Crystal structure and functional mapping of human ASMT,the last enzyme of the melatonin synthesis pathway

Abstract: Melatonin is a synchronizer of many physiological processes. Abnormal melatonin signaling is associated with human disorders related to sleep, metabolism, and neurodevelopment. Here, we present the X‐ray crystal structure of human N‐acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. The polypeptide chain of ASMT consists of a C‐terminal domain, which is typical of other SAM‐dependent O‐methyltransferases, and an N‐terminal domain, which intertwines several helices with another monomer to form the physiologically active dimer. Using radioenzymology, we analyzed 20 nonsynonymous variants identified through the 1000 genomes project and in patients with neuropsychiatric disorders. We found that the majority of these mutations reduced or abolished ASMT activity including one relatively frequent polymorphism in the Han Chinese population (N17K, rs17149149). Overall, we estimate that the allelic frequency of ASMT deleterious mutations ranges from 0.66% in Europe to 2.97% in Asia. Mapping of the variants on to the 3‐dimensional structure clarifies why some are harmful and provides a structural basis for understanding melatonin deficiency in humans.     

Clinical characteristics,molecular profile and outcomes of myeloid sarcoma: a single institution experience over 13 years

Background: Myeloid sarcoma (MS) is characterized by extramedullary infiltration by immature myeloid cells. Owing to rarity of this disease, the clinical features and overall outcomes are yet to be clarified.

Objective: To define clinical characteristics, epidemiology, pathologic findings, treatment options and outcomes in MS.

Methods: We conducted a retrospective review of 23 patients diagnosed with MS at our institute over a period of 13 years (2002–2015).

Results: MS presented mostly as a manifestation of relapsed acute myeloid leukemia, seen in 39% of patients. Skin and subcutaneous soft tissues were the most common sites of anatomic involvement (69.5%). Ninety five percent (n?=?19) were positive for classical myeloid markers with either cytochemical staining (chloracetate-esterase, MPO), flow-cytometry (CD33, CD34, CD13 and CD117), or immunohistochemistry (CD34, CD43, CD68 and lysozyme). Of these, 52% were positive for CD33 (n?=?12), 35% for CD68 (n?=?8), 30% for CD34 (n?=?7), and 26% for lysozyme (n?=?6). Cytogenetic abnormalities were seen in 63% (n?=?12/19) patients on bone-marrow aspirate, with five patients displaying a complex (n?=?3) or monosomal (n?=?2) karyotype. Twenty seven percent patients with a normal karyotype had presence of deleterious mutations (FLT3, ASXL, STAG and JAK2) on further testing with myeloid mutation panel. The Median overall survival (OS) of the entire cohort was 15.9 months (95% CI, 7.4–24.4 months). The OS was significantly better for patients <65 years (24.6 vs. 3.4 months, p?=?0.009) of age, and for those attaining a complete remission (CR) to induction therapy (25.7 vs. 0.8 months, p?Conclusion: Failure to achieve CR with induction therapy, and age >65 years are associated with poor outcomes in MS. Allogeneic stem-cell transplant in first remission appears to be the most effective modality for achieving long-term remissions.     

A prospective randomised comparative study of endoscopic band ligation versus injection sclerotherapy of bleeding internal haemorrhoids in patients with liver cirrhosis

Background and study aimsBleeding internal haemorrhoids are common and used to be treated surgically with too many complications. Endoscopic therapy is trying to take the lead. Sclerotherapy and rubber band ligation are the candidates to replace surgical therapy especially in patients with liver cirrhosis. The aim of this study was to compare endoscopic injection sclerotherapy (EIS) to endoscopic rubber band ligation (EBL) regarding effectiveness and complications in the treatment of bleeding internal haemorrhoids in Egyptian patients with liver cirrhosis.Patients and methodsOne hundred and twenty adult patients with liver cirrhosis and bleeding internal haemorrhoids were randomised into two equal groups; the first treated with EBL using Saeed multiband ligator, and the second with EIS using either ethanolamine oleate 5% or N-butyl cyanoacrylate. All groups were matched as regards age, sex, Child score and pre-procedure Doppler values. Patients were followed up clinically and with abdominal ultrasound/Doppler for 6 months. Endoscopic and endosonography/Doppler was done before and one month after the procedure. Pre and post-procedure data were recorded and analysed.ResultsBoth techniques were highly effective in the control of bleeding from internal haemorrhoids with a low rebleeding [10% in the EBL group and 13.33% in the EIS group] and recurrence [20% in the EBL group 20% in the EIS group] rates. Child score had a positive correlation with rebleeding and recurrence in EIS group only.Pain score and need for analgesia were significantly higher while patient satisfaction was significantly lower in EIS compared to EBL [p < 0.05]. No significant difference between ethanolamine and cyanoacrylate subgroups was found [p > 0.05].ConclusionsBoth EBL and EIS were effective in the treatment of bleeding internal haemorrhoids in patients with liver cirrhosis. EBL had significantly less pain and higher patient satisfaction than EIS. EBL was also safer in patients with advanced cirrhosis.     

Clinical characteristics and outcome of children stung by scorpion

Scorpion envenomation is a health problem in children in tropical and subtropical regions. The aim of this study was to evaluate demographic and clinical characteristics as well as outcomes in referred children to Assiut University Children Hospital during the year 2012 with a history of scorpion sting. The medical files of these patients were reviewed retrospectively for demographic data, time and site of biting, and clinical manifestations. Laboratory investigations of the patients were reviewed for complete blood count (CBC), liver function tests, creatinine phosphokinase (CPK), lactate dehydrogenase (LDH), arterial blood gases, and serum electrolytes. Results showed 111 children with a history of scorpion sting; 69 males and 42 females with a median age of 5 years. Out of the studied patients, 53.2 % were classified as class III of clinical severity with recorded pulmonary edema in 33.3 %, cardiogenic shock in 46.8 %, and severe neurological manifestations in 22.8 %. Twelve patients (10.8 %) were classified as class II with mild systemic manifestations, and 36 % of the patients were classified as class I with only local reaction. Outcomes of these patients were discharge without sequelae in 55.8 %, discharge with sequelae in 26.1 %, and death in 18.1 %. Conclusion: more than half of stung children had a severe clinical presentation and about one fifth died. Aggressive treatment regimens are recommended for such patients to improve the outcome.     

Anatomical variants of lower limb vasculature and implications for free fibula flap: Systematic review and critical analysis

Sound knowledge of the anatomical patterns of lower limb vasculature is crucial for raising the free fibula flap (FFF). The tibial arteries are particularly susceptible to anatomical variations with a dominant role of peroneal artery (PR) for lower leg perfusion, and hence precluding fibular flap harvest. In this systematic review we study the prevalence of lower limbs with dominant peroneal artery (dPR). A systematic review of the MEDLINE and EMBASE databases was conducted using a comprehensive combination of keywords and search algorithm according to PRISMA guidelines. Articles describing the branching patterns of lower limb arteries, in cadaveric or angiographic studies, were included. A total of 5,790 limbs were included from 26 studies. dPR was found in 5.2% of all limbs. The combination of dPR with hypoplastic or aplastic posterior tibial artery was the most common pattern (3.3%) followed by hypoplastic anterior tibial artery (1.5%). Peronea arteria magna (PAM) was seen in 0.4% of limbs. Bilateral variants were seen in 20% of all cases with a dPR. A greater awareness of dPR as anatomical variation and its prevalence among healthy subjects can prevent ischemic donor‐site complications after FFF harvest. Clinical examination alone may not suffice to detect anatomical variations, hence preoperative imaging of lower limb vascular system is recommended. © 2015 Wiley Periodicals, Inc. Microsurgery 36:165–172, 2016.