Vesna Lukinović-Škudar

The impact of neuropathic pain and other comorbidities on the quality of life in patients with diabetes

BackgroundDiabetic polyneuropathy (DPN) is one of the most common complications of diabetes and can exist with or without neuropathic pain. We were interested in how neuropathic pain impairs the quality of life in diabetic patients and what is the role of comorbidities in this condition.MethodsThe study included 80 patients with painful DPN (group “P”) and 80 patients with DPN, but without neuropathic pain (group “D”). Visual analogue scale (VAS) and Leeds assessment of neuropathic symptoms and signs (LANSS) pain scale were used for assessment of neuropathic pain, SF-36 standardized questionnaire for assessment of the quality of life and BDI questionnaire for assessment of depression.ResultsSubjects in group P had statistically significantly lower values compared to group D in all 8 dimensions and both summary values of the SF-36 scale. We ascribe the extremely low results of all parameters of SF-36 scale in group P to painful diabetic polyneuropathy with its complications. The patients in group D showed higher average values in all dimension compared to group P, but also somewhat higher quality of life compared to general population of Croatia in 4 of 8 dimensions, namely vitality (VT), social functioning (SF), role-emotional (RE) and mental health (MH), which was unexpected result.Clinically, the most pronounced differences between two groups were noted in sleeping disorders and problems regarding micturition and defecation , which were significantly more expressed in group P. The similar situation was with walking distance and color-doppler sonography of carotid arteries, which were significantly worse in group P. Consequently, subjects in group P were more medicated than the patients in group D, particularly with tramadol, antiepileptics and antidepressants.ConclusionPainful DPN is a major factor that influences various aspects of quality of life in diabetic patients. Additionally, this study gives an overview of diabetic population in the Republic of Croatia, information that could prove useful in future studies.

Rapamycin enhances dimethyl sulfoxide-mediated growth arrest in human myelogenous leukemia cells.

Abstract Rapamycin and its derivatives have been proposed in the treatment of leukemia based on their cytostatic effects, but their possible role in differentiation therapy is less explored. The aim of the present study was to investigate the possible beneficial effects of the combination of rapamycin and dimethyl sulfoxide (DMSO) on growth arrest and differentiation of acute myelogenous leukemia (AML) cells. In myeloblastic HL-60, promyelocytic NB4, monocytic U937, immature KG-1 and erythro-megakaryocytic K562 cell lines, rapamycin alone had modest inhibitory effects, DMSO inhibited proliferation in a dose-dependent manner, and the combination of rapamycin and DMSO reduced the number of viable cells significantly more than either agent alone. In NB4 cells, rapamycin had no statistically significant effects on the DMSO-mediated increase in expression of CD11b, but increased apoptosis. These results demonstrate that rapamycin enhances DMSO-mediated growth arrest, and suggest that mTOR (mammalian target of rapamycin) inhibitors may have beneficial effects in differentiation therapy of AML.

The activity of extracellular signal-regulated kinase is required during G2/M phase before metaphase-anaphase transition in synchronized leukemia cell lines

The pharmacological inhibitors of extracellular signal-regulated kinase (ERK) have been suggested as a novel molecular target-based therapy for acute myeloid leukemia. Several studies have established the role of ERK in cell cycle progression from G1 to S phase in response to mitogen, but the role of ERK after the restriction point is less clarified. In this study, we used models of aphidicolin and nocodazole-synchronized HL-60 and NB4 leukemia cell lines to determine the kinetics of ERK activity during the progression of the cell cycle and to test the effects of commercially available inhibitors on G2/M progression of synchronized leukemia cells. In aphidicolin-synchronized cells, the activity of ERK was low during early S phase and increased at late S and G2/M phase of the cell cycle. The presence of MEK inhibitors PD 98059 and U0126 caused a delay in G2/M phase. In nocodazole-synchronized cells, the activity of ERK was low during M/G1 transition and MEK inhibitors had no effects on return of the cells to G1 phase. These results demonstrate that the activity of ERK is required during G2/M phase of leukemia cell cycle before the cells reach metaphase–anaphase transition.

5-Aminoimidazole-4-carboxamide ribonucleoside induces differentiation of acute myeloid leukemia cells

Abstract Adenosine monophosphate (AMP)-activated kinase (AMPK) modulators have been shown to exert cytotoxic activity in hematological malignancies, but their role in the differentiation of acute myeloid leukemia (AML) is less explored. In this study, the effects of AMPK agonists on all-trans retinoic acid (ATRA)-mediated differentiation of acute promyelocytic leukemia (APL) and non-APL AML cell lines were investigated. The results show that AMPK agonists inhibit the growth of myeloblastic HL-60, promyelocytic NB4 and monocytic U937 cells. 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR), an AMPK activator, enhances ATRA-mediated differentiation of NB4 cells. In U937 cells, AICAR alone induces the expression of cell surface markers associated with mature monocytes and macrophages. In both cell lines, AICAR increases the activity of mitogen-activated protein kinase (MAPK), and the presence of a MAPK inhibitor reduces the expression of differentiation markers. These results reveal beneficial effects of AICAR in AML, including differentiation of non-APL AML cells.