Impaired glucose metabolism in the heart of obese Zucker rats after treatment with phorbol ester.

OBJECTIVE: To investigate the influence of obesity on the regulation of myocardial glucose metabolism following protein kinase C (PKC) activation in obese (fa/fa) and lean (Fa/?) Zucker rats. DESIGN: Isolated hearts obtained from 17-week-old lean and obese Zucker rats were perfused with 200 nM phorbol 12-myristate 13-acetate (PMA) for different time periods prior to the evaluation of PKC and GLUT-4 translocation. For metabolic studies isolated hearts from 48 h starved Zucker rats were perfused with an erythrocytes-enriched buffer containing increased concentrations (10-100 nM) of PMA. MEASUREMENTS: Immunodetectable PKC isozymes and GLUT-4 were determined by Western blots. Glucose oxidation and glycolysis were evaluated by measuring the myocardial release of 14CO2 and 3H2O from [U-14C]glucose and [5-3H]glucose, respectively. RESULTS: PMA (200 nM) induced maximal translocation of ventricular PKCalpha from the cytosol to the membranes within 10 min. This translocation was 2-fold lower in the heart from obese rats when compared to lean rats. PMA also induced a significant translocation of ventricular GLUT-4 from the microsomal to the sarcolemmal fraction within 60 min in lean but not in obese rats. Rates of basal cardiac glucose oxidation and glycolysis in obese rats were approximately 2-fold lower than those of lean rats. Perfusion with increasing concentrations of PMA (10-100 nM) led to a significant decrease of cardiac glucose oxidation in lean but not in obese rats. CONCLUSION: Our results show that in the heart of the genetically obese Zucker rat, the impairment in PKCalpha activation is in line with a diminished activation of GLUT-4 as well as with the lack of PMA effect on glucose oxidation.

Extramediastinal surgical problems in heart transplant recipients.

BACKGROUND: As heart transplantation has gained wide acceptance, a growing number of recipients are at risk of experiencing extramediastinal surgical problems. STUDY DESIGN: We retrospectively reviewed our experience in the diagnosis and management of surgical problems occurring in 94 consecutive patients having heart transplantation. During the period of the study, we progressively adopted a policy of low-level immunosuppression, aiming toward monotherapy with cyclosporine. RESULTS: Seventy-four extramediastinal surgical problems developed in 44 of 94 patients (47%). The type of problems were gastrointestinal in 17 of 74 (23%), vascular in 13 of 74 (17.5%), urogenital in 8 of 74 (11%), and neurologic in 4 of 74 (5.5%). There were also 9 of 74 cases of trauma (12%), 9 of 74 skin tumors (12%), and 14 of 74 miscellaneous diseases (19%). Sixty-two surgical diseases occurring in 40 patients required 75 surgical interventions, 11 of them (15%) on an emergency basis. Operations were performed for 12 of 74 neoplasms (16%) and 12 of 74 infectious or potentially infectious diseases (16%). Surgical diseases occurred most commonly within the first 6 months after transplantation (20 of 74; 27%). Complications occurred in 8 of 75 surgical interventions (9%). A high proportion of surgical disease was potentially related to immunosuppressive therapy (37 of 74; 50%) or to transplantation itself (7 of 74; 9%). CONCLUSIONS: Extramediastinal diseases after heart transplantation involve most surgical specialties. Most of them are potentially linked with either the immunosuppressive therapy or the transplantation procedure, supporting our low-level immunosuppression policy. Expectant management is not justified in this population, who withstands operations well both early and late after transplantation.

Block of the superior cervical ganglion, description of a novel ultrasound-guided technique in human cadavers.

OBJECTIVE.: Injection of opioids to the superior cervical ganglion (SCG) has been reported to provide pain relief in patients suffering from different kinds of neuropathic facial pain conditions, such as trigeminal neuralgia, postherpetic neuralgia, and atypical facial pain. The classic approach to the SCG is a transoral technique using a so-called "stopper" to prevent accidental carotid artery puncture. The main disadvantage of this technique is that the needle tip is positioned distant from the actual target, possibly impeding successful block of the SCG. A further limitation is that injection of local anesthetics due to potential carotid artery puncture is contraindicated. We hypothesized that the SCG can be identified and blocked using ultrasound imaging, potentially increasing precision of this technique. INTERVENTIONS.: In this pilot study, 20 US-guided simulated blocks of the SCG were performed in 10 human cadavers in order to determine the accuracy of this novel block technique. After injection of 0.1 mL of dye, the cadavers were dissected to evaluate the needle position and coloring of the SCG. RESULTS.: Nineteen of the 20 needle tips were located in or next to the SCG. This corresponded to a simulated block success rate of 95% (95% confidence interval 85-100%). In 17 cases, the SCG was completely colored, and in two cases, the caudal half of the SCG was colored with dye. CONCLUSIONS.: The anatomical dissections confirmed that our ultrasound-guided approach to the SCG is accurate. Ultrasound could become an attractive alternative to the "blind" transoral technique of SCG blocks.

Framingham risk score and alternatives for prediction of coronary heart disease in older adults.

BACKGROUND: Guidelines for the prevention of coronary heart disease (CHD) recommend use of Framingham-based risk scores that were developed in white middle-aged populations. It remains unclear whether and how CHD risk prediction might be improved among older adults. We aimed to compare the prognostic performance of the Framingham risk score (FRS), directly and after recalibration, with refit functions derived from the present cohort, as well as to assess the utility of adding other routinely available risk parameters to FRS.¦METHODS: Among 2193 black and white older adults (mean age, 73.5 years) without pre-existing cardiovascular disease from the Health ABC cohort, we examined adjudicated CHD events, defined as incident myocardial infarction, CHD death, and hospitalization for angina or coronary revascularization.¦RESULTS: During 8-year follow-up, 351 participants experienced CHD events. The FRS poorly discriminated between persons who experienced CHD events vs. not (C-index: 0.577 in women; 0.583 in men) and underestimated absolute risk prediction by 51% in women and 8% in men. Recalibration of the FRS improved absolute risk prediction, particulary for women. For both genders, refitting these functions substantially improved absolute risk prediction, with similar discrimination to the FRS. Results did not differ between whites and blacks. The addition of lifestyle variables, waist circumference and creatinine did not improve risk prediction beyond risk factors of the FRS.¦CONCLUSIONS: The FRS underestimates CHD risk in older adults, particularly in women, although traditional risk factors remain the best predictors of CHD. Re-estimated risk functions using these factors improve accurate estimation of absolute risk.

Modalities and future prospects of gene therapy in heart transplantation.

Heart transplantation is the treatment of choice for many patients with end-stage heart failure. Its success, however, is limited by organ shortage, side effects of immunosuppressive drugs, and chronic rejection. Gene therapy is conceptually appealing for applications in transplantation, as the donor organ is genetically manipulated ex vivo before transplantation. Localised expression of immunomodulatory genes aims to create a state of immune privilege within the graft, which could eliminate the need for systemic immunosuppression. In this review, recent advances in the development of gene therapy in heart transplantation are discussed. Studies in animal models have demonstrated that genetic modification of the donor heart with immunomodulatory genes attenuates ischaemia-reperfusion injury and rejection. Alternatively, bone marrow-derived cells genetically engineered with donor-type major histocompatibility complex (MHC) class I or II promote donor-specific hyporesponsiveness. Genetic engineering of naïve T cells or dendritic cells may induce regulatory T cells and regulatory dendritic cells. Despite encouraging results in animal models, however, clinical gene therapy trials in heart transplantation have not yet been started. The best vector and gene to be delivered remain to be identified. Pre-clinical studies in non-human primates are needed. Nonetheless, the potential of gene therapy as an adjunct therapy in transplantation is essentially intact.

Une insuffisance cardiaque traitée par glucocorticoïdes [A heart insufficiency treated by glucocorticoids]

Arrhythmogenic right ventricular dysplasia was diagnosed in 2000 in this 44-year-old male patient with a history of syncope. An internal defibrillator was implanted. Six years later the patient was readmitted with severe heart failure, and cardiac sarcoidosis was diagnosed by myocardial biopsy. Response to a course of glucorticoids was favourable. We herein review diagnostic strategies and therapeutic options in this rare disorder.

A-kinase anchoring proteins: scaffolding proteins in the heart.

The pleiotropic cyclic nucleotide cAMP is the primary second messenger responsible for autonomic regulation of cardiac inotropy, chronotropy, and lusitropy. Under conditions of prolonged catecholaminergic stimulation, cAMP also contributes to the induction of both cardiac myocyte hypertrophy and apoptosis. The formation of localized, multiprotein complexes that contain different combinations of cAMP effectors and regulatory enzymes provides the architectural infrastructure for the specialization of the cAMP signaling network. Scaffolds that bind protein kinase A are called "A-kinase anchoring proteins" (AKAPs). In this review, we discuss recent advances in our understanding of how PKA is compartmentalized within the cardiac myocyte by AKAPs and how AKAP complexes modulate cardiac function in both health and disease.

Heart Of Iowa Regional Transit Agency, June 30, 2002

Other Audit Reports

Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts.

BACKGROUND: American College of Cardiology/American Heart Association guidelines for the diagnosis and management of heart failure recommend investigating exacerbating conditions such as thyroid dysfunction, but without specifying the impact of different thyroid-stimulation hormone (TSH) levels. Limited prospective data exist on the association between subclinical thyroid dysfunction and heart failure events. METHODS AND RESULTS: We performed a pooled analysis of individual participant data using all available prospective cohorts with thyroid function tests and subsequent follow-up of heart failure events. Individual data on 25 390 participants with 216 248 person-years of follow-up were supplied from 6 prospective cohorts in the United States and Europe. Euthyroidism was defined as TSH of 0.45 to 4.49 mIU/L, subclinical hypothyroidism as TSH of 4.5 to 19.9 mIU/L, and subclinical hyperthyroidism as TSH <0.45 mIU/L, the last two with normal free thyroxine levels. Among 25 390 participants, 2068 (8.1%) had subclinical hypothyroidism and 648 (2.6%) had subclinical hyperthyroidism. In age- and sex-adjusted analyses, risks of heart failure events were increased with both higher and lower TSH levels (P for quadratic pattern <0.01); the hazard ratio was 1.01 (95% confidence interval, 0.81-1.26) for TSH of 4.5 to 6.9 mIU/L, 1.65 (95% confidence interval, 0.84-3.23) for TSH of 7.0 to 9.9 mIU/L, 1.86 (95% confidence interval, 1.27-2.72) for TSH of 10.0 to 19.9 mIU/L (P for trend <0.01) and 1.31 (95% confidence interval, 0.88-1.95) for TSH of 0.10 to 0.44 mIU/L and 1.94 (95% confidence interval, 1.01-3.72) for TSH <0.10 mIU/L (P for trend=0.047). Risks remained similar after adjustment for cardiovascular risk factors. CONCLUSION: Risks of heart failure events were increased with both higher and lower TSH levels, particularly for TSH ≥10 and <0.10 mIU/L.

The Juvenile Accountability Incentive Block Grant (JAIBG) Program in Iowa, 1999 – 2000

The issue of effectively holding juveniles accountable for criminal behavior is a topic of public concern and debate. Congress created the Juvenile Accountability Incentive Block Grant (JAIBG) program and appropriated new federal funds through the Office of Juvenile Justice and Delinquency Prevention (OJJDP). The goals of the program are to reduce juvenile delinquency, improve the juvenile justice system, and increase accountability for juvenile offenders.

Effect of the September 11, 2001 terrorist attack on a state highway patrol trooper's heart rate variability

BACKGROUND: On September 11, 2001, terrorists attacked the United States. By coincidence, a North Carolina highway patrol trooper was wearing an ambulatory ECG Holter monitor at this time as part of an air pollution study. METHODS: Heart rate variability parameters were analyzed: standard deviation of normal to normal beat intervals (SDNN) and percentage of interval differences >50 ms (PNN50). RESULTS: The trooper's heart rate variability changed immediately after learning about the terrorist attacks. Heart rate increased and PNN50 decreased, while SDNN increased strongly. CONCLUSIONS: These changes suggest strong emotional sympathetic stress associated with parasympathetic withdrawal in response to the news about the terrorist attack. [Authors]

Analyses of a novel SCN5A mutation (C1850S): conduction vs. repolarization disorder hypotheses in the Brugada syndrome.

AIMS: Brugada syndrome (BrS) is characterized by arrhythmias leading to sudden cardiac death. BrS is caused, in part, by mutations in the SCN5A gene, which encodes the sodium channel alpha-subunit Na(v)1.5. Here, we aimed to characterize the biophysical properties and consequences of a novel BrS SCN5A mutation. METHODS AND RESULTS: SCN5A was screened for mutations in a male patient with type-1 BrS pattern ECG. Wild-type (WT) and mutant Na(v)1.5 channels were expressed in HEK293 cells. Sodium currents (I(Na)) were analysed using the whole-cell patch-clamp technique at 37 degrees C. The electrophysiological effects of the mutation were simulated using the Luo-Rudy model, into which the transient outward current (I(to)) was incorporated. A new mutation (C1850S) was identified in the Na(v)1.5 C-terminal domain. In HEK293 cells, mutant I(Na) density was decreased by 62% at -20 mV. Inactivation of mutant I(Na) was accelerated in a voltage-dependent manner and the steady-state inactivation curve was shifted by 11.6 mV towards negative potentials. No change was observed regarding activation characteristics. Altogether, these biophysical alterations decreased the availability of I(Na). In the simulations, the I(to) density necessary to precipitate repolarization differed minimally between the two genotypes. In contrast, the mutation greatly affected conduction across a structural heterogeneity and precipitated conduction block. CONCLUSION: Our data confirm that mutations of the C-terminal domain of Na(v)1.5 alter the inactivation of the channel and support the notion that conduction alterations may play a significant role in the pathogenesis of BrS.

Transapical aortic valve implantation without angiography: proof of concept.

Background: Cardiac computed tomographic scans, coronary angiograms, and aortographies are routinely performed in transcatheter heart valve therapies. Consequently, all patients are exposed to multiple contrast injections with a following risk of nephrotoxicity and postoperative renal failure. The transapical aortic valve implantation without angiography can prevent contrast-related complications. Methods: Between November 2008 and November 2009, 30 consecutive high-risk patients (16 female, 53.3%) underwent transapical aortic valve implantation without angiography. The landmarks identification, the stent-valve positioning, and the postoperative control were routinely performed under transesophageal echocardiogram and fluoroscopic visualization without contrast injections. Results: Mean age was 80.1 +/- 8.7 years. Mean valve gradient, aortic orifice area, and ejection fraction were 60.3 +/- 20.9 mm Hg, 0.7 +/- 0.16 cm(2), and 0.526 +/- 0.128, respectively. Risk factors were pulmonary hypertension (60%), peripheral vascular disease (70%), chronic pulmonary disease (50%), previous cardiac surgery (13.3%), and chronic renal insufficiency (40%) (mean blood creatinine and urea levels: 96.8 +/- 54 mu g/dL and 8.45 +/- 5.15 mmol/L). Average European System for Cardiac Operative Risk Evaluation was 32.2 +/- 13.3%. Valve deployment in the ideal landing zone was 96.7% successful and valve embolization occurred once. Thirty-day mortality was 10% (3 patients). Causes of death were the following: intraoperative ventricular rupture (conversion to sternotomy), right ventricular failure, and bilateral pneumonia. Stroke occurred in one patient at postoperative day 9. Renal failure (postoperative mean blood creatinine and urea levels: 91.1 +/- 66.8 mu g/dL and 7.27 +/- 3.45 mmol/L), myocardial infarction, and atrioventricular block were not detected. Conclusions: Transapical aortic valve implantation without angiography requires a short learning curve and can be performed routinely by experienced teams. Our report confirms that this procedure is feasible and safe, and provides good results with low incidence of postoperative renal disorders. (Ann Thorac Surg 2010; 89: 1925-33) (C) 2010 by The Society of Thoracic Surgeons

The early Miocene rotation of the Corso-Sardinian block. New paleomagnetic constraints for the end of the motion

The paleomagnetic investigations carried out in the 70's on Oligo-Miocene volcanics of Sardinia have demonstrated that the island was turned by 35-30 degrees clockwise from 33 Ma up to 3-1-20.5 Ma and rotated counterclockwise in a few million years [De Jong et al., 1969, 1973; Bobier et Coulon, 1970; Coulon et al., 1974; Manzoni, 1974, 1975; Bellon rr nl.. 1977: Edel et Lortscher, 1977; Edel, 1979, 1980]. Since then, the end of the rotation fixed at 19 Ma by Montigny er al. [1981] was the subject of discussions and several studies associating paleomagnetism and radiometric dating were undertaken [Assorgia er al., 1994: Vigliotti et Langenheim, 1995: Deino et al., 1997; Gattacceca rt Deino, 1999]. This is a contribution to this debate that is hampered by thr important secular variation recorded in the volcanics. The only way to get our of this problem is to sample series of successive flows as completely as possible, and to reduce the effect of secular variation by the calculation of means. Sampling was performed north of Bonorva in 5 pyroclastic flows that belong to the upper ignimbritic series SI2 according to Coulon rr nl. [1974] or LBLS according to Assorgia et al. [1997] (fig. I). Ar-40/Ar-39 dating of biotites from the debris flow (MDF) has yielded an age or 18.35 +/- 0.03 Ma [Dubois, 2000]. Five of the investigated sites are located beneath the debris flow ITV, TVB, TVD, SPM85, SPM86), one site was cured in the matrix of the debris flow (MDF) and one in 4 metric blocks included in the flow (DFC). Another site was sampled in the upper ash flow (PDM) that marks the end of the pyroclastic activity, just before the marine transgression. According to micropaleontological and radiometric dating this transgression has occurred between 18.35 and 17.6 Ma [Dubois, 2000]. After removal of a soft viscous component, the thermal demagnetization generally shows a univectorial behaviour of the remanent magnetization (fig. 2a). The maximum unblocking temperatures of 580-620 degrees (tab. I) and a rapid saturation below 100 mT (fig. 3) indicate that the carrier of the characteristic magnetization is magnetite. The exception comes: from the upper site PDM in which were found two characteristic components, one with a normal polarity and low unblocking temperatures up to 350 degreesC and one with a reversed polarity and maximum unblocking temperatures at 580-600 degreesC of magnetite. After calculation of a mean direction for each flow, the mean << Al >> direction 4 degrees /57 degrees (alpha (95) = 13 degrees) computed with the mean directions for the 5 flows may be considered as weakly affected by secular variation. But the results require a more careful examination. The declinations are N to NNW beneath the debris flow. NNW in the debris flow. and NNE (or SSW) above the debris flow, The elongated distribution of the directions obtained at sites TVB and TVD. scattered from the mean direction of TV to the mean direction of MDF is interpreted as due to partial overprinting during the debris How volcanic episode, The low temperature component PDMa is likely related to the alteration seen on thin sections and is also viewed as an overprint. As NNE/SSW directions occur as well below (mean direction << B >> : 5 degrees /58 degrees) as above the debris flow (PDMb : 200 degrees/-58 degrees). the NNW directions (<< C >> : 337 degrees /64 degrees) associated with the debris flow volcanism may be interpreted as resulting from a magnetic field excursion. According to the polarity scale of Cande and Kent [1992, 1995] and the radiometric age of MDF, the directions with normal polarity (TV, TVB, TVD, SPM85. SPM86a. MDF. DFC) may represent the period 5En. while the directions with reversed polarity PDMb and SPM86b were likely acquired during the period 5Dr. Using the mean << Al >> direction, the mean << B >>, or the PDM direction (tab. I). the deviation in declination with the direction of stable Europe 6.4 degrees /58.7 degrees (alpha (95) = 8 degrees) for a selection of 4 middle Tertiary poles by Besse et Courtillot [1991] or 7 degrees /56 degrees (alpha (95) = 3 degrees) for 19 poles listed by Edel [1980] can be considered as negligible. Using the results from the uppermost ignimbritic layer of Anglona also emplaced around 18.3 Ma [Odin rt al.. 1994]. the mean direction << E >> (3 degrees /51.5 degrees) leads to the same conclusion. On the contrary, when taking into account all dated results available for the period 5En (mean direction << D >> 353 degrees /56 degrees for 45 sites) (tab. II). the deviation 13 degrees is much more significant. As the rotation of Sardinia started around 21-20.5 Ma. the assumption of a constant velocity of rotation and the deviations of the Sardinia directions with respect to the stable Europe direction locate the end of the motion between 18.3 and 17.2 or 16.7 Ma (fig. 4). During the interval 18.35-17.5 Ma, the marine transgression took place. At the same period a NE-SW shortening interpreted as resulting from the collision of Sardinia with Apulia affected different parts of the island [Letouzey et al., 1982]. Consequently, the new paleomagnetic results and the tectono-sedimentary evolution are in favour of an end of the rotation at 17.5-18 Ma.