Effects of Ursolic Acid and its Analogues on Soybean 15-Lipoxygenase Activity and the Proliferation Rate of A human Gastric Tumour Cell Line

The authors have previously isolated and purified ursolic acid from heather flowers (Calluna vulgarts). This terpene was found to inhibit HL-60 leukaemic cell proliferation and arachidonic acid oxidative metabolism in various cell species. The effects of ursolic acid and its analogues on soybean 15-lipoxygenase activity and on the proliferation of a human gastric tumour cell line (HGT), have been assessed. These triterpenes inhibited soybean 15-lipoxygenase at its optimal activity (pH 9). The proliferation ofHGT was decreased in a dose-dependent manner. At 20 μM the rank order is: ursolic acid > uvaol > oleanolic acid > methyl ursolate. The carboxylic group at the C28 position of ursolic acid appears to be implicated in the inhibition of both lipoxygenase activity and cell proliferation. Thus methylation of this group decreases these two inhibitory properties. Oleanolic acid, which differs by the position of one methyl group (C20 instead of C19) is less inhibitory than ursolic acid. The lipophilicity of the terpene is also implicated since uvaol appears to be more inhibitory than methyl ursolate

Anticoagulation Control in Warfarin-Treated Patients Undergoing Cardioversion of Atrial Fibrillation (from the Edoxaban Versus Enoxaparin-Warfarin in Patients Undergoing Cardioversion of Atrial Fibrillation Trial).

In the Edoxaban Versus Enoxaparin-Warfarin in Patients Undergoing Cardioversion of Atrial Fibrillation (ENSURE-AF) study (NCT 02072434), edoxaban was compared with enoxaparin-warfarin in 2,199 patients undergoing electrical cardioversion of nonvalvular atrial fibrillation (AF). In this multicenter prospective randomized open blinded end-point trial, we analyzed patients randomized to enoxaparin-warfarin. We determined time to achieve therapeutic range (TtTR); time in therapeutic range (TiTR); their clinical determinants; relation to sex, age, medical history, treatment, tobacco use, race risk (SAMe-TT2R2) score; and impact on primary end points (composite of stroke, systemic embolic event[SEE], myocardial infarction [MI], and cardiovascular death [CVD] and composite of major + clinically relevant nonmajor bleeding). Among 1,104 patients randomized to enoxaparin-warfarin, 27% were naïve to oral anticoagulants. Mean age was 64.2 ± 11 years and mean congestive heart failure, hypertension, age ≥75 (doubled), diabetes mellitus, prior stroke or transient ischemic attack (doubled), vascular disease, age 65-74, female (CHA2DS2-VASc) score was 2.6. Mean TtTR was 7.7 days (median 7 days) and mean TiTR after reaching an international normalized ratio of 2.0 to 3.0 was 71%. In 695 patients who had an INR 2. On multivariate regression, an independent predictor of extended TtTR was creatinine clearance (p = 0.02). TtTR was marginally related to stroke/SEE/MI/CVD (p = 0.06; odds ratio  0.23, 95% confidence interval 0.02 to 1.17) but not to any bleeding. Independent predictors of TiTR were previous vitamin K antagonist experience (p65, concomitant drugs or alcohol (HAS-BLED) score (p = 0.02). TiTR was related to any bleeding (p = 0.02; odds ratio  0.39, 95% confidence interval 0.16 to 0.88), but not stroke/SEE/MI/CVD. In this cohort of warfarin users with a high TiTR no difference was seen between TtTR and TiTR in relation to SAMe-TT2R2 score. In conclusion, even in this short-term study, TiTR was significantly related to bleeding events

Development of 99mTc-N4-NIM for Molecular Imaging of Tumor Hypoxia

The nitro group of 2-nitroimidazole (NIM) enters the tumor cells and is bioreductively activated and fixed in the hypoxia cells. 1,4,8,11-tetraazacyclotetradecane (N4) has shown to be a stable chelator for 99mTc. The present study was aimed to develop 99mTc-cyclam-2-nitroimidazole (99mTc-N4-NIM) for tumor hypoxia imaging. N4-NIM precursor was synthesized by reacting N4-oxalate and 1,3-dibromopropane-NIM, yielded 14% (total synthesis). Cell uptake of 99mTc-N4-NIM and 99mTc-N4 was obtained in 13762 rat mammary tumor cells and mesothelioma cells in 6-well plates. Tissue distribution of 99mTc-N4-NIM was evaluated in breast-tumor-bearing rats at 0.5–4 hrs. Tumor oxygen tension was measured using an oxygen probe. Planar imaging was performed in the tumor-bearing rat and rabbit models. Radiochemical purity of 99mTc-N4-NIM was >96% by HPLC. Cell uptake of 99mTc-N4-NIM was higher than 99mTc-N4 in both cell lines. Biodistribution of 99mTc-N4-NIM showed increased tumor-to-blood and tumor-to-muscle count density ratios as a function of time. Oxygen tension in tumor tissue was 6–10 mmHg compared to 40–50 mmHg in normal muscle tissue. Planar imaging studies confirmed that the tumors could be visualized clearly with 99mTc-N4-NIM in animal models. Efficient synthesis of N4-NIM was achieved. 99mTc-N4-NIM is a novel hypoxic probe and may be useful in evaluating cancer therapy

A study of Immune Response in Cyprinus carpio Infected with Aeromonas hydrophila and Treated by Alhagi maoururum Powder.

أجري البحث لغرض تقدير الاستجابة المناعية لاسماك الكارب الاعتيادي المخمجة ببكتريا Aeromonas hydrophila والمعالجة بمسحوق جذور نبات العاقول ، ولهذا الغرض فقد استعمل بالبحث 60 سمكة كارب اعيادي ووزعت على ستة معاملات , المعاملة الاولى اعطيت 2.5% غم من مسحوق جذور نبات العاقول و3.0% غم الى الحوض الثاني و3.5% للحوض الثالث اما الحوض الرابع فقد اعطيت الاسماك فيه على عليقة سيطرة بدون اضافات وحقنت باللقاح المميت لبكتريا الهايدروفيلا والحوض الخامس اعطيت الاسماك فيه على عليقة سيطرة بدون اضافات وحقنت بالماء الملح الوظيفي , اما المعاملة السادسة عدت معاملة سيطرة بعد تغذيتها على عليقة السيطرة . بينت نتائج البحث الى  تفوق معنوي (p<0.05) في مستوى البروتين الكلي من جراء اضافة مسحوق جذور نبات العاقول على باقي المعاملات وادى التخميج ببكتريا الهايدروفيلا الى اعلى استجابة مناعية ثانوية وكانت الاستجابة المناعية الثانوية في اعلى المستويات لدى استعمال مسحوق جذور نبات العاقول بنسبة 3.5% لعيار تلازن 1280 وتم تشخيص البلاعم الكبيرة ذات الميلانين في المقاطع النسيجية للطحال عند استعمال مسحوق جذور نبات العاقول بكل التراكيز والبكتريا المقتولة بالحرارة والسيطرة ونستخلص من هذه الدراسة ان مسحوق جذور نبات العاقول بتركيز 3.5% له دور كبير في التحفيز المناعي مقارنة مع معاملة السيطرة.  The research was conducted to estimate the immune response of cyprinuscarpio fishes which are infected with A.hydrophila and treated by Alhagi root powder, for this reason atotal number of 60 fishes were used, those fishes were allotted on 6 treatments, The 1st treatment was given 2.5% of Alhagi root powder, The 2nd treatment was given 3.0% , The 3rdtreatment was given 3.5% Alhagi root powder. Mean while the 4thtreatment was given a control diet with out any supplement but fishes in this treatment were injected by A..hydrophila vaccine, the 5thtreatment was given a control diet and injected by the normal saline. Moreover the the 6th treatment was considered as a control treatment and fed on the control diet. Results showed a significant surpassing (p<0.05)of total protein in fishes due to supplementing the powder of Alhagirooton other treatments. Infection with A.hydrophila induced the highest secondary immune response. The war increase of Melano Macrophage Center in the spleen tissues due to supplementing the powder 3.5% of Alhagi root powder as compared to normal spleen . Alhagi root powder was shown to be expand the immune axis when compared to control. &nbsp

Assessment of OMT-28, a synthetic analog of omega-3 epoxyeicosanoids, in patients with persistent atrial fibrillation: Rationale and design of the PROMISE-AF phase II study.

We designed a placebo controlled, double-blind, randomized, dose-finding phase II study on OMT-28 in the maintenance of sinus rhythm after electrical cardioversion (DCC) in patients with persistent atrial fibrillation (PROMISE-AF). OMT-28 is a first-in-class, synthetic analog of 17,18-epoxyeicosatetetraenoic acid, a bioactive lipid mediator generated by cytochrome P450 enzymes from the omega-3 fatty acid eicosapentaenoic acid. OMT-28 improves Ca2+-handling and mitochondrial function in cardiomyocytes and reduces pro-inflammatory signaling. This unique mode of action may provide a novel approach to target key mechanism contributing to AF pathophysiology. In a recent phase I study, OMT-28 was safe and well tolerated and showed favorable pharmacokinetics. The PROMISE-AF study (NCT03906799) is designed to assess the efficacy (primary objective), safety, and population pharmacokinetics (secondary objectives) of three different doses of OMT-28, administered once daily, versus placebo until the end of the follow-up period. Recruitment started in March 2019 and the study will include a total of 120 patients. The primary efficacy endpoint is the AF burden (% time with any AF), evaluated over a 13-week treatment period after DCC. AF burden is calculated based on continuous ECG monitoring using an insertable cardiac monitor (ICM). The primary efficacy analysis will be conducted on the modified intention-to-treat (mITT) population, whereas the safety analysis will be done on the safety population. Although ICMs have been used in other interventional studies to assess arrhythmia, PROMISE-AF will be the first study to assess antiarrhythmic efficacy and safety of a novel rhythm-stabilizing drug after DCC by using ICMs

Homozygous UBA5 Variant Leads to Hypomyelination with Thalamic Involvement and Axonal Neuropathy

The enzyme ubiquitin-like modifier activating enzyme 5 (UBA5) plays an important role in activating ubiquitin-fold modifier 1 (UFM1) and its associated cascade. UFM1 is widely expressed and known to facilitate the post-translational modification of proteins. Variants in UBA5 and UFM1 are involved in neurodevelopmental disorders with early-onset epileptic encephalopathy as a frequently seen disease manifestation. Using whole exome sequencing, we detected a homozygous UBA5 variant (c.895C > T p. [Pro299Ser]) in a patient with severe global developmental delay and epilepsy, the latter from the age of 4 years. Magnetic resonance imaging showed hypomyelination with atrophy and T2 hyperintensity of the thalamus. Histology of the sural nerve showed axonal neuropathy with decreased myelin. Functional analyses confirmed the effect of the Pro299Ser variant on UBA5 protein function, showing 58% residual protein activity. Our findings indicate that the epilepsy currently associated with UBA5 variants may present later in life than previously thought, and that radiological signs include hypomyelination and thalamic involvement. The data also reinforce recently reported associations between UBA5 variants and peripheral neuropathy

POLR3A variants with striatal involvement and extrapyramidal movement disorder

Biallelic variants in POLR3A cause 4H leukodystrophy, characterized by hypomyelination in combination with cerebellar and pyramidal signs and variable non-neurological manifestations. Basal ganglia are spared in 4H leukodystrophy, and dystonia is not prominent. Three patients with variants in POLR3A, an atypical presentation with dystonia, and MR involvement of putamen and caudate nucleus (striatum) and red nucleus have previously been reported. Genetic, clinical findings and 18 MRI scans from nine patients with homozygous or compound heterozygous POLR3A variants and predominant striatal changes were retrospectively reviewed in order to characterize the striatal variant of POLR3A-associated disease. Prominent extrapyramidal involvement was the predominant clinical sign in all patients. The three youngest children were severely affected with muscle hypotonia, impaired head control, and choreic movements. Presentation of the six older patients was milder. Two brothers diagnosed with juvenile parkinsonism were homozygous for the c.1771-6C > G variant in POLR3A; the other seven either carried c.1771-6C > G (n = 1) or c.1771-7C > G (n = 7) together with another variant (missense, synonymous, or intronic). Striatal T2-hyperintensity and atrophy together with involvement of the superior cerebellar peduncles were characteristic. Additional MRI findings were involvement of dentate nuclei, hila, or peridentate white matter (3, 6, and 4/9), inferior cerebellar peduncles (6/9), red nuclei (2/9), and abnormal myelination of pyramidal and visual tracts (6/9) but no frank hypomyelination. Clinical and MRI findings in patients with a striatal variant of POLR3A-related disease are distinct from 4H leukodystrophy and associated with one of two intronic variants, c.1771-6C > G or c.1771-7C > G, in combination with another POLR3A variant