Endogenous morphine: opening new doors for the treatment of pain and addiction

Nitric oxide (NO) signalling is at the forefront of intense research interest because its many effects remain controversial and seemingly contradictory. This paper examines its role as a potential mediator of pain and tolerance. Within this context discussion covers endogenous morphine, documenting its ability to be made in animal tissues, including nervous tissue, and in diverse animal phyla. Supporting morphine as an endogenous signalling molecule is the presence of the newly cloned mu3 opiate receptor subtype found in animal (including human) immune, vascular and neural tissues, which is coupled to NO release. Importantly, this mu opiate receptor subtype is morphine-selective and opioid peptide-insensitive, further highlighting the presence of morphinergic signalling coupled to NO release. These findings provide novel insights into pain and tolerance as morphinergic signalling exhibits many similarities with NO actions. Taken together, a select morphinergic signalling system utilising NO opens the gate for the development of novel pharmaceuticals and/or the use of old pharmaceuticals in new ways.     

Analytical and clinical evaluation of a new heart-type fatty acid-binding protein automated assay.

BACKGROUND: The accurate and rapid recognition of myocardial injury in patients presenting in the emergency department (ED) with chest pain continues to be a clinical challenge. Heart-type fatty acid-binding protein (H-FABP) appears to be one of the best candidates among the new early cardiac markers studied. METHODS: We evaluated the analytical characteristics of a new quantitative and fully automated H-FABP assay (Randox Laboratories Ltd., Crumlin, UK) and compared its clinical performance with respect to the myoglobin (Myo) assay (Dade Behring, Milan, Italy). A precision study was carried out by testing three levels of quality control (QC) material and two in-house pool (P) samples. To test the accuracy of H-FABP determinations in plasma (lithium-heparin) samples, H-FABP concentrations measured in a set of matched sera and plasma samples were compared. A total of 77 non-consecutive patients (51 males and 26 females; 62+/-16 years) who presented to the ED with chest pain suggesting myocardial ischemia were enrolled. The patients were classified into two groups (acute myocardial infarction, n=22; non-acute myocardial infarction, n=55) on the basis of the discharge diagnosis. RESULTS: The between-day imprecision for three levels of control material and serum pool samples was 6.26%-8.04% (range 2.32-44.03 microg/L) and 9.03%-12.63% (range 11.85-65.13 microg/L), respectively. In the serum vs. plasma study, bias was +0.178 (95% CI -0.033 to +0.389). The best cut-off and the associated diagnostic efficacy were 95 microg/L and 89.47% for Myo and 5.09 microg/L and 98.70% for H-FABP, respectively. CONCLUSIONS: H-FABP determination in patients with ischemic symptoms may be a more reliable early indication of cardiac damage than myoglobin.     

Efficacy and Safety of Ramipril in Hypertensive Single-Kidney Patients

The effects of medium-term antihypertensive treatment with the ACE inhibitor ramipril were studied on 10 hypertensive single-kidney patients in a double-blind study versus placebo. Patients with renovascular hypertension were excluded. Compared to placebo, ramipril induces a significant reduction of arterial blood pressure (p < 0.02 for systolic, p < 0.01 for diastolic, and p < 0.05 for mean blood pressure), renal vascular resistance (p < 0.005), and microalbuminuria (p < 0.005), but a significant rise of effective renal plasma flow (p < 0.01) and no significant variation of the glomerular filtration rate. The reduction of microalbuminuria was not related to arterial blood pressure variation. Our study shows that ramipril, in appropriately selected-kidney patients, is effective and safe in reducing arterial blood pressure, bringing about an improvement of renal function and reducing microalbuminuria, which is frequently observed in this condition.     

STI 571 inhibition effect on KITAsn822Lys-mediated signal transduction cascade

OBJECTIVE: Alterations in growth factor signaling pathways may be a frequent collaborating event in AML1-ETO-mediated leukemogenesis. Gain-of-function KIT receptor mutations have been reported in adult AML patients, especially those with core binding factor leukemia (CBFL). We have previously reported a new gain-of-function KIT(Asn822Lys) mutation that is constitutively expressed in the Kasumi-1 CBFL cell line, and has recently been described in two childhood AML patients. To explore the molecular basis of the effects of this mutation in the appropriate context of hemopoietic dysregulation, we investigated KIT downstream signaling in the Kasumi-1 cell line by means of STI 571 (Imatinib, Gleevec) pharmacological inhibition. MATERIALS AND METHODS: We investigated KIT(Asn822Lys) mutant-initiated signaling in Kasumi-1 cell line, and characterized the inhibitory effect of the STI 571 protein tyrosine kinase inhibitor on downstream signaling. RESULTS: The use of STI 571-mediated inhibition impaired the tyrosine phosphorylation of KIT(Asn822Lys) and its association with the p85 subunit of phosphatidylinositol 3'-kinase (p85PI3K). The downstream constitutive phosphorylation of JNK1/2 and STAT3 was also significantly inhibited, but STI 571 had no effect on the constitutive activation of Akt, thus suggesting that it is due to other signaling in Kasumi-1 cells. STI 571 inhibited the KIT-mediated proliferation of Kasumi-1 cells in a dose-dependent manner. CONCLUSIONS: These findings show the role of PI3K in KIT(Asn822Lys)-mediated constitutive activation through the Akt-independent downstream signaling pathway of JNK, and also demonstrate the mutant's susceptibility to STI 571, which may therefore have therapeutic potential in CBFL patients with susceptible KIT mutations.     

Estimating conversion rates: A new empirical strategy with an application to health care in Italy

This study proposes a new empirical strategy for assessing how “efficient” different individuals and groups are in converting their available resources into achievements. Following the capabilities approach, pioneered by Amartya Sen, we employ the concept of “conversion rates” to capture the efficiency of the link from resources to achievements. The methodology is both simpler and more conceptually precise than previous options, this offering the potential to support significant expanded work in this area. The proposed methodology is then tested in relation to health care in Italy. The findings suggest that investments in education may carry particular health benefits for women, which public resources are particularly important for the elderly, and that single individuals pose special challenges because they benefit less from all types of resources than married couples. The results thus highlight significant heterogeneities in the abilities of different groups to convert public, private, and nonfinancial resources into health, and we conclude by noting the possible consequences for health care and public policies.     

Corilagin is a potent inhibitor of NF-kappaB activity and downregulates TNF-alpha induced expression of IL-8 gene in cystic fibrosis IB3-1 cells

Corilagin (beta-1-O-galloyl-3,6-(R)-hexahydroxydiphenoyl-d-glucose), a gallotannin identified in several plants, including Phyllanthus urinaria, has been shown to exhibit versatile medicinal activities. As far as possible anti-inflammatory effects of corilagin, only few reports are available, and the potential use of corilagin as possible therapeutic molecule for cystic fibrosis has not been evaluated. In the present paper we report experiments aimed at determining the activity of corilagin on nuclear factor kappaB (NF-kappaB) binding to DNA target and on the expression of the major pro-inflammatory gene involved in cystic fibrosis, interleukin-8 (IL-8). Both IL-8 mRNA content and IL-8 protein secretion were analyzed in cystic fibrosis bronchial IB3-1 cells stimulated by tumor necrosis factor-alpha (TNF-alpha), one of the most potent pro-inflammatory agents. The data obtained demonstrate that corilagin binds to NF-kappaB, inhibits NF-kappaB/DNA interactions and affects IL-8 gene expression in TNF-alpha treated IB3-1 cells. In addition, corilagin inhibits TNF-alpha induced secretion of MCP-1 and RANTES, exhibiting low or no effect on the release of G-CSF, IL-6 and VEGF. Therefore, corilagin might be of interest for experimental anti-inflammatory therapy of cystic fibrosis.     

Locus heterogeneity of Dent’s disease: OCRL1 and TMEM27 genes in patients with no CLCN5 mutations

Dent′s disease is an X-linked renal tubulopathy caused by mutations mainly affecting the CLCN5 gene. Defects in the OCRL1 gene, which is usually mutated in patients with Lowe syndrome, have recently been shown to lead to a Dent-like phenotype, called Dent’s disease 2. About 25% of Dent’s disease patients do not carry CLCN5/OCRL1 mutations. The CLCN4 and SLC9A6 genes have been investigated, but no mutations have been identified. The recent discovery of a novel mediator of renal amino acid transport, collectrin (the TMEM27 gene), may provide new insight on the pathogenesis of Dent’s disease. We studied 31 patients showing a phenotype resembling Dent’s disease but lacking any CLCN5 mutations by direct sequencing of the OCRL1 and TMEM27 genes. Five novel mutations, L88X, P161HfsX167, F270S, D506N and E720D, in the OCRL1 gene, which have not previously been reported in patients with Dent’s or Lowe disease, were identified among 11 patients with the classical Dent’s disease phenotype. No TMEM27 gene mutations were discovered among 26 patients, 20 of whom had an incomplete Dent’s disease phenotype. Our findings confirm that OCRL1 is involved in the functional defects characteristic of Dent’s disease and suggest that patients carrying missense mutations in exons where many Lowe mutations are mapped may represent a phenotypic variant of Lowe syndrome.