Assessment of the therapeutic potential of a novel phosphoramidate acyclic nucleoside on induced hepatocellular carcinoma in rat model.

AIMS: Hepatocellular Carcinoma (HCC) is renowned as a deadly primary cancer of hepatic origin. Sorafenib is the drug-of-choice for targeted treatment of unresectable end-stage HCC. Unfortunately, great proportion of HCC patients showed intolerance or unresponsiveness to treatment. This study assesses potency of novel ProTide; SH-PAN-19 against N-Nitrosodiethylamine (DEN)-induced HCC in male Wistar rats, compared to Sorafenib. MAIN METHODS: Structural entity of the synthesized compound was substantiated via FT-IR, UV-Vis, 1H NMR and 13C NMR spectroscopic analysis. In vitro, SH-PAN-19 cytotoxicity was tested against 3 human cell lines; hepatocellular carcinoma; HepG-2, colorectal carcinoma; HCT-116 and normal fibroblasts; MRC-5. In vivo, therapeutic efficacy of SH-PAN-19 (300 mg/kg b.w./day) against HCC could be revealed and compared to that of Sorafenib (15 mg/kg b.w./day) by evaluating the morphometric, biochemical, histopathological, immunohistochemical and molecular key markers. KEY FINDINGS: SH-PAN-19 was relatively safe toward MRC-5 cells (IC50 = 307.6 µg/mL), highly cytotoxic to HepG-2 cells (IC50 = 24.9 µg/mL) and prominently hepato-selective (TSI = 12.35). Oral LD50 of SH-PAN-19 was >3000 mg/kg b.w. DEN-injected rats suffered hepatomegaly, oxidative stress, elevated liver enzymes, hypoalbuminemia, bilirubinemia and skyrocketed AFP plasma titre. SH-PAN-19 alleviated the DEN-induced alterations in apoptotic, angiogenic and inflammatory markers. SH-PAN-19 produced a 2.5-folds increase in Caspase-9 and downregulated VEGFR-2, IL-6, TNF-α, TGFß-1, MMP-9 and CcnD-1 to levels comparable to that elicited by Sorafenib. SH-PAN-19 resulted in near-complete pathological response versus partial response achieved by Sorafenib. SIGNIFICANCE: This research illustrated that SH-PAN-19 is a promising chemotherapeutic agent capable of restoring cellular plasticity and could stop HCC progression.

Association between serum vitamin D levels and age in patients with epilepsy: a retrospective study from an epilepsy center in Saudi Arabia.

BACKGROUND: Vitamin D deficiency has been linked to various medical conditions such as bone loss, decreased mineralization, endocrine disorders, and central nervous system disorders, including epilepsy. Vitamin D deficiency is prevalent among patients with epilepsy (PWE). However, the specific association between vitamin D levels and age in PWE is unclear. OBJECTIVES: Identify the relation between vitamin D level and age in PWE and evaluate factors that may play a role in seizure control. DESIGN: Retrospective analytical medical record review SETTING: Outpatient epilepsy research clinic in Saudi Arabia PATIENTS AND METHODS: Between November 2016 and April 2020, we selected eligible PWE aged older than 14 years whose vita-min D levels were recorded at least once after reviewing 1550 patient electronic files. We analyzed data on serum vitamin D level by age and other factors, vitamin D supplement use, seizure classification, and conducted a multivariate logistic regression to assess associations with seizure control. MAIN OUTCOME MEASURES: Relationships between vitamin D levels and age and factors that might affect seizure control. SAMPLE SIZE: 524 patients RESULTS: The prevalence of low serum vitamin D levels was high (86.8%). The median vitamin D level in all patients was low (38 nmol/L), and was lower in young PWE than in adult PWE (P<.01). Only 146 patients received vitamin D supplements. High vitamin D levels were associated with a 40% seizure reduction. CONCLUSION: Vitamin D deficiency is underestimated in PWE in Saudi Arabia, and is more prevalent among young adults and patients on polytherapy than in other PWE. Patients with high vitamin D levels had good seizure control compared with those with low levels. The effect of vitamin D supplements on seizure control should be further investigated in randomized control trials. LIMITATIONS: Retrospective study and no categorization by presence of supplementation. CONFLICT OF INTEREST: None.

Consanguinity in patients with mesial temporal lobe epilepsy due to hippocampal sclerosis in a Saudi population.

OBJECTIVE: To investigate if there is an association between consanguinity and hippocampal sclerosis (HS) in the Saudi population. METHODS: A retrospective case-control study was conducted by assessing the prevalence of consanguinity in patients with pathologically proven HS, who underwent epilepsy surgery at King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia, between January 2004 and December 2015. We reviewed the medical records to extract data, which included; age, gender, duration of epilepsy, history of febrile seizure, family history of epilepsy in a first or second-degree relative, and pathology reports. RESULTS: A total of 120 patients, out of which 40 patients (65% male) having mesial temporal lobe epilepsy due to HS, and 80 controls (56% male) with cryptogenic epilepsy, were identified. Twenty-two patients (53.5%) in the HS group had a history of consanguinity. In the control group, 30 patients (37.5%) had a history of consanguinity. The odds ratio was 2.04 (95% confidence interval = 0.94 - 4.4, p=0.052). A family history of epilepsy was found in 28% of the patients with HS and 32.5% cryptogenic epilepsy. Only 8 patients (19.5%) with HS reported a history of febrile seizure. CONCLUSION: Our retrospective case-control study suggests that consanguinity might increase the likelihood of developing HS.

Purification and characterization of l-glutaminase enzyme from camel liver: Enzymatic anticancer property.

l-Glutaminase has gained an important attention as glutamine-depleting enzyme in treatment of various cancers. Therefore, this study aimed to purify, characterize and investigate antitumor activity of l-glutaminase from camel liver mitochondria (CL-Glu), since no available information about CL-Glu from camel. CL-Glu was purified using cell fractionation, ultrafiltration, DEAE-and CM-cellulose chromatography columns. The purified CL-Glu was a monomer with a molecular weight of 70 ± 3 kDa, isoelectric point of 7.2, optimum temperature of 70 °C and it was active over a broad pH range with a pH optimum at pH 8.0. Its activity had a clear dependence on phosphate ions. The studied enzyme showed sigmoidal kinetics, indicated its allosteric behavior with Km of 36 ± 4 mM and Hill coefficient of 1.5 which suggested a positive cooperatively of active sites. The purified l-glutaminase exerted antitumor activity against different cell lines with the highest cytotoxic activity against Hepatocellular carcinoma cell line (HepG-2) with an IC50 value of 152 µg/ml. In conclusion, l-glutaminase was purified from camel liver using simple methods and its unique properties such as stability at both wide pH range and at high temperature along with its relatively low molecular weight, facilitated its usage in medical applications as antitumor drug.

Non-convulsive seizures and electroencephalography findings as predictors of clinical outcomes at a tertiary intensive care unit in Saudi Arabia.

OBJECTIVE: Electroencephalography (EEG) in the intensive care unit (ICU) is often done to detect non-convulsive seizures (NCS). The outcome of ICU patients with NCS strongly depends on the underlying etiology. The implication of NCS and other EEG findings on clinical outcome independent from their etiology is not well understood and our aim to investigate it. PATIENTS AND METHODS: We retrospectively identified all adult patients in the ICU who underwent EEG monitoring between January 2008 and December 2011. The main goals were to define the rate of NCS or non-convulsive status epilepticus (NCSE) occurrence in our center among patients who underwent EEG monitoring and to examine if NCS/NCSE are associated with poor outcome [defined as death or dependence] with and without adjustment for underlying etiology. The rate of poor outcome among different EEG categories were also investigated. RESULTS: During the study period, 177 patients underwent EEG monitoring in our ICU. The overall outcome was poor in 62.7% of those undergoing EEG. The rate of occurrence of NCS/NCSE was 8.5% and was associated with poor outcome in 86.7% with an odds ratio (OR) of 5.1 (95% confidence interval [CI] 1.09-23.8). This association was maintained after adjusting for underlying etiologies with OR 5.6 (95% CI 1.05-29.6). The rate of poor outcome was high in the presence of periodic discharges and sharp and slow waves of 75% and 61.5%, respectively. CONCLUSIONS: Our cohort of ICU patients undergoing EEGs had a poor outcome. Those who developed NCS/NCSE experienced an even worse outcome regardless of the underlying etiology.

Prolonged hemiplegic migraine.

Hemiplegic migraine is a rare form of migraine variant. It is characterized by recurrent attacks of headache associated with temporary neurological deficit, usually unilateral hemiparesis or hemiplegia. It can be difficult to distinguish from migrainous stroke clinically, and a full neurological work-up and careful review of medical history and symptoms are necessary for the diagnosis. Two forms of hemiplegic migraine are known: familial and sporadic, phenotypically similar, differentiated by the absence of family history of similar attacks in the sporadic form. We report a case of sporadic hemiplegic migraine with unusually prolonged deficit and progression to quadriplegia with complete return to baseline 7 days after onset. Diffusion weighted images helped in excluding infarction.