Enoxaparin Use and Adverse Events in Outpatients With a Continuous Flow Left Ventricular Assist Device at a Single Institution.

BACKGROUND: Patients with left ventricular assist devices (LVADs) are anticoagulated with warfarin and may receive enoxaparin bridging for a subtherapeutic international normalized ratio (INR). There is no guideline regarding enoxaparin bridging in LVAD patients and a dosing strategy to ensure efficacy and safety is uncertain. OBJECTIVE: The objective was to characterize the use of enoxaparin bridging for subtherapeutic INRs and its impact on thrombotic or major bleeding events (MBE) in patients with an LVAD. METHODS: A retrospective review from 6/1/17 to 6/30/18 was performed. Patients with an LVAD were excluded if they had less than 60 days of outpatient anticoagulation or age <18 years old. Patients were divided into 2 cohorts based on enoxaparin exposure. MBE and thrombotic events were classified as related to enoxaparin if events occurred while receiving enoxaparin and up to 7 days or 30 days, respectively, after discontinuation. RESULTS: Seventy-one LVAD patients met inclusion criteria and 50 patients received enoxaparin bridging. Therapeutic-dose enoxaparin was initiated at a mean INR of 1.8 for a mean duration of 2.8 days. In the enoxaparin exposure group, one MBE occurred 6 days after enoxaparin discontinuation, coinciding with an INR increase from 1.8 to 4.7. One thrombotic event occurred 2 days after enoxaparin discontinuation at an INR of 5.0. CONCLUSION: This institution's bridging strategy of therapeutic-dose enoxaparin with a short duration has a low rate of bleeding and thrombotic events. Additional prospective studies of anticoagulation bridging based on characteristics such as type of LVAD device are warranted.

Clinical and Financial Outcomes Evaluation of Multimodal Pharmacist Warfarin Management of a Statewide Urban and Rural Population.

PURPOSE: To evaluate the efficacy, safety, and indirect financial outcomes of pharmacist face-to-face warfarin management with telephone-based distance management utilizing local laboratories or patient self-testing (PST). METHODS: A retrospective analysis of a clinic population of 336 patients on established warfarin therapy distributed statewide in rural and urban settings over a 6-month period was conducted. Participants were stratified into face-to-face management, telephone-based management utilizing local laboratory testing, and telephone-based management utilizing PST. RESULTS: The primary outcome of international normalized ratio (INR) time in therapeutic range (TTR) for face-to-face management was significantly greater than distance management utilizing local laboratory testing (69.0% vs 60.5%, P = .0032). No difference was observed between face-to-face management and PST (69.0% vs 68.0%, P = .25). No significant difference in bleeding or thromboses was observed. Although increased clinician time was utilized during face-to-face encounters compared to telephone encounters (8.7-minute face-to-face, 5.5-minute local laboratory, and 5.4-minute PST), face-to-face encounters tended to be billable at lower levels, whereas telephone-based encounters were billable at higher levels. CONCLUSION: A multimodal approach to pharmacist warfarin management of a patient population distributed statewide in rural and urban locations is effective despite TTR differences associated with INR testing used in distance management. PST may improve warfarin treatment outcomes and adherence in distance management, particularly when the use of alternative oral anticoagulants is inappropriate. Although time and billing differences between face-to-face and distance management exist, clinical and safety outcomes remain acceptable despite encounter complexity and support reimbursement of pharmacist anticoagulation management in all settings.

Comparing Clinical Outcomes of a Pharmacist-Managed Diabetes Clinic to Usual Physician-Based Care.

BACKGROUND: This study analyzed the impact of a pharmacist-managed diabetes clinic on clinical outcomes compared to usual care received from primary care providers (PCPs). This comparison may more definitively demonstrate the value of pharmacist management of chronic disease states. METHODS: Retrospective observational cohort study conducted in patients referred to a pharmacist-managed pharmacotherapy (PT) clinic from July 2009 to October 2014. RESULTS: For the primary outcome, the absolute change in A1c during the usual care phase was +1.53% (95% confidence interval [CI]: 1.10-1.96, P < .0001) versus an absolute change of -1.63% (95% CI: -1.28 to -1.97, P < .0001) in the intervention phase. For secondary outcomes, diabetes-related hospitalizations (10 vs 6, P = .104) and emergency room (ER) visits (27 vs 8, P = .049) decreased in the intervention phase compared to the usual care phase. The rate of diabetes-related interventions made per patient per year in the usual care phase was 2.7 versus 11.1 in the intervention phase ( P < .0001). CONCLUSION: Patients referred to the PT clinic had worsening blood glucose control prior to referral, and their control improved after referral to the clinic. Furthermore, there was an improvement in all diabetes-related outcomes in the intervention phase compared to the usual care phase.

Somatic cells regulate maternal mRNA translation and developmental competence of mouse oocytes.

Germ cells divide and differentiate in a unique local microenvironment under the control of somatic cells. Signals released in this niche instruct oocyte reentry into the meiotic cell cycle. Once initiated, the progression through meiosis and the associated programme of maternal messenger RNA translation are thought to be cell autonomous. Here we show that translation of a subset of maternal mRNAs critical for embryo development is under the control of somatic cell inputs. Translation of specific maternal transcripts increases in oocytes cultured in association with somatic cells and is sensitive to EGF-like growth factors that act only on the somatic compartment. In mice deficient in amphiregulin, decreased fecundity and oocyte developmental competence is associated with defective translation of a subset of maternal mRNAs. These somatic cell signals that affect translation require activation of the PI(3)K-AKT-mTOR pathway. Thus, mRNA translation depends on somatic cell cues that are essential to reprogramme the oocyte for embryo development.

Evaluation of dosing and clinical outcomes in patients undergoing conversion of insulin glargine to insulin detemir.

STUDY OBJECTIVES: To evaluate the dose and frequency of insulin detemir for patients with diabetes mellitus undergoing conversion from insulin glargine to insulin detemir, and to assess glycemic control, weight gain, and risk of hypoglycemia after converting to insulin detemir. DESIGN: Retrospective medical record review. SETTING: Large academic medical center. PATIENTS: Thirty-one patients with type 1 (10 patients) or type 2 (21 patients) diabetes who were converted from insulin glargine to insulin detemir by usual practice between January 1, 2006, and March 3, 2007, after an Iowa Medicaid formulary switch. MEASUREMENT AND MAIN RESULTS: Data were collected for 12 months after conversion from insulin glargine to insulin detemir. No significant change in mean basal insulin dose was noted in patients with type 1 diabetes at the end of 12 months (insulin detemir 31.1 units/day vs baseline insulin glargine 32.0 units/day, p=0.89; insulin detemir 0.41 unit/kg/day vs baseline insulin glargine 0.42 unit/kg/day, p=0.91). In patients with type 2 diabetes, however, the mean basal insulin dose was significantly higher with insulin detemir compared with baseline insulin glargine (74.2 vs 55.8 units/day, p=0.002; 0.68 vs 0.48 unit/kg/day, p=0.001) at the end of 12 months. Twice-daily administration was required in a higher proportion of patients receiving insulin detemir (15 patients [48%]) at 12 months compared with insulin glargine (4 patients [13%]) at baseline (p=0.043). A significant change in hemoglobin A(1c) was not observed in patients with type 1 diabetes (9.7% with insulin detemir vs 9.3% with insulin glargine, p=0.41) or type 2 diabetes (9.4% with insulin detemir vs 9.7% with insulin glargine at baseline, p=0.57) despite the use of higher insulin detemir doses in patients with type 2 diabetes. No significant differences in weight or frequency of hypoglycemia were noted. CONCLUSION: Treatment with insulin detemir appears to require more frequent administration and higher insulin doses compared with insulin glargine in patients with type 2 diabetes, with 33% higher doses, on average, observed in this study. These findings suggest that a unit-for-unit conversion from insulin glargine to insulin detemir, as suggested by the manufacturer of insulin detemir, may not be adequate in patients with type 2 diabetes.

Genome-wide analysis of translation reveals a critical role for deleted in azoospermia-like (Dazl) at the oocyte-to-zygote transition.

Oocyte maturation, fertilization, and early embryonic development occur in the absence of gene transcription. Therefore, it is critical to understand at a global level the post-transcriptional events that are driving these transitions. Here we used a systems approach by combining polysome mRNA profiling and bioinformatics to identify RNA-binding motifs in mRNAs that either enter or exit the polysome pool during mouse oocyte maturation. Association of mRNA with the polysomes correlates with active translation. Using this strategy, we identified highly specific patterns of mRNA recruitment to the polysomes that are synchronized with the cell cycle. A large number of the mRNAs recovered with translating ribosomes contain motifs for the RNA-binding proteins DAZL (deleted in azoospermia-like) and CPEB (cytoplasmic polyadenylation element-binding protein). Although a Dazl role in early germ cell development is well established, no function has been described during oocyte-to-embryo transition. We demonstrate that CPEB1 regulates Dazl post-transcriptionally, and that DAZL is essential for meiotic maturation and embryonic cleavage. In the absence of DAZL synthesis, the meiotic spindle fails to form due to disorganization of meiotic microtubules. Therefore, Cpeb1 and Dazl function in a progressive, self-reinforcing pathway to promote oocyte maturation and early embryonic development.

PDE4D and PDE4B function in distinct subcellular compartments in mouse embryonic fibroblasts.

Signaling through cAMP regulates most cellular functions. The spatiotemporal control of cAMP is, therefore, crucial for differential regulation of specific cellular targets. Here we investigated the consequences of PDE4B or PDE4D gene ablation on cAMP signaling at a subcellular level using mouse embryonic fibroblasts. PDE4B ablation had no effect on the global or bulk cytosol accumulation of cAMP but increased both basal and hormone-dependent cAMP in a near-membrane pool. Conversely, PDE4D ablation enhanced agonist-induced cAMP accumulation in the bulk cytosol as well as at the plasma membrane. Both PDE4B and PDE4D ablation significantly modified the time course and the level of isoproterenol-induced phosphorylation of vasodilator-stimulated phosphoprotein, a membrane cytoskeletal component. A second membrane response through Toll-like receptor signaling, however, was only affected by PDE4B ablation. PDE4D but not PDE4B ablation significantly prolonged cAMP-response element-binding protein-mediated transcription. These findings demonstrate that PDE4D and PDE4B have specialized functions in mouse embryonic fibroblasts with PDE4B controlling cAMP in a discrete subdomain near the plasma membrane.

Receptors for leptin in the otic labyrinth and the cochlear-vestibular nerve of guinea pig are modified in hormone-induced anorexia.

Metabolic syndromic inner ear pathology is a recognized condition in clinical practice but the possible causes remain controversial. We have previously reported that chronically-implanted estrogen implants in guinea pig results in hyperprolactinemia and hearing loss together with otic bone dysmorphology. The animals also present with anorexia. The hormone leptin has major roles in the regulation of satiety as well as bone metabolism and so we hypothesized that leptin might contribute to pathology of the otic labyrinth. We employed immunohistochemistry to investigate leptin receptor (ObR) expression. In control animals, ObR immunolabeling was not detected in the bone of the otic capsule but immunolabeling was observed in the cochlear-vestibular nerve. The labeling was associated with the astrocytic glial dome area, which marks the transition between central and peripheral parts of the nerve. In estrogen-treated animals, positive-ObR immunolabeling was observed in osteoblasts in new bone of the otic capsule and the ObR labeling was reduced in the cochlear-vestibular nerve compared to controls. The data provide evidence that leptin may target the labyrinth - affecting the bone and the nerve - and so could contribute to ongoing protection of the inner ear. Leptin disturbance might contribute to metabolic syndromes involving the audiovestibular system.

Risks and benefits of long-term bisphosphonate therapy.

PURPOSE: The risks and benefits of long-term bisphosphonate therapy were reviewed. SUMMARY: Bisphosphonates are used first line in the treatment of osteoporosis due to their demonstrated ability to reduce the risk of fracture. Benefits on bone mineral density (BMD) and fracture prevention appear to be sustained for 7-10 years; however, the lack of clinical trials extending beyond this treatment period has raised the question of how long therapy should be continued. Furthermore, some reports have suggested the potential for an increased risk of fragility fractures due to oversuppression of bone turnover with long-term bisphosphonate use. Though rare, these fragility fractures appear to have a specific fracture pattern and tend to occur after 3-8 years of bisphosphonate therapy. The use of a drug holiday has been considered as an option to avoid this risk. Data suggest that bisphosphonates have a residual therapeutic effect after being stopped and that fracture benefit appears to be sustained 2-5 years after discontinuation. This sustained benefit, however, was observed only in women with good adherence who were treated with bisphosphonate therapy for at least 2 years and whose BMD was not in the osteoporotic range before discontinuation. CONCLUSION: The benefits of long-term bisphosphonate therapy in patients at high risk of fracture likely outweigh the risks. In lower risk patients, such as those with a BMD in the osteopenic or normal range after two to five years of treatment and no history of fracture, consideration could be given to stopping therapy for two to five years.

Glial cells of the nucleus tractus solitarius as partners of the dorsal hindbrain regulation of energy balance: a proposal for a working hypothesis.

While the evidences emphasizing the role of astroglial cells in numerous aspects of information processing within the brain merges, the literature dealing with the involvement of this cell population in the signalization involved in feeding behavior and energetic homeostasis remains scarce. Nevertheless, some clues are now available indicating that glia could play a dynamic role in the regulation of energy balance, and that strengthening research effort in this field may further our understanding of the mechanisms controlling feeding behaviour. In the present review, we have summarized recent data indicating that the multifaceted glial compartment of the brainstem should be considered in future research aimed at identifying feeding-related processes operating at this level.

Effect of chronic estradiol administration on vimentin and GFAP immunohistochemistry within the inner ear.

Recent data show that hormone replacement therapy, involving estrogen together with progestin, can promote hearing loss (Guimaraes, P., Frisina, S.T., Mapes, F., Tadros, S.F., Frisina, D.R. and Frisina, R.D., 2006. Progestin negatively affects hearing in aged women. Proc. Natl. Acad. Sci. USA. 103, 14246-14249.). But long-term estradiol treatment, which induces hyperprolactinemia in guinea pigs, results in hearing loss and bone dysmorphology of the otic capsule-without much hair cell loss (Horner, K.C., Cazals, Y., Guieu, R., Lenoir, M. and Sauze, N., 2007. Experimental estrogen-induced hyperprolactinemia results in bone-related hearing loss in the guinea pig. Am. J. Physiol., Endocrinol. Metab. 293, E1224-1232.). Since estrogen receptor beta can protect the mouse cochlea against acoustic trauma (Meltser, I., Tahera, Y., Simpson, E., Hultcrantz, M., Charitidi, K., Gustafsson, J.A. and Canlon, B., 2008. Estrogen receptor beta protects against acoustic trauma in mice. J. Clin. Invest. 118, 1563-1570.), we hypothesized that estradiol might activate protective glial-like elements in the inner ear. Immunohistochemistry showed down-regulation of vimentin within the lateral wall and upregulation within the spiral limbus. Glial fibrillary acid protein was increased in the inner sulcus, Hensen cells and Claudius cells. Furthermore, there was increased expression of vimentin in type II cells of the spiral ganglion and type I vestibular hair cells. The observations suggested that estradiol treatment may affect the inner ear ionic homeostasis but protection may be afforded via activated intermediate filaments.

The effect of sex hormones on bone metabolism of the otic capsule--an overview.

Bone resorption, which can occur after the menopause, has long been considered to due to the decrease of estrogen and so estrogen and estrogen/progestin treatment in women has been employed with the aim of slowing down the process. Other important factors have recently been considered, including follicle-stimulating hormone. The hormonal control of bone metabolism has taken on a new dimension since the description, within the last decade, of a major osteoclast inhibiting control system. The receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) produced by osteoblastic lineage cells, must bind with its receptor RANK, located on osteoclasts, in order to allow the maturation and activation of osteoclasts. The potential continuous bone loss is controlled by the decoy receptor osteoprotegerin (OPG) which competitively binds to RANKL and hence blocks the interaction of RANKL-RANK. Estrogen contributes to bone protection since it decreases the response of osteoclasts to RANKL and induces osteoclast apoptosis. But estrogen, alone and especially in synergy with progesterone, is a potent stimulator of prolactin release. Prolactin affects calcium metabolism and hyperprolactinemia associated with pregnancy, lactation, antipsychotic drug treatment, or aging is reflected in decreased bone mineral density. Long-term estrogen treatment in guinea pig results in hyperprolactinemia and has been shown to lead to hearing loss as well as bone dysmorphology of the otic capsule. Recent data show that prolactin decreases OPG and increases RANKL. OPG has been shown to be expressed at high levels in the cochlea and OPG knock-out mice have indeed abnormal remodeling of the otic capsule and resorption of the auditory ossicles. So estrogen-induced hyperprolactinemia could oppose estrogen protection by the knock-down of the OPG bone protection system. This might explain why oral contraception treatment and hormone replacement therapies, involving estrogen together with progestin, increases the risk of otosclerosis and vestibular disorders. Hyperprolactinemia associated with pregnancy and lactation might also underlie the association of increased risk of otosclerosis with multiple pregnancies.

Effect of a pharmacist managed smoking cessation clinic on quit rates.

OBJECTIVE: The purpose of this study was to quantify quit rates, determine factors predicting success, and analyze patients' perceptions at 3 months after participation in the pharmacist-managed Smoking Cessation Group Clinic. METHODS: This was a prospective, single group study that was conducted in patients that had participated in the Smoking Cessation Group Clinic at the University of Iowa Hospitals and Clinics. Clinic participants received structured group counseling covering various topics associated with cessation. Varenicline, bupropion and nicotine replacement therapy were used as smoking cessation aids and selection was based on patient preference and absence of contraindications. The primary outcome of this trial was smoking status at 3 months. The patients were contacted by telephone at 3, and 6 months after the start of the clinic and asked about current smoking status. At 3 months, patients were asked to rate on a Likert scale of 1 to 5 (1=not helpful; 5=very helpful) their perceptions of individual aspects of the clinic and on a scale of 1 to 10 (1=not helpful; 10=very helpful) how they perceived their cessation aid. RESULTS: From February 2007 to January 2008, 21 patients enrolled in the intent-to-treat follow up study. Analysis of data was completed in August 2008. At 3 and 6 months, 47.6% and 52.4%, of patients reported being smoke-free, respectively. At 3 months, factors consistent with success included having more previous quit attempts and type of cessation aid used. These endpoints continued to be significant at 6 months, in addition to attending more clinic sessions, and type of insurance (favoring private insurance). Patients who quit smoking rated their cessation aid as more helpful than those who did not quit smoking (8.56; SD=0.88 verses 6.71; SD=2.81, respectively; p=0.14). The aspect of the clinic most helpful to patients was group interaction (4.53; SD=0.77). CONCLUSION: This study demonstrates that pharmacists can play a vital role with smoking cessation in a group setting. Group setting patient counseling can be an effective tool for pharmacists to reach more people within the same time frame as individual counseling.

Evaluation of anticoagulation in patients with antiphospholipid syndrome.

PURPOSE: The quality of anticoagulation therapy in patients with antiphospholipid syndrome (APS) was evaluated. SUMMARY: The high risk of unnecessary anticoagulation and recent changes in the recommended International Normalized Ratio (INR) target range prompted a performance-improvement initiative to improve the care of patients with APS within the University of Iowa Hospitals and Clinics internal medicine and family medicine anticoagulation clinics. Twenty-three patients with an initial diagnosis of APS were evaluated through chart review to determine the anticoagulation indication, occurrence of thromboembolic events, and INR target range. Confirmation of APS diagnosis was made using Sapporo criteria. Recommendations were made to the patients' physicians for confirmatory APS testing and changes in the anticoagulation regimen. INR target ranges were 2.0-3.0, 2.5-3.5, and 2.5-3.0 for 57%, 39%, and 4% of patients, respectively. Only 6 (26%) of the 23 patients met Sapporo criteria for a definite diagnosis of APS. Of the 17 patients (74%) who did not meet these criteria, 8 (47%) had another indication for indefinite anticoagulation. Repeat APS testing was indicated for 7 patients, 5 of whom met Sapporo criteria for APS. A lower target INR range of 2.0-3.0 was determined appropriate for 6 (26%) of the 23 patients evaluated. CONCLUSION: A majority of patients with an initial diagnosis of APS did not meet criteria for a definite diagnosis of APS. Of those patients, approximately half had another indication for long-term anticoagulation, and one third were receiving warfarin dosages based on an INR target range that was higher than clinically indicated.

Critical role of PDE4D in beta2-adrenoceptor-dependent cAMP signaling in mouse embryonic fibroblasts.

One of the defining properties of beta2-adrenergic receptor (beta(2)AR) signaling is the transient and rapidly reversed accumulation of cAMP. Here we have investigated the contribution of different PDE4 proteins to the generation of this transient response. To this aim, mouse embryonic fibroblasts deficient in PDE4A, PDE4B, or PDE4D were generated, and the regulation of PDE activity, the accumulation of cAMP, and CREB phosphorylation in response to isoproterenol were monitored. Ablation of PDE4D, but not PDE4A or PDE4B, had a major effect on the beta-agonist-induced PDE activation, with only a minimal increase in PDE activity being retained in PDE4D knock-out (KO) cells. Accumulation of cAMP was markedly enhanced, and the kinetics of cAMP accumulation were altered in their properties in PDE4DKO but not PDE4BKO cells. Modest effects were observed in PDE4AKO mouse embryonic fibroblasts. The return to basal levels of both cAMP accumulation and CREB phosphorylation was greatly delayed in the PDE4DKO cells, suggesting that PDE4D is critical for dissipation of the beta2AR stimulus. This effect of PDE4D ablation was in large part due to inactivation of a negative feedback mechanism consisting of the PKA-mediated activation of PDE4D in response to elevated cAMP levels, as indicated by experiments using the cAMP-dependent protein kinase inhibitors H89 and PKI. Finally, PDE4D ablation affected the kinetics of beta2AR desensitization as well as the interaction of the receptor with Galphai. These findings demonstrate that PDE4D plays a major role in shaping the beta2AR signal.

Generation of mouse oocytes defective in cAMP synthesis and degradation: endogenous cyclic AMP is essential for meiotic arrest.

Although it is established that cAMP accumulation plays a pivotal role in preventing meiotic resumption in mammalian oocytes, the mechanisms controlling cAMP levels in the female gamete have remained elusive. Both production of cAMP via GPCRs/Gs/adenylyl cyclases endogenous to the oocyte as well as diffusion from the somatic compartment through gap junctions have been implicated in maintaining cAMP at levels that preclude maturation. Here we have used a genetic approach to investigate the different biochemical pathways contributing to cAMP accumulation and maturation in mouse oocytes. Because cAMP hydrolysis is greatly decreased and cAMP accumulates above a threshold, oocytes deficient in PDE3A do not resume meiosis in vitro or in vivo, resulting in complete female infertility. In vitro, inactivation of Gs or downregulation of the GPCR GPR3 causes meiotic resumption in the Pde3a null oocytes. Crossing of Pde3a(-/-) mice with Gpr3(-/-) mice causes partial recovery of female fertility. Unlike the complete meiotic block of the Pde3a null mice, oocyte maturation is restored in the double knockout, although it occurs prematurely as described for the Gpr3(-/-) mouse. The increase in cAMP that follows PDE3A ablation is not detected in double mutant oocytes, confirming that GPR3 functions upstream of PDE3A in the regulation of oocyte cAMP. Metabolic coupling between oocytes and granulosa cells was not affected in follicles from the single or double mutant mice, suggesting that diffusion of cAMP is not prevented. Finally, simultaneous ablation of GPR12, an additional receptor expressed in the oocyte, does not modify the Gpr3(-/-) phenotype. Taken together, these findings demonstrate that Gpr3 is epistatic to Pde3a and that fertility as well as meiotic arrest in the PDE3A-deficient oocyte is dependent on the activity of GPR3. These findings also suggest that cAMP diffusion through gap junctions or the activity of additional receptors is not sufficient by itself to maintain the meiotic arrest in the mouse oocyte.

Signaling from beta1- and beta2-adrenergic receptors is defined by differential interactions with PDE4.

Beta1- and beta2-adrenergic receptors (betaARs) are highly homologous, yet they play clearly distinct roles in cardiac physiology and pathology. Myocyte contraction, for instance, is readily stimulated by beta1AR but not beta2AR signaling, and chronic stimulation of the two receptors has opposing effects on myocyte apoptosis and cell survival. Differences in the assembly of macromolecular signaling complexes may explain the distinct biological outcomes. Here, we demonstrate that beta1AR forms a signaling complex with a cAMP-specific phosphodiesterase (PDE) in a manner inherently different from a beta2AR/beta-arrestin/PDE complex reported previously. The beta1AR binds a PDE variant, PDE4D8, in a direct manner, and occupancy of the receptor by an agonist causes dissociation of this complex. Conversely, agonist binding to the beta2AR is a prerequisite for the recruitment of a complex consisting of beta-arrestin and the PDE4D variant, PDE4D5, to the receptor. We propose that the distinct modes of interaction with PDEs result in divergent cAMP signals in the vicinity of the two receptors, thus, providing an additional layer of complexity to enforce the specificity of beta1- and beta2-adrenoceptor signaling.

Experimental estrogen-induced hyperprolactinemia results in bone-related hearing loss in the guinea pig.

Our group (Horner KC, Guieu R, Magnan J, Chays A, Cazals Y. Neuropsychopharmacology 26: 135-138, 2002) has earlier described hyperprolactinemia in some patients presenting inner ear dysfunction. However, in that study, it was not possible to determine whether hyperprolactinemia was a cause or an effect of the symptoms. To investigate the effect of hyperprolactinemia on inner ear function, we first developed a model of hyperprolactinemia in estrogen-primed Fischer 344 rats and then performed functional studies on pigmented guinea pigs. Hyperprolactinemia induced, after 2 mo, a hearing loss of approximately 30-40 dB across all frequencies, as indicated by the compound action potential audiogram. During the 3rd mo, the hearing loss continued to deteriorate. The threshold shifts were more substantial in males than in females. Observations under a dissection microscope revealed bone dysmorphology of the bulla and the cochlea. Light microscopy observations of cryostat sections confirmed bone-related pathology of the bony cochlear bulla and the cochlear wall and revealed morphopathology of the stria vascularis and spiral ligament. Scanning electron microscopy revealed loss of hair cells and stereocilia damage, in particular in the upper three cochlear turns and the two outermost hair cell rows. The data provide the first evidence of otic capsule and hair cell pathology associated with estrogen-induced prolonged hyperprolactinemia and suggest that conditions such as pregnancy, anti-psychotic drug treatment, aging, and/or stress might lead to similar ear dysfunctions.

Luteinizing hormone-dependent activation of the epidermal growth factor network is essential for ovulation.

In the preovulatory ovarian follicle, mammalian oocytes are maintained in prophase meiotic arrest until the luteinizing hormone (LH) surge induces reentry into the first meiotic division. Dramatic changes in the somatic cells surrounding the oocytes and in the follicular wall are also induced by LH and are necessary for ovulation. Here, we provide genetic evidence that LH-dependent transactivation of the epidermal growth factor receptor (EGFR) is indispensable for oocyte reentry into the meiotic cell cycle, for the synthesis of the extracellular matrix surrounding the oocyte that causes cumulus expansion, and for follicle rupture in vivo. Mice deficient in either amphiregulin or epiregulin, two EGFR ligands, display delayed or reduced oocyte maturation and cumulus expansion. In compound-mutant mice in which loss of one EGFR ligand is associated with decreased signaling from a hypomorphic allele of the EGFR, LH no longer signals oocyte meiotic resumption. Moreover, induction of genes involved in cumulus expansion and follicle rupture is compromised in these mice, resulting in impaired ovulation. Thus, these studies demonstrate that LH induction of epidermal growth factor-like growth factors and EGFR transactivation are essential for the regulation of a critical physiological process such as ovulation and provide new strategies for manipulation of fertility.