Connectivity of the Cingulate Sulcus Visual Area (CSv) in Macaque Monkeys.

In humans, the posterior cingulate cortex contains an area sensitive to visual cues to self-motion. This cingulate sulcus visual area (CSv) is structurally and functionally connected with several (multi)sensory and (pre)motor areas recruited during locomotion. In nonhuman primates, electrophysiology has shown that the cingulate cortex is also related to spatial navigation. Recently, functional MRI in macaque monkeys identified a cingulate area with similar visual properties to human CSv. In order to bridge the gap between human and nonhuman primate research, we examined the structural and functional connectivity of putative CSv in three macaque monkeys adopting the same approach as in humans based on diffusion MRI and resting-state functional MRI. The results showed that putative monkey CSv connects with several visuo-vestibular areas (e.g., VIP/FEFsem/VPS/MSTd) as well as somatosensory cortex (e.g., dorsal aspects of areas 3/1/2), all known to process sensory signals that can be triggered by self-motion. Additionally, strong connections are observed with (pre)motor areas located in the dorsal prefrontal cortex (e.g., F3/F2/F1) and within the anterior cingulate cortex (e.g., area 24). This connectivity pattern is strikingly reminiscent of that described for human CSv, suggesting that the sensorimotor control of locomotion relies on similar organizational principles in human and nonhuman primates.

Allocentric coding: spatial range and combination rules.

When a visual target is presented with neighboring landmarks, its location can be determined both relative to the self (egocentric coding) and relative to these landmarks (allocentric coding). In the present study, we investigated (1) how allocentric coding depends on the distance between the targets and their surrounding landmarks (i.e. the spatial range) and (2) how allocentric and egocentric coding interact with each other across targets-landmarks distances (i.e. the combination rules). Subjects performed a memory-based pointing task toward previously gazed targets briefly superimposed (200ms) on background images of cluttered city landscapes. A variable portion of the images was occluded in order to control the distance between the targets and the closest potential landmarks within those images. The pointing responses were performed after large saccades and the reappearance of the images at their initial location. However, in some trials, the images' elements were slightly shifted (±3°) in order to introduce a subliminal conflict between the allocentric and egocentric reference frames. The influence of allocentric coding in the pointing responses was found to decrease with increasing target-landmarks distances, although it remained significant even at the largest distances (⩾10°). Interestingly, both the decreasing influence of allocentric coding and the concomitant increase in pointing responses variability were well captured by a Bayesian model in which the weighted combination of allocentric and egocentric cues is governed by a coupling prior.

First-in-human study of pbi-05204, an oleander-derived inhibitor of akt, fgf-2, nf-κΒ and p70s6k, in patients with advanced solid tumors.

BACKGROUND: PBI-05204, a Nerium oleander extract (NOE) containing the cardiac glycoside oleandrin, inhibits the α-3 subunit of Na-K ATPase, as well as FGF-2 export, Akt and p70S6K, hence attenuating mTOR activity. This first-in-human study determined the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of PBI-05204 in patients with advanced cancer. Methods Forty-six patients received PBI-05204 by mouth for 21 of 28 days (3 + 3 trial design). Dose was escalated 100% using an accelerated titration design until grade 2 toxicity was observed. Plasma PK and mTOR effector (p70S6K and pS6) protein expressions were evaluated. Results Dose-limiting toxicities (grade 3 proteinuria, fatigue) were observed at dose level 8 (0.3383 mg/kg/day). Common possible drug-related adverse were fatigue (26 patients, 56.5%), nausea (19 patients, 41.3%) and diarrhea (15 patients, 32.6 %). Electrocardiogram monitoring revealed grade 1 atrioventricular block (N = 10 patients) and grade 2 supraventricular tachycardia (N = 1). The MTD was DL7 (0.2255 mg/kg) where no toxicity of grade ≥ 3 was observed in seven patients treated. Seven patients (15%) had stable disease > 4 months. Mean peak oleandrin concentrations up to 2 ng/mL were achieved, with area under the curves 6.6 to 25.5 µg/L*hr and a half-life range of 5-13 h. There was an average 10% and 35% reduction in the phosphorylation of Akt and pS6 in PBMC samples in 36 and 32 patients, respectively, tested between predose and 21 days of treatment. Conclusions PBI-05204 was well tolerated in heavily pretreated patients with advanced solid tumors. The recommended Phase II dose is 0.2255 mg/kg/day.

Computerized tomographic finding of saddle pulmonary embolism is associated with high mortality in cancer patients.

BACKGROUND: Large pulmonary embolism (PE) is associated with high mortality in cancer patients. Several risk stratification methods have been used in PE setting. While computer-assisted tomography (CT) is now the preferred diagnostic modality for PE, its prognostic value is not well established. METHODS: A retrospective study of patients discharged from our centre between 2000 and 2006 with a PE diagnosis identified 52 patients with thrombus in the main pulmonary artery or the right or left branch. Clinical, echocardiographic and CT data were reviewed; vital status was determined 1 month and 1 year after index event. Patients were divided into saddle (defined as main pulmonary artery thrombus) and non-saddle PE. Multivariate logistic regression was applied to predict vital status, with patient age and CT parameters as predictors. RESULTS: Eighteen out of 52 patients were found to have a saddle PE. No significant difference was found between the group characteristics, although saddle PE patients were more likely to receive thrombolytic therapy (27.8% vs 2.9%, P = 0.02) and have an echocardiogram within 30 days of PE (61.1% vs 29.4%, P = 0.03). Overall mortality at 1 month was 9.6% with no difference between groups. At 1 year, mortality rates in saddle PE were significantly higher (83.3% vs 41.2%, P = 0.004). Presence of saddle PE was associated with an odds ratio of death within 1 year of 7.41 (95% confidence interval: 1.75-31.46, P = 0.007). CONCLUSION: The relatively simple distinction of saddle versus non-saddle PE by CT findings may provide a straightforward method for risk stratification, and remains useful up to 1 year after the index event.

Analysis of the plant architecture via tree-structured statistical models: the hidden Markov tree models.

Plant architecture is the result of repetitions that occur through growth and branching processes. During plant ontogeny, changes in the morphological characteristics of plant entities are interpreted as the indirect translation of different physiological states of the meristems. Thus connected entities can exhibit either similar or very contrasted characteristics. We propose a statistical model to reveal and characterize homogeneous zones and transitions between zones within tree-structured data: the hidden Markov tree (HMT) model. This model leads to a clustering of the entities into classes sharing the same 'hidden state'. The application of the HMT model to two plant sets (apple trees and bush willows), measured at annual shoot scale, highlights ordered states defined by different morphological characteristics. The model provides a synthetic overview of state locations, pointing out homogeneous zones or ruptures. It also illustrates where within branching structures, and when during plant ontogeny, morphological changes occur. However, the labelling exhibits some patterns that cannot be described by the model parameters. Some of these limitations are addressed by two alternative HMT families.

Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy.

BACKGROUND: Familial dilated cardiomyopathy (FDCM) and hypertrophic cardiomyopathy (FHCM) are the 2 most common forms of primary cardiac muscle diseases. Studies indicate that mutations in sarcomeric proteins are responsible for FHCM and suggest that mutations in cytoskeletal proteins cause FDCM. Evidence is evolving, however, that such conclusions are premature. METHODS AND RESULTS: A novel missense mutation in the cardiac troponin T gene was identified by direct sequencing and confirmed by endonuclease restriction analysis in a large family with FDCM that we had previously mapped to chromosome 1q32. The mutation substitutes tryptophan for a highly conserved amino acid, arginine, at amino acid residue 141 (Arg141Trp). The mutation occurs within the tropomyosin-binding domain of cardiac troponin T and alters the charge of the residue. This mutation cosegregates with the disease, being present in all 14 living affected individuals. The mutation was not found in 100 normal control subjects. Clinical features were congestive heart failure with premature deaths. The age of onset and severity of the disease are highly variable, with incomplete penetrance. Because 15 mutations in troponin T are known to cause FHCM, 219 probands with FHCM were screened, and none had the mutation. CONCLUSIONS: Thus, the novel cardiac troponin T mutation Arg141Trp is responsible for FDCM in our family. Because several mutations in troponin T have already been recognized to be responsible for FHCM, it appears that the phenotype, whether it be hypertrophy or dilatation, is determined by the specific mutation rather than the gene.

A pilot safety trial of prolonged (48 h) infusion of the dual endothelin-receptor antagonist tezosentan in patients with advanced heart failure.

STUDY OBJECTIVES: Tezosentan, an IV dual endothelin-receptor antagonist, has demonstrated beneficial hemodynamic effects in patients with advanced heart failure. In addition, no notable differences in safety and tolerability variables were detected between tezosentan-treated and placebo-treated patients when infused over 4 to 6 h. The present study was conducted primarily to assess the safety and tolerability of tezosentan when administered over a prolonged, 48-h treatment period, and secondarily to investigate hemodynamic response. DESIGN: This randomized, double-blind, active-controlled study of continual IV administration of two dosages of tezosentan (20 mg/h and 50 mg/h; n = 6 each) or dobutamine (5 microg/kg/min; n = 2) over 48 h in patients with advanced heart failure was conducted to assess tolerability, safety, and hemodynamic variables (Doppler echocardiography). RESULTS: During tezosentan infusion, no episodes of hypotension requiring withdrawal of therapy occurred, and hemodynamic rebound was not observed after abrupt cessation of the infusion. There were no reports of worsening heart failure in tezosentan-treated patients up to 28 days following the infusion. The most common side effect during the infusion was headache (9 of 12 tezosentan-treated patients and both dobutamine-treated patients). Echocardiographic Doppler measurements suggested improvements in cardiac index, pulmonary capillary wedge pressure, and relaxation properties as well as in diastolic and systolic function in all treatment groups. CONCLUSIONS: Prolonged, 48-h IV dual endothelin-receptor antagonism with tezosentan was well tolerated with no new safety concerns emerging. These data further support the potential role of tezosentan in the treatment of patients with acute heart failure.

Cardiac transplantation: the final therapeutic option for the treatment of heart failure.

End-stage heart failure is still associated with a decrease in quality and prognosis of life. Cardiac transplantation remains the final extraordinary therapeutic option for the treatment of truly irreversible end-stage heart failure in all age groups. The selection process of candidates and the acceptance of patients with relative contra-indications is characterized by the experience and skills of an interdisciplinary transplant team, which should have access to different mechanical circulatory support systems for short-term or long-term use: bridging to transplant as well as for recovery.

Decreased expression of tumor necrosis factor-alpha in failing human myocardium after mechanical circulatory support : A potential mechanism for cardiac recovery.

BACKGROUND: An increasing number of observations in patients with end-stage heart failure suggest that chronic ventricular unloading by mechanical circulatory support may lead to recovery of cardiac function. Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine capable of producing pulmonary edema, dilated cardiomyopathy, and death. TNF-alpha is produced in the myocardium in response to volume overload; however, the effects of normalizing ventricular loading conditions on myocardial TNF-alpha expression are not known. We hypothesize that chronic ventricular unloading by the placement of a left ventricular assist device (LVAD) may eliminate the stress responsible for persistent TNF-alpha expression in human failing myocardium. METHODS AND RESULTS: Myocardial tissue was obtained from normal hearts and from paired samples of 8 patients with nonischemic end-stage cardiomyopathy at the time of LVAD implantation and removal. Tissue sections were stained for TNF-alpha, and quantitative analysis of the stained area was performed. We found that TNF-alpha content decreased significantly after LVAD support. Furthermore, the magnitude of the changes did not correlate with the length of LVAD support, although greater reductions in myocardial TNF-alpha content were found in patients who were successfully weaned off the LVAD who did not require transplantation. CONCLUSIONS: These data show for the first time that chronic mechanical circulatory assistance decreases TNF-alpha content in failing myocardium; furthermore, we suggest that the magnitude of the change may predict which patients will recover cardiac function.

Genetic basis of cardiomyopathy.

The molecular basis of cardiac growth and development is a fundamental question that has intrigued many investigators in cardiovascular research. Adult cardiomyocytes are terminally differentiated and lose their ability to proliferate shortly after birth; however, in response to injury, myocytes have the capacity to synthesize new DNA and exhibit plasticity by a compensatory growth response, as is shown by re-expression of the fetal isoforms of many muscle-specific genes, which is characteristic of the proliferative response. The long-term effects of these compensatory responses may lead to the development and progression of diseases such as hypertrophic cardiomyopathy and dilated cardiomyopathy, because of a single point mutation. This concept has engaged scientists to investigate human models to explore the molecular basis of hypertrophy or dilation of the myocardium.

[Heterotopic heart transplantation: 13-year experience at the Methodist Hospital of the Baylor Medical College]. / Trasplante cardiaco heterotópico: experiencia de trece años en el Hospital Metodista del Colegio de Medicina de Baylor.

UNLABELLED: In order to evaluate our experience in heterotopic cardiac transplantation, we conducted a retrospective analysis of the clinical files of patients who underwent this procedure. RESULTS: A total of 405 heart transplants were performed in our institution. In 24 (5.9%), the grafts were placed heterotopically. In group I (12 patients), the indication was irreversible pulmonary hypertension and in group II (remaining 12 patients), it was marginal grafts or size mismatch. Both groups demonstrated similar demographics and the survival rate was slightly better in group I. Nine patients from group I demonstrated an early reduction in pulmonary pressures which normalized in one year. CONCLUSIONS: The heterotopic heart supports the function of the native ventricles. In 9 patients, the heterotopic heart enables the reversal of a state of pulmonary hypertension previously thought to be irreversible. This finding supports the use of pulmonary vaso-dilators on a chronic basis or the use of a left ventricular assist device pre-transplant with the intention of normalizing pulmonary pressures and allowing the patients to become candidates for orthotopic cardiac transplantation and thereby avoiding the necessity of heterotopic cardiac transplantation.

[Tumor necrosis factor-alpha: a mediator in the pathogenesis of cardiac insufficiency]. / Factor de necrosis tumoral-alpha: un mediador en la patogénesis de la insuficiencia cardiaca.

An increasing body of experimental and clinical work suggesting that tumor necrosis factor alpha plays a pathogenic role in heart failure continues to accumulate. This cytokine is produced in failing but not in normal hearts and experimentally, it's expression is induced by hemodynamic conditions of pressure or volume overload. Specific receptors for this cytokine are present in the heart and dynamic regulation in tumor necrosis factor receptor expression occurs in failing myocardium. In addition, tumor necrosis factor alpha may exert major cardiac effects that contribute to the development of the failing phenotype: induces negative contractil dysfunction, promotes fibrosis, induces cardiomyopathy in experimental animals and it is a major mediator of apoptosis in vivo and in vitro. The knowledge gained from studying the role of tumor necrosis factor alpha in cardiac function draws attention to a series of molecules previously unrecognized as potential mediators in the pathogenesis of heart failure.

Differential expression of heat shock proteins in normal and failing human hearts.

BACKGROUND: Heat shock proteins (hsp) constitute an endogenous stress response that protects cells from injury. Most work on these important proteins has focused on the immediate response to acute stress in cell culture systems and mammalian models of heart disease. Little is known about the expression of the hsps in human hearts. We were interested in whether there was increased expression of the hsps in heart failure, a setting of chronic, sustained stress. Five different hsps were examined: hsp27, hsp60, hsp72, hsc70 and hsp90. METHODS AND RESULTS: Three groups of explanted hearts were studied: dilated cardiomyopathy (DCM), ischemic cardiomyopathy (IHD), and normal controls. Western-blotting with a standard curve of purified protein on each blot was used to quantify the expression of the hsps. Hsp27 was increased almost two-fold in DCM compared to normal hearts, and was significantly greater than in IHD hearts. Levels of hsp60 were doubled in both DCM and IHD hearts (P < 0.05). Hsp72, hsc70 and hsp90 were not significantly changed. CONCLUSIONS: This study shows for the first time that differential changes in hsp levels occur in end-stage heart failure. Since hsps can render cells resistant to apoptosis, and are associated with the mitochondria and the cytoskeleton, which are known to be abnormal in heart failure, these studies may lead to new insights into the pathogenesis of cardiac decompensation.

Subclavian venogram as a guide to lead implantation.

Recent reports have raised doubts regarding the safety and efficacy of the blind subclavian venipuncture technique for intracardiac lead implantation. To permit a more lateral entry, we used a simple subclavian venogram performed through the brachial vein of the ipsilateral arm of 22 consecutive unselected patients undergoing lead implantation (19 permanent pacemakers and 3 intracardiac defibrillators). A total of 35 leads were implanted (31 left pectoral and 4 right pectoral). Lead insertion by venogram technique was used successfully in all patients. Two inconsequential arterial punctures occurred. There were no pneumothoraces infections, or other complications. Lateral placement should facilitate lead manipulation and minimize "subclavian crush." The method of ipsilateral venogram guided lead insertion appears to be safe and reliable and deserves consideration in patients who require permanent lead placement via the subclavian vein approach.

Polymorphic trinucleotide repeat in the MEF2A gene at 15q26 is not expanded in familial cardiomyopathies.

A trinucleotide repeat polymorphism in the MEF2A gene is described. MEF2A is expressed early in cardiac muscle development; thus the possibility of linkage between this polymorphism and familial cardiomyopathies was investigated in three families not linked to genes coding for known sarcomeric proteins. MEF2A was excluded as a candidate for dilated cardiomyopathy (DCM)(LOD of -9.03) and hypertrophic cardiomyopathy (HCM)(LODs of -5.43 and -2.44) in these families. Because expansion of triplet repeats has been shown to be responsible for several inherited diseases, 121 unrelated HCM probands and 28 unrelated DCM probands were examined for evidence of expansion of this repeat. No expansion of this trinucleotide repeat was seen in any of the 149 cardiomyopathy probands.

Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that produces negative inotropic effects in the heart. Recently, elevated levels of TNF-alpha have been reported in patients with advanced congestive heart failure. Although TNF-alpha is thought to exert its deleterious effects by binding to two cell surface receptors, TNFR1 and TNFR2, the level of expression and regulation of TNF receptors in the heart in cardiac disease states is not known. METHODS AND RESULTS: We examined mRNA and protein levels for TNFR1, TNFR2, and TNF-alpha in explanted hearts from organ donors as well as in patients with end-stage dilated cardiomyopathy (DCM) and ischemic heart disease (IHD). Northern blot analysis revealed that mRNA for TNFR1 and TNFR2 was present in nonfailing, DCM, and IHD hearts. TNFR1 and TNFR2 receptor protein levels, as measured by ELISA, were decreased 60% in DCM and IHD patients compared with nonfailing hearts (P < .005). To determine a potential mechanism for the decrease in TNF receptor expression, we measured levels of circulating soluble TNF receptors (sTNFRs) in DCM and IHD patients. This analysis showed that there was a significant one-and-a-half to threefold increase in sTNFRs in DCM (P < .03) and IHD patients (P < .001). Another important finding was that TNF-alpha mRNA and TNF-alpha protein were present in the explanted hearts from DCM and IHD patients but not in nonfailing hearts. CONCLUSIONS: In summary, the results of this study constitute the initial demonstration that TNF receptor proteins are dynamically regulated in patients with advanced congestive heart failure. Moreover, the observation that failing hearts express elevated levels of TNF-alpha suggests that overexpression of this cytokine may be one of several different maladaptive mechanisms responsible for the progressive cardiac decompensation that occurs in advanced heart failure.

Localization of a gene responsible for familial dilated cardiomyopathy to chromosome 1q32.

BACKGROUND: Dilated cardiomyopathy, characterized by ventricular dilatation and decreased systolic contraction, is twofold to threefold more common as a cause of heart failure than hypertrophic cardiomyopathy and costs several billion dollars annually. The idiopathic form occurring early in life, with a 75% mortality in 5 years, is a common reason for transplantation. It is estimated that at least 20% of cases are familial. METHODS AND RESULTS: A family of 46 members spanning four generations underwent history and physical examinations, echocardiographic analysis, and blood sampling for genotyping. Diagnostic criteria, detected by echocardiography, consisted of ventricular dimension of > or = 2.7 cm/m2 with an ejection fraction < or = 50% in the absence of other potential causes. DNA from all members was analyzed by polymerase chain reaction for amplification of short tandem-repeat polymorphic markers located every 10 cM throughout the human genome. Assuming a penetrance of 90%, linkage analysis was performed to map the responsible chromosomal locus. Linkage analysis, after 412 markers were analyzed, indicated the locus to be on chromosome 1q32, with a peak multipoint logarithm of the odds score at D1S414 of 6.37. CONCLUSIONS: The locus identified in this study for familial dilated cardiomyopathy, 1q32, is rich in candidate genes, such as MEF-2, renin, and helix loop helix DNA binding protein MYF-4. Identification of the genetic defect could provide insight into the molecular basis for the cardiac dilatory response in both familial and acquired disorders.

Molecular and clinical aspects of inherited cardiomyopathies.

Hypertrophic cardiomyopathy (HCM) is phenotypically and genotypically a heterogeneous disease. Since 1989, four chromosomal loci have been identified for HCM and the genes residing on three of these have been identified as beta-myosin heavy chain (beta-MHC), cardiac troponin-T and alpha-tropomyosin. These genes code for sarcomeric proteins and exhibit the same phenotype, suggesting that HCM is a disease of the sarcomere. Over 40 missense mutations and one deletion of the beta-MHC gene have been identified. Similarly, missense mutations in the alpha-tropomyosin gene and the cardiac troponin-T gene have been identified. From genetic studies, including de novo mutations, it is established that these mutations are indeed responsible for HCM. The molecular basis of the pathogenesis of the cardiac hypertrophy appears to be a compensatory response to the primary defect. In addition to providing a definitive presymptomatic diagnosis, studies correlating beta-MHC mutations with clinical prognosis suggest they have significant predictive value and can be helpful in genetic counselling and medical management. Dilated cardiomiopathies (DCM), the most common form of cardiomyopathies, have an estimated prevalence of nearly 40 per 100,000 individuals, and are the most common cause for cardiac transplantation in the United States. Familial dilated cardiomyopathy is thought to account for approximately 20% of the so-called cases of idiopathic DCM.

Regulation of procollagen metabolism in the pressure-overloaded rat heart.

To determine the molecular events responsible for the disproportionate accumulation of myocardial fibrillar collagens during sustained hypertension, we examined the in vivo rate of procollagen synthesis, collagen accumulation, and intracellular procollagen degradation 1-16 wk after abdominal aortic banding in young rats. These measurements were correlated with tissue mRNA levels for type I and type III procollagen polypeptides. Banded animals developed moderate, sustained hypertension and mild left ventricular hypertrophy. Increased type III procollagen mRNA levels were detected early after banding and persisted for the entire observation period. Disproportionate collagen accumulation without histological evidence of fibrosis was noted within 1 wk after hypertension induction. Fibrillar collagen accumulation at this time point resulted not from a major increase in procollagen synthesis, but rather a marked decrease in the rate of intracellular procollagen degradation. Interstitial fibrosis, however, was observed 16 wk after banding. Type I procollagen mRNA levels were increased six-fold, but only after 16 wk of hypertension. These results correlated well with the results of in vivo procollagen synthesis experiments at 16 wk, which demonstrated a threefold increase in left ventricular procollagen biosynthesis. We conclude that pretranslational as well as posttranslational mechanisms regulate fibrillar collagen deposition in the myocardial extracellular matrix during sustained hypertension.