Convalescent Plasma Therapy in the management of COVID-19 patients-The newer dimensions.

BACKGROUND: COVID 19 infection caused by novel coronavirus with no specific established treatment. Convalescent Plasma Therapy has been authorized as an off-label therapeutic procedure. We assessed the outcome of convalescent plasma (CP) units versus standard treatment on the complete recovery, improvement and 28 days' mortality of COVID 19 patients. MATERIALS AND METHODS: The present was multi-centric case controlled observational prospective study. The study was conducted for a period of four and half months from July 15 2020 to 30 November 2020 after taking approval from the Expert Committee, Health & Family Welfare Department, Government of Odisha. Plasma therapy was applied on two groups of 1189 serious COVID patients (959 number of pre- critical and 230 number of critical patients) not responding to oxygen therapy. It was compared with non- transfused control group of 1243 patients (996 number of pre-critical and 247 number of critical patients). RESULTS: Discharge was better in (55.5%) transfused than (43%)in non-transfused pre-critical patients and the mortality was lower (44.3%) in transfused, (48.9%) than non-transfused critical patients respectively. Complete recovery was highest in those who were transfused with CP with neutralizing titer more than 1:160 (52.5%), 18-30 years' age group (64%), females (53%), 'O' Rh D positive blood group (51.5%). There was no adverse reaction due to CP transfusion. CONCLUSIONS: CP is effective in improving the recovery rate with earlier discharge and decrease in the 28 days' mortality than in the control non-transfused group. CP with neutralizing antibody titer more than 1:160 has the best outcome with complete recovery and decrease in the mortality. It is more effective in treating pre-critical patients when transfused early, in female patients, in younger age group and in blood group 'O' Rh D positive.

Uncaptured rates of postpartum venous thromboembolism: a US national analysis.

OBJECTIVE: To quantify the proportion of postpartum venous thromboembolism (VTE) readmissions, including those that occur at different hospitals from index admission, and describe risk factors for this outcome. DESIGN: Retrospective observational study. SETTING: US hospitals included in the Nationwide Readmissions Database. SAMPLE: A total of 3 719 238 patients >14 years of age with a delivery-associated hospitalisation in 2014. METHODS: Univariate analysis was performed to identify patient and hospital factors associated with readmissions. Significant factors were included in multivariate logistic regression to identify independent risk factors. Results were weighted for national estimates. MAIN OUTCOME MEASURES: Readmission with VTE to both index and different hospitals at 30, 60 and 90 days. RESULTS: The VTE cumulative readmission rate was 0.053% (n = 1477), 0.063% (n = 1765) and 0.069% (n = 1938) at 30, 60 and 90 days, respectively. Patients were readmitted to different hospitals 31% of the time within 90 days. Risk factors for different hospital VTE readmission were unique and included younger age and initial admission to a small/medium-sized hospital. Initial admission to a for-profit hospital increased the likelihood of readmission to a different hospital. CONCLUSIONS: Nearly one in three postpartum VTEs are missed by the current quality metrics, with significant implications for outcomes and quality. For-profit hospitals have a significant portion of their VTE readmissions hidden, falsely lowering their readmission rates relative to public hospitals. TWEETABLE ABSTRACT: US analysis shows 1 in 3 readmissions for postpartum venous thromboembolism currently missed.

Urinary and Plasma Metabolomics Identify the Distinct Metabolic Profile of Disease State in Chronic Mouse Model of Multiple Sclerosis.

Identification of non-invasive biomarkers of disease progression in multiple sclerosis (MS) is critically needed for monitoring the disease progression and for effective therapeutic interventions. Urine is an attractive source for non-invasive biomarkers because it is easily obtained in the clinic. In search of a urine metabolite signature of progression in chronic experimental autoimmune encephalomyelitis (EAE), we profiled urine at the chronic stage of the disease (day 45 post immunization) by global untargeted metabolomics. Using a combination of high-throughput liquid-and-gas chromatography with mass spectrometry, we found 105 metabolites (P < 0.05) significantly altered at the chronic stage, indicating a robust alteration in the urine metabolite profile during disease. Assessment of altered metabolites against the Kyoto Encyclopedia of Genes and Genomes revealed distinct non-overlapping metabolic pathways and revealed phenylalanine-tyrosine and associated metabolism being the most impacted. Combined with previously performed plasma profiling, eight common metabolites were significantly altered in both of the biofluids. Metaboanalyst analysis of these common metabolites revealed that phenylalanine metabolism and Valine, leucine, and isoleucine biosynthetic pathways are central metabolic pathways in both bio-fluids and could be analyzed further, either for the discovery of therapeutics or biomarker development. Overall, our study suggests that urine and plasma metabolomics may contribute to the identification of a distinct metabolic fingerprint of EAE disease discriminating from the healthy control which may aid in the development of an objective non-invasive monitoring method for progressive autoimmune diseases like MS. Graphical Abstract Untargeted urinary metabolomics of a chronic mouse model of multiple sclerosis identified Phenylalanine, tyrosine & tryptophan metabolism as the significantly altered metabolic pathway. Eight common metabolites were identified when we combined urinary and plasma metabolic signature, which revealed a perturbation of Phenylalanine metabolism and valine, leucine & isoleucine metabolic pathways, involved in CNS dysfunction during diseases. The identified eight metabolic signature of urine and plasma may be of clinical relevance as potential biomarkers and guide towards the identification of specific metabolic pathways as novel drug targets.

Electronic clinical dental records: unintended consequences.

Record keeping is an essential component of delivering safe and appropriate care. In an ever increasing climate of litigation and complaints contemporaneous record keeping has assumed increasing importance, but is time consuming to do well and cover the aspects of care necessary. Practitioners have started using templates and copy and paste notes which, whilst useful, have their limitations and create problems of their own.

Preclinical evaluation of olaparib and metformin combination in BRCA1 wildtype ovarian cancer.

OBJECTIVES: BRCA mutated ovarian cancers show increased responsiveness to PARP inhibitors. PARP inhibitors target DNA repair and provide a second hit to BRCA mutated tumors, resulting in "synthetic lethality". We investigated a combination of metformin and olaparib to provide "synthetic lethality" in BRCA intact ovarian cancer cells. METHODS: Ovarian cancer cell lines (UWB1.289, UWB1.289.BRCA, SKOV3, OVCAR5, A2780 and C200) were treated with a combination of metformin and olaparib. Cell viability was assessed by MTT and colony formation assays. Flow cytometry was used to detect cell cycle events. In vivo studies were performed in SKOV3 or A2780 xenografts in nude mice. Animals were treated with single agent, metformin or olaparib or combination. Molecular downstream effects were examined by immunohistochemistry. RESULTS: Compared to single drug treatment, combination of olaparib and metformin resulted in significant reduction of cell proliferation and colony formation (p<0.001) in ovarian cancer cells. This treatment was associated with a significant S-phase cell cycle arrest (p<0.05). Combination of olaparib and metformin significantly inhibited SKOV3 and A2780 ovarian tumor xenografts which were accompanied with decreased Ki-index (p<0.001). Metformin did not affect DNA damage signaling, while olaparib induced adenosine monophosphate activated kinase activation; that was further potentiated with metformin combination in vivo. CONCLUSION: Combining PARP inhibitors with metformin enhances its anti-proliferative activity in BRCA mutant ovarian cancer cells. Furthermore, the combination showed significant activity in BRCA intact cancer cells in vitro and in vivo. This is a promising treatment regimen for women with epithelial ovarian cancer irrespective of BRCA status.

Release of zinc and cadmium from sludge amended soil as influenced by varying levels of moisture and temperature.

Limited information is available related to the effect of moisture and temperature on release of metals from sludge treated soils. In an incubation experiment, effect of ten levels of sludge (0, 1.12, 2.24, 4.48, 8.96, 17.9, 35.8, 71.6, 142, 285 g kg(-1)), two levels of moisture (field capacity and 2.5 cm standing water) and two levels of temperature (20 and 35 degrees C) on the release of zinc and cadmium was evaluated in acid and alkaline soils. The results indicated that application of sludge was more effective in enhancing EDTA extractable Zn and Cd in acid soil than in alkaline soil. On an average, maximum increase in release of EDTA extractable Zn and Cd were 32.0 and 5.2 fold in sludge treated soil over control. There was decrease in EDTA extractable Zn and Cd by 37.7% and 25.4%, respectively under submergence as compared to that under field capacity. On an average, the amount of EDTA extractable Zn and Cd increased by 22.6% and 43.6%, respectively at 35 degrees C than that at 20 degrees C.

Predicting bioavailability of metals from sludge-amended soils.

We attempted to develop a protocol for fixing the maximum permissible limit of sludge in agricultural lands based on transfer of metals from sludge-amended soils to human food chain. For this purpose, spinach was grown as a test crop on acid and alkaline soils with graded doses of sludge (0, 1.12, 2.24, 4.48, 8.96, 17.9, 35.8, 71.6, 142 and 285 g kg(-1) of soil) in a pot experiment. Biomass yield of spinach was increased due to sludge application in both acid and alkaline soils. Among the chemical extractants, EDTA extracted the highest amount of metals from sludge-amended soil followed by diethylenetriaminepentaacetic acid (DTPA) and CaCl2. Elevated levels of Zn, Cu, Fe, Mn, Ni, Cd and Pb in spinach were observed due to sludge application over control. Application of sludge was more effective in increasing metal content in spinach grown on acid soil than alkaline soil. Solubility-free ion activity model as a function of pH, organic carbon and extractable metal was far more effective in predicting metal uptake by spinach grown on sludge-amended soils as compared to that of chemical extractants. Risk in terms of hazard quotient (HQ) for intake of metals through consumption of spinach by humans grown on sludge-treated soils was computed for different metals separately. In a 90-day pot experiment, safe rates of sludge application were worked out as 4.48 and 71.6 g kg(-1) for acid and alkaline soils, respectively.

Identification of the solid phase in relation to the solubility of nickel in alluvial soils.

The chemical equillibria between nickel (Ni) ion present in soil solution and solid phases govern the solubility vis-a-vis availability of Ni in soil. Therefore, stability of various Ni containing minerals in relation to pH was studied to identify the probable solid phases, which govern the solubility of Ni in some alluvial soils under intensive cultivation in and around Delhi. Free Ni2+ activity (pNi2+) as estimated by Baker soil test, ranged from 13.1 to 16.2. Highest free Ni2+ activity (pNi2+ = 13.1) was recorded in industrial effluent irrigated soil collected from Sonepat, Haryana. Free Ni2+ activity was 13.6 in soil collected from agricultural lands of Keshopur, receiving irrigation through sewage effluents. Soils receiving irrigation through tube well water showed relatively lower free Ni2+ activity (pNi2+ = 14.6 to 16.2). Ni-ferrite in equilibrium with Fe(OH)3 (amorphous) is likely to control the activity of Ni in two intensively Ni contaminated soil having pH around 8. Free Ni2+ activity is likely to be buffered by exchangeable Ni in soils having neutral pH.

Profile of Circulatory Metabolites in a Relapsing-remitting Animal Model of Multiple Sclerosis using Global Metabolomics.

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the CNS. Although, MS is well characterized in terms of the role played by immune cells, cytokines and CNS pathology, nothing is known about the metabolic alterations that occur during the disease process in circulation. Recently, metabolic aberrations have been defined in various disease processes either as contributing to the disease, as potential biomarkers, or as therapeutic targets. Thus in an attempt to define the metabolic alterations that may be associated with MS disease progression, we profiled the plasma metabolites at the chronic phase of disease utilizing relapsing remitting-experimental autoimmune encephalomyelitis (RR-EAE) model in SJL mice. At the chronic phase of the disease (day 45), untargeted global metabolomic profiling of plasma collected from EAE diseased SJL and healthy mice was performed, using a combination of high-throughput liquid-and-gas chromatography with mass spectrometry. A total of 282 metabolites were identified, with significant changes observed in 44 metabolites (32 up-regulated and 12 down-regulated), that mapped to lipid, amino acid, nucleotide and xenobiotic metabolism and distinguished EAE from healthy group (p<0.05, false discovery rate (FDR)<0.23). Mapping the differential metabolite signature to their respective biochemical pathways using the Kyoto Encyclopedia of Genes and Genomics (KEGG) database, we found six major pathways that were significantly altered (containing concerted alterations) or impacted (containing alteration in key junctions). These included bile acid biosynthesis, taurine metabolism, tryptophan and histidine metabolism, linoleic acid and D-arginine metabolism pathways. Overall, this study identified a 44 metabolite signature drawn from various metabolic pathways which correlated well with severity of the EAE disease, suggesting that these metabolic changes could be exploited as (1) biomarkers for EAE/MS progression and (2) to design new treatment paradigms where metabolic interventions could be combined with present and experimental therapeutics to achieve better treatment of MS.

Prediction of the solubility of zinc, copper, nickel, cadmium, and lead in metal-contaminated soils.

Risk assessment of metal-contaminated soil depends on how precisely one can predict the solubility of metals in soils. Responses of plants and soil organisms to metal toxicity are explained by the variation in free metal ion activity in soil pore water. This study was undertaken to predict the free ion activity of Zn, Cu, Ni, Cd, and Pb in metal-contaminated soil as a function of pH, soil organic carbon, and extractable metal content. For this purpose, 21 surface soil samples (0-15 cm) were collected from agricultural lands of various locations receiving sewage sludge and industrial effluents for a long period. One soil sample was also collected from agricultural land which has been under intensive cropping and receiving irrigation through tube well water. Soil samples were varied widely in respect of physicochemical properties including metal content. Total Zn, Cu, Ni, Cd, and Pb in experimental soils were 2,015 ± 3,373, 236 ± 286, 103 ± 192, 29.8 ± 6.04, and 141 ± 270 mg kg(-1), respectively. Free metal ion activity, viz., pZn(2+), pCu(2+), pNi(2+), pCd(2+), and pPb(2+), as estimated by the Baker soil test was 9.37 ± 1.89, 13.1 ± 1.96, 12.8 ± 1.89, 11.9 ± 2.00, and 11.6 ± 1.52, respectively. Free metal ion activity was predicted by pH-dependent Freundlich equation (solubility model) as a function of pH, organic carbon, and extractable metal. Results indicate that solubility model as a function of pH, Walkley-Black carbon (WBC), and ethylenediaminetetraacetic acid (EDTA)-extractable metals could explain the variation in pZn(2+), pCu(2+), pNi(2+), pCd(2+), and pPb(2+) to the extent of 59, 56, 46, 52, and 51%, respectively. Predictability of the solubility model based on pH, KMnO4-oxidizable carbon, and diethylenetriaminepentaacetic acid-extractable or CaCl2-extractable metal was inferior compared to that based on EDTA-extractable metals and WBC.

The posterior epidural ligaments: a cadaveric and histological investigation in the lumbar region.

Purpose. Incidental durotomy is a relatively common complication for patients undergoing posterior spinal surgery. Delineating anatomical variants in the posterior lumbar spinal canal is crucial in reducing future rates of incidental durotomy. Materials and Methods. The ligamentous attachments between the dura mater and ligamentum flavum in the lumbar region of 17 soft-fixed cadavers were investigated. The lumbar vertebral columns were removed, and cross-sectional dissection was performed at levels L1-S1. Anterior retraction of the dorsal dura mater identified attachments between the dorsal surface of the dura mater and the ligamentum flavum. Histological staining of the ligamentous attachments was carried out with hematoxylin and eosin (H&E) and elastic van Gieson (EVG). Results. Posterior epidural ligaments were present in 9 (52.9%) cadavers. Nine (9) separate ligaments were identified in these cadavers, with 3 (33.3%) at L3/L4, 5 (55.5%) at L4/L5, and 1 (11.1%) at L5/S1. Histology confirmed the presence of poorly differentiated collagen-based connective tissue, distinct from the normal anatomy. Conclusions. This study confirms the presence of multiple dorsomedial posterior epidural ligaments at the main sites for posterior spinal surgery (L3-S1). An intraoperative awareness of the variability of such connections may be an important step in reducing static rates of incidental durotomy.

Labile and stabilised fractions of soil organic carbon in some intensively cultivated alluvial soils.

The present investigation was undertaken in view of the limited information on the relative proportion of labile and stabilized fractions of soil organic carbon (SOC) in intensively cultivated lands, particularly under tropics. The specific objectives were i) to study the comparative recovery of SOC by different methods of labile carbon estimation under intensively cultivated lands and ii) to evaluate the impact of agricultural practices on carbon management index. For this purpose, in all, 105 surface soil samples were collected from intensively cultivated tube well and sewage irrigated agricultural lands. These samples were analysed for total as well as labile pools of SOC. Results indicated that Walkley and Black, KMnO4-oxidizable and microbial biomass carbon constituted the total SOC to the extent of 10.2 to 47.4, 1.66 to 23.2 and 0.30 to 5.49%, respectively with the corresponding mean values of 26.2, 9.16 and 2.15%. Lability of SOC was considerably higher in sewage irrigated soils than tube well irrigated soils under intensive cropping. Under soybean-wheat, the higher values of carbon management index (CMI) (279 and 286) were associated with the treatments where entire amount of nitrogen was supplied through FYM. Similar results were obtained under rice-wheat, whereas in case of maize-wheat the highest value of CMI was recorded under treatment receiving NPK through chemical fertilizer along with green manure. There was also a significant improvement in CMI under integrated (chemical fertilizer + organics) and chemical fertilizer-treated plots. The values of CMI ranged from 220 to 272 under cultivated lands receiving irrigation through sewage and industrial effluents.

Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner.

Metformin, the most widely used drug for type 2 diabetes activates 59 adenosine monophosphate (AMP)-activated protein kinase (AMPK), which regulates cellular energy metabolism. Here, we report that ovarian cell lines VOSE, A2780, CP70, C200, OV202, OVCAR3, SKOV3ip, PE01 and PE04 predominantly express -α(1), -ß(1), -γ(1) and -γ(2) isoforms of AMPK subunits. Our studies show that metformin treatment (1) significantly inhibited proliferation of diverse chemo-responsive and -resistant ovarian cancer cell lines (A2780, CP70, C200, OV202, OVCAR3, SKVO3ip, PE01 and PE04), (2) caused cell cycle arrest accompanied by decreased cyclin D1 and increased p21 protein expression, (3) activated AMPK in various ovarian cancer cell lines as evident from increased phosphorylation of AMPKα and its downstream substrate; acetyl co-carboxylase (ACC) and enhanced ß-oxidation of fatty acid and (4) attenuated mTOR-S6RP phosphorylation, inhibited protein translational and lipid biosynthetic pathways, thus implicating metformin as a growth inhibitor of ovarian cancer cells. We also show that metformin-mediated effect on AMPK is dependent on liver kinase B1 (LKB1) as it failed to activate AMPK-ACC pathway and cell cycle arrest in LKB1 null mouse embryo fibroblasts (mefs). This observation was further supported by using siRNA approach to down-regulate LKB1 in ovarian cancer cells. In contrast, met formin inhibited cell proliferation in both wild-type and AMPKα(1/2) null mefs as well as in AMPK silenced ovarian cancer cells. Collectively, these results provide evidence on the role of metformin as an anti-proliferative therapeutic that can act through both AMPK-dependent as well as AMPK-independent pathways.

TCEAL7, a putative tumor suppressor gene, negatively regulates NF-kappaB pathway.

We have previously shown that a frequently downregulated gene, transcription elongation factor A-like 7 (TCEAL7), promoted anchorage-independent growth and modulated Myc activity in ovarian surface epithelial cells immortalized with temperature-sensitive large T antigen and human telomerase reverse transcriptase (OSEtsT/hTERT). Analysis of protein/DNA array showed that TCEAL7 downregulation resulted in an approximately twofold increase in nuclear factor (NF)-kappaB binding to its target DNA sequence. In this study we showed that short hairpin RNA (shRNA)-mediated downregulation of TCEAL7 in two different immortalized OSE cells showed higher NF-kappaB activity, as determined using reporter and gel-shift assays. Transient transfection of TCEAL7 inhibited the activation of NF-kappaB in TCEAL7-downregulated clones, IOSE-523 and in other ovarian cancer cell lines (OVCAR8, SKOV3ip and DOV13), suggesting that TCEAL7 negatively regulates NF-kappaB pathway. Consistent with this observation, TCEAL7-downregulated clones showed higher levels of NF-kappaB targets, such as pro-proliferative (cyclin-D1 and cMyc), pro-angiogenic (interleukin (IL)-6, IL-8 and vascular endothelial growth factor (VEGF)), inflammatory (intercellular adhesion molecule 1 (ICAM-1) and cyclooxygenase-2 (Cox-2)) and anti-apoptotic (B-cell lymphoma-extra large (Bcl-xl)) genes when compared with vector controls. Inhibition of NF-kappaB by IkappaB kinase (IKK) inhibitor (BMS 345541) attenuated cell survival and proliferation of TCEAL-knockdown clones. Although TCEAL7 inhibited p65 transcriptional activity, it did not modulate the cytoplasmic signaling of the NF-kappaB pathway, by itself or by tumor necrosis factor-alpha (TNF-alpha). Chromatin immunoprecipitation (ChIP) assays revealed increased recruitment of p65 and p300 to the promoters of IL-8 and IL-6 in TCEAL7-downregulated clones. Collectively, these results indicate a novel role for TCEAL7 in the negative regulation of NF-kappaB signaling at the basal level by modulating transcriptional activity of NF-kappaB on its target gene promoters, potentially providing a novel mechanism by which NF-kappaB activity may be deregulated in ovarian cancer cells.

Severe form of type 2 reaction in patients of Hansen's disease after withdrawal of thalidomide: case reports.

Thalidomide, a racemic glutamic acid analogue, was first developed in 1954 and subsequently marketed in Europe, Australia and Canada as a sedative and anti-emetic. It was approved by the Food and Drug Administration (FDA) in the USA in 1998 for the treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL) and suppression of the cutaneous manifestations of ENL recurrences. It is a good choice for management in patients who are dependent on corticosteroids. Common side effects of thalidomide are teratogenicity, peripheral neuropathy, sedation and constipation. We report 4 cases of Hansen's disease with recurrent ENL who were adequately managed on thalidomide. On sudden withdrawal of thalidomide, they relapsed with severe type 2 reaction including necrotic ENL.

A role for candidate tumor-suppressor gene TCEAL7 in the regulation of c-Myc activity, cyclin D1 levels and cellular transformation.

The pathophysiological mechanisms that drive the development and progression of epithelial ovarian cancer remain obscure. Recently, we identified TCEAL7 as a transcriptional regulatory protein often downregulated in epithelial ovarian cancer. However, the biological significance of such downregulation in cancer is not currently known. Here, we show that TCEAL7 is downregulated frequently in many human cancers and that in immortalized human ovarian epithelial cells this event promotes anchorage-independent cell growth. Mechanistic investigations revealed that TCEAL7 associates with cyclin D1 promoter containing Myc E-box sequence and transcriptionally represses cyclin D1 expression. Moreover, downregulation of TCEAL7 promotes DNA-binding activity of Myc-Max, and upregulates the promoter activity of c-Myc-target gene, ornithine decarboxylase (ODC), whereas enhanced expression of TCEAL7 inhibits Myc-induced promoter activity of ODC. Our findings suggest that TCEAL7 may restrict ovarian epithelial cell transformation by limiting Myc activity. These results also suggest a potential, alternative mechanism by which c-Myc activity may be deregulated in cancer by the downregulation of TCEAL7.

Performance of a pediatric ambulatory anesthesia program--a developing country experience.

BACKGROUND: The aim of this study was to evaluate the performance of a pediatric ambulatory anesthesia program in a tertiary care teaching hospital in a developing country. METHODS: Data on all pediatric patients (<16 years of age) scheduled to have elective day-care surgery during a 1 year period from January 1999 to December 1999 were collected retrospectively. An audit form was used to determine the specialty of the procedures, anesthesia techniques, postoperative analgesia, perioperative complications, unplanned admissions and outcomes with respect to morbidity and mortality. RESULTS: A total of 763 pediatric ambulatory surgical procedures were performed during the year of 1999. The procedures included general surgery, ENT, orthopedic and plastic surgery. The most common procedure was inguinal hernia repair followed by umbilical hernia repair, adenotonsillectomy and circumcision and 96% of the patients had general anesthesia. There were only three unplanned admissions (0.4%); one for a surgical reason and two for anesthetic reasons. There was no serious morbidity or mortality in any patient. CONCLUSIONS: Performance of pediatric day-care anesthesia has been good in our day-care unit and we have a successful ambulatory surgery program, despite the limitations of a developing country.

Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death.

Globoid cell leukodystrophy (Krabbe disease) is an inherited neurological disorder caused by the pathogenomic accumulation of psychosine (galactosylsphingosine), a substrate for the deficient enzyme galactocerebroside beta-galactosidase. This study underscores the mechanism of action of psychosine in the regulation of oligodendrocyte cell death via the generation of lysophosphatidylcholine (LPC) and arachidonic acid (AA) by the activation of secretory phospholipase A2 (sPLA2). There was a significant increase in the level of LPC, indicating a phospholipase A2 (PLA2)-dependent pathobiology, in the brains of Krabbe disease patients and those of twitcher mice, an animal model of Krabbe disease. In vitro studies of the treatment of primary oligodendrocytes and the oligodendrocyte MO3.13 cell line with psychosine also showed the generation of LPC and the release of AA in a dose- and time-dependent manner, indicating psychosine-induced activation of PLA2. Studies with various pharmacological inhibitors of cytosolic phospholipase A2 and sPLA2 and psychosine-mediated induction of sPLA2 enzymatic activity in media supernatant suggest that psychosine-induced release of AA and generation of LPC is mainly contributed by sPLA2. An inhibitor of sPLA2, 7,7-dimethyl eicosadienoic acid, completely attenuated the psychosine-mediated accumulation of LPC levels, release of AA, and generation of reactive oxygen species, and blocked oligodendroyte cell death, as evident from cell survival, DNA fragmentation, and caspase 3 activity assays. This study documents for the first time that psychosine-induced cell death is mediated via the sPLA2 signaling pathway and that inhibitors of sPLA2 may hold a therapeutic potential for protection against oligodendrocyte cell death and resulting demyelination in Krabbe disease.