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Mutations of the human type Iα regulatory subunit (RIα) of cyclic AMP-dependent protein kinase (PKA; PRKAR1A) lead to altered kinase activity, primary pigmented nodular adrenocortical disease, and tumors of the thyroid and other tissues. To bypass the early embryonic lethality of Prkar1a−/− mice, we established transgenic mice carrying an antisense transgene for Prkar1a exon 2 (X2AS) under the control of a tetracycline-responsive promoter. Down-regulation of Prkar1a by up to 70% was achieved in transgenic mouse tissues and embryonic fibroblasts, with concomitant changes in kinase activity and increased cell proliferation, respectively. Mice developed thyroid follicular hyperplasia and adenomas, adrenocortical hyperplasia, and other features reminiscent of primary pigmented nodular adrenocortical disease, histiocytic and epithelial hyperplasias, lymphomas, and other mesenchymal tumors. These were associated with allelic losses of the mouse chromosome 11 Prkar1a locus, an increase in total type II PKA activity, and higher RIIβ protein levels. This mouse provides a novel, useful tool for the investigation of cyclic AMP, RIα, and PKA functions and confirms the critical role of Prkar1a in tumorigenesis in endocrine and other tissues.

Supplementary Table from Down-Regulation of Regulatory Subunit Type 1A of Protein Kinase A Leads to Endocrine and Other Tumors

Supplementary Figures from Down-Regulation of Regulatory Subunit Type 1A of Protein Kinase A Leads to Endocrine and Other Tumors

Supplementary Figure Legends from Down-Regulation of Regulatory Subunit Type 1A of Protein Kinase A Leads to Endocrine and Other Tumors

To measure the incidence and severity of urinary tract infections (UTI) in intermittent catheter (IC) users with neurogenic and non-neurogenic diagnoses.Administrative health insurance claims data from the IBM MarketScan® Database between January 1, 2015 and December 31, 2019, were analyzed. New IC-users with neurogenic lower urinary tract dysfunction (NLUTD); IC-users without NLUTD (non-NLUTD); and age-and-sex-matched general population without IC use (GEN) were compared. Individuals were followed for one year after initial IC utilization or random index date for GEN. The primary outcome was a patient seeing a physician or attending a hospital for a UTI (measured with a primary or secondary diagnosis code related to a UTI). UTI incidence, hospitalizations, and length of hospital stay were compared.We identified 6944 NLUTD, 5102 non-NLUTD, and 120 426 GEN individuals. The annualized UTI incidence was higher in IC-users (54.9% NLUTD IC-users and 38.9% non-NLUTD IC-users) compared to GEN individuals (9.8%) (p 0.001 between groups). Hospitalization for UTI was more common in NLUTD and non-LUTD (11.3% and 4.0%, respectively) compared with GEN individuals (1.0%) (p 0.001 between groups). NLUTD individuals had a greater average length of hospital stay than non-NLUTD (2.2 ± 3.6 vs. 1.6 ± 2.1 days, p 0.001).IC users had a significantly higher incidence of UTIs than the general population. NLUTD IC-users had a higher incidence of UTIs that required hospitalization compared to non-NLUTD individuals. Strategies to decrease the patient and healthcare burden of UTIs in those that catheterize should be prioritized.

We examined the relationship between glycemic control and urinary tract infections in women with type 1 diabetes mellitus.Women enrolled in the Epidemiology of Diabetes Interventions and Complications study, the observational followup of the Diabetes Control and Complications Trial, were surveyed to assess the rate of physician diagnosed urinary tract infections in the preceding 12 months. The relationship between glycated hemoglobin levels and number of urinary tract infections in the previous 12 months was assessed using a multivariable Poisson regression model.A total of 572 women were evaluated at year 17. Mean age was 50.7 ± 7.2 years, mean body mass index was 28.6 ± 5.9 kg/m(2), mean type 1 diabetes duration was 29.8 ± 5.0 years and mean glycated hemoglobin was 8.0% ± 0.9%. Of these women 86 (15.0%) reported at least 1 physician diagnosed urinary tract infection during the last 12 months. Higher glycated hemoglobin levels were significantly associated with number of urinary tract infections such that for every unit increase (1%) in recent glycated hemoglobin level, there was a 21% (p=0.02) increase in urinary tract infection frequency in the previous 12 months after adjusting for race, hysterectomy status, urinary incontinence, sexual activity in the last 12 months, peripheral and autonomic neuropathy, and nephropathy.The frequency of urinary tract infections increases with poor glycemic control in women with type 1 diabetes. This relationship is independent of other well described predictors of urinary tract infections and suggests that factors directly related to glycemic control may influence the risk of lower urinary tract infections.

Neurogenic bladder is a very broad disease definition that encompasses varied disease and injury states affecting the bladder. The majority of patients with neurogenic bladder dysfunction do not have concomitant intrinsic sphincteric deficiency (ISD), but when this occurs the challenges of management of urinary incontinence from neurogenic bladder are compounded. There are no guidelines for surgical correction of ISD in adults and most of the literature on treatment of the problem comes from treatment of children with congenital diseases, such as myelomeningocele. Our goal, in this review, is to present some of the common surgical options for ISD [including artificial urinary sphincters, bladder slings, bladder neck reconstruction (BNR) and urethral bulking agents] and the evidence underlying these treatments in adults with neurogenic bladder.