CD73-generated extracellular adenosine in chronic lymphocytic leukemia creates local conditions counteracting drug-induced cell death

Extracellular adenosine (ADO), generated from ATP or ADP through the concerted action of the ectoenzymes CD39 and CD73, elicits autocrine and paracrine effects mediated by type 1 purinergic receptors. We have tested whether the expression of CD39 and CD73 by chronic lymphocytic leukemia (CLL) cells activates an adenosinergic axis affecting growth and survival. By immunohistochemistry, CD39 is widely expressed in CLL lymph nodes, whereas CD73 is restricted to proliferation centers. CD73 expression is highest on Ki-67(+) CLL cells, adjacent to T lymphocytes, and is further localized to perivascular areas. CD39(+)/CD73(+) CLL cells generate ADO from ADP in a time- and concentration-dependent manner. In peripheral blood, CD73 expression occurs in 97/299 (32%) CLL patients and pairs with CD38 and ZAP-70 expression. CD73-generated extracellular ADO activates type 1 purinergic A2A receptors that are constitutively expressed by CLL cells and that are further elevated in proliferating neoplastic cells. Activation of the ADO receptors increases cytoplasmic cAMP levels, inhibiting chemotaxis and limiting spontaneous drug-induced apoptosis of CLL cells. These data are consistent with the existence of an autocrine adenosinergic loop, and support engraftment of leukemic cells in growth-favorable niches, while simultaneously protecting from the action of chemotherapeutic agents.     

The genotype nucleophosmin mutated and FLT3‐ITD negative is characterized by high bax/bcl‐2 ratio and favourable outcome in acute myeloid leukaemia

Nucleophosmin gene (NPM1) mutations characterize acute myeloid leukaemia (AML) with normal karyotype and frequently co‐exist with FLT3 internal tandem duplications (ITD). We evaluated bcl‐2, bax, NPM1 and FLT3‐ITD in 222 AML patients. Bax/bcl‐2 ratio >0·35 and NPM1 without FLT3‐ITD were significantly associated (P = 0·0001). NPM1‐mutated (mt)/FLT3‐ITD negative patients showed a higher complete remission (CR) rate (90%, P = 0·0002) and a longer overall survival (OS, P = 0·00007). NPM1‐mt/FLT3‐ITD negative plus bax/bcl‐2 > 0·35 subset showed a very high CR rate (96%), very long OS (P = 0·00005) and disease‐free survival (P = 0·004). The favourable prognosis of NPM1‐mt/FLT3‐ITD negative patients might be explained by a higher bax/bcl‐2 ratio.     

An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors

The vanilloid receptor VR1 is a nonselective cation channel that is most abundant in peripheral sensory fibers but also is found in several brain nuclei. VR1 is gated by protons, heat, and the pungent ingredient of "hot" chili peppers, capsaicin. To date, no endogenous compound with potency at this receptor comparable to that of capsaicin has been identified. Here we examined the hypothesis, based on previous structure-activity relationship studies and the availability of biosynthetic precursors, that N-arachidonoyl-dopamine (NADA) is an endogenous "capsaicin-like" substance in mammalian nervous tissues. We found that NADA occurs in nervous tissues, with the highest concentrations being found in the striatum, hippocampus, and cerebellum and the lowest concentrations in the dorsal root ganglion. We also gained evidence for the existence of two possible routes for NADA biosynthesis and mechanisms for its inactivation in rat brain. NADA activates both human and rat VR1 overexpressed in human embryonic kidney (HEK)293 cells, with potency (EC(50) approximately 50 nM) and efficacy similar to those of capsaicin. Furthermore, NADA potently activates native vanilloid receptors in neurons from rat dorsal root ganglion and hippocampus, thereby inducing the release of substance P and calcitonin gene-related peptide (CGRP) from dorsal spinal cord slices and enhancing hippocampal paired-pulse depression, respectively. Intradermal NADA also induces VR1-mediated thermal hyperalgesia (EC(50) = 1.5 +/- 0.3 microg). Our data demonstrate the existence of a brain substance similar to capsaicin not only with respect to its chemical structure but also to its potency at VR1 receptors.     

Hyaluronic acid and aspartate aminotransferase levels normalized by liver function can reflect sinusoidal impairment in chronic liver disease.

BACKGROUND/AIM: To evaluate the relationship between hyaluronic acid/aminopyrine breath test (HA/ABT) ratio and fibrosis score in chronic hepatitis, and between HA/ABT and clinical staging (child-turcotte-pugh'score, CTP; and model for end stage liver disease, MELD) in cirrhosis, as well as to evaluate the aspartate aminotransferase (AST)/ABT in relation to the HA/ABT. METHODS: We studied 48 patients with histologically proven chronic hepatitis C (CHC) and 35 patients with compensated cirrhosis (CIR). RESULTS: HA/ABT and AST/ABT showed a more significant correlation with the fibrosis score than HA or ABT or AST alone in the 48 CHC patients: r=0.568 (P<0.0001), r=0.610 (P<0.0001), r=0.450 (P=0.0021), r=-0.449 (P=0.0021), and r=0.472(P=0.0012), respectively. Progressive liver damage (fibrosis 1-2 vs fibrosis 3-6 vs cirrhosis) was significantly (P<0.05) reflected by both HA/ABT (mean+/-SEM: 4.0+/-0.9 vs 18.1+/-4.2 vs 149.9+/-33.1) and AST/ABT (6.3+/-1.8 vs 12.7+/-1.6 vs 42.1+/-14.6). A strong relationship was found between HA/ABT and AST/ABT (r=0.755 P<0.0001). In cirrhotic patients, the most significant relationship was observed between HA/ABT and CTP r=0.483 and P=0.0049, and MELD r=0.523 and P=0.0023. CONCLUSION: Considering that HA levels in chronic hepatitis depend on the progressive impairment of sinusoidal endothelial cells (SEC), related to progressive fibrosis, HA/ABT ratio would seem to be the most specific reflection of progressive impairment of the SEC. AST/ABT could be used as a possible surrogate of HA in identifying SEC impairment in chronic hepatitis.     

Left ventricular hypertrophy in patients with autonomic failure

BACKGROUND: In autonomic failure (AF), supine hypertension may predispose patients to end-organ damage. The pathophysiology of hypertensive heart disease in AF is not known. The aim of the present study was to evaluate the prevalence and predisposing factors of left ventricular hypertrophy (LVH) in patients with AF. METHODS: We studied 25 patients with AF (67 +/- 8 years); 80% were being treated for orthostatic hypotension. Twenty patients with essential hypertension (68 +/- 6 years) were considered as the control group. All subjects underwent echocardiography for measurement of left ventricular mass (LVM). The patients with AF underwent a 24-h BP monitoring and long-term blood pressure (BP) variability was calculated as standard deviation (SD) of the average of the half-hour mean values. RESULTS: The LVM is comparable in patients with AF and hypertensive controls (145 +/- 35 g/m2 v 127 +/- 32 g/m2, P = .07). The proportion of patients with LVH is similar in both populations (AF 80%, hypertensive 70%). The patients with AF were divided into two groups, with and without LVH. The SDs are significantly higher in AF patients with LVH than in those with normal LVM (SD 24-h systolic BP: 22 +/- 4 v 14 +/- 1 mm Hg, P = .001). CONCLUSIONS: A high proportion of patients with AF show LVH. The LVM values are comparable with those of patients with essential hypertension. The development of LVH seems to depend on high BP variability, characteristic of AF patients. Detection of LVH may help in the choice of treatment for orthostatic hypotension and in the prevention of heart failure.     

High frequency of MYH gene mutations in a subset of patients with familial adenomatous polyposis

BACKGROUND & AIMS: Inherited colorectal polyposis has been linked to constitutive mutations of the APC tumor suppressor gene. Recently, germline mutations in the base excision repair gene MYH have been associated with a recessively inherited form of the disease. The aim of this study was to evaluate germline mutation frequencies of both MYH and APC susceptibility genes in Italian patients with attenuated familial adenomatous polyposis. METHODS: The analysis was performed in 14 unrelated patients by using the protein truncation test for APC and genomic DNA sequencing for MYH. RESULTS: Overall, we identified 7 of 14 (50%) mutation carriers. Two patients were heterozygotes for an APC truncating mutation (2 of 14 [14%]), whereas 5 proved to be homozygotes or compound heterozygotes for MYH gene alterations (5 of 14 [36%]). Two MYH missense mutations, Y165C and G382D, already found to be frequent among patients from northern Europe, were also preponderant in our survey. Individuals with APC-associated syndrome showed a dominant family history of polyposis, whereas patients with MYH-associated disease were either apparently sporadic cases or had a family history consistent with recessive inheritance. MYH biallelic mutation carriers were up to 60% (5 of 8) among patients showing at least 30 adenomas and a family history with no vertical transmission of polyposis. CONCLUSIONS: On the basis of our data, patients with attenuated familial adenomatous polyposis with >30 adenomas and no obvious vertical transmission of the disease should be considered for MYH gene testing.     

Prospective multicenter randomized trial of fast ventricular tachycardia termination by prolonged versus conventional anti-tachyarrhythmia burst pacing in implantable cardioverter-defibrillator patients-Atp DeliVery for pAiNless ICD thErapy (ADVANCE-D) Trial results

Purpose

The purpose of the trial was to quantify and compare the efficacy of two different sequences of burst anti-tachycardia pacing (ATP) strategies for the termination of fast ventricular tachycardia.

Methods

The trial was prospective, multicenter, parallel and randomized, enrolling patients with an indication for implantable cardioverter-defibrillator implantation.

Results

From February 2004, 925 patients were randomized and followed-up for 12 months. Eight pulses ATP terminated 64% of episodes vs. 70% in the 15-pulse group (p?=?0.504). Fifteen pulses proved significantly better in patients without a previous history of heart failure (p?=?0.014) and in patients with LVEF?≥?40% (p?=?0.016). No significant differences between groups were observed with regard to syncope/near-syncope occurrence.

Conclusion

In the general population, 15-pulse ATP is as effective and safe as eight-pulse ATP. The efficacy of ATP on fast ventricular arrhythmias confirmed once more the striking importance of careful device programming in order to reduce painful shocks.     

Large brachial and common carotid artery diameter in postmenopausal women with carotid atherosclerosis

Background and purposeIt is recognized that arteries can enlarge to compensate atherosclerosis. The role of diameter enlargement of unaffected arteries is not well known. We hypothesized that brachial and common carotid arteries diameters were larger in subjects with carotid atherosclerosis compared to subjects without these lesions.MethodsWe measured diameters in the common carotid and brachial arteries. Intimal medial thickness (IMT) of carotid arteries and carotid atherosclerosis were also evaluated using ultrasound in 83 cases and 83 disease-free control subjects.ResultsCommon carotid and brachial diameter was greater in cases (subjects with carotid atherosclerosis) than controls (subjects without carotid atherosclerosis) after adjustment for confounding variables (P < 0.02). Common carotid diameter was also larger in individuals with greater IMT (P < 0.0001), whereas brachial artery diameter was not. Subjects with more than one carotid plaque had larger arterial diameters than those with one or without plaques.ConclusionsCommon carotid and brachial artery diameters are both larger in cases than controls. This result suggests that vascular remodeling is a systemic process and not only a local response to atherosclerosis. The relationship between diameters and burden of disease could also suggest a link between vascular remodeling and severity of disease. Finally, if confirmed in prospective studies, brachial artery diameter could help to identify subjects at high cardiovascular risk, at least in postmenopausal women.     

The endocrine function of adipose tissue: an update

Adipose tissue secretes bioactive peptides, termed 'adipokines', which act locally and distally through autocrine, paracrine and endocrine effects. In obesity, increased production of most adipokines impacts on multiple functions such as appetite and energy balance, immunity, insulin sensitivity, angiogenesis, blood pressure, lipid metabolism and haemostasis, all of which are linked with cardiovascular disease. Enhanced activity of the tumour necrosis factor and interleukin 6 are involved in the development of obesity-related insulin resistance. Angiotensinogen has been implicated in hypertension and plasminogen activating inhibitor-1 (PAI-1) in impaired fibrinolysis. Other adipokines like adiponectin and leptin, at least in physiological concentrations, are insulin sparing as they stimulate beta oxidation of fatty acids in skeletal muscle. The role of resistin is less understood. It is implicated in insulin resistance in rats, but probably not in humans. Reducing adipose tissue mass, through weight loss in association with exercise, can lower TNF-alpha and IL-6 levels and increase adiponectin concentrations, whereas drugs such as thiazolinediones increase endogenous adiponectin production. In-depth understanding of the pathophysiology and molecular actions of adipokines may, in the coming years, lead to effective therapeutic strategies designed to protect against atherosclerosis in obese patients.     

Power spectral analysis of heart rate variability as a predictive test in choosing the most effective length for tilt-training

BACKGROUND: In patients with refractory neurally mediated syncope, tilt training--standing motionless against a wall for increased periods of time per day over one month--can often eliminate recurrent episodes and reduce presyncopal symptoms. We designed dual retrospective and prospective studies to assess cardiovascular autonomic function in subjects with recurrent syncope and identify the most effective length of tilt training between one and three months. METHODS AND RESULTS: In the retrospective study, before tilt training, and in the prospective study, before and after training, all subjects underwent a recording for short-term spectral analysis of heart rate and systolic blood pressure variability. Before tilt-training, autonomic nervous system function differs in patients with recurrent neurally mediated syncope who respond to tilt training for one month and those who do not. "Responders", patients experiencing no episodes of syncope during the 12-month follow-up, had higher low-frequency power of RR (LF(RR)) (p < 0.05) and LF(RR) in normalized units (NU) (p < 0.001) and lower high-frequency power (HF(RR)) (p < 0.05) and HF(RR)NU (p < 0.001) than "non-responders", patients reporting at least one syncopal episode during the 12-month follow-up. In the retrospective study, no difference was found between spectral data for "non-responders" with positive responses to tilt test with and without nitro derivatives. Prolonging tilt-training to three months increased the number of responders (late-responders) by 80% (p < 0.001) and power spectral analysis of heart rate variability (HRV) before tilt training can identify late-responders by their low LF(RR)NUs (<40) and high HF(RR)Nus (>60). Furthermore in late-responders, tilt training brings about a change in cardiovascular autonomic function: at 3 months, LF(RR)NUs increase and HF(RR)NU diminish. CONCLUSION: Power spectral analysis of HRV seems to be a useful tool to preselect patients who are most likely to benefit from prolonged therapy, thus increasing compliance.