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.

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.

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.

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.

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.

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.

Marijuana effect and delta-9-tetrahydrocannabinol plasma level.

delta-9-Tetrahydrocannabinol (THC) kinetics and dynamics of self-reported psychologic "high" effect are analyzed in six subjects who smoked marijuana cigarettes of three different potencies. Correlation of the pharmacologic response to smoking a marijuana cigarette with plasma THC levels was done with compartmental models and phase plots. It was concluded that the effect compartment for psychologic high is directly coupled to the central (plasma) compartment. It was observed that effect is directly proportional to mean THC levels from approximately 1 to 4 hr after the start of smoking a marijuana cigarette.

The Gln-Arg 191 polymorphism of the human paraoxonase gene is not associated with the risk of coronary artery disease among Chinese in Taiwan.

Paraoxonase (PON1) is a high density lipoprotein-associated enzyme capable of hydrolyzing lipid peroxides, and thus, might protect lipoproteins from oxidation. A common polymorphism due to an amino acid substitution (Gln-Arg) at codon 191 is considered to be a major determinant of variation in serum PON1 activity. Recent studies have suggested that the PON1-191 polymorphism is an independent risk factor for coronary atherosclerosis in patients with or without diabetes mellitus. The association of PON1-191 polymorphism genotypes and coronary artery disease (CAD) among Chinese subjects in Taiwan was examined. The genotype of 218 angiographically documented CAD patients and the same number of age- and sex-matched control subjects was determined. Genotypes AA, AB and BB were present in 25 (11%), 102 (47%) and 91 (42%) of control subjects, respectively, and in 30 (14%), 96 (44%) and 92 (42%) of CAD patients, respectively (chi2 = 0.57, P = 0.75 between groups). The frequency of the A allele was 0.36 for the control group and 0.35 for CAD patients (P = 0.94). No significant differences in the PON1-191 genotype frequencies could be found between groups when multivariate logistic regression analysis was performed, or different subgroups of age, sex or risk factors were analyzed. Among control subjects, there was also no significant difference between genotypes of the PON1-191 polymorphism and various clinical and lipid variables. In conclusion, our data suggest that there is no association between the Gln-Arg 191 polymorphism of the human PON1 gene and CAD among Chinese subjects in Taiwan.

Insertional tagging of at least two loci associated with resistance to adenine arabinoside in Toxoplasma gondii, and cloning of the adenosine kinase locus.

A genetic approach has been exploited to investigate adenylate salvage pathways in the protozoan parasite Toxoplasma gondii, a purine auxotroph. Using a new insertional mutagenesis vector designed to facilitate the rescue of tagged loci even when multiple plasmids integrate as a tandem array, 15 independent clonal lines resistant to the toxic nucleoside analog adenine arabinoside (AraA) were generated. Approximately two-thirds of these clones lack adenosine kinase (AK) activity. Parallel studies identified an expressed sequence tag (EST) exhibiting a small region of weak similarity to human AK, and this locus was tagged in several AK-deficient insertional mutants. Library screening yielded full-length cDNA and genomic clones. The T. gondii AK gene contains five exons spanning a approximately 3 kb locus, and the predicted coding sequence was employed to identify additional AK genes and cDNAs in the GenBank and dbEST databases. A genomic construct lacking essential coding sequence was used to create defined genetic knock-outs at the T. gondii AK locus, and AK activity was restored using a cDNA-derived minigene. Hybridization analysis of DNA from 13 AraA-resistant insertional mutants reveals three distinct classes: (i) AK-mutants tagged at the AK locus; (ii) AK- mutants not tagged at the AK locus, suggesting the possibility that another locus may be involved in regulating AK expression; and (iii) mutants with normal AK activity (potential transport mutants).

On-line multiplane transesophageal echocardiography for balloon mitral commissurotomy.

This study describes in detail the technique and results of on-line multiplane transesophageal echocardiographic guidance of balloon mitral commissurotomy in 150 consecutive patients with symptomatic mitral stenosis. The mitral valve area improved significantly and there were no in-hospital deaths, strokes, or emergency valve operations.

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.

Noninvasive predictors of systemic embolism in mitral stenosis. An echocardiographic and clinical study of 500 patients.

Few predictors of systemic embolism in patients with mitral stenosis have been identified by noninvasive methods. This study used the most powerful noninvasive diagnostic tool, transthoracic echocardiography, as well as other noninvasive clinical information to look for predictors. Five hundred consecutive patients with a mitral valve area of 2 cm2 or less were studied. They were divided into two groups: group 1 consisted of 143 patients with a history of systemic embolism and group 2 consisted of 357 patients with no history of systemic embolism. Using a stepwise logistic regression on a random subsample of 400 patients, 4 independent predictors were found: the presence of atrial fibrillation (p = 0.003, relative risk [RR] = 2.3, 95% CI = 1.3, 4.2), the absence of significant tricuspid regurgitation (p = 0.008, RR = 2.5, 95% CI = 1.3, 4.9), the absence of aortic regurgitation (p = 0.022, RR = 2.2, 95% CI = 1.1, 4.2), and the presence of left atrial smoky echoes (p = 0.039, RR = 1.7, 95% CI = 1.1, 3.0). When the above model, together with significant interaction terms, was applied to the remaining 100 patients, both the Hosmer-Lemeshow and Brown goodness-of-fit statistics were not significant (p = 0.888 and p = 0.248, respectively), indicating that the fit was adequate and the model was validated. Thus, important noninvasive predictors of systemic embolism in patients with mitral stenosis can easily be obtained. Subgroups of patients with high risk of systemic embolism can be identified. This may refine our therapeutic strategies to prevent the catastrophe of systemic embolism.

Moving right atrial mass associated with hepatoma. Two cases detected by echocardiography.

Hepatoma with right atrial (RA) metastasis is rare, and to our knowledge, the echocardiographic description of a RA mass associated with hepatoma has never been described. Herein we report two cases of hepatoma, whose two-dimensional echocardiograms demonstrated a RA mass protruding into right ventricle during diastole, mimicking RA myxoma. However, in contrast to RA myxoma, these RA masses could be traced to the inferior venae cavae, which were dilated and filled with tumor echoes. Since prompt diagnosis and removal of these RA masses might prevent sudden cardiac death, we advocate performing echocardiographic examination in patients with hepatoma, who have cardiac symptoms or signs.

Imaging of multiple coronary artery fistulas to right ventricle by transthoracic and transesophageal echocardiography.

A 20-year-old woman presented with extremely rare multiple coronary artery fistulas with left circumflex and right coronary arteries as the feeding vessels and two distinct sites of drainage into the posterior wall of the right ventricle near the apex in close proximity. The large left fistula was well depicted by transthoracic echocardiography, whereas the transesophageal approach better delineated part of the smaller right fistula.

Preoperative and postoperative echocardiographic studies of pulmonic valvular endocarditis.

The echocardiographic manifestations of pulmonic valvular endocarditis in a patient with underlying heart disease consisting of a ventricular septal defect and infundibular stenosis are reported. The abnormal shaggy echoes observed on the pulmonic valve were confirmed to be vegetations based on surgical and pathologic findings. This was further proven by the disappearance of the shaggy echoes after surgical excision of the vegetations. We conclude that echocardiograms can detect the presence and disappearance of pulmonic valvular vegetations, which may be of aid in the diagnosis of pulmonic valvular endocarditis.

Perforated aneurysm of the anterior mitral valve. A Doppler and two-dimensional echocardiographic report.

Antemortem diagnosis of a perforated MV aneurysm by Doppler echocardiography, as well as two-dimensional echocardiography (2-DE), has not been reported. Herein we present such a case.

Video-assisted cardiac surgery. Preliminary experience in reoperative mitral valve surgery.

OBJECTIVES: Video-assisted endoscopic techniques had been applied in the surgical correction of patent ductus arteriosus, vascular ring, or coronary artery disease. However, it has been used only recently in the correction of reoperative mitral valve lesions. DESIGN: Video-assisted cardiac operations were performed on four patients who had received surgical interventions on their mitral valves and needed emergent reoperation. PATIENTS: Four patients (3 men and 1 woman) received emergency surgery from September to December 1995 for thrombosis of mechanical mitral prosthesis (2 patients) and severe mitral regurgitation with previously failed mitral valve repair (2 patients). Six previous operations had been performed on these mitral valves. Patient ages ranged from 26.7 to 68.1 years (mean, 47.3 years). Preoperatively, acute pulmonary edema occurred in two patients, cerebral emboli occurred in one patient, and sepsis was found in one patient. Mechanical ventilatory support was used in two patients before operation. INTERVENTION: The operations were performed through right anterior minithoracotomy, guided by video-assisted endoscopic techniques with femoro-femoral extracorporeal circulation. The operative procedures were thrombectomy of mitral prosthesis in two patients, mitral valve repair in one patient, and mitral valve replacement in one patient. RESULTS: The duration of extracorporeal circulation was 166 to 320 min (222 +/- 67 min) and the operation time was 4.6 to 6.8 h (6.1 +/- 1.0 h). All patients recovered from the operations rapidly with uneventful postoperative courses except 1 patient who had sepsis preoperatively and died 2 months later. CONCLUSION: Our experience demonstrates that video-assisted cardiac surgery is technically feasible and could be performed in reoperation of the mitral valve.

Importance of adequate gas-mixing in contrast echocardiography.

Microbubble formation has been accepted as the mechanism producing contrast echoes. Comparisons of the contrast effects of various agents have been studied extensively, but the importance of gas-mixing has been less appreciated. To test the hypothesis that good gas-mixing, by facilitating microbubble formation, would enhance contrast effect, this study compared the contrast echocardiograms of ten adult patients before and after mixing carbon dioxide with various contrast agents. Contrast agents tested included a 5 percent glucose in water, vitamin B complex, vitamin C, and Cardiogreen solutions. First, we recorded echocardiograms by injecting each diluted contrast solution alone, then repeated the examinations using 10 ml of each diluted solution with 1 ml of carbon dioxide (CO2), mixed by means of a four-way stopcock. Satisfactory or excellent results were obtained in seven of ten, ten of ten, ten of ten, and ten of ten tests, respectively, after thorough gas-mixing, vs one of ten, seven of ten, eight of ten, and six of ten, respectively, before gas-mixing. We conclude that the addition of sufficient amounts of gas, followed by thorough mixing, is of great importance in contrast echocardiography. Consistently good results can be achieved with vitamin C, vitamin B or Cardiogreen solutions by this simple and safe method.

Minimal access surgical techniques in coronary artery bypass grafting for triple-vessel disease.

BACKGROUND: Minimal access surgical techniques in coronary artery bypass grafting have been used mainly in the management of single-vessel disease. METHODS: Fifteen patients, 11 men and 4 women with a mean age of 64.1 years (range, 35.7 to 78.0 years), underwent operation for triple-vessel disease using minimal access techniques. The procedures were performed through a limited left parasternal thoracotomy using femorofemoral extracorporeal circulation. The myocardium was protected by the antegrade infusion of cold blood cardioplegic solution while the aorta was cross-clamped. RESULTS: Under direct vision, the left saphenous vein grafts were connected sequentially to the diagonal branch, obtuse marginal branch, and posterior descending branch, and the left internal thoracic artery graft was anastomosed to the left anterior descending artery in each patient. The mean aortic cross-clamp time was 86 +/- 17 minutes (range, 67 to 125 minutes). The mean duration of extracorporeal circulation was 112 +/- 22 minutes (range, 82 to 162 minutes). The postoperative course was uneventful in all patients. Follow-up was complete in all patients at a mean of 7.4 months (range, 6.0 to 8.5 months), and there were no late deaths or angina. Coronary angiography in 8 patients showed patent grafts. CONCLUSIONS: Our experience demonstrates that minimal access surgical techniques in coronary artery bypass grafting are technically feasible and may be an alternative approach in the surgical revascularization of triple-vessel disease.