taxation? Colin ponders...
European Commission told to draft financial transaction tax by year-end
The EC has been instructed to draft a European Union (EU) directive authorising an EU financial transaction tax, which would apply to ten of the EU's 28 member states
Administrators from KPMG appointed to City Motor Holdings
Steve Absolom and Will Wright from KPMG Restructuring have been appointed joint administrators to City Motor Holdings and associated companies
Johnston Carmichael appointed as joint administrators for Axon Well
Partners from Johnston Carmichael have been appointed as joint administrators to Axon Well Interventions Products UK


text:
Hacked By: selectLOL
Hack Information:
Hackbar: Press 1 Toggle health - 2 Attack again
Game Information
The Fae's Wyrd is a retro-inspired party-base RPG game. It uses randomly generated treasures and levels to provide a new experience every game.
Cheats: Hackbar: Press [1] Toggle Health - [2] Toggle Light Power - ...
Hacked By: leverage419
Cheats: Hackbar: Press [1] Win Level
Hacked By: leverage419
Cheats: Hackbar: Press [1] Toggle health - [2] Toggle energy - [3] M...
Hacked By: selectLOL
Cheats: Hackmenu (Backslash(\) Open/Close): [1] Toggle Fuel - [2] To...
Hacked By: leverage419, cilibiudragos
go slect lol =epic
selectLOL , DPetty and Martin F0R3VER
Registered Users: 477038
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There are 860 users online
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text: Item is not available Find Another One Others Looked At... Winchester Model 1890 3rd Model Takedown... SELLER: Silver Creek Outfitters 1 $1,250.00 Winchester Model 61 ( 1957 ) SELLER: glenvilleguns 1 $1,050.00 Winchester Model 61 .22LR SELLER: Silver Creek Outfitters 1 $1,100.00 Winchester Model 61 22LR SELLER: Silver Creek Outfitters 1 $1,100.00 M61 WINCHESTER .22S/L/LR LAST YEAR PRODU... SELLER: L and M Enterprises USA LLC 1 $4,100.00 Very clean WINCHESTER model 61 22 lr. Ma... SELLER: The Hunters Shop 1 $1,195.00 Guns Rifles Winchester Rifles Modern Pump Winchester Model | 772 | 4 | Lc | 187.4977ms Winchester Model 62 For Sale from tucker92 | Positive feedback: 100% View | Verified Seller | 2 Completed Sales View Sellers Items This item is no longer available. Description Shipping and Payment More Info First year production Winchester Model 62 in very fine condition except for a slight barrel expansion about 9 inches from the muzzel. Barely noticable. Operation is not affected. Shoots fine. Ask questions. NOTE: Rifle will be shipped by a nonlicensee per ATF regulations. Make sure your dealer is aware of and agrees with this regulation. See Description Trades Accepted: No Condition: Used, Minor Wear Caliber: .22 Long Rifle Location: NY Share Item Item #: 976965628 This item is no longer available. Price: Shipping: $20.00 (or Arrange local transfer) Accepted Payment Methods: Returns: No Returns tucker92 Seller Since: Jan. 2007 Seller Level: Basic This seller is NOT an FFL City: MACEDON State: NY Your Recently Viewed Items


text:
Do you have a question? Post it now! No Registration Necessary. Now with pictures!
- Subject
- Posted on
- Mini-PCI wireless cards - advice please
- 01-04-2005
- Paul D.Smith
January 4, 2005, 7:46 pm
adding a wireless (54/g) wireless LAN card. Whilst I know desktop hardware
well, I'm less knowledgable on laptops so some questions...
- Do these mini-PCI cards typically have external or just internal antenna?
- What is the range of such a card?
- Would it be better to just buy a PCMCIA card instead? Yes/No/Why?
Thanks for any guidance offered.
Paul DS.
Please remove the "x-" if replying to sender.
- Paul Rubin
January 4, 2005, 12:15 pm
Re: Mini-PCI wireless cards - advice please
They have no antennas at all. They depend on an antenna being
connected. Laptops set up for wifi mini-pci cards typically have nice
big internal antennas inside the screen assembly.
If the laptop has a nice big antenna inside the screen assembly, the
wifi range can be greater than a pcmcia card would have.
A pc card gives you more flexibility, but fills a pc card slot, and
has its own antenna sticking out the side of the machine that can snag
or bump on things, so you have to remove it when you transport the
laptop, etc. All in all, if you can use it, an internal mini-pci card
is nicer. But it's not always possible.
January 4, 2005, 2:51 pm
Re: Mini-PCI wireless cards - advice please
You want to check that mini-pci slot carefully to verify that it is not
simply an empty space - some vendors do not install a main board that
has any connector in the slot if the laptop was not ordered originally
with the mini-pci card. Also you must see two antenna wires to connect
to the card.
From my limited experience, the newest mini-pci cards are very good,
better than any pc-card i've used. Much more sensitive to weaker
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text:
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Precision Printing specialises in the swift and accurate printing of Brochures, Reports and other Marketing materials. We have been serving businesses. -
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Advertising for : 'Swedish Summer (Girl)'
Home - Brazil - State of São Paulo - São Paulo - São Paulo - Swedish Summer (Girl)
Learn more about this example of Advertising
Industry of the client: Clothing & Accessories
Service provided: Advertising
Tags: Print, Commercials Archive, Apparel, Clothing, Footwear, Duvan Adverts
DAVID, based at São Paulo, Brazil has been asked to develop Swedish Summer (Girl) for their brand DuvanProduct: Duvan Shopping Mall in 2013. This customer case is known in the marketing & communication market for Print, Commercials Archive, Apparel, Clothing, Footwear, Clothing, footwear, Duvan Adverts.
Other ideas of Advertising
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Print - Commercials Archive - Business equipment - services - Printers - Scanners - Supplies - Samsung Adverts
Services delivered: magazine ads, business advertising, marketing campaign, tv ads, advertising
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Services delivered: marketing campaign, magazine ads, tv ads, business advertising, advertising
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Services delivered: tv ads, advertising, magazine ads, marketing campaign, business advertising
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Advertising - Automotive
Print - Commercials Archive - services - Repair parts - Other Vehicles - Auto Products - GENUINE MOTOR ACCESSORIES Adverts
Services delivered: tv ads, marketing campaign, magazine ads, business advertising, advertising
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Welding Mobile
2108 Wrights Mill Rd Auburn, Alabama 36830(334) 887-5436
Print | Save | Directions
AboutWelding Mobile is located at the address 2108 Wrights Mill Rd in Auburn, Alabama 36830. They can be contacted via phone at (334) 887-5436 for pricing, hours and directions.
Welding Mobile has an annual sales volume of 0 - 500K. .For more information contact James Moore, Owner
For maps and directions to Welding Mobile view the map to the right. For reviews of Welding Mobile see below.
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Key Contacts
- James Moore
- Phone: (334) 887-5436


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QR Code Link to This Post ANTIQUE ART, Movie and Sports Memorabilia, Jewelry, Crystal, Old Bottles, Old Toys, High End Clothing, Vintage Clothing, Purses, New Stuff, Watches (have bands, batteries and pins if you need a repair), Albums, Baseball Cards, Tools and LOTS MORE. 8-3PM Friday 10/28, 8-2pm Sat 10/29… → Read More
ESTATE SALE -SAT Oct 29 8:30 - 4:00, SUN Oct 30th 11:00 - 3:00 (NOTE TIMES)
Hunting Gear, Turkey calls, old time fishing lures and gear, Kubota L200 Tractor), Gun cabinet, tools, workbench, Collectables, EASTERN Airlines memorabilia, Old records, books...much more.. PHOTO GALLERY: www.wrightestatesales.vpweb.com… → Read More
The Cotton Pickin' Warehouse at the Mill Market SATURDAY! November 5, 2016 Antiques, Unique and Vintage Items Bringing the historic cotton mill district back to life! Outdoor vendor space available The first Saturday of every month 9am-4pm Free Admission 83 East Adams Street in Forsyth Georgia For vendor information or… → Read More
Household goods, tools, crafts, books,cd's And much more!… → Read More
YardSales.net is the fastest growing yard sale site, with 13 sale photos and 38 garage sales in Griffin, Georgia. YardSales.net offers you the best list of Griffin yard sales every week.
Auntique, Unique, & Collectible Auction
New sale - 1 day ago
New sale - 2 days ago


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Richmond voters must weigh in on camp plan
To the editor:
In a Town Meeting on Wednesday, Nov. 18, citizens of Richmond will decide whether to buy the Girl Scouts' Camp Marion White for $1.375 million. Advocates see the purchase as a once-in-a-lifetime opportunity to acquire beautiful wooded property along the shore of Richmond Pond and turn it into a town park. Opponents believe there is little likelihood that such a park would be used enough to justify the purchase price, capital improvements, liabilities, and ongoing operational and maintenance costs that would follow.
This is a big decision for a small town. My plea to the people of Richmond is to come out and vote, no matter which side you are on. A small turnout could result in grumbling and resentment afterward. A large turnout would ensure that winners and losers both knew that the outcome reflected the true wishes of most people in town.
We'll all have to live with the decision, whatever it is, so let's do it the right way and maintain the spirit of community that makes this town such a pleasant place to live.


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Oatmeal cookies
Gail Tripp
i have also made these into bars just cook 15-20 minutes using a jelly roll pan
- 1 1/4 c
- flour
- 1 tsp
- baking soda
- 1/4 c
- sugar
- 1 c
- butter soft
- 3/4 c
- brown sugar, firmly packed
- 1 pkg
- vanilla instant pudding
- 2
- eggs
- 3 1/2 c
- quick cooking oats
Directions Step-By-Step
1mix flour with baking soda set aside combine butter, the sugars and pudding mix in large bowl or stand mixer
2beat until smooth and creamy. beat in eggs gradually add flour mix then stir in oats
3batter will be STIFF this is where stand mixer comes in handy.
4drop by desired size on parchment lined cookie sheets bake @ 375 degrees 10-12 mins
5let stand one minute transfer to rack to cool
can add raisins and nuts if desired
store in airtight container
About this Recipe
Course/Dish: Cookies


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Security Doors in Waite Park, MN
There are lots of different security doors Waite Park, MN has to offer, and it is incredibly important that you make a point of looking into some of them before making a final decision. The Waite Park security doors that you put on your home will determine just how easy it will be for a potential intruder to get through them, which is why it's so important that you research these options. A lot of homeowners are getting Waite Park security doors installed on their houses because they make them so much safer and more secure.
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The steel security doors Waite Park, MN has to offer are certainly worth looking into, especially if you want your house to be as secure as possible. These doors come in a variety of sizes and styles, so you shouldn't have any problem at all finding one that appeals to your particular tastes. You will want to get the best security door Waite Park, MN has to offer, because otherwise you are risking the safety of yourself and your family. Since there are so many of these doors to choose from, you will want to make a point of carefully reviewing your options before making a final decision on a security doors in Waite Park, MN.
Beumer Outdoors15517 Fruit Farm Rd St Joseph, MN 56374
Wh Builders427 Sundial Dr Waite Park, MN 56387
TOTAL DOOR DESIGN902 Division St Waite Park, MN 56387
True North Tower310 60th St NW Sauk Rapids, MN 56379
St. Cloud Lodging Group115 37th Ave N. Saint Cloud, Mn 563034051 Us Saint Cloud, MN 56303
St. Cloud Acoustics, Inc.30762 Pearl Drive Po Box 758 Saint Joseph, MN 56374


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Family business eventsFind out about upcoming events and training tailored for family businesses Resources Frequently Asked QuestionsFind answers to the most frequently asked questions about starting, growing and exiting a business. You might be thinking about starting a business but unsure of the costs or how to get the ball rolling. The individual that is advertising or selling a get rich quick scheme wants your money, and also the suggestion of getting rich fast (with no effort in any way) is the quickest method to persuade a newbie to purchase.
You wrote: where you find loads of different types of prawns, crabs, clams, squid, octopus, sea urchins etc etc. It came by understanding how to market efficiently on the web, although their success did not come by luck. You can voyeur it in details and from different angles as she moves silently but at the same time so significantly on the bed.
Our goal is first to understand your business needs and then build solutions that cost effectively address those needs. We may disclose your personal information to selected third parties who may then send information to you about goods and services. The staff of the place was also very helpful providing recommendations and answering all the questions and doubts.