Melatonin, one of the evolutionarily most ancient, highly conserved and most pleiotropic hormones still operative in man, couples complex tissue functions to defined changes in the environment. Showing photoperiod-associated changes in its activity levels in mammals, melatonin regulates, chronobiological and reproductive systems, coat phenotype and mammary gland functions. However, this chief secretory product of the pineal gland is now recognized to also exert numerous additional functions which range from free radical scavenging and DNA repair via immunomodulation, body weight control and the promotion of wound healing to the coupling of environmental cues to circadian clock gene expression and the modulation of secondary endocrine signalling (e.g. prolactin release, oestrogen receptor-mediated signalling). Some of these activities are mediated by high-affinity membrane (MT1, MT2) or specific cytosolic (MT3/NQO2) and nuclear hormone receptors (ROR alpha), while others reflect receptor-independent antioxidant activities of melatonin. Recently, it was shown that mammalian (including human) skin and hair follicles are not only melatonin targets, but also sites of extrapineal melatonin synthesis. Therefore, we provide here an update of the relevant cutaneous effects and mechanisms of melatonin, portray melatonin as a major skin protectant and sketch how its multi-facetted functions may impact on skin biology and pathology. This is illustrated by focussing on recent findings on the role of melatonin in photodermatology and hair follicle biology. After listing a number of key open questions, we conclude by defining particularly important, clinically relevant perspectives for how melatonin may become therapeutically exploitable in cutaneous medicine.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-0625.2008.00767.x

Melatonin as a major skin protectant: from free radical scavenging to DNA damage repair.

The prevalence rate of thalassemia, which is endemic in Southeast Asia, the Middle East, and the Mediterranean, exceeds 100,000 live births per year. There are many genetic variants in thalassemia with different pathological severity, ranging from a mild and asymptomatic anemia to life-threatening clinical effects, requiring lifelong treatment, such as regular transfusions in thalassemia major (TM). Some of the thalassemias are non-transfusion-dependent, including many thalassemia intermedia (TI) variants, where iron overload is caused by chronic increase in iron absorption due to ineffective erythropoiesis. Many TI patients receive occasional transfusions. The rate of iron overloading in TI is much slower in comparison to TM patients. Iron toxicity in TI is usually manifested by the age of 30-40 years, and in TM by the age of 10 years. Subcutaneous deferoxamine (DFO), oral deferiprone (L1), and DFO-L1 combinations have been effectively used for more than 20 years for the treatment of iron overload in TM and TI patients, causing a significant reduction in morbidity and mortality. Selected protocols using DFO, L1, and their combination can be designed for personalized chelation therapy in TI, which can effectively and safely remove all the excess toxic iron and prevent cardiac, liver, and other organ damage. Both L1 and DF could also prevent iron absorption. The new oral chelator deferasirox (DFX) increases iron excretion and decreases liver iron in TM and TI. There are drawbacks in the use of DFX in TI, such as limitations related to dose, toxicity, and cost, iron load of the patients, and ineffective removal of excess iron from the heart. Furthermore, DFX appears to increase iron and other toxic metal absorption. Future treatments of TI and related iron-loading conditions could involve the use of the iron-chelating drugs and other drug combinations not only for increasing iron excretion but also for preventing iron absorption.

/pdf/efficacy-and-safety-of-iron-chelation-therapy-with-u8dweh4qsy.pdf

Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent thalassemia syndromes.

Introduction There is overwhelming medical and scientific consensus that cigarette smoking causes lung cancer, heart disease, emphysema, and other serious diseases in smokers. In the Total Exposure Study, 29 biomarkers of potential harm (BOPH) were measured in a cross-sectional sample of 3,585 adult smokers (AS) and 1,077 nonsmokers (NS). The BOPH included markers of oxidative stress, inflammation, platelet activation, endothelial function, lipid metabolism, hematology, metabolism, the cardiovascular system, lung function, kidney function, and liver function. Methods Multiple stepwise regression was used to examine the effect of demographic factors (age, gender, body mass index [BMI], and race) and smoking (number of cigarettes smoked per day or nicotine equivalents [NE] per 24 hr and smoking duration) on each BOPH. Results As compared with NS, AS had >10% higher levels of 8-epi-prostaglandin F(2α) (8-epi-PG F(2α), 42%), 11-dehydrothromboxane B₂ (11-DHTB, 29%), white blood cell (WBC) count (19%), high-sensitivity C-reactive protein (15%), triglycerides (16%), and alkaline phosphatase (11%) and had 18% lower total bilirubin. Multiple stepwise regression revealed that although NE (milligrams per 24 hours) was statistically significant for 18 of the 29 BOPH, it was the most important factor only for WBCs and 11-DHTB. Smoking duration was the most important factor for forced expiratory volume in 1 second. In contrast, BMI was the most important factor for 12 BOPH. Conclusions These results contribute to the understanding of the relationship between tobacco smoking and potential biological effects.

Biomarkers of Potential Harm Among Adult Smokers and Nonsmokers in the Total Exposure Study

Thalassemia and the hypercoagulable state

Genetic regulation of plasma von Willebrand factor levels in health and disease.

Objectives: This study aimed at determining the effects of cigarette smoking based on gender, on several hematological parameters and von Willebrand factor protein in the asymptomat

/pdf/effects-of-cigarette-smoking-on-hematological-parameters-and-2kdkhe0hfz.pdf

Effects of cigarette smoking on hematological parameters and von Willebrand factor functional activity levels in asymptomatic male and female Arab smokers.

Introduction: Patients with thalassemia major often present with a hypercoagulable state, the pathogenesis of which is still not understood. Materials and Methods:</i&gt

Hypercoagulable State and Methylenetetra- hydrofolate Reductase (MTHFR) C677T Mutation in Patients with Beta-Thalassemia Major in Kuwait

complications. JAK2V617F mutation primarily affects the proliferation of the red cell lineage but its impact on the phenotype of circulating RBCs is poorly documented. Our group showed increased adhesion of PV RBCs to endothelial cells mediated by erythroid Lu/BCAM and endothelial laminin a5 chain [4]. Recently, we showed that this abnormal adhesion stems from JAK2V617F-mediated Lu/BCAM activation through a Rap1/Akt signaling pathway [5]. Blocking this pathway by JAK2 specific inhibitors led to significant decrease of PV RBC adhesion [5]. Here, we extended our findings by a quantitative analysis to determine the relationship between the rate of RBC adhesion to laminin and the JAK2V617F allele burden. We first asked whether variation between patients in RBC adhesion was related to Lu/BCAM expression on the surface of PV RBCs. Indeed, Lu/BCAM erythroid expression is heterogeneous within the same individual, including a variable surface expression level and a proportion of Lu/BCAM-negative RBCs. We performed adhesion assays with blood samples from 17 JAK2V617F-positive PV patients, with no cytotoxic antiproliferative treatment, and determined the number of RBCs adhering to laminin at 3 dyn/cm. The adhesion values were variable, ranging from 14 to 1021 RBCs/mm (Supporting Information Table S1). The percentage of Lu/BCAM-positive RBCs as assessed by flow cytometry ranged from 38% to 90%, and the expression level, estimated by the mean fluorescence intensity (MFI), from 1249 to 3153 (Supporting Information Table S1). The number of adherent RBCs was plotted against the percentage of Lu/BCAM-positive RBCs or the MFI of each blood sample. We found no correlation between the number of adherent RBCs and the percentage of Lu/BCAM-positive RBCs (r 5 0.468 and P 5 0.058 at 3 dyn/cm, Fig. 1A), and between RBC adhesion and Lu/BCAM MFI values (r 5 0.345 and P 5 0.174 at 3 dyn/cm, Fig. 1B). These results indicated that Lu/ BCAM expression alone did not account for the variability of PV RBC adhesion, in accordance with the role of Lu/BCAM phosphorylation in the adhesion of PV RBCs to laminin [5]. Because Lu/BCAM phosphorylation is driven by a JAK2V617F-dependent pathway in PV RBCs [5], we asked whether RBC adhesion was influenced by JAK2V617F expression level. To date the most commonly used tool for evaluating the mutational load in one individual is by measuring the mutant allele burden in blood cell DNA. The JAK2V617F allele burden was determined for the 17 PV patients using an allele specific quantitative PCR (MutaquantVR , Qiagen) and ranged from 20 to 68% (Supporting Information Table S1). RBC adhesion values were plotted against the percentage of JAK2V617F. Statistical analysis showed a significant correlation between RBC adhesion and JAK2V617F percentage (r 5 0.571 and P 5 0.016, Fig. 1C) that was improved when the interval of Lu/ BCAM-positive RBCs was restricted to 65–90% (r 5 0.849 and P 5 0.0009, n 5 11 patients), indicating that for equivalent Lu/BCAM expression, higher JAK2V617F levels would drive higher RBC adhesion to laminin (Fig. 1D). As RBCs are enucleated, it is not possible to estimate the level of JAK2V617F using DNA or RNA based PCR assays. However, clonogenic assays showed that patients with higher JAK2V617F mutant allele burden in blood DNA carried more mutated erythroid progenitor cells [6]. Our study revealed RBC adhesion as a biological marker to estimate the V617F mutational load at the protein level in PV RBCs; although indirect, this marker has the potential of informing about the functional level of JAK2V617F in the circulation. This functional assay should be evaluated in a prospective study because it is a rapid and routinely manageable tool to estimate the mutant kinase activity in PV RBCs, which may help assessing the disease progression and the risk of evolution, in particular of thrombotic events in which abnormal adhesion of JAK2V617F-positive RBCs to endothelium could play a role. Furthermore, such a tool may be important to monitor the efficacy of JAK2 inhibitors in PV patients during the very early stages of their treatment by assessing the effect of these inhibitors on JAK2V617F activity in RBCs very shortly after their administration giving important information on their pharmacokinetics in the blood circulation. A European patent application (n8 EP13305131.8) was filed for this study, with the international extension n8 PCT/EP2014/052153.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ajh.24027

Response to hydroxyurea among Kuwaiti patients with sickle cell disease and elevated baseline HbF levels.

Kuwaiti patients with sickle cell disease generally have a mild phenotype, but exhibit considerable heterogeneity, in spite of high Hb F levels. We have carried out a cross-sectional study of patie...

The Sub-Phenotypes of Sickle Cell Disease in Kuwait.

Although not regularly transfused, patients with non-transfusion-dependent thalassemia (NTDT) are prone to iron overload and its complications. Their molecular, phenotypical and laboratory characteristics vary in different populations and there is a need to document local prevailing patterns. We have reviewed the records of our patients with NTDT in Kuwait and documented their clinical and molecular characteristics in addition to iron status [serum ferritin and liver magnetic resonance imaging (MRI) T2*], management and complications. There were 41 patients, made up of 20 with β-thalassemia intermedia (β-TI), 18 with Hb H (β4) disease and three with Hb E (HBB: c.79G > A)-β-thalassemia (Hb E-β-thal); their ages ranged from 3 to 36 years (mean 12.5 ± 7.7). While 18 (43.9%) had been transfused at least once, only three (7.3%) had been transfused on multiple occasions. Three patients had serum ferritin >500 ng/mL; while four of 38 had mild or moderate liver iron overload. Seven (35.0%) of the β-TI pat...

Nada Y. Mustafa

Papers

Effects of cigarette smoking on hematological parameters and von Willebrand factor functional activity levels in asymptomatic male and female Arab smokers.

Hypercoagulable State and Methylenetetra- hydrofolate Reductase (MTHFR) C677T Mutation in Patients with Beta-Thalassemia Major in Kuwait

Response to hydroxyurea among Kuwaiti patients with sickle cell disease and elevated baseline HbF levels.

The Sub-Phenotypes of Sickle Cell Disease in Kuwait.

Clinical and Molecular Characteristics of Non-Transfusion-Dependent Thalassemia in Kuwait