Comparison of rates of and charges from pregnancy complications in users of extended and cyclic combined oral contraceptive (COC) regimens: a brief report

Objective

To evaluate pregnancy complication rates and related charges in users of 84/7, 21/7 and 24/4 combined oral contraceptives (COCs).

Study design

Data were obtained from the i3 InVision Data Mart™ retrospective claims database. Subjects were aged 15–40 years, first prescribed a COC between 1/1/2006 and 4/1/2011 and continuously insured for ≥ 1 year. 84/7 users were matched 1:1 to 21/7 and 24/4 users.

Results

Pregnancy-related complication rates and associated charges were significantly lower with 84/7 vs. 21/7 and 24/4 regimens.

Conclusion

Preliminary data suggest 84/7 regimens may be associated with fewer pregnancy complications and lower related charges.     

Increased body temperature accelerates aggregation of the Leu-68-->Gln mutant cystatin C, the amyloid-forming protein in hereditary cystatin C amyloid angiopathy.

Hereditary cystatin C amyloid angiopathy is adominantly inherited disorder, characterized by dementia, paralysis, and deathfrom cerebral hemorrhage in early adult life. A variant of the cysteineproteinase inhibitor, cystatin C, is deposited as amyloid in the tissues of thepatients and their spinal-fluid level of cystatin C is abnormally low. Thedisease-associated Leu-68-->Gln mutant (L68Q) cystatin C has been produced inan Escherichia coli expression system and isolated by use of denaturing buffers,immunosorption, and gel filtration. Parallel physicochemical and functionalinvestigations of L68Q-cystatin C and wild-type cystatin C revealed that bothproteins effectively inhibit the cysteine proteinase cathepsin B (equilibriumconstants for dissociation, 0.4 and 0.5 nM, respectively) but differconsiderably in their tendency to dimerize and form aggregates. While wild-typecystatin C is monomeric and functionally active even after prolonged storage atelevated temperatures, L68Q-cystatin C starts to dimerize and lose biologicalactivity immediately after it is transferred to a nondenaturing buffer. Thedimerization of L68Q-cystatin C is highly temperature-dependent, with a rise inincubation temperature from 37 to 40 degrees C resulting in a 150% increase indimerization rate. The aggregation at physiological concentrations is likewiseincreased at 40 compared to 37 degrees C, by approximately 60%. These propertiesof L68Q-cystatin C have bearing upon our understanding of the pathophysiologicalprocess of hereditary cystatin C amyloid angiopathy. They might also be ofclinical relevance, since medical intervention to abort febrile periods ofcarriers of the disease trait may reduce the in vivo formation of L68Q-cystatinC aggregates.     

Missense models [Gustm(E536A)Sly,Gustm(E536Q)Sly,and Gustm(L175F)Sly] of murine mucopolysaccharidosis type VII produced by targeted mutagenesis

Human mucopolysaccharidosis VII (MPS VII, Sly syndrome) results from a deficiency of beta-glucuronidase (GUS) and has been associated with a wide range in severity of clinical manifestations. To study missense mutant models of murine MPS VII with phenotypes of varying severity, we used targeted mutagenesis to produce E536A and E536Q, corresponding to active-site nucleophile replacements E540A and E540Q in human GUS, and L175F, corresponding to the most common human mutation, L176F. The E536A mouse had no GUS activity in any tissue and displayed a severe phenotype like that of the originally described MPS VII mice carrying a deletion mutation (gus(mps/mps)). E536Q and L175F mice had low levels of residual activity and milder phenotypes. All three mutant MPS models showed progressive lysosomal storage in many tissues but had different rates of accumulation. The amount of urinary glycosaminoglycan excretion paralleled the clinical severity, with urinary glycosaminoglycans remarkably higher in E536A mice than in E536Q or L175F mice. Molecular analysis showed that the Gus mRNA levels were quantitatively similar in the three mutant mouse strains and normal mice. These mouse models, which mimic different clinical phenotypes of human MPS VII, should be useful in studying pathogenesis and also provide useful models for studying enzyme replacement therapy and targeted correction of missense mutations.     

Intestinal alkaline phosphatase in patients with liver disease

Electrophoretic separation of the different isoenzymes of alkaline phosphatase was done, using polyacrylamide gel electrophoresis. In some patients with liver disease, two isoenzymes of alkaline phosphatase were detected—one corresponding to liver and the other, to intestinal fraction. In 17 of 51 patients with nutritional cirrhosis and in 6 of 14 with chronic active hepatitis, the intestinal band was observed in their fasting sera. Intestinal isoenzyme was not found, however, in the fasting sera of 23 patients with viral hepatitis, 16 with metastatic disease to the liver, 11 with obstructive jaundice or 33 healthy volunteers. The presence of intestinal isoenzyme was not dependent on the value of total serum phosphatase activity.Supported in part by Grant IN-27L P/4 from the American Cancer Society, grants from the Kelsey-Leary Foundation of Houston, and Grants RR 134 and 350 from the General Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health.Presented in part at the meeting of the Southern Section of the American Federation for Clinical Research, New Orleans, Louisiana, January 1971.     

Immunochemical evidence for a common variable region in three immunoglobulin classes in the same individual.

One IgG1(kappa), one IgM(kappa), and one IgA1(kappa) monoclonal (M)-component were purified from one human serum. Rabbit antisera were raised against the IgG and IgM M-components and were absorbed until specific for idiotypic determinants on these molecules. All three M-components gave reactions of immunological identity when tested by double radial immunodiffusion with either of the two idiotype-specific antisera. Both heavy and light chains were isolated from each of the three M-components and all preparations inhibited formation of idiotypic precipitates. None of these preparations formed precipitates with idiotype-specific antisera alone. When heavy or light chains of one M-component were hybridized with light or heavy chains from the other M-components the resultant molecules precipitated with anti-idiotypic serum. Hybrids with chains from polyclonal IgG were not precipitable with such antiserum. These results indicate that the variable region of the heavy chains of these M-components of three different immunoglobulin classes are closely similar, if not identical.     

Propafenone--a new agent for the treatment of ventricular arrhythmias

Over the last several years a number of new and potent antiarrhythmic agents have been developed. One of these promising new drugs, propafenone hydrochloride (Rhythmol), will soon be available for use in this country. Although similar in some aspects to flecainide and encainide, the drug possesses some unique characteristics. The purpose of this review is to summarize the pharmacologic and physiologic effects of propafenone and to outline its clinical use.     

Glycosylation-independent targeting enhances enzyme delivery to lysosomes and decreases storage in mucopolysaccharidosis type VII mice

Enzyme-replacement therapy is an established means of treating lysosomal storage diseases. Infused therapeutic enzymes are targeted to lysosomes of affected cells by interactions with cell-surface receptors that recognize carbohydrate moieties, such as mannose and mannose 6-phosphate, on the enzymes. We have tested an alternative, peptide-based targeting system for delivery of enzymes to lysosomes in a murine mucopolysaccharidosis type VII (MPS VII) model. This strategy depends on the interaction of a fragment of insulin-like growth factor II (IGF-II), with the IGF-II binding site on the bifunctional, IGF-II cation-independent mannose 6-phosphate receptor. A chimeric protein containing a portion of mature human IGF-II fused to the C terminus of human beta-glucuronidase was taken up by MPS VII fibroblasts in a mannose 6-phosphate-independent manner, and its uptake was inhibited by the addition of IGF-II. Furthermore, the tagged enzyme was delivered effectively to clinically significant tissues in MPS VII mice and was effective in reversing the storage pathology. The tagged enzyme was able to reduce storage in glomerular podocytes and osteoblasts at a dose at which untagged enzyme was much less effective. This peptide-based, glycosylation-independent lysosomal targeting system may enhance enzyme-replacement therapy for certain human lysosomal storage diseases.     

Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis

The protein defective in hereditary hemochromatosis, called HFE, is similar to MHC class I-type proteins and associates with beta2-microglobulin (beta2M). Its association with beta2M was previously shown to be necessary for its stability, normal intracellular processing, and cell surface expression in transfected COS cells. Here we use stably transfected Chinese hamster ovary cell lines expressing both HFE and beta2M or HFE alone to study the effects of beta2M on the stability and maturation of the HFE protein and on the role of HFE in transferrin receptor 1 (TfR1)-mediated iron uptake. In agreement with prior studies on other cell lines, we found that overexpression of HFE, without overexpressing beta2M, resulted in a decrease in TfR1dependent iron uptake and in lower iron levels in the cells, as evidenced by ferritin and TfR1 levels measured at steady state. However, overexpression of both HFE and beta2M had the reverse effect and resulted in an increase in TfR1-dependent iron uptake and increased iron levels in the cells. The HFE-beta2M complex did not affect the affinity of TfR1 for transferrin or the internalization rate of transferrin-bound TfR1. Instead, HFE-beta2M enhanced the rate of recycling of TfR1 and resulted in an increase in the steady-state level of TfR1 at the cell surface of stably transfected cells. We propose that Chinese hamster ovary cells provide a model to explain the effect of the HFE-beta2M complex in duodenal crypt cells, where the HFE-beta2M complex appears to facilitate the uptake of transferrin-bound iron to sense the level of body iron stores. Impairment of this process in duodenal crypt cells leads them to be iron poor and to signal the differentiating enterocytes to take up iron excessively after they mature into villus cells in the duodenum of hereditary hemochromatosis patients.     

Carbonic anhydrase XIV is enriched in specific membrane domains of retinal pigment epithelium, Muller cells, and astrocytes

Carbonic anhydrases (CAs) are ubiquitous enzymes important to many cell types throughout the body. They help determine levels of H(+) and HCO(-)(3) and thereby regulate intracellular and extracellular pH and volume. CA XIV, an extracellular membrane-bound CA, was recently shown to be present in brain and retina. Here, we analyze the subcellular distribution of CA XIV in retina by high-resolution immunogold cytochemistry and show that the distribution in retina (on glial cells but not neurons) is different from that reported for brain (on neurons but not glia). In addition, CA XIV is strongly expressed on retinal pigment epithelium (RPE). The specific membrane domains that express CA XIV were endfoot and nonendfoot membranes on Muller cells and astrocytes and apical and basolateral membranes of RPE. Gold particle density was highest on microvilli plasma membranes of RPE, where it was twice that of glial endfoot and Muller microvilli membranes and four times that of other glial membrane domains. Neither neurons nor capillary endothelial cells showed detectable labeling for CA XIV. This enrichment of CA XIV on specific membrane domains of glial cells and RPE suggests specialization for buffering pH and volume in retinal neurons and their surrounding extracellular spaces. We suggest that CA XIV is the target of CA inhibitors that enhance subretinal fluid absorption in macular edema. In addition, CA XIV may facilitate CO(2) removal from neural retina and modulate photoreceptor function.     

Transgene produces massive overexpression of human beta -glucuronidase in mice,lysosomal storage of enzyme,and strain-dependent tumors

beta-Glucuronidase (GUSB) is a lysosomal enzyme important in the normal step-wise degradation of glycosaminoglycans. Deficiency of GUSB causes the lysosomal storage disease mucopolysaccharidosis VII (MPS VII, Sly disease). Affected patients have widespread progressive accumulation of beta-glucuronide-containing glycosaminoglycans in lysosomes. Enzyme replacement, bone marrow transplantation, and gene therapy can correct lysosomal storage in the MPS VII mouse model. Gene therapy in MPS VII patients and animals may result in massive overexpression of GUSB in individual tissues, and the toxicity of such overexpression is incompletely investigated. To gain insight into the effect of massive overexpression of GUSB, we established 19 transgenic mouse lines, two of which expressed very high levels of human GUSB in many tissues. The founder overexpressing mice had from >100- to several thousand-fold increases in tissue and serum GUSB. The enzyme expression in most tissues decreased in subsequent generations in one line, and expression in liver and marrow fell in subsequent generations of the other. Both lines had morphologically similar widespread lysosomal storage of GUSB and secondary elevations of other lysosomal enzymes, a finding characteristic of lysosomal storage disease. One line developed tumors, and one did not. These transgenic models show that massive overexpression of a lysosomal enzyme can be associated with dramatic morphological alterations, which, at least in one of the two lines, had little clinical consequence. For the other transgenic line, the high frequency of tumor development in F(2) FVB progeny suggests that the vector used to generate the transgenic lines has an integration site-dependent potential to be oncogenic, at least in this strain background.