Changing patterns in medication prescription for gestational diabetes during a time of guideline change in the USA: a cross-sectional study.

OBJECTIVE: To define patterns of prescription and factors associated with choice of pharmacotherapy for gestational diabetes mellitus (GDM), namely metformin, glyburide and insulin, during a period of evolving professional guidelines. DESING: Cross-sectional study. SETTING: US commercial insurance beneficiaries from Market-Scan (late 2015 to 2018). STUDY DESIGN: We included women with GDM, singleton gestations, 15-51 years of age on pharmacotherapy. The exposure was pharmacy claims for metformin, glyburide and insulin. MAIN OUTCOMES: Pharmacotherapy for GDM with either oral agent, metformin or glyburide, compared with insulin as the reference, and secondarily, consequent treatment modification (addition and/or change) to metformin, glyburide or insulin. RESULTS: Among 37 762 women with GDM, we analysed data from 10 407 (28%) with pharmacotherapy, 21% with metformin (n = 2147), 48% with glyburide (n = 4984) and 31% with insulin (n = 3276). From late 2015 to 2018, metformin use increased from 17 to 29%, as did insulin use from 26 to 44%, whereas glyburide use decreased from 58 to 27%. By 2018, insulin was the most common pharmacotherapy for GDM; metformin was more likely to be prescribed by 9% compared with late 2015/16, but glyburide was less likely by 45%. Treatment modification occurred in 20% of women prescribed metformin compared with 2% with insulin and 8% with glyburide. CONCLUSIONS: Insulin followed by metformin has replaced glyburide as the most common pharmacotherapy for GDM among a privately insured US population during a time of evolving professional guidelines. Further evaluation of the relative effectiveness and safety of metformin compared with insulin is needed. TWEETABLE ABSTRACT: Insulin followed by metformin has replaced glyburide as the most common pharmacotherapy for gestational diabetes mellitus in the USA.

CK1δ/GSK3ß/FBXW7α axis promotes degradation of the ZNF322A oncoprotein to suppress lung cancer progression.

Overexpression of Cys2His2 zinc-finger 322A (ZNF322A) oncogenic transcription factor is associated with lung tumorigenesis. However, the mechanism of ZNF322A overexpression remains poorly understood. Here, we discover that protein stability of ZNF322A is regulated by coordinated phosphorylation and ubiquitination through the CK1δ/GSK3ß/FBXW7α axis. CK1δ and GSK3ß kinases sequentially phosphorylate ZNF322A at serine-396 and then serine-391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7α leading to ZNF322A protein destruction. Overexpression of FBXW7α induces ZNF322A protein degradation, thereby blocks ZNF322A transcription activity and suppresses ZNF322A-induced tumor growth and metastasis in vitro and in vivo. Clinically, overexpression of ZNF322A correlates with low FBXW7α or defective CK1δ/GSK3ß-mediated phosphorylation in lung cancer patients. Multivariate Cox regression analysis indicates that patients with ZNF322A high/FBXW7 low expression profile can be used as an independent factor to predict the clinical outcome in lung cancer patients. Our results reveal a new mechanism of ZNF322A oncoprotein destruction regulated by the CK1δ/GSK3ß/FBXW7α axis. Deregulation of this signaling axis results in ZNF322A overexpression and promotes cancer progression.

Graphic Mining of High-Order Drug Interactions and Their Directional Effects on Myopathy Using Electronic Medical Records.

We propose to study a novel pharmacovigilance problem for mining directional effects of high-order drug interactions on an adverse drug event (ADE). Our goal is to estimate each individual risk of adding a new drug to an existing drug combination. In this proof-of-concept study, we analyzed a large electronic medical records database and extracted myopathy-relevant case control drug co-occurrence data. We applied frequent itemset mining to discover frequent drug combinations within the extracted data, evaluated directional drug interactions related to these combinations, and identified directional drug interactions with large effect sizes. Furthermore, we developed a novel visualization method to organize multiple directional drug interaction effects depicted as a tree, to generate an intuitive graphical and visual representation of our data-mining results. This translational bioinformatics approach yields promising results, adds valuable and complementary information to the existing pharmacovigilance literature, and has the potential to impact clinical practice.

A Mixture Dose-Response Model for Identifying High-Dimensional Drug Interaction Effects on Myopathy Using Electronic Medical Record Databases.

Interactions between multiple drugs may yield excessive risk of adverse effects. This increased risk is not uniform for all combinations, although some combinations may have constant adverse effect risks. We developed a statistical model using medical record data to identify drug combinations that induce myopathy risk. Such combinations are revealed using a novel mixture model, comprised of a constant risk model and a dose-response risk model. The dose represents the number of drug combinations. Using an empirical Bayes estimation method, we successfully identified high-dimensional (two to six) drug combinations that are associated with excessive myopathy risk at significantly low local false-discovery rates. From the curve of a dose-response model and high-dimensional drug interaction data, we observed that myopathy risk increases as the drug interaction dimension increases. This is the first time that such a dose-response relationship for high-dimensional drug interactions was observed and extracted from the medical record database.

Tongue abscess induced by embedded remnant fishbone.

The authors reported a 56-year-old man with progressive pain over left bottom of oral cavity involving tongue for 3 days. He had a puncture history of tongue by fishbone, which was immediately removed 3 weeks ago. The subsequent contrast-enhanced computed tomography scan of neck disclosed an abscess formation with a faint linear radiopaque material inside, consisting with remnant fishbone retention. The patient was treated conservatively with intravenous antibiotics, followed by an uneventful course during subsequent follow-up for more than 9 months until now. Tongue abscess is a rare but potentially life threatening clinical entity. Foreign body puncture-related tongue abscess should be listed as a differential diagnosis in cases with acute tongue swelling.

OS053. Trophoblast invasion in the mesometrial triangle of atp infused pregnant rats.

INTRODUCTION: Poor placentation (disturbed and decreased trophoblast invasion) is a hallmark of preeclampsia (PE), which is a major complication of pregnancy. Unfortunately, the cause and mechanism of disturbed trophoblast invasion is still unknown. OBJECTIVES: The pro-inflammatory agent ATP has been shown to induce PE-like signs, after a single infusion in pregnant rats. These PE-like characteristics include proteinuria and decreased fetal weight. Since purinergic ATP receptors are expressed on trophoblast cells, we aimed to study the effect of ATP infusion on trophoblast invasion in pregnant rats in this pilot study. METHODS: Pregnant rats received a single ATP (n=4) or saline (control,ni=5) infusion via a permanent jugular vein cannula on day 14 of pregnancy. At the time of maximal trophoblast invasion (day 17 of pregnancy) rats were sacrificed and placentas with mesometrial triangle were collected, fixed in zinc-buffer and embedded in paraffin. 4 µm sections were stained with monoclonal α-cytokeratin antibodies. In the mesometrial triangle, the maternal part of the rat placenta, the percentage of surface area of trophoblast invasion was evaluated using computerized image analysis. Also, the depth and width of invasion were analyzed by subdividing the mesometrial triangle in three concentric depth levels of equal width. In addition, trophoblast invaded versus non-invaded spiral arteries in the mesometrial triangle were quantified. RESULTS: In the mesometrial triangle, no changes in percentage of surface area of trophoblast invasion and percentage of invaded spiral arteries were observed after ATP infusion. However, the pattern of trophoblast invasion appeared to be disturbed in ATP infused rats, with a decreased depth of invasion and an increased width of invasion, resulting in a trend towards a decreased depth/width ratio of trophoblast invasion in ATP infused rats. CONCLUSION: In this (pilot) study we showed an altered trophoblast invasion pattern in the mesometrial triangle of the placenta, although no significant differences in the total surface area of trophoblast invasion were seen in experimental versus control pregnant animals. e mechanism by which ATP induces this altered trophoblast invasion pattern and its potential contribution to the pathophysiology of this experimental PE in the pregnant rat awaits further investigation.

Identifying LRRC16B as an oncofetal gene with transforming enhancing capability using a combined bioinformatics and experimental approach.

Oncofetal genes are expressed in embryos or fetuses, are downregulated or undetectable in adult tissues, and then re-expressed in tumors. Known oncofetal genes, such as AFP, GCB, FGF18, IMP-1 and SOX1, often have important clinical applications or pivotal biological functions. To find new oncofetal-like genes, we used the public information of expressed sequence tags to systematically analyze gene expression patterns and identified a novel oncofetal-like gene, LRRC16B. It increased the proliferation, anchorage-independent growth and tumorigenesis of transformed cells in xenografts, possibly through its effects on cyclin B1 protein levels. These findings exemplify the feasibility of using bioinformatics to find new oncofetal-like genes and suggest that more genes with important functional roles will be uncovered in the candidate gene list.

Possible mechanism by which rapamycin increases cyclosporine nephrotoxicity.

It is well known that the combination of cyclosporine A (CsA) with rapamycin produces serious nephrotoxicity. Herein we suggest a mechanism by which rapamycin increases CsA nephrotoxicity. Previously, we demonstrated that activation of Akt/protein kinase B protects against cyclosporine nephrotoxicity and prevents apoptosis. Recently, it has been shown that Akt phosphorylation activates mammalian target of rapamycin (m-TOR) and inhibits programmed cell death including apoptosis and autophagy. Akt is believed to be an importance factor for cell survival. In theory, blockade of the Akt pathway through inhibition of m-TOR may increase cyclosporine-induced apoptosis. We added cyclosporine and rapamycin to cultures of ER52K proximal renal tubule cells, leading to a significantly decreased survival rate. The nephrotoxicity was associated with increased apoptosis by cleavage of caspase-3 and decreased phosphorylation of m-TOR and AktSer473, findings that support this hypothesis. This nephrotoxic effect may explain the clinical finding that patients treated with rapamycin alone exhibited better renal function than those treated with concomitant cyclosporine therapy.

Trends in the use of oral antidiabetic drugs by outpatients in Taiwan: 1997-2003.

OBJECTIVE: To define the prescribing patterns of oral antidiabetic drugs (OADs) in Taiwan over a 7-year period (1997-2003) and to critically comment on changes observed. METHODS: A cross-sectional study design was implemented using data from Taiwan's National Health Insurance Research Database between January 1997 and December 2003. Outpatients who were 18 years or older and had at least an OAD claim during the study period were identified. The unit of analysis was each OAD prescription for diabetic outpatient visits. The prescribing trends were described in terms of annual changes in prescribing rates and patterns. RESULTS: The numbers of OAD prescriptions rose 1.23-fold. The sulfonylurea (SU) class was the most commonly used OAD, but the prescribing rates for this class declined over time. The biguanide (BG) class was the second most frequently prescribed OAD class and its prescribing rate initially increased, peaked in 2000, and then substantially decreased. The largest increase in prescribing was for acarbose use. The prescribing rates of two new classes of OAD, meglitinide (MG) and thiazolidinedione (TZD), also significantly increased within a short period of time. A trend towards combination therapy was observed away from monotherapy. The SU class was the most commonly prescribed as monotherapy. SU plus BG was the most commonly prescribed dual therapy. Triple oral therapy showed a significant ninefold increase. CONCLUSION: The prescribing rates of OADs are shifting from the older OADs (i.e. SUs) to newer OADs [i.e. alpha-glucosidase inhibitor (AGI), MGs, and TZDs]. The prescribing patterns of OADs are moving toward combination therapy, especially triple oral therapy.

Three-dimensional analysis of post-caloric nystagmus caused by postural change.

In order to record caloric nystagmus (CN) using three-dimensional videonystagmography (3D VNG) 14 subjects were placed in the supine position with the head tilted up 30 degrees relative to the earth's horizontal plane. After the primary-phase CN had terminated, the subjects were repositioned from a supine to a sitting position, with the head anteflexed 30 degrees for recording the post-caloric nystagmus (PCN). In addition, 8 of the original subjects were placed in the supine position but with the head turned 40 degrees to the left so that the irrigated (right) ear was oriented upwards. After the primary-phase CN had terminated, the subjects were rotated by 180 degrees so that the irrigated ear was oriented downwards to record PCN. The results indicated that both methods successfully provoked horizontal and vertical CN. For torsional CN, the irrigated ear up/down method produced a higher provocation rate (75%) than the supine/sitting method (50%), but the difference was not significant. Comparing the provocation rate of the PCN for the horizontal component revealed that the two methods do not differ significantly. However, when comparing the provocation rates of PCN for the vertical component, the irrigated ear up/down method showed a higher rate (82%) than the supine/sitting method (18%). Thus using 3D VNG coupled with postural change during caloric testing, the horizontal or vertical components of PCN can be successfully provoked.

Unusual electrocardiographic manifestations in acute isolated right ventricular infarction.

Electrocardiographic (ECG) manifestation of ST-segment elevation in the precordial leads during acute myocardial infarction is usually due to anterior myocardial infarction secondary to occlusion of the left coronary artery. Herein, we reported a rare case of isolated right ventricular infarction (RVI) in which the ECG mimicked that of acute anterior left ventricular infarction (LVI). A 64-year-old man had acute isolated RVI documented by positive cardiac enzymes and echocardiographic and angiographic findings. He developed hypotension. His ECG showed ST-segment elevation in the precordial leads V1 to V3 simulating that of acute anterior wall infarction. Coronary angiogram revealed total occlusion of the proximal right coronary artery with well-established collaterals from the left coronary artery to the posterior descending artery. This case report reminds us that the presence of diffuse ST-segment elevation in the precordial leads could be due to acute isolated RVI rather than acute anterior LVI. The differentiation of these two entities is important, as their therapies are quite different.

Multicentricity of intraparotid facial nerve schwannomas.

Facial nerve schwannomas are uncommon neoplasms. Multiple schwannomas of the facial nerve in the parotid region are rare. Research regarding the pathogenesis of multiple facial nerve schwannomas is incomplete. Both the neoplastic bridging of tumor cells and tumor multicentricity have been hypothesized. We present a case of multiple intraparotid facial nerve schwannomas. In this case, the histologic features of the tumors support the multicentric hypothesis.

BAD/BCL-[X(L)] heterodimerization leads to bypass of G0/G1 arrest.

The pro-apoptotic molecule BAD binds BCL-[X(L)] or BCL2 and inactivates their survival function. In addition to their anti-apoptotic function, BCL2 and BCL-[X(L)] also delay cell cycle entry from quiescence. We found that the BH3-only molecule BAD also exerted a cell cycle effect. BAD expression resulted in failure to cell cycle block in growth arrest conditions. In low serum and in confluence, fibroblasts constitutively or inducibly expressing BAD persisted in S phase, continued to incorporate BrdU, and exhibited sustained cyclin E/cdk2 activity. Mutation analysis indicated that the cell cycle effect of BAD was not dependent on its phosphorylation status or subcellular localization, but strictly co-segregated with BCL-[X(L)] binding. bclx(-/-) MEFs expressing BAD and bad(-/-) MEFs both arrested in G0/G1 in low serum similar to wild-type controls, suggesting that the ability to overcome the G0/G1 checkpoint resulted from the presence of BAD/BCL-x(L) heterodimers, rather than the absence of BCL-[X(L)] or BAD. These data provide evidence that in addition to regulating apoptosis, the BAD/BCL-[X(L)] heterodimer has a novel cell cycle function.

Importance of hyperhomocysteinemia as a risk factor for venous thromboembolism in a Taiwanese population. A case-control study.

OBJECTIVE: To determine the current status of hyperhomocysteinemia, which is a known risk for venous thrombosis (DVT), in Taiwan. SUBJECTS: 101 unselected patients with a minimum of one episode of deep leg DVT, either initial inpatients or current compliant outpatients in a teaching hospital. METHODS: Various thrombophilic risks, gene polymorphism and clinical predisposition were evaluated. RESULTS AND CONCLUSIONS: Patients presented higher fast total plasma homocysteine (hcy) levels than age- and sex-matched controls did (14.1 vs. 9.94 microM). Based on the 95th percentile of control values, hyperhomocysteinemia had a four- to nine-fold risk for DVT, irrespective of clinical predisposition, as well as other thrombophilic risks surveyed. Polymorphism of a metabolizing enzyme, methylenetetrahydrofolate reductase (MTHFR), was not associated with DVT, although homozygous thermolabile mutation tended to have higher plasma hcy levels. Factor V Leiden was absent in analysis of 80 patients. In complete evaluation (hcy, antithrombin (AT), protein S (PS), protein C (PC), lupus anticoagulant (LA), anticardiolipin antibody) of a subset of 83 patients hyperhomocysteinemia was the most prevalent risk (33.7%), with PC or PS deficiencies following (22.9%). Thus, hyperhomocysteinemia is a prominent risk for DVT in Taiwan.

Low prevalence of coronary arterial disease in Chinese adults with mitral stenosis.

BACKGROUND: We attempted to evaluate the prevalence of coronary artery disease in Chinese adults with severe rheumatic mitral stenosis. METHODS: We prospectively performed coronary angiography in 119 consecutive Chinese patients older than 40 years old (mitral valve area less than 1.5 cm2) who were about to undergo balloon mitral commissurotomy for significant rheumatic mitral stenosis. The exclusion criteria were the presence of left atrial cavitary thrombi or mitral regurgitation greater than grade 3. RESULTS: There were 32 men (26%) and 87 women (74%) with a mean age of 55 +/- 9.7 years (ranging from 40 to 78). Ninety-two patients (77%) were in atrial fibrillation. The prevalence of risk factors for atherosclerotic cardiovascular disease were hypertension (22%), diabetes mellitus (4%), hypercholesterolemia > or = 240 mg/dL (5%), hypertriglyceridemia > or = 150 mg/dL (13%), and cigarette use (7%). Coronary artery disease on angiography was defined as stenosis of more than 50% of the luminal diameter. We found that only 2 patients (1.7%) had coronary artery disease. CONCLUSION: The prevalence of coronary artery disease was much lower than in previous reports, some of which, however, had already pointed out the relatively low prevalence of coronary artery disease in rheumatic mitral disease. The definite mechanisms require further study.

Emerging new frontiers in cardiac pacing: cardiac pacing in heart failure.

Indications for pacing have leapt beyond sinus node dysfunction and atrioventricular (AV) block. Pacing for the purpose of improving hemodynamics has become the prime subject of exploration. Several studies have reported hemodynamic and clinical improvement with bi-ventricular pacing and AV sequential pacing. Data is still pouring in from the various ongoing trials regarding the beneficial effects of these methods of pacing. This is especially true in a subset of patients with intractable heart failure. There are several indicators to identify these patients. Those who have intra-ventricular conduction defects and those who demonstrate hemodynamic improvement after temporary pacing are certainly the candidates who will benefit most from this new form of pacing. Prolonged PR interval or left bundle branch block with intractable heart failure also falls into this category. The rationale of pacing in heart failure is to correct the cardiac dysynchrony that occurs frequently in these patients. Cardiac dysynchrony can occur due to ineffective synchronization between atria and ventricles (AV dysynchrony) or due to lack of synchronization within the two ventricles (ventricular dysynchrony). This is overcome by AV sequential pacing or by multi chamber pacing using the coronary sinus as portal of entry of the electrode into the cardiac vein to pace the left ventricle. Pacing leads and generators have been designed to suit the new found methods of pacing. Clinical trials are in full swing to establish the efficacy of these methods.

Proteolysis of integrin alpha5 and beta1 subunits involved in retinoic acid-induced apoptosis in human hepatoma Hep3B cells.

Our previous report demonstrated that all-trans-retinoic acid (ATRA) induces detachment and death under serum starvation in several human tumor cell lines. In this study, we examined the influence of cell-extracellular matrix interaction on the ability of ATRA to induce apoptosis. Plating of human hepatoma Hep3B cells onto poly-hydroxyethylmethacrylate-coated plates in the absence of serum resulted in the acceleration of ATRA-induced apoptosis. In contrast, ATRA-induced apoptosis was significantly suppressed by plating cells onto Matrigel-coated plates but not suppressed by culturing onto collagen-, laminin-, vitronectin-, or fibronectin-coated plates. Exogenously added soluble collagen, laminin, fibronectin, vitronectin or Matrigel failed to suppress ATRA-induced apoptosis. Results from the adhesion assay indicated that the cell attachment to fibronectin was significantly inhibited by ATRA. Treatment with perturbing antibody against integrin alpha5 or beta1 subunits resulted in promotion of ATRA-induced apoptosis. Moreover, the proteolytic cleavage of alpha5beta1 integrin and focal adhesion kinase (FAK) proteins is linked to the early phase of the ATRA-induced apoptotic process. Furthermore, ATRA-induced detachment, death, and cleavage of alpha5beta1 integrin and FAK were drastically suppressed by plating cells onto Matrigel-coated plates. These findings provide evidence that abrogation of cell adhesion, through proteolysis of alpha5beta1 integrin and FAK, is closely linked to ATRA-induced apoptosis in Hep3B cells.

Protein phosphatase 2A activates the proapoptotic function of BAD in interleukin- 3-dependent lymphoid cells by a mechanism requiring 14-3-3 dissociation.

BAD is a proapoptotic member of the BCL-2 family of proteins, which play a major role in regulating apoptosis in cytokine-dependent hematopoietic cells. The function of BAD is regulated by reversible phosphorylation. Deprivation of survival factors induces BAD dephosphorylation, resulting in apoptosis. Serine-threonine phosphatase activity dephosphorylated BAD in interleukin-3-dependent FL5.12 lymphoid cells. Inhibition of PP2A activity by treatment of cells with PP2A-selective inhibitors, okadaic acid and fostriecin, prevented BAD dephosphorylation in these cells. Conversely, BAD dephosphorylation was not inhibited by the PP1-selective inhibitor tautomycin. In cell-free extracts, BAD phosphatase activity was also inhibited by the PP2A-selective inhibitors okadaic acid and fostriecin, but not by the PP1-specific protein inhibitor I-2. Dissociation of 14-3-3 from BAD was a prerequisite for BAD dephosphorylation in vitro, suggesting a mechanism by which 14-3-3 can regulate the activation of the proapoptotic function of BAD in vivo. Significantly, the inhibition of BAD phosphatase activity rescued cell death induced by survival factor withdrawal in FL5.12 cells expressing wild-type BAD but not phosphorylation-defective mutant BAD. These data indicate that PP2A, or a PP2A-like enzyme, dephosphorylates BAD and, in conjunction with 14-3-3, modulates cytokine-mediated survival.

The C677T mutation of the methylenetetrahydrofolate reductase gene is not associated with the risk of coronary artery disease or venous thrombosis among Chinese in Taiwan.

OBJECTIVES: We sought to investigate the association between the methylenetetrahydrofolate reductase (MTHFR) gene C677T mutation and the risk of coronary artery disease (CAD), myocardial infarction (MI) and venous thrombosis (VT) in a Chinese population in Taiwan. METHODS: The subjects included 218 CAD patients, 107 VT patients, and their age- and sex-matched controls. DNA was extracted from the blood and genotypes were determined by polymerase chain reaction, restriction mapping with HinfI and gel electrophoresis. RESULTS: The distribution of MTHFR genotypes was similar in the CAD cases and controls; the genotype TT was present in 6.0% of CAD patients, as compared to 6.9% of CAD control subjects (p = 0.165; odds ratio = 0. 86; 95% confidence interval = 0.40-1.85). The frequency of the T allele was also similar in CAD cases and controls (25.5% vs. 24.8%; p = 0.788). There was no significant association between TT homozygosity and the risk of MI. The genotype distributions and the frequency of the T allele were also similar in VT cases and controls. CONCLUSIONS: Our data suggest that there is no association between the C677T mutation of the human MTHFR gene and the risk of CAD or VT among Chinese in Taiwan.

Sinoatrial nodal artery aneurysm with right ventricular outflow tract compression: report of a case.

We described a 16-year-old boy with sinoatrial nodal (SAN) artery aneurysm that drained into right atrium and compressed right ventricular outflow tract. The patient was clinically asymptomatic. Hemodynamic study revealed a 15 mm Hg peak systolic pressure gradient at right ventricular outflow tract. The fistula was successfully excised without sequalae. Cathet. Cardiovasc. Intervent. 51:328-331, 2000.