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1.
Mol Ther ; 2023 Jan 28.
Article in English | MEDLINE | ID: mdl-36710491

ABSTRACT

Chronic pain remains a significant burden worldwide while treatments are often limited by safety or efficacy. The decarboxylated form of L-arginine, agmatine, antagonizes N-methyl-D-aspartate receptors, inhibits nitric oxide synthase, and reverses behavioral neuroplasticity. We hypothesized that expressing the proposed synthetic enzyme for agmatine in the sensory pathway could reduce chronic pain without motor deficits. Intrathecal delivery of an adeno-associated viral vector carrying the gene for arginine decarboxylase prevented the development of chronic neuropathic pain as induced by spared nerve injury in mice and rats and persistently reversed established hypersensitivity 266 days post-injury. Spinal long-term potentiation was inhibited by both exogenous agmatine and AAV-hADC vector pre-treatment but was enhanced in rats treated with anti-agmatine immunoneutralizing antibodies. These data suggest that endogenous agmatine modulates the neuroplasticity associated with chronic pain. Development of approaches to access this inhibitory control of neuroplasticity associated with chronic pain may yield important non-opioid pain-relieving options.

2.
Mol Genet Metab Rep ; 34: 100956, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36704405

ABSTRACT

Hunter syndrome is a rare x-linked recessive genetic disorder that affects lysosomal metabolism due to deficiency of iduronate-2-sulfatase (IDS), with subsequent accumulation of glycosaminoglycans heparan and dermatan sulfates (GAG). Enzyme replacement therapy is the only FDA-approved remedy and is an expensive life-time treatment that alleviates some symptoms of the disease without neurocognitive benefit. We previously reported successful treatment in a mouse model of mucopolysaccharidosis type II (MPS II) using adeno-associated viral vector serotype 9 encoding human IDS (AAV9.hIDS) via intracerebroventricular injection. As a less invasive and more straightforward procedure, here we report intravenously administered AAV9.hIDS in a mouse model of MPS II. In animals administered 1.5 × 1012 vg of AAV9.hIDS at 2 months of age, we observed supraphysiological levels of IDS enzyme activity in the circulation (up to 9100-fold higher than wild-type), in the tested peripheral organs (up to 560-fold higher than wild-type), but only 4% to 50% of wild type levels in the CNS. GAG levels were normalized on both sides of the blood-brain-barrier (BBB) in most of tissues tested. Despite low levels of the IDS observed in the CNS, this treatment prevented neurocognitive decline as shown by testing in the Barnes maze and by fear conditioning. This study demonstrates that a single dose of IV-administered AAV9.hIDS may be an effective and non-invasive procedure to treat MPS II that benefits both sides of the BBB, with implications for potential use of IV-administered AAV9 for other neuronopathic lysosomal diseases.

3.
Hum Gene Ther ; 34(1-2): 8-18, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36541357

ABSTRACT

The mucopolysaccharidoses (MPS) are a group of recessively inherited conditions caused by deficiency of lysosomal enzymes essential to the catabolism of glycosaminoglycans (GAG). MPS I is caused by deficiency of the lysosomal enzyme alpha-L-iduronidase (IDUA), while MPS II is caused by a lack of iduronate-2-sulfatase (IDS). Lack of these enzymes leads to early mortality and morbidity, often including neurological deficits. Enzyme replacement therapy has markedly improved the quality of life for MPS I and MPS II affected individuals but is not effective in addressing neurologic manifestations. For MPS I, hematopoietic stem cell transplant has shown effectiveness in mitigating the progression of neurologic disease when carried out in early in life, but neurologic function is not restored in patients transplanted later in life. For both MPS I and II, gene therapy has been shown to prevent neurologic deficits in affected mice when administered early, but the effectiveness of treatment after the onset of neurologic disease manifestations has not been characterized. To test if neurocognitive function can be recovered in older animals, human IDUA or IDS-encoding AAV9 vector was administered by intracerebroventricular injection into MPS I and MPS II mice, respectively, after the development of neurologic deficit. Vector sequences were distributed throughout the brains of treated animals, associated with high levels of enzyme activity and normalized GAG storage. Two months after vector infusion, treated mice exhibited spatial navigation and learning skills that were normalized, that is, indistinguishable from those of normal unaffected mice, and significantly improved compared to untreated, affected animals. We conclude that cognitive function was restored by AAV9-mediated, central nervous system (CNS)-directed gene transfer in the murine models of MPS I and MPS II, suggesting that gene transfer may result in neurodevelopment improvements in severe MPS I and MPS II when carried out after the onset of cognitive decline.


Subject(s)
Cognitive Dysfunction , Iduronate Sulfatase , Mucopolysaccharidosis II , Mucopolysaccharidosis I , Nervous System Diseases , Humans , Animals , Mice , Aged , Quality of Life , Mucopolysaccharidosis II/genetics , Mucopolysaccharidosis II/therapy , Mucopolysaccharidosis I/genetics , Mucopolysaccharidosis I/therapy , Central Nervous System/metabolism , Iduronidase/genetics , Iduronidase/metabolism , Iduronate Sulfatase/genetics , Cognitive Dysfunction/metabolism , Glycosaminoglycans/metabolism , Disease Models, Animal
4.
Hum Gene Ther ; 2022 Nov 23.
Article in English | MEDLINE | ID: mdl-36226412

ABSTRACT

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is an X-linked recessive lysosomal disease caused by deficiency of iduronate-2-sulfatase (IDS). The absence of IDS results in the accumulation of the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate. Currently, the only approved treatment option for MPS II is enzyme replacement therapy (ERT), Elaprase. However, ERT is demanding for the patient and does not ameliorate neurological manifestations of the disease. Using an IDS-deficient mouse model that phenocopies the human disease, we evaluated hematopoietic stem and progenitor cells (HSPCs) transduced with a lentiviral vector (LVV) carrying a codon-optimized human IDS coding sequence regulated by a ubiquitous MNDU3 promoter (MNDU3-IDS). Mice treated with MNDU3-IDS LVV-transduced cells showed supraphysiological levels of IDS enzyme activity in plasma, peripheral blood mononuclear cells, and in most analyzed tissues. These enzyme levels were sufficient to normalize GAG storage in analyzed tissues. Importantly, IDS levels in the brains of MNDU3-IDS-engrafted animals were restored to 10-20% than that of wild-type mice, sufficient to normalize GAG content and prevent emergence of cognitive deficit as evaluated by neurobehavioral testing. These results demonstrate the potential effectiveness of ex vivo MNDU3-IDS LVV-transduced HSPCs for treatment of MPS II.

5.
J Neonatal Perinatal Med ; 2022 May 16.
Article in English | MEDLINE | ID: mdl-35599502

ABSTRACT

Optimal fluid management of preterm babies with suspected or confirmed diagnosis of patent ductus arteriosus (PDA) is frequently challenging for neonatal care physician because of paucity of clinical trials. There is wide variation in practice across neonatal units, resulting in significant impact on outcomes in Extremely Low Birth Weight (ELBW) babies with hemodynamically significant PDA. A delicate balance is required in fluid management to reduce mortality and morbidity in this population. The purpose of this review is to lay out the current understanding about fluid and electrolyte management in ELBW babies with hemodynamically significant PDA and highlight areas for future research.

6.
Front Mol Neurosci ; 14: 618360, 2021.
Article in English | MEDLINE | ID: mdl-34040503

ABSTRACT

Mucopolysaccharidosis type I (MPS I) is an inherited metabolic disorder caused by deficiency of the lysosomal enzyme alpha-L-iduronidase (IDUA). The two current treatments [hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT)], are insufficiently effective in addressing neurologic disease, in part due to the inability of lysosomal enzyme to cross the blood brain barrier. With a goal to more effectively treat neurologic disease, we have investigated the effectiveness of AAV-mediated IDUA gene delivery to the brain using several different routes of administration. Animals were treated by either direct intracerebroventricular (ICV) injection, by intrathecal (IT) infusion into the cerebrospinal fluid, or by intranasal (IN) instillation of AAV9-IDUA vector. AAV9-IDUA was administered to IDUA-deficient mice that were either immunosuppressed with cyclophosphamide (CP), or immunotolerized at birth by weekly injections of human iduronidase. In animals treated by ICV or IT administration, levels of IDUA enzyme ranged from 3- to 1000-fold that of wild type levels in all parts of the microdissected brain. In animals administered vector intranasally, enzyme levels were 100-fold that of wild type in the olfactory bulb, but enzyme expression was close to wild type levels in other parts of the brain. Glycosaminoglycan levels were reduced to normal in ICV and IT treated mice, and in IN treated mice they were normalized in the olfactory bulb, or reduced in other parts of the brain. Immunohistochemical analysis showed extensive IDUA expression in all parts of the brain of ICV treated mice, while IT treated animals showed transduction that was primarily restricted to the hind brain with some sporadic labeling seen in the mid- and fore brain. At 6 months of age, animals were tested for spatial navigation, memory, and neurocognitive function in the Barnes maze; all treated animals were indistinguishable from normal heterozygous control animals, while untreated IDUA deficient animals exhibited significant learning and spatial navigation deficits. We conclude that IT and IN routes are acceptable and alternate routes of administration, respectively, of AAV vector delivery to the brain with effective IDUA expression, while all three routes of administration prevent the emergence of neurocognitive deficiency in a mouse MPS I model.

7.
Int J Infect Dis ; 108: 27-36, 2021 Jul.
Article in English | MEDLINE | ID: mdl-34029705

ABSTRACT

OBJECTIVE: To estimate the burden of active infection and anti-SARS-CoV-2 IgG antibodies in Karnataka, India, and to assess variation across geographical regions and risk groups. METHODS: A cross-sectional survey of 16,416 people covering three risk groups was conducted between 3-16 September 2020 using the state of Karnataka's infrastructure of 290 healthcare facilities across all 30 districts. Participants were further classified into risk subgroups and sampled using stratified sampling. All participants were subjected to simultaneous detection of SARS-CoV-2 IgG using a commercial ELISA kit, SARS-CoV-2 antigen using a rapid antigen detection test (RAT) and reverse transcription-polymerase chain reaction (RT-PCR) for RNA detection. Maximum-likelihood estimation was used for joint estimation of the adjusted IgG, active and total prevalence (either IgG or active or both), while multinomial regression identified predictors. RESULTS: The overall adjusted total prevalence of COVID-19 in Karnataka was 27.7% (95% CI 26.1-29.3), IgG 16.8% (15.5-18.1) and active infection fraction 12.6% (11.5-13.8). The case-to-infection ratio was 1:40 and the infection fatality rate was 0.05%. Influenza-like symptoms or contact with a COVID-19-positive patient were good predictors of active infection. RAT kits had higher sensitivity (68%) in symptomatic people compared with 47% in asymptomatic people. CONCLUSION: This sentinel-based population survey was the first comprehensive survey in India to provide accurate estimates of the COVID-19 burden. The findings provide a reasonable approximation of the population immunity threshold levels. Using existing surveillance platforms coupled with a syndromic approach and sampling framework enabled this model to be replicable.


Subject(s)
COVID-19 , Antibodies, Viral , Cross-Sectional Studies , Humans , Immunoglobulin G , India/epidemiology , Prevalence , SARS-CoV-2
8.
Preprint in English | medRxiv | ID: ppmedrxiv-20243949

ABSTRACT

BackgroundGlobally, the routinely used case-based reporting and IgG serosurveys underestimate the actual prevalence of COVID-19. Simultaneous estimation of IgG antibodies and active SARS-CoV-2 markers can provide a more accurate estimation. MethodsA cross-sectional survey of 16416 people covering all risk groups was done between 3-16 September 2020 using the state of Karnatakas infrastructure of 290 hospitals across all 30 districts. All participants were subjected to simultaneous detection of SARS-CoV-2 IgG using a commercial ELISA kit, SARS-CoV-2 antigen using a rapid antigen detection test (RAT), and reverse transcription-polymerase chain reaction (RT-PCR) for RNA detection. Maximum-likelihood estimation was used for joint estimation of the adjusted IgG, active, and total prevalence, while multinomial regression identified predictors. FindingsThe overall adjusted prevalence of COVID-19 in Karnataka was 27 {middle dot}3% (95% CI: 25 {middle dot}7-28 {middle dot}9), including IgG 16 {middle dot}4% (95% CI: 15 {middle dot}1 - 17 {middle dot}7) and active infection 12 {middle dot}7% (95% CI: 11 {middle dot}5-13 {middle dot}9). The case-to-infection ratio was 1:40, and the infection fatality rate was 0 {middle dot}05%. Influenza-like symptoms or contact with a COVID-19 positive patient are good predictors of active infection. The RAT kits had higher sensitivity (68%) in symptomatic participants compared to 47% in asymptomatic. InterpretationThis is the first comprehensive survey providing accurate estimates of the COVID-19 burden anywhere in the world. Further, our findings provide a reasonable approximation of population immunity threshold levels. Using the RAT kits and following the syndromic approach can be useful in screening and monitoring COVID-19. Leveraging existing surveillance platforms, coupled with appropriate methods and sampling framework, renders our model replicable in other settings.

9.
Mol Genet Metab Rep ; 24: 100604, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32461912

ABSTRACT

Mucopolysaccharidosis type I (MPS I) is an inherited metabolic disorder caused by deficiency of alpha-L-iduronidase (IDUA), resulting in accumulation of heparan and dermatan sulfate glycosaminoglycans (GAGs). Individuals with the most severe form of the disease (Hurler syndrome) suffer from neurodegeneration, intellectual disability, and death by age 10. Current treatments for this disease include allogeneic hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT). However, these treatments do not address CNS manifestations of the disease. In this study we compared the ability of intravenously administered AAV serotypes 9 and rh10 (AAV9 and AAVrh10) for delivery and expression of the IDUA gene in the CNS. Adult C57BL/6 MPS I mice were infused intravenously with either AAV9 or AAVrh10 vector encoding the human IDUA gene. Treated animals demonstrated supraphysiological levels and widespread restoration of IDUA enzyme activity in the plasma and all organs including the CNS. High levels of IDUA enzyme activity were observed in the plasma, brain and spinal cord ranging from 10 to 100-fold higher than heterozygote controls, while levels in peripheral organs were also high, ranging from 1000 to 10,000-fold higher than control animals. In general, levels of IDUA expression were slightly higher in peripheral organs for AAVrh10 administered animals although these differences were not significant except for the lung. Levels of IDUA expression between AAV 9 and rh10 were roughly equivalent in the brain. Urinary and tissue GAGs were significantly reduced starting at 3 weeks after vector infusion, with restoration of normal GAG levels by the end of the study in animals treated with either AAV9 or rh10. These results demonstrate that non-invasive intravenous AAV9 or AAVrh10-mediated IDUA gene therapy is a potentially effective treatment for both systemic and CNS manifestations of MPS I, with implications for the treatment of other metabolic and neurological diseases as well.

10.
Craniomaxillofac Trauma Reconstr ; 11(4): 265-272, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30574269

ABSTRACT

This article aims to analyze the changing Le Fort fracture patterns using computed tomography (CT) scans with three-dimensional (3D) reconstruction. A prospective observational study was conducted on 60 patients with midface trauma, who had reported to MS Ramaiah Group of Hospitals, Bangalore, between January 2015 and October 2016. CT scans using 1.6 mm axial, sagittal, coronal sections were taken and their 3D reconstruction was made. The images were studied and compared with the standard Le Fort lines. The deviations from the classical Le Fort lines were analyzed and recorded. A note was also made of any additional fixation that was required for these deviations. Descriptive analysis was done and the results expressed in numbers and percentages. Study revealed that the most common cause for the midface fractures was found to be road traffic accidents (81.7%) with a male preponderance (88.3%) and peak incidence in 21 to 30 years of age (40%). Among the 60 patients, 18 (30%) patients had fracture patterns similar to the ideal Le Fort lines, 4 (6.6%) had a combination of Le Fort patterns, and 38 (66.3%) patients had deviations seen from the ideal Le Fort lines. Four types of deviations were recorded, namely, D1(60%), D2(5.4%), D3(10.9%), and D4(23.6%). It was observed that D1 and D3 required additional fixation. Majority of the cases presented as a deviation from ideal Le Fort fractures. CT was a valuable tool in the assessment of these fracture patterns. Deviations, if any, could be better analyzed using the 3D reconstruction images. Proper diagnosis and detection of these deviations make the planning for fixation easier. Repetition of these deviations could propose a newer or modified classification system for Le Fort fractures.

11.
J Adv Res ; 9: 87-95, 2018 Jan.
Article in English | MEDLINE | ID: mdl-30046490

ABSTRACT

The freshwater Testudine species have gained importance in recent years, as most of their population is threatened due to exploitation for delicacy and pet trade. In this regard, Lissemys punctata, a freshwater terrapin, predominantly distributed in Asian countries has gained its significance for the study. A pilot study report on mitochondrial markers (Cyt b and D-loop) conducted on L. punctata species from southern Karnataka, India was presented in this investigation. A complete region spanning 1.14 kb and ∼1 kb was amplified by HotStart PCR and sequenced by Sanger sequencing. The Cyt b sequence revealed 85 substitution sites, no indels and 17 parsimony informative sites, whereas D-loop showed 189 variable sites, 51 parsimony informative sites with 5' functional domains TAS, CSB-F, CSBs (1, 2, 3) preceding tandem repeat at 3' end. Current data highlights the intraspecific variations in these target regions and variations validated using suitable evolutionary models points out that the overall point mutations observed in the region are transitions leading to no structural and functional alterations. The mitochondrial data generated uncover the genetic diversity within species and conservationist can utilize the data to estimate the effective population size or for forensic identification of animal or its seizures during unlawful trade activities.

12.
Plant Physiol Biochem ; 124: 10-19, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29324242

ABSTRACT

The temporal expression of the field bean (Dolichos lablab) galactose specific lectin, DLL-II, during germination, post-germination and seed development was evaluated using Native-PAGE followed by activity staining, immunodetection and quantitative Real Time PCR (qPCR). A rapid and steep decline in the polyphenol oxidase (PPO) and hemagglutinating activity during the initial stages of germination, which did not correlate with the slow decline in total protein was observed. During post germination period, PPO and hemagglutination activities were negligible, whereas a rapid resorption of the protein was evident. These results suggest that DLL-II is not a storage protein. The presence of mRNA in the quiescent seed and initial stages of germination are indicative of a very stable mRNA. DLL-II was expressed in high copies during seed development and increased dramatically between 10 and 20 days after flowering (DAF), suggesting a switch over stage in DLL-II expression. Transcript levels reached a maximum at the mature stage of seed development. Among the non-seed tissues examined, root showed the highest level. The high affinity binding to kinetin and indole acetic acid, the key hormones that regulate root development and its vascular differentiation add a new dimension to the physiological role of DLL-II in the seed. This finding, coupled with the PPO and hemagglutinating activity makes DLL-II, truly a multifunctional protein.


Subject(s)
Dolichos/metabolism , Gene Expression Regulation, Plant/physiology , Germination/physiology , Plant Lectins/biosynthesis , Seeds/metabolism , Gene Expression Profiling
13.
J Maxillofac Oral Surg ; 16(4): 471-478, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29038630

ABSTRACT

PURPOSE: Bone loss following extraction is maximum in horizontal dimension. Height is also reduced which is pronounced on the buccal aspect. Various surgical procedures are available to correct the bone volume viz. GBR, onlay bone grafting, alveolar distraction and sandwich osteotomy. Sandwich osteotomy has been found to increase the vertical alveolar bone height successfully. OBJECTIVES: The objective of the study was to assess the effect of alveolar segmental sandwich osteotomy on alveolar height and crestal width. MATERIALS AND METHODOLOGY: A prospective study was undertaken from December 2012 to August 2014. Seven patients with 12 implant sites with a mean age of 36 years were recruited. All seven patients with 12 implant sites underwent alveolar segmental sandwich osteotomy and interpositional bone grafting. Alveolar bone height was assessed radiographically preoperatively, immediate post-op, and at 3 months post-op. Alveolar bone width was assessed radiographically preoperatively and at 3 months post-op. Statistical significance was inferred at p < 0.05. RESULTS: The mean vertical augmentation at immediate post-op was 6.58 mm (p = 0.001). The vertical augmentation that was achieved 3 months post-op was a mean of 3.75 mm which was statistically significant (p = 0.004). The change in alveolar height from immediate post-op to 3 month post-op was a mean 1.69 mm. The mean change in alveolar crestal width at 3 months was a mean of -0.29 mm (p = 0.57). CONCLUSION: Sandwich osteotomy can be used as an alternative technique to increase alveolar bone height prior to implant placement. Moderate alveolar deficiency can be predictably corrected by this technique.

14.
Hum Gene Ther ; 28(7): 576-587, 2017 07.
Article in English | MEDLINE | ID: mdl-28462595

ABSTRACT

Mucopolysaccharidosis type I (MPS I) is a progressive, multi-systemic, inherited metabolic disease caused by deficiency of α-L-iduronidase (IDUA). Current treatments for this disease are ineffective in treating central nervous system (CNS) disease due to the inability of lysosomal enzymes to traverse the blood-brain barrier. A noninvasive and effective approach was taken in the treatment of CNS disease by intranasal administration of an IDUA-encoding adeno-associated virus serotype 9 (AAV9) vector. Adult IDUA-deficient mice aged 3 months were instilled intranasally with AAV9-IDUA vector. Animals sacrificed 5 months post instillation exhibited IDUA enzyme activity levels that were up to 50-fold that of wild-type mice in the olfactory bulb, with wild-type levels of enzyme restored in all other parts of the brain. Intranasal treatment with AAV9-IDUA also resulted in the reduction of tissue glycosaminoglycan storage materials in the brain. There was strong IDUA immunofluorescence staining of tissue sections observed in the nasal epithelium and olfactory bulb, but there was no evidence of the presence of transduced cells in other portions of the brain. This indicates that reduction of storage materials most likely occurred as a result of enzyme diffusion from the olfactory bulb and the nasal epithelium into deeper areas of the brain. At 8 months of age, neurocognitive testing using the Barnes maze to assess spatial navigation demonstrated that treated IDUA-deficient mice were no different from normal control animals, while untreated IDUA-deficient mice exhibited significant learning and navigation deficits. This novel, noninvasive strategy for intranasal AAV9-IDUA instillation could potentially be used to treat CNS manifestations of human MPS I.


Subject(s)
Central Nervous System/metabolism , Dependovirus/metabolism , Gene Transfer Techniques , Iduronidase/genetics , Iduronidase/therapeutic use , Mucopolysaccharidosis I/pathology , Mucopolysaccharidosis I/therapy , Nervous System Diseases/prevention & control , Administration, Intranasal , Animals , Central Nervous System/pathology , Central Nervous System/physiopathology , Cognition , Green Fluorescent Proteins/metabolism , Humans , Iduronidase/metabolism , Lysosomes/metabolism , Mice , Mucopolysaccharidosis I/physiopathology , Nasal Mucosa/metabolism , Nasal Mucosa/pathology , Nervous System Diseases/pathology , Nervous System Diseases/physiopathology , Neurons/metabolism , Olfactory Bulb/metabolism , Olfactory Bulb/pathology , Transduction, Genetic
15.
Int J Biomater ; 2015: 165428, 2015.
Article in English | MEDLINE | ID: mdl-26649041

ABSTRACT

Wound closure is a part of any surgical procedure and the objective of laceration repair or incision closure is to approximate the edges of a wound so that natural healing process may occur. Over the years new biomaterials have been discovered as an alternate to conventional suture materials. Cyanoacrylate bioadhesives are one among them. They carry the advantages of rapid application, patient comfort, resistance to infection, hemostatic properties, and no suture removal anxiety. Hence this study was undertaken to study the effect of long chain cyanoacrylate as an adhesive for intraoral wound closure and also to explore its hemostatic and antibacterial effects. Isoamyl-2-cyanoacrylate (AMCRYLATE) was used as the adhesive in the study. In conclusion isoamyl cyanoacrylate can be used for intraoral wound closure, as an alternative to sutures for gluing the mucoperiosteum to bone, for example, after impaction removal, periapical surgeries, and cleft repair. Its hemostatic and antibacterial activity has to be further evaluated.

16.
J Maxillofac Oral Surg ; 14(Suppl 1): 87-92, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25838677

ABSTRACT

Osteosarcomas are highly malignant bone tumours. Its appearance in craniofacial bones is a rare entity and accounts for only 1% of all head and neck malignancies. We present an uncommon case report of a 42 year old male patient with osteosarcoma of left maxilla, which was successfully excised under general anesthesia. The patient reported to us with a history of pain, swelling, pus discharge and tooth extraction, which led to the differential diagnosis of suppurative osteomyelitis, dentoalveolar abscess, benign odontogenic tumour, an infected cyst etc. Histopathological examination of incisional biopsy was reported as chondromyxoid fibroma which is a rare benign tumour. However the excisional biopsy specimen was reported as osteosarcoma of maxilla. The clinical presentation, diagnostic challenges and its therapeutic approach are addressed. This case serves to emphasize the need to recognize osteosarcoma when it presents in unexpected locations, especially because of its rarity.

17.
Arch Biochem Biophys ; 566: 15-25, 2015 Jan 15.
Article in English | MEDLINE | ID: mdl-25527163

ABSTRACT

Legume Bowman-Birk inhibitors (BBIs) that inhibit mammalian proteases exist as dimers in solution. The structural basis governing dimerization of HGI-III (horsegram seed BBI) was investigated. An intra-monomer salt bridge (D76-K71) stabilizes an atypical hook-like conformation at the C-terminus. We postulate that this hook, positions D75 to enable an inter-monomer salt-bridge D75(a)-K24(b), which results in dimerization. We verify this by K71A and D76A mutations of HGI-III. The mutants were both monomers, likely due to destabilization of the C-terminal hook. Dimerization was sustained in a double mutant K71D/D76K that was anticipated to form a similar hook critical for dimerization. Conversely, K24(b) that interacts with D75(a) of the loop is the specificity determining residue that interacts with trypsin to inhibit its activity. The inter-monomer salt bridge D75(a)-K24(b) must be disrupted for the inhibition of trypsin, requiring HGI-III to transition into a monomer. Size exclusion studies and a model of HGI-III-trypsin complex support this notion. Interestingly, isoforms of the inhibitor present in germinated seeds (HGGIs) are monomers; and most strikingly, the C-termini of these inhibitors are truncated with the loss the C-terminal hook critical for dimerization. The tendency of HGI-III to self-associate seems to relate to its physiological function of a storage protein.


Subject(s)
Protease Inhibitors/chemistry , Trypsin/chemistry , Animals , Binding Sites , Cattle , Escherichia coli/genetics , Escherichia coli/metabolism , Fabaceae/chemistry , Gene Expression , Molecular Dynamics Simulation , Mutation , Protease Inhibitors/isolation & purification , Protein Binding , Protein Multimerization , Protein Structure, Tertiary , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/isolation & purification , Structure-Activity Relationship , Thermodynamics
18.
J Investig Clin Dent ; 2(2): 148-50, 2011 May.
Article in English | MEDLINE | ID: mdl-25426609

ABSTRACT

Toothbrush, the innocent cleaning aid, has been reported to cause life threatening oropharyngeal injuries in pediatric literature. A case of a 4-year-old child reporting to an emergency department with a toothbrush impaled in her mouth while her father was forcefully brushing her teeth is reported here. Hemostasis was achieved by digital pressure and the impaled toothbrush was removed surgically. Uneventful recovery was noted. Parental anxiety and a lack of patient cooperation was noted. Such impaled objects fractured and left behind have been reported to cause serious space infections and mediastinitus. Advising parents to be careful with their children's toothbrush is important as prevention of injuries from such commonly used object could be easily achieved.


Subject(s)
Foreign Bodies/etiology , Mouth Mucosa/injuries , Toothbrushing/instrumentation , Wounds, Penetrating/etiology , Child, Preschool , Female , Humans , Oral Hemorrhage/etiology , Toothbrushing/adverse effects
19.
PLoS One ; 9(10): e107565, 2014.
Article in English | MEDLINE | ID: mdl-25299597

ABSTRACT

Curcumin and capsaicin are dietary xenobiotics with well-documented anti-inflammatory properties. Previously, the beneficial effect of these spice principles in lowering chronic inflammation was demonstrated using a rat experimental model for arthritis. The extent of lowering of arthritic index by the spice principles was associated with a significant shift in macrophage function favoring the reduction of pro-inflammatory molecules such as reactive oxygen species and production and release of anti-inflammatory metabolites of arachidonic acid. Beyond the cellular effects on macrophage function, oral administration of curcumin and capsaicin caused alterations in serum protein profiles of rats injected with adjuvant to develop arthritis. Specifically, a 72 kDa acidic glycoprotein, GpA72, which was elevated in pre-arthritic rats, was significantly lowered by feeding either curcumin or capsaicin to the rats. Employing the tandem mass spectrometric approach for direct sequencing of peptides, here we report the identification of GpA72 as T-kininogen I also known as Thiostatin. Since T-kininogen I is an early acute-phase protein, we additionally tested the efficiency of curcumin and capsaicin to mediate the inflammatory response in an acute phase model. The results demonstrate that curcumin and capsaicin lower the acute-phase inflammatory response, the molecular mechanism for which is, in part, mediated by pathways associated with the lowering of T-kininogen I.


Subject(s)
Acute-Phase Proteins/metabolism , Capsaicin/pharmacology , Curcumin/pharmacology , Inflammation/drug therapy , Kininogens/metabolism , Animals , Arachidonic Acid/metabolism , Diet/methods , Disease Models, Animal , Glycoproteins/metabolism , Inflammation/metabolism , Male , Mass Spectrometry/methods , Rats , Rats, Wistar , Reactive Oxygen Species/metabolism
20.
Front Neuroanat ; 8: 66, 2014.
Article in English | MEDLINE | ID: mdl-25147505

ABSTRACT

We report the pattern of transgene expression across brain regions after intrathecal delivery of adeno-associated virus serotype 5 (AAV5). Labeling in hindbrain appeared to be primarily neuronal, and was detected in sensory nuclei of medulla, pontine nuclei, and all layers of cerebellar cortex. Expression in midbrain was minimal, and generally limited to isolated neurons and astrocytes in the cerebral peduncles. GFP immunoreactivity (-ir) in thalamus was most prominent in medial geniculate nucleus, and otherwise limited to posterior nuclei of the dorsal and lateral margins. Labeling was also observed in neurons and astrocytes of the hippocampal formation and amygdaloid complex. In the hippocampal formation, GFP-ir was found in neuronal cell bodies of the rostral ventral portion, but was largely restricted to fiber-like staining in the molecular layer of dentate gyrus and stratum lacunosum-moleculare of the rostral dorsal region. GFP-ir was seen in neurons and astroglia throughout caudal cortex, whereas in rostral regions of neocortex it was limited to isolated neurons and non-neuronal cells. Labeling was also present in olfactory bulb. These results demonstrate that intrathecal delivery of AAV5 vector leads to transgene expression in discrete CNS regions throughout the rostro-caudal extent of the neuraxis. A caudal-to-rostral gradient of decreasing GFP-ir was present in choroid plexus and Purkinje cells, suggesting that spread of virus through cerebrospinal fluid plays a role in the resulting transduction pattern. Other factors contributing to the observed expression pattern likely include variations in cell-surface receptors and inter-parenchymal space.

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