Transgenic over-expression of YY1 induces pathologic cardiac hypertrophy in a sex-specific manner.

YY1 can activate or repress transcription of various genes. In cardiac myocytes in culture YY1 has been shown to regulate expression of several genes involved in myocyte pathology. YY1 can also acutely protect the heart against detrimental changes in gene expression. In this study we show that cardiac over-expression of YY1 induces pathologic cardiac hypertrophy in male mice, measured by changes in gene expression and lower ejection fraction/fractional shortening. In contrast, female animals are protected against pathologic gene expression changes and cardiac dysfunction. Furthermore, we show that YY1 regulates, in a sex-specific manner, the expression of mammalian enable (Mena), a factor that regulates cytoskeletal actin dynamics and whose expression is increased in several models of cardiac pathology, and that Mena expression in humans with heart failure is sex-dependent. Finally, we show that sex differences in YY1 expression are also observed in human heart failure. In summary, this is the first work to show that YY1 has a sex-specific effect in the regulation of cardiac pathology.

Robotic-assisted laparoscopic pyelolithotomy with intracorporeal pyeloscopy in a horseshoe kidney.

Horseshoe kidneys are one of the most common congenital genitourinary malformations and can increase the complexity of common urologic procedures, especially nephrolithiasis. We present a patient who underwent robotic-assisted laparoscopic pyelolithotomy with intracorporeal pyeloscopy and stone basketing to treat a left lower pole stone burden located in a horseshoe kidney. This procedure provided benefits of expanded maneuverability, dexterity, and stability, which resulted in successful elimination of stone burden on post-operative imaging. We believe that robotic-assisted laparoscopic pyelolithotomy with intracorporeal pyeloscopy should be considered as a treatment option in similar cases of complicated nephrolithiasis due to complex renal anatomy.

Temporal analysis of mRNA and miRNA expression in transgenic mice overexpressing Arg- and Gly389 polymorphic variants of the ß1-adrenergic receptor.

Several studies in humans or transgenic animals have reported that the 389 Arg or Gly polymorphic variation of the ß1-adrenergic receptor (AR) is associated with differential responses to beta-blocker therapy and/or myocardial disease progression. Analysis of changes in gene expression is an important means of defining molecular differences associated with structural or functional phenotypic variations. To determine if structural and functional myocardial phenotypic differences between ß1389 Arg vs. Gly transgenic overexpressors are associated with qualitative and/or quantitative differences in gene expression, a comprehensive analysis of mRNAs and miRNAs expressed in the hearts of 3 and 6-8 mo old ß1-Arg389 and ß1-Gly389 overexpressor transgenic mice was performed. Changes in mRNA and miRNA expression were analyzed by arrays and partially confirmed by RT-qPCR. Bioinformatic analysis demonstrated that several genes, including those involved in PKA and CaMK signaling pathways, are regulated in a temporal- or phenotype-specific manner. Furthermore, expression signature analyses indicated that miRNAs have the potential to target expression of a number of genes involved in multiple cardiomyopathy-related pathways, and changes in miRNA expression can precede the onset of disease. Differences in gene expression between ß1-Arg389 and ß1-Gly389 transgenic mice are largely quantitative rather than qualitative and are associated with the development of cardiomyopathy in a time-dependent manner. Chronic ß1-AR overdrive results in increased expression of components of the CaMK pathway, with correspondingly decreased levels of components of the PKA pathway. Based on the temporal and genotype-specific pattern of miRNA expression, miRNAs are likely to be important predictors of disease states, especially when miRNA expression is paired with mRNA expression, and that miRNA/mRNA expression signatures have the potential to be useful in determining the underlying risk associated with cardiac disease progression.

Tissue procurement strategies affect the protein biochemistry of human heart samples.

The ability to analyze the biochemical properties of human cardiac tissue is critical both to an understanding of cardiac pathology and also to the development of novel pharmacotherapies. However current strategies for tissue procurement are not uniform and are potentially biased. In this study we contrasted several commonly used approaches for tissue sampling in order to determine their impact on contractile protein biochemistry. Not surprisingly our results show that different tissue handling strategies have the potential to produce a wide variation in the phosphorylation and proteolysis of selected contractile proteins. However this was not uniform: phosphorylation of troponin I (TnI) and myosin light chain 2 (MLC2) varied significantly depending on approach whereas changes in desmin and myosin binding protein C (MyBP-C) were relatively unaffected. Moreover, some strategies increased whereas others reduced TnI phosphorylation, suggesting a dynamic balance between kinase and phosphatase activities. Overall, procurement strategies that involved maintenance of tissue in cardioplegia solution deviated most dramatically from prompt and rapid tissue immersion in liquid nitrogen.

Late recurrence of Seminoma in the pelvis: A case report.

Recurrence of pure seminoma in atypical lymph node sites, such as the pelvis are rare masses that show clinical signs late in disease progression. We report a case of a 73-year-old male that presented with urinary retention and pain in his left lower extremity with a history of right radical orchiectomy and adjuvant radiation for a stage 1 pure seminoma 30 years prior. CT showed a left pelvic mass concerning for malignancy. Patient subsequently underwent surgical excision of mass that pathology identified as recurrence of pure seminoma. This case report emphasizes etiology of pure seminoma and late, contralateral pelvic recurrence.

A PDE3A Promoter Polymorphism Regulates cAMP-Induced Transcriptional Activity in Failing Human Myocardium.

BACKGROUND: The phosphodiesterase 3A (PDE3A) gene encodes a PDE that regulates cardiac myocyte cyclic adenosine monophosphate (cAMP) levels and myocardial contractile function. PDE3 inhibitors (PDE3i) are used for short-term treatment of refractory heart failure (HF), but do not produce uniform long-term benefit. OBJECTIVES: The authors tested the hypothesis that drug target genetic variation could explain clinical response heterogeneity to PDE3i in HF. METHODS: PDE3A promoter studies were performed in a cloned luciferase construct. In human left ventricular (LV) preparations, mRNA expression was measured by reverse transcription polymerase chain reaction, and PDE3 enzyme activity by cAMP-hydrolysis. RESULTS: The authors identified a 29-nucleotide (nt) insertion (INS)/deletion (DEL) polymorphism in the human PDE3A gene promoter beginning 2,214 nt upstream from the PDE3A1 translation start site. Transcription factor ATF3 binds to the INS and represses cAMP-dependent promoter activity. In explanted failing LVs that were homozygous for PDE3A DEL and had been treated with PDE3i pre-cardiac transplantation, PDE3A1 mRNA abundance and microsomal PDE3 enzyme activity were increased by 1.7-fold to 1.8-fold (p < 0.05) compared with DEL homozygotes not receiving PDE3i. The basis for the selective up-regulation in PDE3A gene expression in DEL homozygotes treated with PDE3i was a cAMP response element enhancer 61 nt downstream from the INS, which was repressed by INS. The DEL homozygous genotype frequency was also enriched in patients with HF. CONCLUSIONS: A 29-nt INS/DEL polymorphism in the PDE3A promoter regulates cAMP-induced PDE3A gene expression in patients treated with PDE3i. This molecular mechanism may explain response heterogeneity to this drug class, and may inform a pharmacogenetic strategy for a more effective use of PDE3i in HF.

Renal medullary carcinoma with an ophthalmic metastasis.

Renal medullary carcinoma (RMC) is a rare, aggressive primary renal malignancy that classically occurs in adolescent males with sickle cell trait and universally presents with metastatic disease at presentation. We report a case of medullary carcinoma in a young man with likely ophthalmic metastasis. We also review relevant literature available to date. The patient is a 20-year-old African-American male with a past medical history significant to for sickle cell trait who presented to the University Medical Center with cough and the right eye pain for 1 month as well as painless gross hematuria for 1 week. A chest and abdominal computed tomography showed a 7 cm hypodense right renal mass with bilateral hilar adenopathy, and multiple bilateral pulmonary nodules. A renal biopsy was performed and showed RMC. Ophthalmic exam revealed the right retinal hemorrhage concerning for a metastatic lesion. Palliative chemotherapy was offered to the patient, however, he and his family chose to enroll in hospice care considering his poor prognosis. He subsequently passed away 33 days after presentation. To our knowledge, there is only one other case of ophthalmic metastasis in a patient with metastatic RMC. Thus, we present this case to contribute to current literature regarding orbital metastasis in this largely fatal disease.

Patients Willing to Wait: Arrival Time, Wait Time and Patient Satisfaction in an Ambulatory Urology Clinic.

INTRODUCTION: We evaluated the relationship of patient satisfaction to arrival and wait times. We also sought to determine factors that patients considered important to the visit experience. METHODS: A total of 361 participants completed a survey in clinic to record wait times in various areas of the clinic and then rate satisfaction levels with these times and with the care received. A total of 211 participants ranked 6 factors related to the patient experience in the order considered important. RESULTS: Early, on time and late arriving patients spent 26.0, 15.5 and 17.1 minutes in the waiting room and had a total visit duration of 82.5, 67.9 and 72.0 minutes, respectively. Significant differences existed between these times when the early group was compared with the on time and late groups. Early patients were significantly more satisfied with wait time in the waiting room and total clinic visit time compared to late patients. Receiving treatment or relief from a medical problem was the most important factor valued by this population. CONCLUSIONS: Surprisingly, patients with longer waits were more satisfied with the time in the waiting room and overall visit duration, indicating that other variables influence patient satisfaction with perceived wait times. This study provides evidence that wait time might not be as important to patients or impact patient satisfaction as previously thought. On average wait time was ranked fifth in regard to what was important. Longer wait times did not seem to impact patient satisfaction when asked about overall satisfaction with the care received.

Why patients should arrive late: The impact of arrival time on patient satisfaction in an academic clinic.

INTRODUCTION: When considering quality improvement of healthcare practices, patient flow, wait time, and satisfaction are important factors to monitor. Patient wait time can affect satisfaction with the care received, and it can be dependent on many different factors. The purpose of this study was to investigate the impact of patients' arrival times to his/her appointment (early vs. on time vs. late) on patients' wait times and satisfaction. METHODS: 171 patients in an otolaryngology outpatient clinic completed surveys that asked them to record wait times in various areas of the clinic and to provide a satisfaction level for these wait times. Statistical analysis tested for any significant differences in wait time and satisfaction for patients that arrived early, on time, or late. RESULTS: Late, on time, and early arriving patients spent 18.2, 30.7, and 38.8min in the waiting room, respectively. Late, on time, and early arriving patients had a total visit length of 57.4, 68.6, and 81.9min, respectively. There was a significant difference with total time spent in the clinic (p=0.0034) and for overall satisfaction with the total length of the visit (p=0.0202) between late and early arriving patients. CONCLUSIONS: This study indicates patients arriving late had shorter wait times and, not surprisingly, were more satisfied with the visit. The study provides evidence that patients view their wait as starting when they arrive to the clinic and not the actual time of the appointment. It questions the traditional scheduling systems that many clinics still use and proposes that there may be "out-of-the-box" approaches that positively impact patient satisfaction.

Gene expression and ß-adrenergic signaling are altered in hypoplastic left heart syndrome.

BACKGROUND: The purpose of the current study was to define the myocellular changes and adaptation of the ß-adrenergic receptor (ß-AR) system that occur in the systemic right ventricle (RV) of children with hypoplastic left heart syndrome (HLHS). METHODS: Explanted hearts from children with HLHS and non-failing controls were used for this study. HLHS patients were divided into 2 groups: "compensated" (C-HLHS), infants listed for primary transplant with normal RV function and absence of heart failure symptoms, and "decompensated" (D-HLHS), patients listed for transplant after failed surgical palliation with RV failure and/or refractory protein-losing enteropathy or plastic bronchitis. RESULTS: Compared with non-failing control RVs, the HLHS RV demonstrated decreased sarcoplasmic reticulum calcium-adenosine triphosphatase 2a and α-myosin heavy chain (MHC) gene expression, decreased total ß-AR due to down-regulation of ß1-AR, preserved cyclic adenosine monophosphate levels, and increased calcium/calmodulin-dependent protein kinase II (CaMKII) activity. There was increased atrial natriuretic peptide expression only in the C-HLHS group. Unique to those in the D-HLHS group was increased ß-MHC and decreased α-MHC protein expression (MHC isoform switching), increased adenylyl cyclase 5 expression, and increased phosphorylation of the CaMK target site on phospholamban, threonine 17. CONCLUSIONS: The HLHS RV has an abnormal myocardial gene expression pattern, downregulation of ß1-AR, preserved cyclic adenosine monophosphate levels, and increased CaMKII activity compared with the non-failing control RV. There is MHC isoform switching, increased adenylyl cyclase 5, and increased phosphorylation of phospholamban threonine 17 only in the D-HLHS group. Although abnormal gene expression and changes in the ß-AR system precede clinically evident ventricular failure in HLHS, additional unique adaptations occur in those with HLHS and failed surgical palliation.

Combinatorial pharmacogenetic interactions of bucindolol and ß1, α2C adrenergic receptor polymorphisms.

BACKGROUND: Pharmacogenetics involves complex interactions of gene products affecting pharmacodynamics and pharmacokinetics, but there is little information on the interaction of multiple genetic modifiers of drug response. Bucindolol is a ß-blocker/sympatholytic agent whose efficacy is modulated by polymorphisms in the primary target (ß(1) adrenergic receptor [AR] Arg389 Gly on cardiac myocytes) and a secondary target modifier (α(2C) AR Ins [wild-type (Wt)] 322-325 deletion [Del] on cardiac adrenergic neurons). The major allele homozygotes and minor allele carriers of each polymorphism are respectively associated with efficacy enhancement and loss, creating the possibility for genotype combination interactions that can be measured by clinical trial methodology. METHODOLOGY: In a 1,040 patient substudy of a bucindolol vs. placebo heart failure clinical trial, we tested the hypothesis that combinations of ß(1)389 and α(2C)322-325 polymorphisms are additive for both efficacy enhancement and loss. Additionally, norepinephrine (NE) affinity for ß(1)389 AR variants was measured in human explanted left ventricles. PRINCIPAL FINDINGS: The combination of ß(1)389 Arg+α(2C)322-325 Wt major allele homozygotes (47% of the trial population) was non-additive for efficacy enhancement across six clinical endpoints, with an average efficacy increase of 1.70-fold vs. 2.32-fold in ß(1)389 Arg homozygotes+α(2C)322-325 Del minor allele carriers. In contrast, the minor allele carrier combination (13% subset) exhibited additive efficacy loss. These disparate effects are likely due to the higher proportion (42% vs. 8.7%, P = 0.009) of high-affinity NE binding sites in ß(1)389 Arg vs. Gly ARs, which converts α(2C)Del minor allele-associated NE lowering from a therapeutic liability to a benefit. CONCLUSIONS: On combination, the two sets of AR polymorphisms 1) influenced bucindolol efficacy seemingly unpredictably but consistent with their pharmacologic interactions, and 2) identified subpopulations with enhanced (ß(1)389 Arg homozygotes), intermediate (ß(1)389 Gly carriers+α(2C)322-325 Wt homozygotes), and no (ß(1)389 Gly carriers+α(2C)322-325 Del carriers) efficacy.