Constance L. Chik

Postpartum Diabetes Screening Adherence rate and the performance of fasting plasma glucose versus oral glucose tolerance test

OBJECTIVE To determine the rate of adherence to postpartum glycemic testing in women with gestational diabetes mellitus (GDM) and the performance of fasting plasma glucose (FPG) versus the 75-g oral glucose tolerance test (OGTT) in detecting postpartum glucose intolerance. RESEARCH DESIGN AND METHODS The study was a retrospective cohort of 1,006 women with GDM attending a pregnancy diabetes clinic. RESULTS Postpartum screening was completed in 438 (48%) women. Women nonadherent to testing had higher parity (1.10 vs. 0.87) and were less likely to require insulin for management of their GDM. Among women who were tested, 89 (21%) had an abnormal result, only 25 (28%) of whom were identified by FPG. Factors associated with abnormal postpartum diabetes screening include non-Caucasian ethnicity, previous GDM, higher A1C, and OGTT values during pregnancy and treatment with insulin. CONCLUSIONS The rate of postpartum diabetes screening is low, and FPG lacks sensitivity as a screening test in comparison with OGTT.

α1D L-Type Ca2+-Channel Currents: Inhibition by a β-Adrenergic Agonist and Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) in Rat Pinealocytes

Abstract: In this study the subunits of the dihydropyridine‐sensitive L‐type Ca2+ channels (L‐channels) expressed in rat pinealocytes were characterized using reverse transcription (RT)‐PCR analysis, and the modulation of these channels by adrenergic agonists and by pituitary adenylate cyclase‐activating polypeptide (PACAP) was studied using the patch‐clamp technique. RT‐PCR analysis showed that rat pinealocytes expressed α1D, α2b, β2, and β4 Ca2+‐channel subunit mRNAs. Other α1 subunit transcripts were either not expressed or present at very low levels, indicating that the pinealocytes express predominantly α1D L‐channels. Electrophysiological studies confirmed that the pineal expressed a single population of L‐channels. The L‐channel currents were inhibited by two agonists that elevate cyclic AMP: the β‐adrenergic agonist isoproterenol and PACAP. Similar inhibition was observed with a cyclic AMP analogue, 8‐bromo‐cyclic AMP. The presence of a cyclic AMP antagonist, Rp‐adenosine 3′,5′‐cyclic monophosphorothioate, blocked the inhibition by isoproterenol and PACAP. Norepinephrine, a mixed α‐ and β‐adrenergic agonist, also inhibited the L‐channel currents, but the inhibition was smaller. The smaller inhibition by norepinephrine was secondary to the simultaneous activation of α‐ and β‐adrenergic receptors. These results indicate that (a) pinealocytes express predominantly α1D L‐channels, and (b) the β‐adrenergic agonist isoproterenol and PACAP inhibit the L‐channel currents through elevation of cyclic AMP. However, an α‐adrenergic‐mediated mechanism also appears to be involved in the effect of norepinephrine on the L‐channel currents.

Pineal function: Impact of microarray analysis

Microarray analysis has provided a new understanding of pineal function by identifying genes that are highly expressed in this tissue relative to other tissues and also by identifying over 600 genes that are expressed on a 24-h schedule. This effort has highlighted surprising similarity to the retina and has provided reason to explore new avenues of study including intracellular signaling, signal transduction, transcriptional cascades, thyroid/retinoic acid hormone signaling, metal biology, RNA splicing, and the role the pineal gland plays in the immune/inflammation response. The new foundation that microarray analysis has provided will broadly support future research on pineal function.

Pituitary adenylate cyclase-activating polypeptide: control of rat pineal cyclic AMP and melatonin but not cyclic GMP.

Abstract: In this study, the effects of pituitary adenylate cyclase‐activating polypeptide (PACAP) on cyclic nucleotide accumulation and melatonin (MT) production in dispersed rat pinealocytes were measured. Treatment with PACAP (10−7M) increased MT production 2.5‐fold. PACAP (10−7M) also increased cyclic AMP accumulation four‐ to fivefold; this effect was potentiated two‐ to three‐fold by α1‐adrenergic activation. This potentiation appears to involve protein kinase C (PKC) because α1‐adrenergic activation is known to translocate PKC and the PACAP‐stimulated cyclic AMP accumulation was potentiated ninefold by a PKC activator, 4β‐phorbol 12‐myristate 13‐acetate (PMA). Phenylephrine and PMA also potentiated the PACAP‐stimulated MT accumulation. These results indicate that cyclic AMP is one second messenger of PACAP in the pineal gland and that the effects of PACAP on cyclic AMP and MT production can be potentiated by an α1‐adrenergic → PKC mechanism. In addition to these findings, it was observed that PACAP treatment with or without phenylephrine or PMA did not alter cyclic GMP accumulation. This indicates that PACAP is the first ligand identified that increases cyclic AMP accumulation in the pineal gland without increasing cyclic GMP accumulation. That PACAP fails to activate the vasoactive intestinal peptide/cyclic GMP pathway suggests that the vasoactive intestinal peptide receptors present in the pineal may be distinct from the type II PACAP receptors.

3',5'-cyclic guanosine monophosphate activates mitogen-activated protein kinase in rat pinealocytes.

Abstract : The role of 3′,5′‐cyclic guanosine monophosphate (cGMP) in the activation of mitogen‐activated protein kinases (MAPKs) was investigated in rat pinealocytes. Treatment with dibutyryl cGMP (DBcGMP) dosedependently increased the phosphorylation of both p44 and p42 isoforms of MAPK. This effect of DBcGMP was abolished by PD98059 (a MAPK kinase inhibitor), H7 (a nonspecific protein kinase inhibitor), and KT5823 [a selective cGMP‐dependent protein kinase (PKG) inhibitor]. Elevation of cellular cGMP content by treatment with norepinephrine, zaprinast (a cGMP phosphodiesterase inhibitor), or nitroprusside was effective in activating MAPK. Natriuretic peptides that were effective in elevating cGMP levels in this tissue were also effective in activating MAPK. Our results indicate that, in this neuroendocrine tissue, the cGMP/PKG signaling pathway is an important mechanism used by hormones and neurotransmitters in activating MAPK.

Adrenergic regulation of mitogen-activated protein kinase in rat pinealocytes: opposing effects of protein kinase A and protein kinase G.

The role of adrenergic stimulation in the regulation of mitogen-activated protein kinase (MAPK) in rat pinealocytes was investigated by measuring phosphorylated MAPK using Western blot analysis and a MAPK enzymatic assay. Stimulation with the endogenous neurotransmitter, norepinephrine (NE; a mixed alpha- and beta-adrenergic agonist), concentration dependently increased the phosphorylation of both p44 and p42 isoforms of MAPK. This effect of NE was blocked by PD98059 and U0126 (two inhibitors of MEK). Treatment with prazosin or propranolol significantly reduced the effect of NE on MAPK phosphorylation, suggesting the involvement of both alpha- and beta-adrenergic receptors. Investigation into the intracellular mechanisms of NE action revealed that the increase in MAPK phosphorylation was blocked by KT5823 (a protein kinase G inhibitor), but was enhanced by H89 (a protein kinase A inhibitor). Calphostin C (a protein kinase C inhibitor) and KN93 (a Ca2+/calmodulin-dependent protein kinase inhibitor) also attenuated NE-mediated MAPK activation, but to a lesser degree. Furthermore, inhibition of MAPK phosphorylation by (Bu)2cAMP was effective in reducing MAPK activation by (Bu)2cGMP, an active phorbol ester or ionomycin. These results indicate that the effect of NE on MAPK phosphorylation represents mainly the integration of two signaling mechanisms, protein kinase A and protein kinase G, each having an opposite effect on MAPK phosphorylation.The role of adrenergic stimulation in the regulation of mitogen-activated protein kinase (MAPK) in rat pinealocytes was investigated by measuring phosphorylated MAPK using Western blot analysis and a MAPK enzymatic assay. Stimulation with the endogenous neurotransmitter, norepinephrine (NE; a mixed α- and β-adrenergic agonist), concentration dependently increased the phosphorylation of both p44 and p42 isoforms of MAPK. This effect of NE was blocked by PD98059 and UO126 (two inhibitors of MEK). Treatment with prazosin or propranolol significantly reduced the effect of NE on MAPK phosphorylation, suggesting the involvement of both α- andβ -adrenergic receptors. Investigation into the intracellular mechanisms of NE action revealed that the increase in MAPK phosphorylation was blocked by KT5823 (a protein kinase G inhibitor), but was enhanced by H89 (a protein kinase A inhibitor). Calphostin C (a protein kinase C inhibitor) and KN93 (a Ca2+/calmodulin-dependent protein kinase inhibitor) also attenuated NE-me...

Impact of gestational diabetes mellitus and high maternal weight on the development of diabetes, hypertension and cardiovascular disease: a population-level analysis

To examine the association between gestational diabetes mellitus (GDM) and high maternal weight and the risk of development of chronic disease.

Thyroid medullary carcinoma with thyroglobulin immunoreactivity in sporadic multiple endocrine neoplasia type 2-B

Background. Thyroid carcinomas historically have been divided into two groups according to their presumedly separate embryonic origins: those of neuroectodermal derivation (parafollicular or medullary carcinoma [MCT]) and those of foregut endodermal origin (follicular and papillary carcinomas). The validity of this concept has been questioned by the recognition that some MCT may show immunocytochemical and ultrastructural evidence of follicular components, and display features of follicular function (e. g., organification of iodine, immunoreactivity for thyroglobulin).

Potentiation of Agonist‐Stimulated Cyclic AMP Accumulation by Tyrosine Kinase Inhibitors in Rat Pinealocytes

Abstract: To study cross‐talk mechanisms in rat pinealocytes, the role of tyrosine kinase or kinases in the regulation of adrenergic‐stimulated cyclic AMP production was investigated. Both norepinephrine‐ and isoproterenol‐stimulated cyclic AMP accumulation were increased by two distinct tyrosine kinase inhibitors, genistein or erbstatin, in a concentration‐dependent manner. A similar increase was observed with two other inhibitors, tyrphostin B44 and herbimycin. In contrast, daidzein, an inactive analogue of genistein, was ineffective; whereas vanadate, a phosphotyrosine phosphatase inhibitor, reduced the adrenergic‐stimulated cyclic AMP accumulation. The tyrosine kinase inhibitors were effective in potentiating the cholera toxin‐or forskolin‐stimulated cyclic AMP accumulation, indicating that their sites of action are at the postreceptor level. Neither an activator nor inhibitors of protein kinase C influenced the potentiation of the cyclic AMP responses by genistein, suggesting that the potentiation effect by tyrosine kinase inhibitors does not involve the phospholipase C/protein kinase C pathway. However, when the phosphodiesterase was inhibited by isobutylmethylxanthine, genistein failed to potentiate and vanadate did not inhibit the adrenergic‐stimulated cyclic AMP accumulation, indicating that the phosphodiesterase is a probable site of action for these inhibitors. These results suggest that cyclic AMP metabolism in the pinealocytes is tonically inhibited by tyrosine kinase acting on the cyclic AMP phosphodiesterase.

Hypercalcemia of malignancy in the palliative care patient: A treatment strategy

Hypercalcemia of malignancy is most commonly due to the effects of parathyroid hormone-related peptide, which acts as a humoral factor to cause generalized osteoclast-mediated bone resorption and reabsorption of calcium by the kidney tubule, and may also act as a local resorptive factor adjacent to bone metastases. Local resorptive mechanisms are less common causes of malignant hypercalcemia than previously believed. Treatment begins with intravenous fluid rehydration, followed by a furosemide diuresis and the bisphosphonate pamidronate, 60-90 mg, intravenously. Gallium nitrate is an efficacious but inconvenient alternative to pamidronate. Calcitonin combined with pamidronate is a reasonable initial therapy for severe hypercalcemia to hasten normalization of the serum calcium. Steroids should be reserved for hypercalcemia due to tumor production of 1,25 dihydroxyvitamin D, or for steroid-responsive malignancies. Oral or parenteral bisphosphonates can be used to maintain normocalcemia. In addition to improving the morbidity of acute hypercalcemia, bisphosphonate therapy has been shown to reduce bone pain and pathological fractures in patients with bone metastases, and calcitonin also has a potent analgesic effect in these patients. Treatment for hypercalcemia should therefore be considered in the majority of patients in the palliative care setting.