The effect of somatic mutations in mitochondrial DNA on the survival of patients with primary brain tumors.

AIM: To assess the presence of mitochondrial (mt) DNA somatic mutations, determine the relationship between clinicopathological characteristics and mutations, and assess the survival outcomes in Malay patients with primary brain tumors. METHODS: The study enrolled 54 patients with primary brain tumors. DNA extracted from paired tissue and blood samples was subjected to Sanger sequencing to identify alterations in the entire mtDNA. The associations between clinicopathological characteristics and mutations were evaluated. Cox-regression multivariate analysis was conducted to identify factors significantly associated with survival, and Kaplan-Meier analysis was used to compare the survival of patients with and without mutations. RESULTS: Overall, 29.6% of the patients harbored 19 somatic mutations distributed across 15 loci within the mtDNA. Notably, 36.8% of these mutations were not previously documented in MITOMAP. One newly identified mutation caused a frameshift in the ATPase6 gene, resulting in a premature stop codon. Three mutations were classified as deleterious in the MitImpact2 database. Overall, 1097 mtDNA polymorphisms were identified across 331 different locations. Patients with mutations exhibited significantly shorter survival than patients without mutations. CONCLUSIONS: mtDNA mutations negatively affected the survival outcomes of Malaysian patients with primary brain tumors. However, studies with larger samples are needed to confirm the association between mutation burden and survival rates.

Light and the Brain: A Clinical Case Depicting the Effects of Light on Brainwaves and Possible Presence of Plasma-like Brain Energy.

Light is an electromagnetic radiation that has visible and invisible wavelength spectrums. Visible light can only be detected by the eyes through the optic pathways. With the presence of the scalp, cranium, and meninges, the brain is seen as being protected from direct exposure to light. For that reason, the brain can be viewed as a black body lying inside a black box. In physics, a black body tends to be in thermal equilibrium with its environment and can tightly regulate its temperature via thermodynamic principles. Therefore, a healthy brain inside a black box should not be exposed to light. On the contrary, photobiomodulation, a form of light therapy for the brain, has been shown to have beneficial effects on some neurological conditions. The proposed underlying mechanisms are multiple. Herein, we present our intraoperative findings of rapid electrocorticographic brainwave changes when the brain was shone directly with different wavelengths of light during awake brain surgery. Our findings provide literature evidence for light's ability to influence human brain energy and function. Our proposed mechanism for these rapid changes is the presence of plasma-like energy inside the brain, which causes fast brain activities that are akin to lightning strikes.

The Assessment of White Matter Integrity Alteration Pattern in Patients with Brain Tumor Utilizing Diffusion Tensor Imaging: A Systematic Review.

Alteration in the surrounding brain tissue may occur in the presence of a brain tumor. The present study aims to assess the characteristics and criteria of the pattern of white matter tract microstructure integrity alteration in brain tumor patients. The Scopus, PubMed/Medline, and Web of Science electronic databases were searched for related articles based on the guidelines established by PRISMA. Twenty-five studies were selected on the morphological changes of white matter tract integrity based on the differential classification of white matter tract (WMT) patterns in brain tumor patients through diffusion tensor imaging (DTI). The characterization was based on two criteria: the visualization of the tract-its orientation and position-and the DTI parameters, which were the fractional anisotropy and apparent diffusion coefficient. Individual evaluations revealed no absolute, mutually exclusive type of tumor in relation to morphological WMT microstructure integrity changes. In most cases, different types and grades of tumors have shown displacement or infiltration. Characterizing morphological changes in the integrity of the white matter tract microstructures is vital in the diagnostic and prognostic evaluation of the tumor's progression and could be a potential assessment for the early detection of possible neurological defects that may affect the patient, as well as aiding in surgery decision-making.

A mini-review on anticancer-related properties of azithromycin and its potential activities in overcoming the challenges of glioblastoma.

The resistance, plasticity and heterogeneity of cancer cells, including glioblastoma (GB) cells, have prompted the investigation of various agents for possible adjuncts and alternatives to existing therapies. This includes a macrolide antibiotic, azithromycin (AZI). It possesses intriguing anticancer properties in a range of cancer models in vitro, such as antiproliferative, pro-apoptotic, anti-autophagy and anti-angiogenic effects. In fact, AZI is renowned for its ability to eradicate cancer stem cells by inhibiting mitochondrial biogenesis and respiration. AZI-containing regimens in cancer patients for different purposes have shown favourable (i.e., attributed to its antibacterial activity) and unfavourable outcomes. Whilst its direct anticancer effects have yet to be clinically proven. To that end, this review provides a summary of AZI anticancer studies and delineates its potential activities in overcoming the challenges of GB.

Introduction of a newly created AW stereotactic frame: a phantom-based accuracy evaluation and an initial experience in clinical usage.

BACKGROUND: A new stereotactic frame was created in 2015, based on a linear algorithm. It is called Albert Wong (AW) frame. A simple AW stereo-calculator was also designed based on Excel® (Microscoft Corporation, Redmond, WA) programme for the frame. OBJECTIVE: The aim of this study is to test the accuracy of the AW frame by a direct head to head comparison with CRW® frame (Integra Life Sciences, Plainsboro, NJ) on a phantom. METHODS: This is a prospective pilot cross-sectional phantom study with a total of 42 (21 for AW and 21 for CRW®) laboratory testings performed in 2017 at our institute to compare the accuracies of both frames in a consecutive manner. A phantom (BL phantom) was newly created, where targets can be placed at different heights and positions on a platform attached under the frame for accuracy testing comparing between the AW and CRW® frames. RESULTS: A comparable accuracy testing results were observed between the AW and CRW® frames of 0.64 mm versus 1.07 mm respectively. Approval from the local ethics committee for a clinical trial was obtained. We report on three case illustrations who had the AW frame-based biopsies with definitive diagnoses and without any post-biopsy related complication. CONCLUSION: AW frame successfully demonstrated a good accuracy of 0.64 mm in phantom testing using the BL phantom by a linear algorithmic calculation. The clinical trial with three patients demonstrated definitive diagnoses and safety with its use.

Insights regarding mitochondrial DNA copy number alterations in human cancer (Review).

Mitochondria are the critical organelles involved in various cellular functions. Mitochondrial biogenesis is activated by multiple cellular mechanisms which require a synchronous regulation between mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). The mitochondrial DNA copy number (mtDNA­CN) is a proxy indicator for mitochondrial activity, and its alteration reflects mitochondrial biogenesis and function. Despite the precise mechanisms that modulate the amount and composition of mtDNA, which have not been fully elucidated, mtDNA­CN is known to influence numerous cellular pathways that are associated with cancer and as well as multiple other diseases. In addition, the utility of current technology in measuring mtDNA­CN contributes to its extensive assessment of diverse traits and tumorigenesis. The present review provides an overview of mtDNA­CN variations across human cancers and an extensive summary of the existing knowledge on the regulation and machinery of mtDNA­CN. The current information on the advanced methods used for mtDNA­CN assessment is also presented.

The Utilization of Diffusion Tensor Imaging as an Image-Guided Tool in Brain Tumor Resection Surgery: A Systematic Review.

The diffusion tensor imaging technique has been recognized as a neuroimaging tool for in vivo visualization of white matter tracts. However, DTI is not a routine procedure for preoperative planning for brain tumor resection. Our study aimed to systematically evaluate the effectiveness of DTI and the outcomes of surgery. The electronic databases, PubMed/MEDLINE and Scopus, were searched for relevant studies. Studies were systematically reviewed based on the application of DTI in pre-surgical planning, modification of operative planning, re-evaluation of preoperative DTI data intraoperatively, and the outcome of surgery decisions. Seventeen studies were selected based on the inclusion and exclusion criteria. Most studies agreed that preoperative planning using DTI improves postoperative neuro-deficits, giving a greater resection yield and shortening the surgery time. The results also indicate that the re-evaluation of preoperative DTI intraoperatively assists in a better visualization of white matter tract shifts. Seven studies also suggested that DTI modified the surgical decision of the initial surgical approach and the rate of the GTR in tumor resection surgery. The utilization of DTI may give essential information on white matter tract pathways, for a better surgical approach, and eventually reduce the risk of neurologic deficits after surgery.

Risk Factors Associated with Outcome of Spontaneous Intracerebral Haemorrhage: Hospital Kuala Lumpur Experience.

Background: Stroke is the third leading cause of death in Malaysia. This study aims to evaluate the mortality risk factors of spontaneous intracerebral haemorrhage (ICH) in Hospital Kuala Lumpur, Malaysia. Methods: A single centre prospective cohort study was performed between 1 May 2017 and 30 April 2018 for patients above 18 years old with spontaneous ICH. Patients exhibiting haemorrhage due to tumours and ruptured arteriovenous malformations were excluded. The demographics, clinical parameters, radiology findings, surgical intervention, mortality at 30 days and outcome based on modified Rankin score (MRS) grading were recorded. Selected variables were incorporated into a binary logistic regression to determine the outcome predictors of mortality. Results: A total of 292 patients were recruited into the study. The findings showed that the mean age of ICH patients was 48.9 years old. Most of the lesions were located in the putamen (45.9%). More than half (61.0%) of the patients presented with a good outcome whereas 39.0% of the patients presented with a poor outcome. The mortality rate at 30 days was 29.1%. The important predictors for mortality were male (odds ratio [OR] = 0.343; P = 0.043), concomitant use of warfarin and aspirin (OR = 14.696; P = 0.007), ischaemic heart disease [IHD] (OR = 0.007; P = 0.003), brainstem bleed (OR = 0.001; P = 0.001), the presence of intraventricular haemorrhage [IVH] (OR = 0.198; P = 0.049) and surgery. Conclusion: Most diagnosed ICH patients in Malaysia were at a younger age (mean of 48.9 years old) with the significant mortality predictors were IVH, IHD, surgery and brainstem bleed.

Preliminary Comparison of Transseptal Microscopic Versus Endoscopic Transsphenoidal Surgery in a University Teaching Hospital.

Background: Transsphenoidal surgery (TSS) is an increasing preferred treatment for sella lesions. In a university teaching hospital, the novel endoscopic TSS was adopted with ongoing resident teaching. We evaluated a single institutional series of preliminary comparisons of transseptal microscopic with endoscopic TSS. Methods: A retrospective data analysis included 37 patients and 19 patients who underwent microscopic and endoscopic TSS, respectively. The demographic characteristics of the patients, intra-operative analyses, morbidity, mortality and visual assessments were included in this analysis. Results: The study included 31 men and 25 women, and median age at surgery was 49 years old (range 14-70 years old). There were no differences between the rates of cerebrospinal fluid (CSF) fistula, sinus complications, anterior pituitary hormone deficiency and diabetes insipidus between the groups. Total length of stay and intensive care unit stay were similar between the groups. Patients who underwent endoscopic TSS were at significantly increased risk of epistaxis (P = 0.010), respiratory event (P = 0.014) and post-operative visual deterioration prior to discharge (P = 0.032). Conclusion: Endoscopic TSS is a promising procedure that allows sufficient visualisation of the surgical field and adequate tumour removal. It is comparable to microscopic TSS but has a higher complication rate notably due to steep learning curve required to gain the expertise.

Exploring the cytotoxicity and anticancer effects of doxycycline and azithromycin on human glioblastoma multiforme cells.

BACKGROUND: Previous studies had reported on the cytotoxic activities of generic antibiotics such as doxycycline (DOXY) and azithromycin (AZI) in multiple types of human cancers. Given that resistance to standard anti-glioblastoma multiforme (GBM) drug [temozolomide (TMZ)] is common and inevitable, alternative candidates are greatly needed. PURPOSE AND METHOD: The present study was undertaken to explore the cytotoxicity and anticancer effects of DOXY and AZI on human GBM U87 cells via 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), Hoechst, Annexin V-FITC/PI, and clonogenic assays. CompuSyn software was used to determine the combination index (CI) for DOXY+AZI. RESULT: Individual treatment with DOXY and AZI decreased U87 cell viability in dose- and time-dependent, and quantitatively comparable to TMZ. Nevertheless, combinations of both antibiotics evidenced antagonistic behaviour in U87 cells. Increased apoptotic event was also observed with the individual treatment of DOXY and AZI. Furthermore, the proliferative and clonogenic capability of 21-day survived U87 cells was completely terminated by DOXY and AZI, but not TMZ. CONCLUSION: The antiproliferative and apoptosis-inducing activity exhibited by both antibiotics against U87 cells demonstrates their potential as a likely alternative to combat GBM. It would be interesting to find out more about their molecular players and cytotoxic effects in different types of GBM cells, including glioma stem cells (GSCs).

Vacuum Drains versus Passive Drains versus No Drains in Decompressive Craniectomies-A Randomized Controlled Trial on Subgaleal Drain Complication Rates (VADER Trial).

OBJECTIVE: Subgaleal drains are generally deemed necessary for cranial surgeries including decompressive craniectomies (DCs) to avoid excessive postoperative subgaleal hematoma (SGH) formation. Many surgeries have moved away from routine prophylactic drainage but the role of subgaleal drainage in cranial surgeries has not been addressed. METHODS: This was a randomized controlled trial at 2 centers. A total of 78 patients requiring DC were randomized in a 1:1:1 ratio into 3 groups: vacuum drains (VD), passive drains (PD), and no drains (ND). Complications studied were need for surgical revision, SGH amount, new remote hematomas, postcraniectomy hydrocephalus (PCH), functional outcomes, and mortality. RESULTS: Only 1 VD patient required surgical revision to evacuate SGH. There was no difference in SGH thickness and volume among the 3 drain types (P = 0.171 and P = 0.320, respectively). Rate of new remote hematoma and PCH was not significantly different (P = 0.647 and P = 0.083, respectively), but the ND group did not have any patient with PCH. In the subgroup analysis of 49 patients with traumatic brain injury, the SGH amount of the PD and ND group was significantly higher than that of the VD group. However, these higher amounts did not translate as a significant risk factor for poor functional outcome or mortality. VD may have better functional outcome and mortality. CONCLUSIONS: In terms of complication rates, VD, PD, and ND may be used safely in DC. A higher amount of SGH was not associated with poorer outcomes. Further studies are needed to clarify the advantage of VD regarding functional outcome and mortality, and if ND reduces PCH rates.

Quantum and Electromagnetic Fields in Our Universe and Brain: A New Perspective to Comprehend Brain Function.

The concept of wholeness or oneness refers to not only humans, but also all of creation. Similarly, consciousness may not wholly exist inside the human brain. One consciousness could permeate the whole universe as limitless energy; thus, human consciousness can be regarded as limited or partial in character. According to the limited consciousness concept, humans perceive projected waves or wave-vortices as a waveless item. Therefore, human limited consciousness collapses the wave function or energy of particles; accordingly, we are only able to perceive them as particles. With this "limited concept", the wave-vortex or wave movement comes into review, which also seems to have a limited concept, i.e., the limited projected wave concept. Notably, this wave-vortex seems to embrace photonic light, as well as electricity and anything in between them, which gives a sense of dimension to our brain. These elements of limited projected wave-vortex and limitless energy (consciousness) may coexist inside our brain as electric (directional pilot wave) and quantum (diffused oneness of waves) brainwaves, respectively, with both of them giving rise to one brain field. Abnormality in either the electrical or the quantum field or their fusion may lead to abnormal brain function.

Accumulation of Mitochondrial DNA Microsatellite Instability in Malaysian Patients with Primary Central Nervous System Tumors.

AIM: To determine the mitochondrial microsatellite instability (mtMSI) status in a series of Malaysian patients with brain tumors. Furthermore, we analyzed whether the mtMSI status is associated with the clinicopathological features of the patients. MATERIAL AND METHODS: Forty fresh frozen tumor tissues along with blood samples of brain tumor patients were analyzed for mtMSI by PCR amplification of genomic DNAs, and the amplicons were directly sequenced in both directions using Sanger sequencing. RESULTS: Microsatellite analysis revealed that 20% (8 out of 40) of the tumors were mtMSI positive with a total of 8 mtMSI changes. All mtMSI markers were detected in D310 and D16184 of the D-loop region. Additionally, no significant association was observed between mtMSI status and clinicopathological features. CONCLUSION: The variations, specifically the mtMSI, suggest that the mitochondrial DNA (mtDNA) can be targeted for genomic alteration in brain tumors. Therefore, the specific role of mtDNA alteration in brain tumor development and prognosis requires further investigation.

Role of toll-like receptor 4 antagonist Lipopolysaccharide-Rhodobacter sphaeroides on acute stress-induced voluntary ethanol preference and drinking behaviour: In vivo Swiss Albino mouse model.

The present study focused on investigating the effect of toll-like receptor 4 (TLR4) antagonist Lipopolysaccharide-Rhodobacter sphaeroides(LPS-RS) on acute, stress-induced voluntary ethanol preference and drinking behaviour, neuronal components activation, and gene expression associated with stress and addictive behaviour. This study involved the exposure of restraint stress and social isolation using Swiss Albino mice. Two-bottle choice ethanol preference analysis was used in the evaluation of voluntary ethanol seeking and drinking behaviour. Several behavioural assessments were carried out to assess fear and anxiety-like behaviour, neuromuscular ability, motor coordination and locomotion. Morphological and immunoreactivity analysis and gene expression analysis were done after the completion of behavioural assessments. TLR4 antagonist LPS-RS treated stressed-mice showed a significant decrease in ethanol drinking compared with stressed mice. Behavioural results showed that stress exposure induced fear and anxiety-like behaviour; however; no significant deficit was found on motor coordination, neuromuscular ability, locomotion and exploratory behaviour among groups. Morphological analysis showed no significant change in the prefrontal cortex and hippocampus among all groups, while immunoreactivity analysis showed higher expression of c-Fos in prefrontal cortex and hippocampus, higher TLR4 expression in the prefrontal cortex and glial fibrillary acidic protein (GFAP) in hippocampus among stressed-animals. Stressed-mice also showed significant increase in TLR4, Nuclear Factor-Kappa B (NF-kB), inducible nitric oxide synthase (iNOS), dopamine receptor D2 (DRD2), cyclic adenosine monophosphate (cAMP) response element binding protein-1 (CREB-1) and opioid receptor MU-1 (OPRM-1) genes expression compared with control and LPS-RS treated stressed-mice. As a conclusion, the antagonism of TLR4 could provide therapeutic value in the treatment of stress-induced addiction.

Disconnecting surgery at alveus and cornu ammonis of hippocampus, amygdala superficialis, and amygdala medial nuclei for epilepsy associated with attention deficit hyperactivity disorder.

The neural basis for epilepsy and attention deficit hyperactivity disorder (ADHD) is currently incompletely known. We reported a young girl with both epilepsy and ADHD, who had a calcified lesion in the right basolateral amygdalo-hippocampal region extending to the ventral striatum. The child underwent disconnecting surgery and biopsy of the lesion. Fascinatingly, the child's behavior changed immediately after the surgery from inattentive and impulsive to nearly normal behavior experiencing no more breakthrough seizures since after 3 years of surgery. The Schaltenbrand Wahren Brain Atlas revealed alveus, cornu ammonis, amygdala superficialis, and medium as the disconnected region in this surgery.

Prevalence of mitochondrial DNA common deletion in patients with gliomas and meningiomas: A first report from a Malaysian study group.

BACKGROUND: The 4977-bp common deletion (mtDNA) is a well-established mitochondrial genome alteration that has been described in various types of human cancers. However, to date, no studies on mtDNA in brain tumors have been reported. The present study aimed to determine mtDNA prevalence in common brain tumors, specifically, low- and high-grade gliomas (LGGs and HGGs), and meningiomas in Malaysian cases. Its correlation with clinicopathological parameters was also evaluated. METHODS: A total of 50 patients with pathologically confirmed brain tumors (13 LGGs, 20 HGGs, and 17 meningiomas) were enrolled in this study. mtDNA was detected by using polymerase chain reaction (PCR) technique and later confirmed via Sanger DNA sequencing. RESULTS: Overall, mtDNA was observed in 16 (32%) patients and it was significantly correlated with the type of tumor group and sex, being more common in the HGG group and in male patients. CONCLUSION: The prevalence of mtDNA in Malaysian glioma and meningioma cases has been described for the first time and it was, indeed, comparable with previously published studies. This study provides initial insights into mtDNA in brain tumor and these findings can serve as new data for the global mitochondrial DNA mutations database.

Quantum Physics Perspective on Electromagnetic and Quantum Fields Inside the Brain.

Brain energy is associated commonly with electrochemical type of energy. This energy is displayed in the form of electromagnetic waves or better known as brainwaves. This concept is a classical concept (Newtonian) in which the studied object, that is the brain is viewed as a large anatomical object with its functional brainwaves. Another concept which incorporates quantum principles in it can also be used to study the brain. This perspective viewing the brain as purely waves, including its anatomical substrate. Thus, there are two types of energy or field exist in our brain: electromagnetic and quantum fields. Electromagnetic field is thought as dominant energy in purely motor and sensory inputs to our brain, whilst quantum field or energy is perceived as more influential in brain cognitions. The reason for this notion lies in its features which is diffused, non-deterministic, varied, complex and oneness.