Mixed vitiligo of Blaschko lines: a newly discovered presentation of vitiligo responsive to combination treatment.

Vitiligo, depigmenting disorder of the skin and mucous membranes, affects up to 1% of the population worldwide. It is classified into four major types: segmental, non-segmental, mixed, and unclassified type. Non-segmental vitiligo refers to non-dermatomal distribution of lesions, while dermatomal distribution of lesions is present in patients with segmental vitiligo. Segmental vitiligo can also follow Blaschko lines - pathways of epidermal cell migration and proliferation during the development of the fetus. Here, we present patient with segmental and non-segmental vitiligo following Blaschko lines with excellent therapeutic response to combined therapy. Prior to our report, a case of segmental and non-segmental vitiligo followed by Blaschko lines was never described, therefore we suggest the term "mixed vitiligo of Blaschko lines" to describe this entity. This is also a rare case in which 90% repigmentation was achieved in patient with segmental and nonsegmental vitiligo following Blaschko lines in only 2 months of combined therapy.

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

BACKGROUND: Diabetic 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. METHODS: The 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. RESULTS: Subjects 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. CONCLUSION: Painful 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.

The Association of Essential Metals with APOE Genotype in Alzheimer's Disease.

BACKGROUND: The major confirmed genetic risk factor for late-onset, sporadic Alzheimer's disease (AD) is variant ɛ4 of apolipoprotein E gene (APOE). It is proposed that ApoE, a protein involved in transport of cholesterol to neurons can cause neurodegeneration in AD through interaction with metals. Previous studies mostly associated copper, iron, zinc, and calcium with ApoE4-mediated toxicity. OBJECTIVE: To test the association of essential metals with APOE genotype. METHODS: We compared plasma and cerebrospinal fluid (CSF) levels of copper, zinc, iron, sodium, magnesium, calcium, cobalt, molybdenum, manganese, boron, and chromium, and CSF ferritin levels among AD, mild cognitive impairment (MCI) patients, and healthy controls (HC) with different APOE genotype. RESULTS: Sodium, copper, and magnesium levels were increased in carriers of ɛ4 allele. Additionally, the increase in sodium, calcium and cobalt plasma levels was observed in carriers of ɛ4/ɛx genotype. The decrease in boron plasma levels was observed in carriers of ɛ4 allele and ɛ4/ɛ4 genotype. Additionally, CSF zinc levels as well as plasma sodium levels were increased in AD patients compared to HC. CONCLUSION: These results indicate that the molecular underpinnings of association of essential metals and metalloids with APOE should be further tested and clarified in vivo and in vitro.

Two waves of the nuclear phospholipase C activity in serum-stimulated HL-60 cells during G(1) phase of the cell cycle.

Phosphatidylinositol-specific phospholipase C (PI-PLC) is activated in cell nuclei during the cell cycle progression. We have previously demonstrated two peaks of an increase in the nuclear PI-PLC activities in nocodazole-synchronized HL-60 cells. In this study, the activity of nuclear PI-PLC was investigated in serum-stimulated HL-60 cells. In serum-starved HL-60 cells, two peaks of the activity of nuclear PI-PLC were detected at 30 min and 11 h after the re-addition of serum with no parallel increase in PLC activity in cytosol, postnuclear membranes or total cell lysates. An increase in the serine phosphorylation of b splicing variant of PI-PLCbeta(1) was detected with no change in the amount of PI-PLCbeta(1b) in nuclei isolated at 30 min and 11 h after the addition of serum. PI-PLC inhibitor ET-18-OCH(3) and MEK inhibitor PD 98059 completely abolished serum-mediated increase at both time-points. The addition of inhibitors either immediately or 6 h after the addition of serum had inhibitory effects on the number of cells entering S phase. These results demonstrate that two waves of nuclear PI-PLCbeta(1b) activity occur in serum-stimulated cells during G(1) phase of the cell cycle and that the later increase in the PLC activity is equally important for the progression into the S phase.

Nuclear phospholipase C-beta1b activation during G2/M and late G1 phase in nocodazole-synchronized HL-60 cells.

In this study, the activity of nuclear phosphatidylinositol-specific phosholipase C (PI-PLC) was investigated in HL-60 cells blocked at G(2)/M phase by the addition of nocodazole, and released into medium as synchronously progressing cells. Two peaks of an increase in the nuclear PI-PLC activities were detected; an early peak reached a maximum at 1 h after release from the nocodazole block, and a second increase was detected at 8.5 h after the release. Immunoprecipitation studies indicated that the increase in the activity was due to the activation of the nuclear PI-PLC-beta(1). Western blot analysis demonstrated no changes in the level of both a and b splicing variants of PI-PLC-beta(1) in the nuclei of cells isolated at either 1 h or 8.5 h after the block. However, an increase in the serine-phosphorylation of PI-PLC-beta(1b) was detected in the nuclei of HL-60 cells isolated at 1 and 8.5 h after the block, and the presence of MEK-inhibitor PD98059 completely inhibited both the serine phosphorylation and the increase in the PI-PLC activities in vitro. The presence of PI-PLC inhibitor prevented the progression of HL-60 cells through the G(1) into S phase of the cell cycle. These results demonstrate that two peaks of nuclear PI-PLC activities, which are due to a PD98059-sensitive phosphorylation of nuclear PLC-beta(1b) on serine, occur at the G(2)/M and late G(1) phase and are necessary for the progression of the cells through the cell cycle.

Activation of phosphoinositide 3-kinase C2 beta in the nuclear matrix during compensatory liver growth.

In the nuclear matrix harvested 20 h after partial hepatectomy, an increase in immunoprecipitable PI3K-C2beta activity is observed, which is sensitive to wortmannin (10 Mm) and shows strong preference for PtdIns over PtdIns(4)P as a substrate. On western blots PI3K-C2beta revealed a single immunoreactive band of 180 kD, whereas 20 h after partial hepatectomy gel shift of 18kDa was noticed in the nuclear matrix, suggesting that observed activation of enzyme is achieved by proteolysis. As it is know that PI3K-C2alpha is associated with nuclear speckles [Didichenko SA, Thelen M. Phosphatidylinositol 3-kinase C2alpha contains a nuclear localization sequence and associates with nuclear speckles. J Biol Chem 2001;276:48135-42.], the data presented in this report show that in the nuclear matrix PI3K-C2beta is activated during the compensatory liver growth, which clearly demonstrates that different class II PI3K enzymes have different subnuclear localization and therefore might have different intranuclear functions.

Inositol pyrophosphates modulate cell cycle independently of alteration in telomere length.

Synthesis of inositol pyrophosphates through activation of Kcs1 plays an important role in the signalling response required for cell cycle progression after mating pheromone arrest. Overexpression of Kcs1 doubled the level of inositol pyrophosphates when compared to wild type cells and 30 min following the release from α-factor block further increase in inositol pyrophosphates was observed, which resulted that cells overexpressing Kcs1 reached G2/M phase earlier than wild type cells. Similar effect was observed in ipk1Δ cells, which are unable to synthesize IP6-derived inositol pyrophosphates (IP7 and IP8) but will synthesize IP5-derived inositol pyrophosphates (PP-IP4 and (PP)2-IP3). Although ipk1Δ cells have shorter telomeres than wild type cells, overexpression of Kcs1 in both strains have similar effect on cell cycle progression. As it is known that PP-IP4 regulates telomere length through Tel1, inositol polyphosphates, cell cycle and telomere length were determined in tel1Δ cells. The release of the cells from α-factor block and overexpression of Kcs1 in tel1Δ cells produced similar effects on inositol pyrophosphates level and cell cycle progression when compared to wild type cells, although tel1Δ cells possesses shorter telomeres than wild type cells. It can be concluded that telomere length does not affect cell cycle progression, since cells with short telomeres (ipk1Δ and tel1Δ) progress through cell cycle in a similar manner as wild type cells and that overexpression of Kcs1 in cells with either short or normal telomeres will increase S phase progression without affecting telomere length. Furthermore, IP5-derived inositol pyrophosphates can compensate for the loss of IP6-derived inositol pyrophosphates, in modulating S phase progression of the cell cycle.

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

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.

Topical propranolol cream in treatment of superficial infantile hemangiomas: a literature review and 4 years of clinical experience.

The clinical efficacy and safety profile of propranolol 1% cream in treatment of superficial infantile hemangiomas (IHs) were determined in a preliminary randomized group of eight infants. Five boys and three girls, 3 to 12 months old, with an IHs superficial capillary type on the forehead, posterior side of the neck, forearm, abdomen, or posterior side of the trunk were examined at our outpatient clinic between 2011 and 2014. Topical propranolol was applied twice daily for 10 months with clinical evaluation and photographic documentation performed every 1 to 2 months. Size, texture, and color changes were monitored. Therapeutic efficacy was evaluated using the Archauer system: Grade I (bad) reduction in size < 25%, Grade II (medium) reduction between 26% and 50%, Grade III (good) reduction between 51% and 75%, and Grade IV (excellent) reduction > 75%. The majority of hemangiomas treated, 62.5%, achieved Grade IV. A Grade III outcome was noticed in one patient with an IH (12.5%) and Grade II in 25% of patients with IHs on the abdomen. The treatment was well tolerated without side effects, which indicates that topical application of 1% propranolol is a safe, effective, and cheap therapeutic option for treating superficial IHs.

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

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 G(1) 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 G(2)/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 G(2)/M phase of the cell cycle. The presence of MEK inhibitors PD 98059 and U0126 caused a delay in G(2)/M phase. In nocodazole-synchronized cells, the activity of ERK was low during M/G(1) transition and MEK inhibitors had no effects on return of the cells to G(1) phase. These results demonstrate that the activity of ERK is required during G(2)/M phase of leukemia cell cycle before the cells reach metaphase-anaphase transition.