The incidence of cerebral venous thrombosis (CVT) is anecdotally considered to be higher in parts of South India as compared with the West. The higher prevalence of CVT in this population is not accounted for by genetic thrombophilias, implicating acquired risk factors. As hyperhomocysteinemia and vitamin B12 deficiency are common in this population, we expected unique risk factors related to the diet. This case-control study was done to examine the acquired risk factors and dietary patterns in these patients. Patients with CVT admitted from June 2021 to January 2023 were included in the study. Healthy attendants of other patients attending the emergency department for other neurological illnesses were recruited as controls. Clinical and biochemical data of patients were collected. Diet was assessed using a food frequency questionnaire. The contribution of food items to various nutrients (calories, protein, methionine, vitamin B12, folate, pyridoxine, and riboflavin) was calculated and compared with the recommended dietary allowance (RDA) and controls. The study enrolled 104 patients and 109 controls. The mean age of patients was 34.9 years (SD = 13.4). Hyperhomocysteinemia, anemia, alcohol consumption, folate deficiency, and vitamin B12 deficiency were observed in 63.5%, 46.2%, 45.2%, 37.5%, and 26%, respectively. Patients with a history of alcohol consumption had significantly higher homocysteine and lower folate. The diet of the patients had significantly higher odds of being protein-deficient OR:21.020.001 5.284.6-;p< and folate-deficient OR:3.40.04 1.110.4-;p= as compared with controls on multiple linear regression analysis. Poor nutrition, in the form of hyperhomocysteinemia and anemia, was the most common risk factor in the study population. Crucially, these risk factors are modifiable. Further large-scale studies are needed to determine the incidence of CVT in this area and to evaluate the role of dietary interventions for risk modification.

BACKGROUND:Ischemic stroke among young adults is a significant public health concern globally. Given vitamin B6's critical roles in homocysteine metabolism and oxidative stress regulation, we aimed to investigate the association between plasma vitamin B6 levels and the risk of ischemic stroke in young South Indian adults. METHODS:This case-control study included 171 young ischemic stroke patients and 249 age-matched healthy controls. Plasma vitamin B6 and total homocysteine (tHcy) levels were quantified using ion-pairing reverse-phase high-performance liquid chromatography (RP-HPLC), while plasma vitamin B12 and folate were measured via chemiluminescence immunoassay. Serum malondialdehyde (MDA) and ferric reducing antioxidant power (FRAP) were determined by spectrofluorimetry and spectrophotometry, respectively. RESULTS:Median plasma vitamin B6 levels were significantly lower in ischemic stroke patients (40.9 nmol/L) than in controls (65.6 nmol/L; p < 0.0001). Vitamin B6 insufficiency (<30 nmol/L) was present in 12.3% of cases and 0.7% in controls. Lower vitamin B6 levels were independently associated with increased stroke risk (adjusted odds ratio = 1.53; p < 0.0001). In stroke cases, vitamin B6 levels correlated negatively with tHcy (r = -0.886) and MDA (r = -0.295). ROC analysis demonstrated excellent discriminative power for vitamin B6 (AUC = 0.929), indicating strong potential as a biomarker for ischemic stroke risk in young individuals. CONCLUSION:In conclusion, it was clearly observed that reduced levels of vitamin B6 had a significant association with ischemic stroke in young adults. To further extend this knowledge on the effects of vitamin B6 in young adults, additional studies need to be conducted.

Abstract The prevalence of intracranial aneurysms (IAs) and aneurysmal subarachnoid hemorrhage (aSAH) due to IA rupture, is higher in postmenopausal compared with premenopausal women and men in the same age group. This is presumably due to reduced levels of the vascular protective hormone, estradiol. Experimental studies have revealed direct effects of estradiol on the vascular endothelium. Our aim was to determine the influence of estradiol and estrogen receptors on cerebral vasculature and the role of estrogen-mediated nitric oxide (NO) pathway in the formation and rupture of IAs. We measured circulatory estradiol and NO levels and the relative expression of genes involved in estrogen-mediated NO synthesis in 349 aSAH patients and 360 age- and gender-matched controls. We observed significantly reduced serum estradiol and NO levels in aSAH patients compared with controls. The expression of endothelial NO synthase gene (NOS3), estrogen receptor genes (ESR1, ESR2), and the kinases (SRC, AKT1, PIK3R1) involved in NO synthesis was significantly reduced in IA tissues compared with controls. Serum estradiol positively and significantly correlated with NO levels. Our results indicate that the activity of endothelial NO synthase and the bioavailability of NO may be regulated by estradiol and estrogen receptors to maintain cerebral vascular tone.

Background & objectives Vitamin D deficiency (VDD) and variations in the vitamin D receptor (VDR) gene are implicated in the pathogenesis of coronary artery disease (CAD). This study investigated the association between VDD, VDR gene variants (ApaI, BsmI, FokI, and TaqI), and CAD risk among South Indians. Methods The case-control study was conducted in 250 CAD patients and 260 matched controls. Serum vitamin D levels were measured by ELISA. Genotyping for VDR ApaI (A>C, rs7975232), BsmI (A>G, rs1544410), FokI (T>C, rs2228570), and TaqI (C>T, rs731236) was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Results VDD was significantly higher among CAD patients (90%) than in controls (63%). Individuals with vitamin D levels <20 ng/ml were 5.7 times more likely to have CAD when compared to those with vitamin D levels ≥ 20 ng/ml (P<0.001, OR=5.74, 95% CI=2.92-11.30). No correlation was observed between vitamin D levels and CAD risk factors, systolic and diastolic blood pressure (r=-0.105, P=0.095, r=-0.049, P=0.437), and blood glucose (r=-0.067, P=0.304). A trend for negative correlation of vitamin D levels with cholesterol (r=-0.112, P=0.094) and triglyceride levels (r=-0.133, P=0.061) was observed. The VDR TaqI variant showed significant association with reduced CAD risk in the overall analysis (Model II, OR=0.60, 95% CI=0.39-0.90, P=0.016). The FokI variant was associated with an increased risk of CAD in males (Model III, OR=5.9, 95% CI=2.09-16.85, P=0.001). However, combined analysis of VDD and VDR gene variants indicated that neither FokI 'ff' (P=0.145) nor TaqI 'tt' (P=0.138) genotypes significantly altered CAD risk in vitamin D-deficient subjects. Interpretation & conclusions The findings of this study suggested that VDD was significantly higher among the CAD patients and increases the risk of CAD by 5.7-fold.This study revealed the differing roles of VDR gene variants in CAD susceptibility and the influence of gender and other covariates.

AIM:On-aspirin platelet reactivity, wherein patients show sub-optimal or no response to antiplatelet therapy, occurs in 5-60% of subjects. The genetic etiology of such reactivity in patients with vascular diseases, especially ischemic stroke in the Indian population, is unknown. This study aimed to examine the genetic variations in the pathways of platelet aggregation and aspirin metabolism that could predict aspirin response. METHODS:This is a prospective cohort study, which included 293 ischemic stroke patients on 150 mg aspirin for over 7 days. Platelet aggregation was assessed using light transmission aggregometry with 10 µM ADP and 0.5 mM arachidonic acid as agonist. After excluding patients with serum salicylic acid levels < 30 µg/mL, 230 individuals were analyzed. Candidate gene variants in COX1, COX2, GpIIb/IIIa, P2RY1, PEAR1, ITGB3, and UGT1A6, were genotyped using PCR-RFLP or allelic discrimination assays. RESULTS:The T allele of P2RY1 (rs1371097 C > T) was significantly associated with inadequate platelet response with an odds ratio of 1.71 (95% CI: 1.122-2.61; p = 0.0131). Carriers of this allele had a 3.46-fold increased risk of inadequate response after adjustment for age and gender. CONCLUSIONS:The P2RY1 (rs1371097 C > T) variant may be a potential genetic marker for inadequate response to aspirin in Indian ischemic stroke patients.

Early diagnosis and intervention in children with autism spectrum disorder (ASD) is crucial. At present, diagnosis of ASD is primarily based on subjective tools. Identifying metabolic biomarkers will aid in early diagnosis of ASD complementing the assessment tools. The study aimed to conduct targeted metabolomic analysis and determine the plasma metabolites that can discriminate children with ASD from typically developing children (TD), and to determine the utility of machine learning in classifying ASD children based on the metabotypes. This was a multi-centric, analytical, case-control study conducted between April 2021–April 2023. Fasting plasma samples were obtained from seventy ASD and fifty-eight TD children, aged 2 to 12 years. Samples were quantitively analysed for 52 targeted metabolites (13 amino acids, 37 acylcarnitines, adenosine and 2-deoxyadenosine levels) using tandem mass spectrometry. An in-depth statistical analysis was performed. A total of 26 metabolites (11 amino acids, 14 acyl carnitines and adenosine) were found to be significantly (p < 0.005) different between ASD and TD children. Adenosine and amino acid levels were significantly decreased in ASD children. Among acyl carnitines, short- and long-chain acyl carnitine levels were significantly decreased, while medium-chain acyl carnitine levels were significantly increased in ASD children. Octenoylcarnitine-C8:1 (Cut-off value- 0.025 mmol/L, AUC- 0.683) and adenosine (Cut-off value- 0.025 mmol/L, AUC- 0.673) were found to predict children with ASD at a sensitivity of 55.7

Glutaric aciduria type-1 (GA-1) is a rare metabolic disorder due to mutation in GCDH gene resulting in varied clinical manifestations. Here we report a case of late-onset GA-1 with acute myelo-neuropathy and chronic renal failure. Institutional ethics committee approval was obtained and genetic analysis was done by clinical exome sequencing.Here we present 19 year-old-adolescent male with chronic renal disease for 2 years presented with 5 months history of sudden onset weakness of proximal and distal lower limbs and bladder retention. This was preceded by recurrent episodes of vomiting. On clinical examination he had features of myeloneuropathy. Laboratory evaluation showed significant elevation of blood glutaryl carnitine with very low free carnitine, while extensive white matter signal changes with diffusion restriction, subependymal nodules and involvement of internal capsule were evidenced on brain magnetic resonance imaging. Diagnosis was confirmed by clinical exome sequencing which showed a pathogenic homozygous missense mutation in exon 11 of GCDH gene (c.120C>T, p.His403Tyr).This report expands phenotypic spectrum of GA-1 to include late onset acute myelo-neuropathy with chronic renal failure. A high index of suspicion is required since early treatment might decelerate further disease progression.

Clopidogrel resistance/high on-treatment platelet reactivity (HTPR) has been associated with interindividual variability in the clopidogrel treatment response in different ethnicities leading to adverse coronary events. The current study evaluated the effect of genetics and clinical factors on platelet inhibition in clopidogrel-treated South Indian CAD patients. We genotyped 15 genetic polymorphisms in the genes associated with the pharmacokinetics and pharmacodynamics of clopidogrel. We observed a high prevalence of the poor metabolizer CYP2C19*2 (34%) variant and CYP2C19-based high-risk metabolizer phenotype such intermediate and poor metabolizer (IM + PM) with 68.5% in CAD patients. The platelet function test revealed that 31% of the CAD cases were HTPR phenotypes (VASP PRI > 50%). The CYP2C19*2 [OR 2.37 (95% CI 1.16-4.84), p = 0.02], high risk CYP2C19 metabolizer phenotypes [OR 1.72 (95% CI 1.08-2.77), p = 0.02] showed increased risk of HTPR. However, PON1 (rs662) favoured better response to clopidogrel [OR 0.50 (95% CI 0.32-0.80), p = 0.004]. Similarily, the multivariate linear regression showed that the CYP2C19*2 (rs4244285) and P2RY12 (rs6809699) and clinical factors (BMI, type II diabetes, and biguanides usage) were associated with high platelet reactivity, while PON1 (rs662) contributed to better platelet inhibition by clopidogrel. The current study revealed predictive integrated pharmacogenomics tool to identify the genetic and clinical factors that determine the clopidogrel response for personalized therapeutic management of CAD patients of South Indian ethnicity.

BACKGROUND:There is limited literature investigating the catecholamine levels in patients with paroxysmal sympathetic hyperactivity (PSH) after traumatic brain injury (TBI). The primary objective of this study was to correlate the severity of PSH (assessed using the PSH-Assessment measure [AM]) with plasma catecholamine levels at a resting state. METHODS:In this prospective case-control study, blood samples for epinephrine and norepinephrine estimation were obtained at rest on three consecutive days, only for 'cases' of PSH after severe TBI (s-TBI) and for control patients (matched for age, gender, and Glasgow coma scale [GCS]. RESULTS:Twenty-seven patients with PSH and 16 controls were recruited. The median PSH-AM score was 20 and 9 in cases and controls, respectively. The epinephrine and norepinephrine levels at rest did not correlate with the severity of PSH assessed during PSH paroxysms (p = 0.949 and 0.975). Norepinephrine levels increased in PSH patients over the 3 consecutive days, once PSH was diagnosed (p = 0.022). The length of hospital stay was longer and the motor-GCS score was lower in PSH patients, with no differences in other outcomes between the groups. CONCLUSION:Catecholamine levels in the inter-paroxysmal interval cannot be correlated with PSH severity assessed during the paroxysms. However, the results of the study need to be confirmed by a larger sample size as the study is underpowered.

Background and Aims: Anesthetic induction plays a pivotal role in determining the operative course and the outcome in patients with acute traumatic brain injury (TBI). The present study compared the effect of anesthetic induction with etomidate, thiopentone, and propofol primarily on systemic hemodynamics and regional cerebral oxygenation (rScO2) and secondarily on the serum cortisol levels in TBI patients. Material and Methods: In this prospective observational study, eligible patients were recruited and divided into three groups as per the induction agent received. Data collected were hemodynamic parameters and rScO2 levels at baseline, following 3 min of preoxygenation, and over 10 min of induction. Serum cortisol levels were measured before and after 24 h of induction. The statistical analysis was done using R software. Results: A total of 115 patients were included: 32, 33, and 50 in thiopentone, propofol, and etomidate groups, respectively. A significant increase (P < 0.001) in bilateral rScO2 was noted in all three groups following anesthetic induction. Intergroup comparison of the propofol and the etomidate groups revealed significantly lesser increase in contralateral rScO2 (P = 0.019) and a greater fall in mean arterial pressure (P = 0.003) on using propofol as an induction agent. Trend changes in bilateral rScO2 and hemodynamic parameters were comparable between thiopentone and etomidate groups. An insignificant fall in serum cortisol was observed in etomidate (P = 0.332) and thiopentone (P = 0.364) groups, but a significant increase was observed in the propofol group (P = 0.004). The Glasgow coma scale (GCS) score at discharge improved significantly in all the groups (P < 0.001). Conclusions: In TBI patients, anesthetic induction with etomidate resulted in least hemodynamic changes compared to induction with thiopentone and propofol. The rScO2 increased in all three groups after induction, with the maximal increase observed with etomidate compared to propofol and thiopentone. Insignificant fall in serum cortisol was observed with etomidate and thiopentone, but not with propofol. Outcome at discharge, assessed with GCS, was comparable in all the groups.

Purpose: The study aims to evaluate the role of substance P in cerebral edema and outcomes associated with acute TBI. Method: Patients with acute TBI who presented within 6 h and a CT scan showed predominantly cerebral edema were included in the study. Substance P level was assessed from a serum sample collected within 6 h of trauma. We also evaluated the brain-specific gravity using the Brain View software. Result: A total of 160 (128 male) patients were recruited. The median serum substance P concentration was 167.89 (IQR: 101.09-238.2). Substance P concentration was high in the early hours after trauma (p = 0.001). The median specific gravity of the entire brain was 1.04. Patients with a low Glasgow coma scale (GCS) at admission had a high concentration of the substance P. In the univariate analysis, low GCS, elevated serum concentrations of substance P level, high Rotterdam grade, high cerebral edema grade, a high international normalized ratio value, and high blood sugar levels were associated with poor outcomes at six months. In logistic regression analysis, low GCS at admission, high cerebral edema grade, and elevated blood sugar level were strongly associated with poor outcomes at six months. The area under the receiver operating characteristic curve was 0.884 (0.826-0.941). Conclusion: Serum substance P is strongly associated with the severity of cerebral edema after TBI. However, brain-specific gravity does not directly correlate with posttraumatic cerebral edema severity. Serum substance P does not influence the clinical outcome of traumatic brain injury.

Abstract An estimated 5–60% of patients experience inadequate antiplatelet effects after taking aspirin. We investigated the gene variants that might determine the outcome of the aspirin response in stroke patients. A total of 293 ischemic stroke patients who were taking 150 mg of aspirin for more than 7 days, were enrolled and only 230 patients with serum salicylate levels > 30 µg/mL were included. Variants in COX1 (rs1236913 C > T), COX2 (rs20417 G > C), GpIIb/IIIa (rs5981 T > C), P2RY1 (rs701265 A > G & rs1371097 C > T), PEAR1 (rs2768759 C > A), ITGB3 (rs2317676 A > G) and UGT1A6 (rs1105879 A > G & rs2070959 A > C) were genotyped. Platelet aggregation tests were carried out by light transmittance aggregometry using adenosine-di-phosphate and arachidonic acid as agonists. The ‘T’ allele of P2RY1 (rs1371097 C > T) polymorphism was significantly associated with inadequate platelet response as measured by platelet aggregometry (OR, 95%, 1.71, 1.122–2.61; p = 0.0131). Presence of a single copy of the ‘T’ allele in P2RY1 (rs1371097 C > T) increased the risk of inadequate response by 3.46 times (adjusted OR (95%), 3.46 (0.043); p = 0.043).

Objective: Homer1, a postsynaptic protein coded by the HOMER1 gene, presumably has a role in homeostatic plasticity that dampens neuronal responsiveness when the input activity is too high. HOMER1 polymorphism has been studied in major psychiatric disorders such as schizophrenia. The objective of this study is to investigate if polymorphisms of the HOMER1 gene are associated with psychosis in Parkinson's disease (PD-P). Methods: One hundred patients with Parkinson's disease (PD) and 100 healthy controls were enrolled consecutively in a PD-P biomarker study at the National Institute of Mental Health and Neurosciences, Bangalore, India. Of the 100 PD patients, 50 had psychosis (PD-P) and 50 did not have psychosis (PD-NP). Two single-nucleotide polymorphisms of HOMER1 (rs4704559 and rs4704560) were analyzed from the DNA isolated from peripheral blood. The allele and genotype frequencies in the PD-P and PD-NP groups were compared. Results: Analysis of HOMER1 rs4704560 revealed a significant difference in both genotype and allele levels between PD-P and PD-NP groups. There was an overrepresentation of T-allele (42% vs. 16%; P < 0.001) and TT genotype (24% vs. 6%; P < 0.001) in the PD-P group compared to PD-NP group. There was no significant difference between PD-P and PD-NP groups when various genotypes and allele frequencies related to HOMER1 rs4704559 were compared. Conclusion: PD-P is probably associated with overrepresentation of T-allele of HOMER1 rs4704560, and larger studies are warranted to confirm our results.

Inborn Errors of Metabolism (IEM), though heterogenous, are not uncommon. Neurologic manifestations predominate. Without universal newborn screening, early diagnosis and treatment may lessen neuromorbidity. Hence, this study was done to understand small molecule neurometabolic disorders' presentation, diagnostic clues, and outcome. Small molecule neurometabolic disorder was diagnosed in 45 children (postneonatal onset) over 14 years (2008-2022) in a tertiary care hospital. Clinical and laboratory data were retrospectively analyzed. There were 26 boys and 19 girls. The median age at diagnosis was 19 months (interquartile range [IQR] 8-38 months). The median diagnostic delay was 12 months in chronic encephalopathy (IQR 1-24 months) and 1 month (IQR 0.2- 5.5 months) in the acute encephalopathy group (p <= 0.01). The presentation mode was chronic encephalopathy/myopathy in 29 (64.4%) and acute encephalopathy in 11 (24.4%). Diagnostic clues included unexplained developmental delay (n = 27, 60%), tone abnormalities (n = 26, 57.7%), movement disorder and ataxia (n = 16, 35.5%), acute encephalopathy (n = 11, 24.4%), neuroregression (n = 10, 22.2%), macrocephaly (n = 10, 22.2%), and alopecia (n = 4, 8.9%). Diagnostic/suggestive blood-spot tandem mass spectrometry (TMS) was seen in 34/38 (89.5%) children. Neuroimaging helped clinch the diagnosis in 17 (47%) children. Diagnostic categories were organic acidemias (n = 25, 55.6%), urea cycle disorders (n = 11, 24.4%), aminoacidopathies (n = 5, 11.1%), and fatty acid oxidation disorders (n = 4, 8.9%). The neurodevelopmental outcome was normal in 13 (28.8%), mild delay in 12 (26.6%), severe delay in 11 (24.4%), 3 deaths (6.6%), and 6 (13.3%) children being lost to follow-up. Overall, the outcome was favorable in 55% of cases. Unexplained developmental delay with tone abnormalities with or without movement disorders is a joint presentation of late-onset neurometabolic diseases. Neuroimaging studies and laboratory tests like blood-spot TMS help identify many small molecule disorders.

AbstractTraumatic brain injury (TBI) is a multistep interaction of brain antigens, cytokine-mediated humeral, and cellular immune reactions. Because of the limitations of clinical and radiological evaluation in TBI, there has been a considerable advancement toward the need for developing biomarkers that can predict the severity of TBI. Blood-based brain biomarkers hold the potential to predict the absence of intracranial injury and thus decrease unnecessary brain computed tomographic scanning. Various biomarkers have been studied that detects neuronal, axonal, and blood–brain barrier integrity. Biomarkers are still under investigation and hold promise in the future evaluation of TBI patients. They can be used for grading as well as a prognostication of head injury.

Ravikumar, Nagaraj Angadi; Dhar, Debjyoti; Mahale, Rohan; Reddy, Ambati Mounika; Shreedevi, Athyadi U.; Prabhu, Sameetha; Saini, Jitender; Christopher, Rita; Mailankody, Pooja; Mathuranath, PS; Padmanabha, Hansashree Author Information

Background and objectives: Very long-chain fatty acyl-lysophosphatidylcholines (VLCFA-LysoPCs) are measured in dried blood spots (DBS) for identifying X-linked adrenoleukodystrophy (X-ALD) and other inherited peroxisomal disorders. Our study aimed to establish age- and gender-specific reference intervals for a panel of LysoPCs measured by tandem mass spectrometry in DBS. Methods: LysoPCs (26:0-, 24:0-, 22:0- and 20:0-LysoPCs) were estimated by flow injection analysis-tandem mass spectrometry (FIA-MS/MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods in 3.2 mm blood spots of 2689 anonymized, putative normal subjects (1375 males, and 1314 females) aged between 2 days and 65 years. Samples were divided into groups: Neonates (0-1month), Infants (>1m-1year), Children and Adolescents (>1-18years), and Adults (>18years). Reference intervals were determined using the percentile approach and represented as the median with the 1st and 99th percentile lower and upper limits. Results: The percentage coefficient of variation (CV) for repeatability assays of internal and external quality control samples were within acceptable limits. Significant differences (P <0.0001, P <0.01) were observed in the concentrations of 26:0-, 24:0-, 22:0- and 20:0-LysoPCs and their ratios, 26:0/22:0-, 24:0/22:0-, 26:0/20:0-and 24:0/20:0-LysoPC in neonates and infants when compared to children, adolescents, and adults. Levels of 26:0-, 24:0- and 22:0-LysoPCs decreased, whereas 20:0-LysoPC increased with age. There were no significant gender-based differences in the concentration of LysoPCs. Conclusion: We established age- and gender-specific reference intervals for a panel of LysoPCs in DBS. These reference values would be helpful when interpreting LysoPC values in DBS during screening for X-ALD and other peroxisomal disorders.

Ethylmalonic encephalopathy is a rare neurometabolic disorder with central nervous system involvement and vasculopathy. It is presented in infancy with developmental delay, acrocyanosis, petechiae, chronic diarrhea, and early death. This was a retrospective study of confirmed cases of ethylmalonic aciduria from a tertiary care hospital over a period of 5 years from January 2015 to December 2020. Case details including analysis of clinical history, investigations, and outcomes are presented. Of six cases, male-to-female ratio was 4:2. Mean age of presentation was 35.5 months (range: 14-83 months). Consanguinity, global developmental delay, failure to thrive, skin rashes, microcephaly, hypotonia, and exaggerated deep tendon reflexes were observed in all cases. Chronic diarrhea was presented in five cases. The serum levels of C4 carnitine and urinary levels of ethylmalonic acid were increased in all cases. Magnetic resonance imaging (MRI) of the brain showed heterogenous bilateral symmetrical changes in the basal ganglia in five cases, and in one case, MRI could not be done. Genetic testing in two cases showed a homozygous variant in ETHE1 gene. Four children died, while the other two cases showed a decreased in recurrent encephalopathies and diarrhea after starting metronidazole. All children had global developmental delay, failure to thrive, skin rashes, central hypotonia, increased C4 carnitine levels in the serum, and increased ethylmalonic acid in the urine. Chronic diarrhea, acrocyanosis, and basal ganglia change in the MRI of the brain also give important clues for diagnosis. Metronidazole is useful in preventing recurrent episodes of encephalopathy.

Objectives: This study aimed to determine the association of the NF-KB inflammatory signaling pathway with vitamin D status in older cerebral small vessel disease (SVD) patients.Methods: We measured serum 25(OH)D, pro-and anti-inflammatory cytokines, and mRNA levels of the vitamin D -activating enzyme, CYP27B1, as well as NF-kB, COX-2, the chemokine-CCL2, IL-1 beta, IL-6, TNF-alpha, TGF-beta, and IL-10, in cerebral SVD patients aged >= 60 years presenting with vascular dementia and age and gender-matched healthy controls.Results: Low vitamin D status (insufficiency: serum 25(OH)D 12-20 ng/ml; deficiency: <= 12 ng/ml) was more prevalent among patients compared to controls. The mRNA levels of NF-kB, COX-2, CCL2, IL-1 beta, and IL-6, and serum levels of pro-inflammatory cytokines (IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha) were significantly higher in cases compared to controls. There was a significant correlation between CYP27B1 and NF-kB, COX-2, CCL2, and IL-1 beta gene expression. Serum IL-1 alpha, IL-1 beta, and IL-6 concentrations and the expression of CCL-2, NF-kB2, and NF-kB3 genes were higher in vitamin D-deficient subjects compared to vitamin D-sufficient subjects. There was a sig-nificant negative correlation between serum 25(OH)D and IL-1 alpha, IL-6, and TNF-alpha, and a positive correlation between 25(OH)D and IL-10.Conclusion: Low vitamin D is associated with an inflammatory response via NF-kB signaling, which could play a role in the etio-pathogenesis of SVD. Further large-scale studies are required to validate our findings.