Evaluating the prevalence and risk factors for depression in patients with temporal lobe epilepsy with hippocampal sclerosis: A cross-sectional multicenter study.

BACKGROUND: Epilepsy frequently accompanies Major Depressive Disorder (MDD). Notably, people with temporal lobe epilepsy and hippocampal sclerosis may face an increased susceptibility to MDD, as evidence indicates the involvement of the limbic system in the development of emotional symptoms. OBJECTIVES: To determine the prevalence and predictors of depression in temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) and compare them to those of other epilepsy types. METHODS: A sample of 293 epilepsy patients, including 159 non-TLE-HS and 134 TLE-HS, were recruited from three hospitals. Of these, 215 completed a two-section electronic survey. The first section collected demographic and epilepsy data, while the second used the Arabic version of the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). RESULTS: Of 215 patients, 104 (48%) had TLE-HS-38 with right TLE-HS (37%), 56 with left TLE-HS (54%), and 10 with bilateral TLE-HS (10%). The prevalence and severity of depression was assessed with an NDDI-E score of 15 or higher identified 35 patients (16%) with MDD. Valproic acid and lamotrigine were associated with higher NDDI-E scores. No such associations were found for levetiracetam or carbamazepine. Polytherapy in TLE-HS showed a significant correlation with daily poor concentration. CONCLUSION: We explored the differences in depression prevalence between TLE-HS and other epilepsy types and concluded they are minimal but slightly higher in TLE-HS. Predictors of depression such as seizure frequency and disease duration influenced MDD prevalence in TLE-HS. Lamotrigine and valproate were linked to higher NDDI-E scores.

Health related quality of life in a Saudi population of patients with epilepsy.

OBJECTIVES: To assess the quality of life for epilepsy patients in Saudi Arabia. Epilepsy, one of the most prevalent chronic neurological conditions in the world, frequently results in a low quality of life. METHODS: This cross-sectional study analyzed data between September 2020 and September 2021 from 102 adult patients with epilepsy in outpatient clinics department of Epilepsy Program at King Fahad Medical City compared it to 108 healthy controls during the same study period. Sociodemographics and clinical data were gathered using the Arabic version of the Rand 36-Item Short Form Survey (SF-36) questionnaire and the Quality of Life in Epilepsy Inventory (QOLIE-31). RESULTS: Patients with epilepsy had lower SF-36 scores when compared to the control for role limitation due to physical health, role limitations due to emotional health, and general health. The QOLIE-31 revealed that gender was associated with energy/fatigue (p=0.028), medication effect (p=0.016), and social function (p=0.003); only social functioning showed a significant association (p=0.023) with employment. CONCLUSION: Quality of life for patients with epilepsy was found to be significantly impacted in Saudi Arabia. Certain factors found in this study differentiate it from data that has already been released. This might be due to Arab differences in family support as well as cultural and religious beliefs.

Sleep quality, daytime sleepiness, and insomnia in patient with epilepsy: A single center experience from Saudi Arabia.

OBJECTIVES: To measure the burden of insomnia and daytime sleepiness (DTS) and their effects on sleep quality, and the risk factors of poor quality of sleep. METHODS: We conducted a cross-sectional study of 218 epilepsy patients. We administered well-validated and previously translated questionnaires to assess sleep quality, insomnia, and DTS using the Pittsburgh Sleep Quality Index, Insomnia Severity Index, and Epworth Sleepiness Scale, respectively. RESULTS: Approximately 75% of participants reported poor sleep quality. Moreover, 42.2% did not have insomnia, while 37.6%, 17.9%, and 2.3% had subthreshold insomnia and clinical insomnia of moderate and severe severity, respectively. Roughly 64.2% of participants had normal sleep, 17.8% had an average amount of DTS, and 16.9% and 0.9% may and should seek medical attention, respectively. Compared to normal sleepers, patients with clinical insomnia were 5.45 times likely to experience poor sleep quality, whereas patients with an average amount of DTS and who were recommended to seek medical attention were 6.84 and 44.15 times likely to experience poor sleep quality, respectively. Patients who had seizures every month were 2.51 times likely to experience poor quality sleep, compared to patients who had seizures annually. CONCLUSION: We found a higher prevalence of poor quality of sleep, insomnia, and excessive DTS in our sample of Saudi epilepsy patients.

Public awareness of first-aid management of seizures in Saudi Arabia.

BACKGROUND: First aid measures in cases of epileptic seizures are crucial. Misconceptions about seizure first-aid measures are probably common. Most of the previous data focused on teachers and healthcare providers. The objective of this study was to assess the awareness of seizure first-aid measures and their associated factors in a community sample in Saudi Arabia. METHODS: A cross-sectional study was carried out using an online questionnaire between July 2020 and February 2021. Those who had never heard of epilepsy and healthcare workers were excluded. Overall and individual scores were calculated for first-aid measures during and after the seizures as well as calling the ambulance. RESULTS: A total of 1542 participants were included in the study. The overall awareness score of seizure first-aid measures was 57.3%. The awareness of the need to call the ambulance in special circumstances was the highest individual score (78.3%), followed by measures after the seizure (54.2%), and finally measures during the seizure (48.4%). For the latter, the awareness of injury prevention measures was the highest (74.9%), while the awareness of treatment options was the lowest (12.2%). Overall awareness score was significantly higher in older age (p = 0.015), female gender (p < 0.001), divorced status (p = 0.014), knowing someone with epilepsy (p < 0.001), attending a course or workshop about seizure first-aid (p < 0.001), watching a video on seizure first-aid on any platform (p < 0.001), and having basic life support training (p < 0.001). CONCLUSIONS: The awareness of seizure first-aid measures is still inadequate among the public in Saudi Arabia. The current finding underscores the importance of simulation videos on social media and/or field-training campaigns to improve the public awareness of seizure first-aid measures.

Prevalence of Medically Resistant Epilepsy in Saudi Arabia.

OBJECTIVES: The objective of this study was to evaluate the prevalence of medically resistant epilepsy (MRE) in our hospital and to compare the prevalence with that in other populations. METHODS: We retrospectively analyzed the data of patients who visited the epilepsy clinics at King Fahd University Hospital, Al-Khobar, Saudi Arabia between January 2017 and December 2018. This study included patients aged ≥14 years who had at least 2 unprovoked seizures 24 h apart. Patients who had provoked seizure(s), paroxysmal events, or syncope or had incomplete medical records were excluded. The definition and classification of the International League Against Epilepsy were used. Moreover, we searched the En-glish literature using PubMed and Google Scholar to compare the prevalence of MRE between our population and other populations. RESULTS: In total, 1,151 patients were screened, and 751 patients were included in the final analysis. Of the 751 patients, 229 (male: 56.3%, female: 43.7%; mean age: 32.07 years, and standard deviation, 12.2 years) had MRE, with a cumulative prevalence of 30%. The etiology was as follows: unknown, 63.3% (n = 145); structural, 31.9% (n = 73); genetic, 3.1% (n = 7); and infectious, 1.7% (n = 4). None of the patients had metabolic or immune-related etiologies. CONCLUSION: The prevalence of MRE in our population (30%) is close to that in other populations (30-36.5%). Early identification of such patients is crucial to improve their management.

Energy and caloric restriction, and fasting and cancer: a narrative review.

Dietary interventions have a significant impact on body metabolism. The sensitivity of cancer cells to nutrient and energy deficiency is an evolving characteristic of cancer biology. Preclinical studies provided robust evidence that energy and caloric restrictions could hinder both cancer growth and progression, besides enhancing the efficacy of chemotherapy and radiation therapy. Moreover, several, albeit low-powered, clinical trials have demonstrated clinical benefits in cancer patients. Future research will inform and firmly establish the potential efficacy and safety of these dietary interventions. Here, we review the current evidence and ongoing research investigating the relationship between various dietary restriction approaches and cancer outcomes.

Catalytic Mechanism of Aromatic Nitration by Cytochrome P450 TxtE: Involvement of a Ferric-Peroxynitrite Intermediate.

The cytochromes P450 are heme-dependent enzymes that catalyze many vital reaction processes in the human body related to biodegradation and biosynthesis. They typically act as mono-oxygenases; however, the recently discovered P450 subfamily TxtE utilizes O2 and NO to nitrate aromatic substrates such as L-tryptophan. A direct and selective aromatic nitration reaction may be useful in biotechnology for the synthesis of drugs or small molecules. Details of the catalytic mechanism are unknown, and it has been suggested that the reaction should proceed through either an iron(III)-superoxo or an iron(II)-nitrosyl intermediate. To resolve this controversy, we used stopped-flow kinetics to provide evidence for a catalytic cycle where dioxygen binds prior to NO to generate an active iron(III)-peroxynitrite species that is able to nitrate l-Trp efficiently. We show that the rate of binding of O2 is faster than that of NO and also leads to l-Trp nitration, while little evidence of product formation is observed from the iron(II)-nitrosyl complex. To support the experimental studies, we performed density functional theory studies on large active site cluster models. The studies suggest a mechanism involving an iron(III)-peroxynitrite that splits homolytically to form an iron(IV)-oxo heme (Compound II) and a free NO2 radical via a small free energy of activation. The latter activates the substrate on the aromatic ring, while compound II picks up the ipso-hydrogen to form the product. The calculations give small reaction barriers for most steps in the catalytic cycle and, therefore, predict fast product formation from the iron(III)-peroxynitrite complex. These findings provide the first detailed insight into the mechanism of nitration by a member of the TxtE subfamily and highlight how the enzyme facilitates this novel reaction chemistry.

How Does Replacement of the Axial Histidine Ligand in Cytochrome c Peroxidase by Nδ-Methyl Histidine Affect Its Properties and Functions? A Computational Study.

Heme peroxidases have important functions in nature related to the detoxification of H2O2. They generally undergo a catalytic cycle where, in the first stage, the iron(III)-heme-H2O2 complex is converted into an iron(IV)-oxo-heme cation radical species called Compound I. Cytochrome c peroxidase Compound I has a unique electronic configuration among heme enzymes where a metal-based biradical is coupled to a protein radical on a nearby Trp residue. Recent work using the engineered Nδ-methyl histidine-ligated cytochrome c peroxidase highlighted changes in spectroscopic and catalytic properties upon axial ligand substitution. To understand the axial ligand effect on structure and reactivity of peroxidases and their axially Nδ-methyl histidine engineered forms, we did a computational study. We created active site cluster models of various sizes as mimics of horseradish peroxidase and cytochrome c peroxidase Compound I. Subsequently, we performed density functional theory studies on the structure and reactivity of these complexes with a model substrate (styrene). Thus, the work shows that the Nδ-methyl histidine group has little effect on the electronic configuration and structure of Compound I and little changes in bond lengths and the same orbital occupation is obtained. However, the Nδ-methyl histidine modification impacts electron transfer processes due to a change in the reduction potential and thereby influences reactivity patterns for oxygen atom transfer. As such, the substitution of the axial histidine by Nδ-methyl histidine in peroxidases slows down oxygen atom transfer to substrates and makes Compound I a weaker oxidant. These studies are in line with experimental work on Nδ-methyl histidine-ligated cytochrome c peroxidases and highlight how the hydrogen bonding network in the second coordination sphere has a major impact on the function and properties of the enzyme.

Properties and reactivity of µ-nitrido-bridged dimetal porphyrinoid complexes: how does ruthenium compare to iron?

Methane hydroxylation by metal-oxo oxidants is one of the Holy Grails in biomimetic and biotechnological chemistry. The only enzymes known to perform this reaction in Nature are iron-containing soluble methane monooxygenase and copper-containing particulate methane monooxygenase. Furthermore, few biomimetic iron-containing oxidants have been designed that can hydroxylate methane efficiently. Recent studies reported that µ-nitrido-bridged diiron(IV)-oxo porphyrin and phthalocyanine complexes hydroxylate methane to methanol efficiently. To find out whether the reaction rates are enhanced by replacing iron by ruthenium, we performed a detailed computational study. Our work shows that the µ-nitrido-bridged diruthenium(IV)-oxo reacts with methane via hydrogen atom abstraction barriers that are considerably lower in energy (by about 5 kcal mol‒1) as compared to the analogous diiron(IV)-oxo complex. An analysis of the electronic structure implicates similar spin and charge distributions for the diiron(IV)-oxo and diruthenium(IV)-oxo complexes, but the strength of the O‒H bond formed during the reaction is much stronger for the latter. As such a larger hydrogen atom abstraction driving force for the Ru complex than for the Fe complex is found, which should result in higher reactivity in the oxidation of methane.

Second-Coordination Sphere Effect on the Reactivity of Vanadium-Peroxo Complexes: A Computational Study.

Vanadium-oxo and vanadium-peroxo complexes are common intermediates in biology and are, for instance, found in the catalytic cycle of vanadium haloperoxidases. In biomimetic chemistry synthetic models have been created that mimic the structural features of the coordination environment of these vanadium-oxo and vanadium-peroxo species. Recently, two novel vanadium-oxo complexes were trapped and characterized with a trigonal bipyramidal ligand design with either a solvent exposed vanadium center or the vanadium inside a cage, designated as the bowl-shaped configuration and the dome-shaped structure, respectively. Density functional theory calculations are reported here on these bowl- and dome-shaped structures where we study the reaction with t-butylhydroperoxide to form the vanadium-peroxo species and its reaction with thioanisole. Although the structural features of the vanadate core are close for both structures, the calculations display a strong second-coordination sphere effect of the ligand architecture on the barrier heights of the reaction with a terminal oxidant even though the rate-determining transition states show little structural differences. A similar observation is seen for the reaction of the two vanadium-peroxo species with thioanisole. Overall, the calculations implicate that vanadium-peroxo is an efficient oxidant of sulfoxidation reactions, although it is not as efficient as analogous iron(IV)-oxo heme and nonheme oxidants that react with substantially lower barriers. The reactivity differences are analyzed with thermochemical cycles and valence bond patterns that explain the differences in chemical properties and identify how the ligands affect the chemical reactivity with substrates.

Hydrogen Atom Abstraction by High-Valent Fe(OH) versus Mn(OH) Porphyrinoid Complexes: Mechanistic Insights from Experimental and Computational Studies.

High-valent metal-hydroxide species have been implicated as key intermediates in hydroxylation chemistry catalyzed by heme monooxygenases such as the cytochrome P450s. However, in some classes of P450s, a bifurcation from the typical oxygen rebound pathway is observed, wherein the FeIV(OH)(porphyrin) species carries out a net hydrogen atom transfer reaction to form alkene metabolites. In this work, we examine the hydrogen atom transfer (HAT) reactivity of FeIV(OH)(ttppc) (1), ttppc = 5,10,15-tris(2,4,6-triphenyl)-phenyl corrole, toward substituted phenol derivatives. The iron hydroxide complex 1 reacts with a series of para-substituted 2,6-di-tert-butylphenol derivatives (4-X-2,6-DTBP; X = OMe, Me, Et, H, Ac), with second-order rate constants k2 = 3.6(1)-1.21(3) × 104 M-1 s-1 and yielding linear Hammett and Marcus plot correlations. It is concluded that the rate-determining step for O-H cleavage occurs through a concerted HAT mechanism, based on mechanistic analyses that include a KIE = 2.9(1) and DFT calculations. Comparison of the HAT reactivity of 1 to the analogous Mn complex, MnIV(OH)(ttppc), where only the central metal ion is different, indicates a faster HAT reaction and a steeper Hammett slope for 1. The O-H bond dissociation energy (BDE) of the MIII(HO-H) complexes were estimated from a kinetic analysis to be 85 and 89 kcal mol-1 for Mn and Fe, respectively. These estimated BDEs are closely reproduced by DFT calculations and are discussed in the context of how they influence the overall H atom transfer reactivity.

Selective Formation of an FeIV O or an FeIII OOH Intermediate From Iron(II) and H2 O2 : Controlled Heterolytic versus Homolytic Oxygen-Oxygen Bond Cleavage by the Second Coordination Sphere.

We demonstrate that the devised incorporation of an alkylamine group into the second coordination sphere of an FeII complex allows to switch its reactivity with H2 O2 from the usual formation of FeIII species towards the selective generation of an FeIV -oxo intermediate. The FeIV -oxo species was characterized by UV/Vis absorption and Mössbauer spectroscopy. Variable-temperature kinetic analyses point towards a mechanism in which the heterolytic cleavage of the O-O bond is triggered by a proton transfer from the proximal to the distal oxygen atom in the FeII -H2 O2 complex with the assistance of the pendant amine. DFT studies reveal that this heterolytic cleavage is actually initiated by an homolytic O-O cleavage immediately followed by a proton-coupled electron transfer (PCET) that leads to the formation of the FeIV -oxo and release of water through a concerted mechanism.

Transperineal template-guided prostate saturation biopsies in men with suspicion of prostate cancer: a pilot study from Pakistan.

Traditionally, transrectal ultrasound (TRUS)-guided biopsies are done for the diagnosis of prostate cancer (PCa) in Pakistan. The transperineal template-guided saturation biopsy (TTSB) approach has been recently introduced in Pakistan and we share diagnostic yields and pathological findings of specimens taken for PCa diagnosis in men with elevated serum total prostate specific antigen (PSA) and negative TRUS-guided prostate biopsies. In all, 16 patients investigated at the Department of Urology, Sindh Institute of Urology and Transplantation (SIUT), underwent TTSB. The mean age of patients was 67.8 ± 8.8 (range: 55 - 84) years. The median PSA was 9.5 (IQR: 7.9 - 19.8) ng/ ml. The duration of symptoms before biopsy ranged from 1 month to 144 months. The prostate was enlarged with mean weight of 73.5 ± 55.5 g. Histopathology revealed PCa in 5 of 16 (31.2%) cases. The Gleason score was 6 (3+3), 7 (3+4) and 8 (4+4) in 1 case each (6.3%) and 10 (5+5) in 2 cases (12.5%). At least two cores were positive in all positive cases. None of the patients required antibiotics post-procedure. In conclusion, the TTSB technique is a promising option for patients with elevated PSA level and negative transrectal prostate biopsies for the detection of PCa in our setting.

The predictive and prognostic role of phosphatase phosphoinositol-3 (PI3) kinase (PIK3CA) mutation in HER2-positive breast cancer receiving HER2-targeted therapy: a meta-analysis.

The association between PIK3CA mutation and resistance to anti-HER2 therapy (AHT) is not precisely defined. This meta-analysis intended to explore the clinical utility of PIK3CA mutation in HER2-positive breast cancer treated with AHT. Literature search identified 19 eligible studies. There were 1720 patients with advanced, 828 with early and 1290 patients treated in the neoadjuvant setting. In metastatic breast cancer, AHT showed no differential objective response benefit between the wild type (WT) and the mutated type (MT) PIK3CA subgroups (odds ratio [OR] = 1.09; 95 % CI 0.60-2.00; P = 0.78). AHT favorable affected progression-free survival (PFS) irrespective of PIK3CA mutation. There was no PFS difference between WT and MT regardless of the offered therapy. In early breast cancer, trastuzumab combined with the same chemotherapy conferred consistent relapse-free survival benefit in WT and MT subgroups (WT: HR = 0.59; 95 % CI 0.44-0.80; P < 0.001 vs. MT: HR = 0.42; 95 % CI 0.24-0.74; P < 0.001). In the neoadjuvant setting, AHT-based therapy produced a 72 % higher pathologic complete response (pCR) rate in WT as compared with that in MT PIK3CA tumors (OR = 1.72; 95 % CI 1.29-2.13; P < 0.001). In that setting, there was no disease-free or overall survival difference based on PIK3CA mutational status. In this meta-analysis, AHT did not achieve differential benefit according to PIK3CA mutation in HER2-positive metastatic or early breast cancer; however, in the neoadjuvant setting, patients harboring WT PIK3CA tumors attained a higher pCR rate.

Bleomycin pulmonary toxicity in adult Saudi patients with Hodgkin's lymphoma.

BACKGROUND: Bleomycin pulmonary toxicity (BPT) has been described in Hodgkin's lymphoma (HL) patients treated with bleomycin-containing chemotherapy regimens. METHODOLOGY: We reviewed the records of 164 consecutive HL patients. RESULTS: BPT was observed in 24 of 164 patients (15%). Older age and history of concomitant lung disease were significantly associated with approximately threefold (odds ratio: 3.38; 95% CI: 1.25-9.13; p = 0.02) and sevenfold (odds ratio: 7.19; 95% CI: 2.64-19.54; p < 0.0001) increase in BPT risk, respectively. The actuarial 5-year progression-free and overall survival for BPT and non-BPT groups, were not significantly different. CONCLUSION: In Saudi Arabian HL patients, the risk of BPT and its effect on survival outcome were comparable to that reported from developed countries.

Ultrastructural Changes of the Smooth Muscle in Esophageal Atresia.

Esophageal atresia (EA) with or without tracheo-esophageal fistula (TEF) is a relatively rare congenital anomaly. Despite the advances in the management techniques and neonatal intensive care, esophageal dysmotility remains a very common problem following EA/TEF repair. Our current study aimed to describe the most significant ultrastructural changes of the smooth muscle cells (SMCs) trying to highlight some of the underlying mechanisms of esophageal dysmotility following EA/TEF repair. Twenty-three biopsies were obtained from the tip of the lower esophageal pouch (LEP) of 23 patients during primary repair of EA/TEF. Light microscopic examination was performed with hematoxylin and eosin (HE), and Van Gieson's stains. Ultrastructural examination was done using transmission electron microscopy (TEM). Histopathological examination showed distortion of smooth muscle layer and deposition of an abundant amount of fibrous tissue in-between smooth muscles. Using TEM, SMCs exhibited loss of the cell-to-cell adhesion, mitochondrial vacuolation, formation of myelin figures, and apoptotic fragmentation. There were also plasmalemmal projections and formation of ghost bodies. Interestingly, SMCs were found extending pseudopodia-like projections around adjacent collagen fibers. Engulfed collagen fibers by SMCs underwent degradation within autophagic vacuoles. Degeneration of SMCs and deposition of abundant extracellular collagen fibers are prominent pathological changes in LEP of EA/TEF. These changes might contribute to the pathogenesis of esophageal dysmotility in patients who have survived EA/TEF.