Insulin and insulin-like growth factor 1 (IGF-1) receptor signaling pathways differentially modulate cardiac growth under resting conditions and following exercise training. These effects are mediated by insulin receptor substrate 1 (IRS1) and IRS2, which also differentially regulate resting cardiac mass. To determine the role of IRS isoforms in mediating the hypertrophic and metabolic adaptations of the heart to exercise training, we subjected mice with cardiomyocyte-specific deletion of either IRS1 (CIRS1 knockout [CIRS1KO] mice) or IRS2 (CIRS2KO mice) to swim training. CIRS1KO hearts were reduced in size under basal conditions, whereas CIRS2KO hearts exhibited hypertrophy. Following exercise swim training in CIRS1KO and CIRS2KO hearts, the hypertrophic response was equivalently attenuated, phosphoinositol 3-kinase (PI3K) activation was blunted, and prohypertrophic signaling intermediates, such as Akt and glycogen synthase kinase 3␤ (GSK3␤), were dephosphorylated potentially on the basis of reduced Janus kinase-mediated inhibition of protein phosphatase 2a (PP2A). Exercise training increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1␣) protein content, mitochondrial capacity, fatty acid oxidation, and glycogen synthesis in wild-type (WT) controls but not in IRS1-and IRS2-deficient hearts. PGC-1␣ protein content remained unchanged in CIRS1KO but decreased in CIRS2KO hearts. These results indicate that although IRS isoforms play divergent roles in the developmental regulation of cardiac size, these isoforms exhibit nonredundant roles in mediating the hypertrophic and metabolic response of the heart to exercise. C ardiac hypertrophy is the growth response of the heart to increased workload and has been categorized as physiological or pathological hypertrophy. Cardiac hypertrophy is considered pathological if contractile dysfunction occurs after an initial phase of compensation, which ultimately results in heart failure. Common causes for pathological hypertrophy are valvular disease and hypertension. In contrast, physiological hypertrophy is characterized by adaptive myocyte growth with a new steady state and preserved contractile function, as exemplified by the response to chronic exercise training, also known as "athlete's heart" (1). The differences between physiological and pathological cardiac hypertrophy have been attributed in part to differences in intracellular signaling pathways. For example, insulin receptor-and insulinlike growth factor 1 (IGF-1) receptor-mediated signaling to phosphatidylinositol 3-kinase (PI3K) and Akt1 have been implicated in physiological cardiac hypertrophy, whereas activation of G protein-coupled pathways, such as angiotensin II and adrenergic signaling, has been associated with pathological hypertrophy (2, 3).We previously reported that cardiomyocyte-selective deletion of the insulin receptor (CIRKO) reduced heart size by 20 to 30% (4), whereas under basal conditions IGF-1 receptor deletion was without effect (5). CIRKO hearts exhibit increased ...

The induction of autophagy in the mammalian heart during the perinatal period is an essential adaptation required to survive early neonatal starvation; however, the mechanisms that mediate autophagy suppression once feeding is established are not known. Insulin signaling in the heart is transduced via insulin and IGF-1 receptors (IGF-1Rs). We disrupted insulin and IGF-1R signaling by generating mice with combined cardiomyocyte-specific deletion of Irs1 and Irs2. Here we show that loss of IRS signaling prevented the physiological suppression of autophagy that normally parallels the postnatal increase in circulating insulin. This resulted in unrestrained autophagy in cardiomyocytes, which contributed to myocyte loss, heart failure, and premature death. This process was ameliorated either by activation of mTOR with aa supplementation or by genetic suppression of autophagic activation. Loss of IRS1 and IRS2 signaling also increased apoptosis and precipitated mitochondrial dysfunction, which were not reduced when autophagic flux was normalized. Together, these data indicate that in addition to prosurvival signaling, insulin action in early life mediates the physiological postnatal suppression of autophagy, thereby linking nutrient sensing to postnatal cardiac development.

Introduction: This study aimed to determine if gentamicin bladder instillations reduce the rate of symptomatic urinary tract infection (UTI) in neurogenic bladder (NGB) patients on intermittent selfcatheterization (ISC) who have recurrent UTIs. Secondary aims were to examine the effects of intravesical gentamicin on the organism resistance patterns. Methods: We retrospectively reviewed our prospective NGB database. Inclusion criteria were NGB patients performing ISC exclusively for bladder drainage with clinical data available for six months before and six months after initiating prophylactic intravesical gentamicin instillations. Symptomatic UTIs were defined as symptoms consistent with UTI plus the need for antibiotic treatment. Results: Twenty-two patients met inclusion criteria; etiology of NGB was 63.6% spinal cord injury, 13.6% multiple sclerosis. Median time since injury/diagnosis was 14 years and 6/22 (27.3%) had undergone urological reconstruction. Patients had fewer symptomatic UTI's (median 4 vs. 1 episodes; p<0.004) and underwent fewer courses of oral antibiotics after initiating gentamicin (median 3.5 vs. 1; p<0.01). Days of oral antibiotic therapy decreased from 15 before to five after gentamicin, but this did not reach significance. There were fewer telephone encounters for UTI concerns per patient (median 3 vs. 0; p=0.03). The proportion of multidrug-resistant organisms in urine cultures decreased from 58.3% to 47.1% (p=0.04) and the rate of gentamicin resistance did not increase. Adverse events were mild and rare. Conclusions: Gentamicin bladder instillations decrease symptomatic UTI episodes and reduce oral antibiotics in patients with NGB on ISC who were suffering from recurrent UTIs. Antibiotic resistance decreased while on gentamicin instillations.

Phosphoinositide-dependent protein kinase-1 (PDPK1) is an important mediator of phosphatidylinositol 3-kinase (PI3K) signaling. We previously reported that PI3K but not Akt signaling mediates the increase of mitochondrial oxidative capacity to physiological cardiac hypertrophy. To determine if PDPK1 regulates these metabolic adaptations we examined mice with cardiomyocyte-specific heterozygous knockout of PDPK1 (cPDPK1+/−) after 5 wk. exercise swim training. Akt phosphorylation at Thr308 increased by 43% in wildtype (WT) mice but not in cPDPK1+/− mice following exercise training. Ventricular contractile function was not different between WT and cPDPK1+/− mice at baseline. In addition, exercise did not influence ventricular function in WT or cPDPK1+/− mice. Heart weight normalized to tibia length ratios increased by 13.8% in WT mice (6.2 ± 0.2 vs. 7.1 ± 0.2, P=0.001), but not in cPDPK1+/− (6.2 ± 0.3 vs. 6.5 ± 0.2, P=0.20) mice after swim training. Diastolic LV dimension increased in WT mice (3.7 ± 0.1 vs. 4.0 ± 0.1 mm, P=0.01) but not in cPDPK1+/− (3.8 ± 0.1 vs. 3.7 ± 0.1 mm, P=0.56) following swim training. Maximal mitochondrial oxygen consumption (VADP, nmol/min/mg) using palmitoyl carnitine as a substrate was significantly increased in mice of all genotypes following swim training (WT: 13.6 ± 0.6 vs.16.1 ± 0.9, P=0.04; cPDPK1+/−: 12.4 ± 0.6 vs.15.9 ± 1.2, P=0.04). These findings suggest that PDPK1 is required for exercise-induced cardiac hypertrophy but does not contribute to exercise-induced increases in mitochondrial function.

Objectives: Most patients with pancreatic cancer have high symptom burden and poor outcomes. Palliative care (PC) can improve the quality of care through expert symptom management, although the optimal timing of PC referral is still poorly understood. We aimed to assess the association of early PC on health care utilization and charges of care for pancreatic cancer patients.Materials and Methods: We selected patients with pancreatic cancer diagnosed between 2000 and 2009 who received at least 1 PC encounter using the Surveillance, Epidemiology, and End Results (SEER)-Medicare. Patients who had unknown follow-up were excluded. We defined "early PC" if the patients received PC within 30 days of diagnosis.Results: A total of 3166 patients had a PC encounter; 28% had an early PC. Patients receiving early PC were more likely to be female and have older age compared with patients receiving late PC (P < 0.001). Patients receiving early PC had fewer emergency department (ED) visits (2.6 vs. 3.0 visits, P = 0.004) and lower total charges of ED care ($3158 vs. $3981, P < 0.001) compared with patients receiving late PC. Patients receiving early PC also had lower intensive care unit admissions (0.82 vs. 0.98 visits, P = 0.006) and total charges of intensive care unit care ($14,466 vs. $18,687, P = 0.01). On multivariable analysis, patients receiving early PC were significantly associated with fewer ED visits (P = 0.007) and lower charges of ED care (P = 0.018) for all patients.Conclusions: Early PC referrals were associated with lower ED visits and ED-related charges. Our findings support oncology society guideline recommendations for early PC in patients with advanced malignancies such as pancreatic cancer.