Chloroquine synergizes doxorubicin efficacy in cervical cancer cells through flux impairment and down regulation of proteins involved in the fusion of autophagosomes to lysosomes.

Drug repurposing holds abundant opportunity in the development of novel anticancer drugs. Chloroquine (CQ), a FDA approved anti-malarial drug, is demonstrated to enhance anticancer efficacy of standard anticancer drugs including doxorubicin (DOX) in several types of cancer cells. Here, we aimed to exploit the chemosensitizing effects of CQ against DOX in human cervical cancer (HeLa) cells that remains to be investigated yet. We show that a combination of DOX (40 nM) and CQ (40 µM) resulted in a synergistic cytotoxicity (combination index; CI < 1) in HeLa cells compared to the DOX or CQ alone. Synergistic effect of the combination (DOX + CQ) was associated with the impaired autophagic flux and enhanced apoptosis. Following treatment with the combination (DOX + CQ), the level of p62/SQSTM and LC-3II proteins was increased, while a decrease was noted in the expression of LAMP-2, Syntaxin17, Rab 5, and Rab 7 proteins that play critical roles in the fusion of autophagosomes to lysosomes. Autophagy inhibition by combination (DOX + CQ) enhanced the apoptotic cell death synergistically by increasing the cleavage of procaspase-3 and PARP1. Further, a prior incubation of HeLa cells with Z-VAD-FMK (a pan-caspase inhibitor) for 4 h, suppressed the combination (DOX + CQ)-induced cell death. Our data suggest that a combination of DOX + CQ had a better anti-cancer efficacy in HeLa cells than either of the drugs alone. Thus, CQ, as a repurposed drug, may hold the potential to synergize anticancer effects of DOX in cervical cancer cells.

Defective quality control autophagy in Hyperhomocysteinemia promotes ER stress and consequent neuronal apoptosis through proteotoxicity.

Homocysteine (Hcy), produced physiologically in all cells, is an intermediate metabolite of methionine and cysteine metabolism. Hyperhomocysteinemia (HHcy) resulting from an in-born error of metabolism that leads to accumulation of high levels of Hcy, is associated with vascular damage, neurodegeneration and cognitive decline. Using a HHcy model in neuronal cells, primary cortical neurons and transgenic zebrafish, we demonstrate diminished autophagy and Hcy-induced neurotoxicity associated with mitochondrial dysfunction, fragmentation and apoptosis. We find this mitochondrial dysfunction is due to Hcy-induced proteotoxicity leading to ER stress. We show this sustained proteotoxicity originates from the perturbation of upstream autophagic pathways through an aberrant activation of mTOR and that protetoxic stress act as a feedforward cues to aggravate a sustained ER stress that culminate to mitochondrial apoptosis in HHcy model systems. Using chemical chaperones to mitigate sustained ER stress, Hcy-induced proteotoxicity and consequent neurotoxicity were rescued. We also rescue neuronal lethality by activation of autophagy and thereby reducing proteotoxicity and ER stress. Our findings pave the way to devise new strategies for the treatment of neural and cognitive pathologies reported in HHcy, by either activation of upstream autophagy or by suppression of downstream ER stress. Video Abstract.

Development and evaluation of Hedyotis corymbosa (L.) extract containing phytosomes: a preclinical approach for treatment of neuropathic pain in rodent model.

PURPOSE: The study was aimed to encapsulate Hedyotis corymbosa extract (HCE) into phytosomes to improve its therapeutic efficacy in neuropathic pain by enhancing the bioavailability of chief chemical constituent Hedycoryside -A (HCA). METHODS: For preparing phytosomes complexes (F1, F2, and F3), HCE and phospholipids were reacted in disparate ratio. F2 was chosen to assess its therapeutic efficacy in neuropathic pain induced by partial sciatic nerve ligation. Nociceptive threshold and oral bioavailability were also estimated for F2. RESULTS: Particle size, zeta potential and entrapment efficiency for F2 were analysed as 298.1 ± 1.1 nm, -3.92 ± 0.41 mV and 72.12 ± 0.72% respectively. F2 gave enhanced relative bioavailability (158.92%) of HCA along with a greater neuroprotective potential showing a significant antioxidant effect and augmentation (p < 0.05) in nociceptive threshold with the diminution in damage to nerves. CONCLUSION: F2 is an optimistic formulation for enhancing the HCE delivery for the effective treatment of neuropathic pain.

WheatQTLdb V2.0: a supplement to the database for wheat QTL.

We recently developed a database for hexaploid wheat QTL (WheatQTLdb; www.wheatqtldb.net), which included 11,552 QTL affecting various traits of economic importance. However, that database did not include valuable QTL from other wheat species and/or progenitors of hexaploid wheat. Therefore, an updated and improved version of wheat QTL database (WheatQTLdb V2.0) was developed, which now includes information on hexaploid wheat (Triticum aestivum) and the following seven other related species: T. durum, T. turgidum, T. dicoccoides, T. dicoccum, T. monococcum, T. boeoticum, and Aegilops tauschii. WheatQTLdb V2.0 includes a much-improved list of QTL, including 27,518 main effect QTL, 202 epistatic QTL, and 1321 metaQTL. This newly released WheatQTLdb V2.0 also has additional valuable options to search and choose the QTL, category-wise, and trait-wise data for their use in research or breeding programs.

WheatQTLdb: a QTL database for wheat.

During the last three decades, QTL analysis in wheat has been conducted for a variety of individual traits, so that thousands of QTL along with the linked markers, their genetic positions and contribution to phenotypic variation (PV) for concerned traits are now known. However, no exhaustive database for wheat QTL is currently available at a single platform. Therefore, the present database was prepared which is an exhaustive information resource for wheat QTL data from the published literature till May, 2020. QTL data from both interval mapping and genome-wide association studies (GWAS) have been included for the following classes of traits: (i) morphological traits, (ii) N and P use efficiency, (iii) traits for biofortification (Fe, K, Se, and Zn contents), (iv) tolerance to abiotic stresses including drought, water logging, heat stress, pre-harvest sprouting and salinity, (v) resistance to biotic stresses including those due to bacterial, fungal, nematode and insects, (vi) quality traits, and (vii) a variety of physiological traits, (viii) developmental traits, and (ix) yield and its related traits. For the preparation of the database, literature was searched for data on QTL/marker-trait associations (MTAs), curated and then assembled in the form of WheatQTLdb. The available information on metaQTL, epistatic QTL and candidate genes, wherever available, is also included in the database. Information on QTL in this WheatQTLdb includes QTL names, traits, associated markers, parental genotypes, crosses/mapping populations, association mapping panels and other useful information. To our knowledge, WheatQTLdb prepared by us is the largest collection of QTL (11,552), epistatic QTL (107) and metaQTL (330) data for hexaploid wheat to be used by geneticists and plant breeders for further studies involving fine mapping, cloning, and marker-assisted selection (MAS) during wheat breeding.

Single-trait, multi-locus and multi-trait GWAS using four different models for yield traits in bread wheat.

A genome-wide association study (GWAS) for 10 yield and yield component traits was conducted using an association panel comprising 225 diverse spring wheat genotypes. The panel was genotyped using 10,904 SNPs and evaluated for three years (2016-2019), which constituted three environments (E1, E2 and E3). Heritability for different traits ranged from 29.21 to 97.69%. Marker-trait associations (MTAs) were identified for each trait using data from each environment separately and also using BLUP values. Four different models were used, which included three single trait models (CMLM, FarmCPU, SUPER) and one multi-trait model (mvLMM). Hundreds of MTAs were obtained using each model, but after Bonferroni correction, only 6 MTAs for 3 traits were available using CMLM, and 21 MTAs for 4 traits were available using FarmCPU; none of the 525 MTAs obtained using SUPER could qualify after Bonferroni correction. Using BLUP, 20 MTAs were available, five of which also figured among MTAs identified for individual environments. Using mvLMM model, after Bonferroni correction, 38 multi-trait MTAs, for 15 different trait combinations were available. Epistatic interactions involving 28 pairs of MTAs were also available for seven of the 10 traits; no epistatic interactions were available for GNPS, PH, and BYPP. As many as 164 putative candidate genes (CGs) were identified using all the 50 MTAs (CMLM, 3; FarmCPU, 9; mvLMM, 6, epistasis, 21 and BLUP, 11 MTAs), which ranged from 20 (CMLM) to 66 (epistasis) CGs. In-silico expression analysis of CGs was also conducted in different tissues at different developmental stages. The information generated through the present study proved useful for developing a better understanding of the genetics of each of the 10 traits; the study also provided novel markers for marker-assisted selection (MAS) to be utilized for the development of wheat cultivars with improved agronomic traits. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-021-01240-1.

Biopurification of dairy farm wastewater through hybrid constructed wetland system: Groundwater quality and health implications.

Groundwater is under heavily threat owing to enormous infilteration of dairy farm originated wastewater into it. The anoxic environment in the groundwater due to mixing of organic rich wastewater can produce significant alterations in the groundwater quality. It is therefore necessary to treat such wastewaters before discharging to surrounding areas. Therefore, in this study we evaluated a hybrid constructed wetland (CW) system(40 m2 area) consisting of three beds, i.e. Vertical (16 m2) - Horizontal (18 m2) - Vertical (6 m2) connected in series for the treatment of dairy farm wastewater under typical high humid climate in northern India. Tropical perennial plant such as Arundo donax L. was grown on both vertical beds, whereas Hibiscus esculentus L. and Solanum melongena L. were grown on the horizontal bed of the system.The average purification of TSS, BOD3, total N, and P was significant (p < 0.05) in HF bed and recorded as 92.2 ± 6.1, 95 ± 3.8, 83.6 ± 9.0 and 86.1 ± 10.0% respectively.The average load of BOD3, total N, and P in the influent and effluent was recorded (with no significant differences, p > 0.05) as 7.0 ± 7.17, 1.9 ± 0.7, 0.72 ± 0.5 g m-2 day-1and 0.3 ± 0.2, 0.3 ± 0.2 and 0.04 ± 0.01 g m-2 day-1 respectively.The average values of total biomass content of Arundo donax L. were differed significantly and recorded as 0.31 ± 0.06, 0.43 ± 0.17, and 0.43 ± 0.16 g g-1 fresh wt. in control, VF-1, and VF-2 respectively. Therefore, the hybrid CW system can be efficiently used for the treatment of dairy farm wastewater with implications on groundwater and health. Future research may focus on performance analysis of upgraded combined anaerobic reactor and hybrid CW system planted with series of macrophytes for on-site treatment of high strength dairy farm wastewater in tropical regions.

Isolation of new phytometabolites from Alpinia galanga willd rhizomes.

The current research was aimed to isolate newer phyto-metabolites from rhizomes of Alpinia galanga plant. Study involved preparation of Alpinia galanga rhizome methanolic extract, followed by normal phase column chromatography assisted isolation of new phytometabolites (using different combinations of chloroform and methanol), and characterization (by UV, FTIR, 13C-NMR, 1H-NMR, COSY, DEPT and Mass spectrometry). The isolation and characterization experiment offered two phytometabolites: an ester (Ag-1) and tetrahydronapthalene type lactone (Ag-2). Present study concludes and reports the two phytometabolites, benzyl myristate (Ag-1) and 3-Methyl-6α, 8ß-diol-7-carboxylic acid tetralin-11, 9ß-olide (Ag-2) for the first time in Alpinia galanga rhizome. The study recommends that these phytometabolites Ag-1 and Ag-2 can be utilized as effective analytical biomarkers for identification, purity and quality control of this plant in future.

Severe Necrotizing Pneumonia in Children: A Challenge to Intensive Care Specialist.

OBJECTIVE: Necrotizing pneumonia (NP) is recently recognized as a complication of pneumonia. The data on NP are scant from developing world and we aimed to describe the characteristic features of NP in our children. STUDY DESIGN: Single center retrospective cohort analysis. PATIENT SELECTION: Institutional database of children treated for pneumonia between September 2014 and May 2018 was searched to identify children with NP. METHODS: The demographic characteristics, laboratory results, and clinical information were recorded for patients selected as NP and analyzed. RESULTS: In total, 10 patients (3.7%) of NP were identified out of 272 patients with pneumonia. Median age was 3 years (range: 3 months to 12years). All cases had severe respiratory distress and 70% required mechanical ventilation and inotropic support. The causative pathogens were identified in 6/10 children (60%) with Staphylococcus aureus being most common (4/10). Pleural effusion and pneumothorax were seen in six cases. Four cases had bilateral pleural effusion and three had bilateral pneumothorax. Intercostal drainage (ICD) was placed in 70% and bilateral ICD was placed in 40% cases. Bronchopleural fistula (BPF) developed in two cases and one had bilateral BPF. Median [inter quartile range] ICD days and hospital stay were 9 (6-14) and 13.5 (7.5-18.5) days, respectively. Mean (±SD) total antibiotic (in hospital plus outpatient) days were 28.8 ± 9.6 days. Four cases had airway hemorrhage and in three cases this was massive and fatal. CONCLUSION: NP is a relatively rare but severe complication of pneumonia distinct from pediatric acute respiratory distress, pleural effusion and empyema. Airway hemorrhage is the most fatal complication.

Phytochemicals based chemopreventive and chemotherapeutic strategies and modern technologies to overcome limitations for better clinical applications.

Naturally occurring phytochemicals or plant derivatives are now being explored extensively for their health's benefits and medicinal uses. The therapeutic effect of phytochemicals has been reported in several pathophysiological settings such as inflammatory disorders, metabolic disorders, liver dysfunction, neurodegenerative disorders, and nephropathies. However, the most warranted therapeutic effects of phytochemicals were mapped to their anticancerous and chemopreventive action. Moreover, combining phytochemicals with standard chemotherapy has shown promising results in cancer therapy with minimal side effects and better efficacy. Many phytochemicals, like curcumin, resveratrol, and epigallocatechin-3-gallate, have been extensively investigated for their chemopreventive as well as chemotherapeutic effects. However, poor bioavailability, low solubility, hydrophobicity, and obscure target specificity restrict their therapeutic applications in the clinic. There has been a continually increasing interest to formulate nanoformulations of phytochemicals by using various nanocarriers, such as liposomes, micelles, nanoemulsions, and nanoparticles, to improve their bioavailability and target specificity, thereby maximizing the therapeutic potential. In the present review, we have summarized chemopreventive as well as chemotherapeutic action of some common phytochemicals and their major limitations in clinical application. Also, we have given an overview of strategies that can improve the efficacy of phytochemicals for their chemotherapeutic value in clinical settings.

Severe Sepsis and Septic Shock Associated with Chikungunya Fever in an Adolescent.

Chikungunya is usually a benign disease, and little is known on the occurrence of severe clinical complications. We describe a 12-year-old boy with rapid onset septic shock and multi-organ failure associated with chikungunya fever. Severe sepsis and septic shock can be associated with chikungunya.

Intricatinol synergistically enhances the anticancerous activity of cisplatin in human A549 cells via p38 MAPK/p53 signalling.

Platinum containing drugs are widely used to treat advanced lung carcinomas. However, their clinical success is still limited due to severe side effects, and drug resistance. Alternative approaches are warranted to augment efficacy of platinum based chemotherapeutic drugs with minimal side effects. Intricatinol (INT), a homoisoflavonoid, has been shown to possess anti-tubercular, antioxidant, hypoglycaemic, and hypolipidemic activity. However, its anticancer activity largely remains unknown. In the present study, we have evaluated anticancer potential of INT alone or in combination with cisplatin (CIS) in non-small cell lung carcinoma (A549) cells. Treatment with INT alone reduced the viability of A549 cells in a dose-dependent manner. Interestingly, the combination of low doses of INT and CIS exerted a synergistic effect and induced apoptosis as evident by DNA fragmentation and Annexin V positive cells. Enhanced Bax:Bcl-2 ratio, loss of Δψm, cytochrome c release, cleavage of caspase 3 and PARP1 strongly corroborated our findings. Further, increased expression of p53, p38 MAPK and their phosphorylated counterparts, loss of clonogenicity and reduced migration potential were also recorded with INT + CIS treatment. Most interestingly, INT could not induce any significant cell death in primary mouse embryonic fibroblasts (MEFs). Moreover, no additive or synergistic effect was noted with INT + CIS in MEFs under similar treatment conditions. In conclusion, INT has a selective anticancer potential and could synergize cytotoxicity of CIS. Therefore, the combination of INT and CIS may serve as an effective anticancer strategy for the treatment of non-small cell lung carcinoma.

Impaired lysosomal activity mediated autophagic flux disruption by graphite carbon nanofibers induce apoptosis in human lung epithelial cells through oxidative stress and energetic impairment.

BACKGROUND: Graphite carbon nanofibers (GCNF) have emerged as a potential alternative of carbon nanotubes (CNT) for various biomedical applications due to their superior physico-chemical properties. Therefore in-depth understanding of the GCNF induced toxic effects and underlying mechanisms in biological systems is of great interest. Currently, autophagy activation by nanomaterials is recognized as an emerging toxicity mechanism. However, the association of GCNF induced toxicity with this form of cell death is largely unknown. In this study, we have assessed the possible mechanism; especially the role of autophagy, underlying the GCNF induced toxicity. METHODS: Human lung adenocarcinoma (A549) cells were exposed to a range of GCNF concentrations and various cellular parameters were analyzed (up to 48 h). Transmission electron microscopy, immunofluorescent staining, western blot and quantitative real time PCR were performed to detect apoptosis, autophagy induction, lysosomal destabilization and cytoskeleton disruption in GCNF exposed cells. DCFDA assay was used to evaluate the reactive oxygen species (ROS) production. Experiments with N-acetyl-L-cysteine (NAC), 3-methyladenine (3-MA) and LC3 siRNA was carried out to confirm the involvement of oxidative stress and autophagy in GCNF induced cell death. Comet assay and micronucleus (MN) assay was performed to assess the genotoxicity potential. RESULTS: In the present study, GCNF was found to induce nanotoxicity in human lung cells through autophagosomes accumulation followed by apoptosis via intracellular ROS generation. Mechanistically, impaired lysosomal function and cytoskeleton disruption mediated autophagic flux blockade was found to be the major cause of accumulation rather than autophagy induction which further activates apoptosis. The whole process was in line with the increased ROS level and their pharmacological inhibition leads to mitigation of GCNF induced cell death. Moreover the inhibition of autophagy attenuates apoptosis indicating the role of autophagy as cell death process. GCNF was also found to induce genomic instability. CONCLUSION: Our present study demonstrates that GCNF perturbs various interrelated signaling pathway and unveils the potential nanotoxicity mechanism of GCNF through targeting ROS-autophagy-apoptosis axis. The current study is significant to evaluate the safety and risk assessment of fibrous carbon nanomaterials prior to their potential use and suggests caution on their utilization for biomedical research.

Severe Hypertriglyceridemia Causing Pancreatitis in a Child with New-onset Type-I Diabetes Mellitus Presenting with Diabetic Ketoacidosis.

The triad of pancreatitis, hypertriglyceridemia, and diabetic ketoacidosis and its treatment has not been extensively discussed in the pediatric literature. We report a 4-year-old child with severe hypertriglyceridemia, pancreatitis, and diabetic ketoacidosis. Hypertriglyceridemia and pancreatitis with diabetic ketoacidosis can be successfully managed with insulin and hydration therapy in children. Early recognition of this triad is important as insulin requirements, recovery duration, and prognosis can be altered.

Deltamethrin induced RIPK3-mediated caspase-independent non-apoptotic cell death in rat primary hepatocytes.

Deltamethrin (DLM), a synthetic pyrethroid insecticide, is used all over the world for indoor and field pest management. In the present study, we investigated the elicited pathogenesis of DLM-induced hepatotoxicity in rat primary hepatocytes. DLM-induced cell death was accompanied with increased ROS generation, decreased mitochondrial membrane potential and G2/M arrest. Pre-treatment with N-acetyl cysteine/butylated hydroxyanisole/IM54 could partly rescue hepatocytes suggesting that ROS might play a role in DLM-induced toxicity. Interestingly, DLM treatment resulted in a caspase-independent but non-apoptotic cell death. Pre-treatment with pan-caspase inhibitor (ZVAD-FMK) could not rescue hepatocytes. Unaltered caspase-3 activity and absence of cleaved caspase-3 also corroborated our findings. Further, LDH release and Transmission electron microscopy (TEM) analysis demonstrated that DLM incites membrane disintegrity and necrotic damage. Immunochemical staining revealed an increased expression of inflammatory markers (TNFα, NFκB, iNOS, COX-2) following DLM treatment. Moreover, the enhanced RIPK3 expression in DLM treated groups and prominent rescue from cell death by GSK-872 indicated that DLM exposure could induce programmed necrosis in hepatocytes. The present study demonstrates that DLM could induce hepatotoxicity via non-apoptotic mode of cell death.

Current perspectives of molecular pathways involved in chronic inflammation-mediated breast cancer.

Inflammation has multifaceted role in cancer progression including initiation, promotion and invasion by affecting the immune surveillance and associated signaling pathways. Inflammation facilitates the over-expression of cytokines, chemokines and growth factors involved in progression of different cancers including breast cancer progression. Deregulation of biological processes such as oxidative stress, angiogenesis, and autophagy elicit favorable immune response towards chronic inflammation. Apart from the role in carcinogenesis, chronic inflammation also favors the emergence of drug resistance clones by inducing the growth of breast cancer stem-like cells. Immunomodulation mediated by cytokines, chemokines and several other growth factors present in the tumor microenvironment regulate chronic inflammatory response and alter crosstalk among various signaling pathways such as NF-κB, Nrf-2, JAK-STAT, Akt and MAPKs involved in the progression of breast cancer. In this review, we focused on cellular and molecular processes involved in chronic inflammation, crosstalk among different signaling pathways and their association in breast cancer pathogenesis.

Effect of ethanolic extract of Zingiber officinale Roscoe on central nervous system activity in mice.

Zingiber officinale Roscoe, commonly known as ginger, is a traditional herb used to treat various disorders. In this study, we evaluated potential pharmacological effects of ethanolic extracts of Z. Officinale with respect to central nervous system (CNS) activity in mice. Role of ethanolic extract of ginger on CNS activity in mice was studied using models of elevated plus maze test, barbiturate-induced sleeping time, tail suspension test, hot-plate and tail-flick test. Ginger extract was administered to mice at single doses of 50 and 200 mg/kg, perorally while diazepam (1 mg/kg), morphine (5 mg/kg) and imipramine (30 mg/kg) intraperitoneally were used as standard drugs. The results showed that the ginger extract at all dose levels significantly exhibited anxiolytic activityincreased the sleeping latency but reduced the sleeping time. Tail suspension test showed that the extract at both the doses was able to induce a significant decrease in the immobility time, similar to imipramine, a recognized antidepressant drug. Tail-flick and hot-plate tests demonstrated antinociceptive property of ginger extract, similar to morphine, a recognized antinociceptive agent. Higher dose level (200 mg/kg) showed better protective effects. Phytochemical screening of ethanolic extract revealed the presence of various phytoconstituents such as phenolic compounds, flavonoids, tannins, anthocyanins, carbohydrates, glycosides, proteins, resins and volatile oils. The possible mechanism by which ginger exhibited the significant beneficial effects on various CNS models in mice could be attributed to its antioxidant potential.

Spore immobilization and its analytical performance for monitoring of aflatoxin M1 in milk.

Immobilization of Bacillus megaterium spores on Eppendorf tubes through physical adsorption has been used in the detection of aflatoxin M1 (AFM1) in milk within real time of 45 ± 5 min using visual observation of changes in a chromogenic substrate. The appearance of a sky-blue colour indicates the absence of AFM1 in milk, whereas no colour change indicates the presence of AFM1 in milk at a 0.5 ppb Codex maximum residue limit. The working performance of the immobilized spores was shown to persist for up to 6 months. Further, spores immobilized on 96-well black microtitre plates by physical adsorption and by entrapment on sensor disk showed a reduction in detection sensitivity to 0.25 ppb within a time period of 20 ± 5 min by measuring fluorescence using a microbiological plate reader through the addition of milk and fluorogenic substrate. A high fluorescence ratio indicated more substrate hydrolysis due to spore-germination-mediated release of marker enzymes of spores in the absence of AFM1 in milk; however, low fluorescence ratios indicated the presence of AFM1 at 0.25 ppb. Immobilized spores on 96-well microtitre plates and sensor disks have shown better reproducibility after storage at 4 °C for 6 months. Chromogenic assay showed 1.38% false-negative and 2.77% false-positive results while fluorogenic assay showed 4.16% false-positive and 2.77% false-negative results when analysed for AFM1 using 72 milk samples containing raw, pasteurized, and dried milk. Immobilization of spores makes these chromogenic and fluorogenic assays portable, selective, cost-effective for real-time detection of AFM1 in milk at the dairy farm, reception dock, and manufacturing units of the dairy industry.

Orbitocranial complications of acute sinusitis in children.

BACKGROUND: Orbitocranial complications (OCCs) of sinusitis are uncommon but potentially life threatening. OCCs carry high morbidity, mortality, and significant long-term sequelae. Late recognition leads to even worse outcomes. OBJECTIVE: To present four case reports showing that aggressive management of complications of sinusitis-like OCC decreases long-term sequelae and mortality in pediatric patients. CASE REPORTS: Four pediatric patients diagnosed with OCC were treated at our institution from April 2012 to March 2013. Three were boys and one was a girl; ages ranged from 4-14 years. Magnetic resonance imaging and computed tomography were the most useful imaging modalities. All patients received broad-spectrum antibiotics. Additional interventions consisted of endoscopic sinus surgery, subdural empyema drainage, and orbital decompression. CONCLUSION: The difficult complications of acute sinusitis in the pediatric age group should be anticipated, recognized early, and aggressively managed to prevent morbidity and a fatal outcome.