Percutaneous elevation of proximal tibia depressed fractures using modified new instrument.

Proximal tibia depression fracture often occur isolated or in conjunction with complex fracture presentations and elevation of such depression is required to retard arthritis in long term. Conventional open reduction by sub meniscal approach has many percutaneous alternatives from arthroscopy assisted reduction to balloon tibioplasty. Few authors even reported usage of PCL jig and percutaneous pins to elevate, while the primary author has previously described an instrument to elevate the depressed fragment percutaneously. With the shortcomings of the same instrument, authors have designed modifications in the same to address anterior and posterior extensions of depression without widening the metaphyseal window. In this article, we describe the size and concept of the modified design and its efficacy to address depression injuries.

Accuracy of three different customized lingual orthodontic appliance systems in achieving predicted results on maxillary anterior teeth: A Retrospective Cohort Study.

OBJECTIVE: To comparatively evaluate the ability of three different customized lingual appliance systems in achieving predicted results with respect to the mesiodistal crown tip, labiolingual crown inclination, in-out position of Maxillary permanent anterior teeth, and Maxillary arch form. METHODS: Three commercial houses: Incognito, iLingual 3D, and Lingual matrix were analysed in this study. The final sample size consisted of 42 cases. Fourteen digital prediction and posttreatment models of the maxillary arch were provided by three orthodontic offices each using a different system. Discrepancies between the prediction and posttreatment model in mesiodistal tip, labiolingual inclination, in-out position of anterior teeth, and arch form were analyzed. RESULTS: Incognito displayed the highest accuracy in all parameters except for in-out positioning. Lingual Matrix showed greater precision in achieving planned mesiodistal positions than labiolingual inclination while it was just the opposite for iLingual 3D. All three systems proved to be clinically reliable in achieving the predicted in-out positions of permanent Maxillary anterior teeth. CONCLUSION: These systems were considerably accurate in achieving planned treatment goals with minute deviations from the predicted value.

Synapse loss and progress of Alzheimer's disease -A network model.

We present observational evidence from studies on primary cortical cultures from AD transgenic mice, APPSwe/PS1ΔE9 (APP/PS1) mice, for significant decrease in total spine density at DIV-15 and onward. This indicates reduction in potential healthy synapses and strength of connections among neurons. Based on this, a network model of neurons is developed, that explains the consequent loss of coordinated activity and transmission efficiency among neurons that manifests over time. The critical time when structural connectivity in the brain undergoes a phase-transition, from initial robustness to irreparable breakdown, is estimated from this model. We also show how the global efficiency of signal transmission in the network decreases over time. Moreover, the number of multiple paths of high efficiency decreases rapidly as the disease progresses, indicating loss of structural plasticity and inefficiency in choosing alternate paths or desired paths for any pattern of activity. Thus loss of spines caused by ß-Amyloid (Aß) peptide results in disintegration of the neuronal network over time with consequent cognitive dysfunctions in Alzheimer's Disease (AD).

Bilateral Xanthomas of Tendoachilles in A Patient of Cerebrotendinous Xanthomatosis - A Rare Case Report and Review of Literature.

INTRODUCTION: Cerebrotendinous xanthomatosis is a very rare disorder of cholesterol metabolism with autosomal recessive inheritance. It can present to the out-patient clinics of orthopaedic department with painful and swollen tendoachilles on one or both sides. It is commonly mistaken for a local disorder and excision may be recommended without realizing its systemic nature. CASE REPORT: We find such a rare and perplexing case in a 19 year boy who presented with painful swellings of both achilles tendons causing signification limitation of walking distance. This was initially interpreted as a localized benign disorder and was offered surgical treatment. Excision of the swollen achilles tendon followed by reconstruction using peroneus brevis tendon was done, first on the more symptomatic right side. The diagnosis of cerebrotendinous xanthomatosis was made retrospectively after histopathological as well as biochemical analyses and appropriate medical therapy was initiated. CONCLUSION: Cerebrotendinous xanthomatosis commonly manifests with bilateral swollen tendoachilles, which is actually a part of systemic pathology with poor prognosis. High suspicion is warranted and surgical excision should not be the primary option without the confirmation of the cause. A detailed history with clinical assessment followed by the laboratory investigations certainly leads to the correct diagnosis. The treatment is more of medical means and appropriate medication can even retard the disease progression, if initiated early in life.

Biological Reconstruction of the Knee Joint in a Case of Giant Cell Tumor of the Tibia of 15yrs Followup- A Case Report.

INTRODUCTION: A 40 year old male patient presented to us with Giant Cell Tumor of upper end of Tibia involving both condyles with a breach in the posterior cortex. In this case report we tried to retain the joint function by biological reconstruction using the Patella after the wide excision of the tumor mass. CASE REPORT: A radical excision of the upper end of the Tibia was done. The Patella was used as an articular surface supported by ipsilateral Fibula as struts, thus the joint was reconstructured biologically. The case was followed for 15years. CONCLUSION: The tumor was excised in toto, the knee joint was restored by the Patella and the Fibular struts. The results were discussed in details.

Outcome of locking compression plates in humeral shaft nonunions.

BACKGROUND: Nonunion of diaphyseal fractures of the humerus are frequently seen in clinical practice (incidence of up to 15% in certain studies) and osteosynthesis using dynamic compression plates, intra medullary nails and Ilizarov fixators have been reported previously. Locking compression plates (LCP) are useful in the presence of disuse osteoporosis, segmental bone loss and cortical defects that preclude strong fixation. We report a prospective followup study of the outcome of the use of LCP for humeral nonunion following failed internal fixation in which implants other than LCP had been used. MATERIALS AND METHODS: Twenty four patients with nonunion of humeral shaft fractures following failed internal fixation were included in the study. The mean followup period was 3.4 years (range: 2.4 to 5.7 years) and the minimum followup period was 2 years. Mean age of the patients was 41.04 years (range: 24 to 57 years). All 24 patients underwent osteosynthesis using LCP and autologous bone grafting (cortico-cancellous iliac crest graft combined with or without fibular strut graft). Main outcome measurements included radiographic assessment of fracture union and pre and postoperative functional evaluation using the modified Constant and Murley scoring system. RESULTS: 23 out of 24 fractures united following osteosynthesis. Average time to union was 16 weeks (range: 10 to 28 weeks). Complications included delayed union (n = 2), transient radial nerve palsy (n = 2) and persistent nonunion (n = 1). Functional evaluation using the Constant and Murley score showed excellent results in 11, good in 10, fair in two and poor outcome in one patient. CONCLUSIONS: Locking compression plating and cancellous bone grafting is a reliable option for achieving union in humeral diaphyseal nonunion with failed previous internal fixation and results in good functional outcome in patients with higher physiological demands.

A New Device for Percutaneous Elevation of the Depressed Fractures of Tibial Condyles.

INTRODUCTION: Monocondylar tibia plateau fractures with non-comminuted fragments can be treated using percutaneous screws. Currently indirect methods of reduction are used and thus the technique is limited to fragments with less than 5 mm depression. The first author has designed a device for direct elevation and reduction of the fragments thus potentially expanding the indications of percutaneous screws to fragments with >5mm depression. TECHNICAL NOTE: A total of ten cases were treated by this method of percutaneous elevation of the depressed fractures of lateral condyles of the Tibia using this device. Device was inserted through a bony window on the anteromedial surface of tibia. The inner piston of the device in slowly hammered inside thus elevating the depressed fragment. Elevation of fragment could be achieved in all the cases. The fractures were fixed with cancellous screws applied percutaneously. There were no cases with loss of fixation or subsidence of the fragment. All cases achieved radiological union and have good knee function at follow up. CONCLUSION: The new device is able to elevate unicondylar tibia plateau fragments with no subsidence or loss of fixation in our series. A longer follow up in a larger sample will be needed to establish the technique.

Activation of p38 MAPK in the substantia nigra leads to nuclear translocation of NF-kappaB in MPTP-treated mice: implication in Parkinson's disease.

Activation and translocation of the transcription factor nuclear factor kappa B (NF-kappaB) from cytoplasm to the nucleus has been reported in models of Parkinson's disease (PD). Our focus was to discern the upstream events which ultimately lead to NF-kappaB nuclear translocation using animal model of PD. We demonstrate that p38 activation results in downstream phosphorylation of NF-kappaB and accumulation of p65 subunit of NF-kappaB selectively in ventral midbrain but not in striatum. Treatment with p38 inhibitor, SB239063, prevented downstream phosphorylation of IkappaB alpha and p65 translocation to the nucleus in the ventral midbrain. Phosphorylation of anti-apoptotic Bcl2, an NF-kappaB target gene by p38 to inactive pBcl2ser87 was also attenuated by SB239063. Increased staining of p65 in the nuclei of cells in the substantia nigra but not in the ventral tegmental area of MPTP-treated mice further suggests a role for NF-kappaB in PD. In agreement with the above, sustained caspase activation is seen in the ventral midbrain but not in striatum. We demonstrate the region specific p38-mediated activation of NF-kappaB following MPTP treatment demonstrating the role of p38/NF-kappaB signaling in the pathogenesis and progression of the disease. Selective inhibitors of p38 may therefore, help preserve the surviving neurons in PD and slow down the disease progression.

Unique cytochromes P450 in human brain: implication in disease pathogenesis.

Cytochromes P450 is a family of heme proteins that metabolize xenobiotics including drugs. Unique human brain cytochrome P450 enzymes metabolize xenobiotics including drugs to active/inactive metabolites through biotransformation pathways that are different from the well-characterized ones in liver. We have identified an alternate spliced functional transcript of CYP2D7 containing partial inclusion of intron 6 in human brain but not in liver or kidney from the same individual. Genotyping revealed the presence of the frame-shift mutation 138delT only in those subjects who expressed the brain variant CYP2D7, which metabolizes codeine exclusively to morphine unlike hepatic CYP2D6 that metabolizes codeine to nor codeine and morphine. CYP1A1 bioactivates polycyclic aromatic hydrocarbons to reactive DNA binding metabolites and initiates carcinogenesis. We have identified a unique splice variant of CYP1A1 having deletion of 87 bp of exon 6 which is present in human brain but not in liver of the same individual. We present evidence for the existence of biotransformation pathways in human brain that are dissimilar from known pathways in liver. Identification and characterization of novel CNS-specific P450 enzymes generated by alternate splicing of known genes or as yet unidentified genes may help predict consequences of exposure to xenobiotics including pesticides in the brain.

Differential metabolism of alprazolam by liver and brain cytochrome (P4503A) to pharmacologically active metabolite.

Cytochrome P450 (P450) is a superfamily of enzymes which mediates metabolism of xenobiotics including drugs. Alprazolam, an anti-anxiety agent, is metabolized in rat and human liver by P4503A1 and P4503A4 respectively, to 4-hydroxy alprazolam (4-OHALP, pharmacologically less active) and alpha-hydroxy alprazolam (alpha-OHALP, pharmacologically more active). We examined P450 mediated metabolism of alprazolam by rat and human brain microsomes and observed that the relative amount of alpha-OHALP formed in brain was higher than liver. This biotransformation was mediated by a P450 isoform belonging to P4503A subfamily, which is constitutively expressed in neuronal cells in rat and human brain. The formation of larger amounts of alpha-OHALP in neurons points to local modulation of pharmacological activity in brain, at the site of action of the anti-anxiety drug. Since hydroxy metabolites of alprazolam are hydrophilic and not easily cleared through blood-CSF barrier, alpha-OHALP would potentially have a longer half-life in brain.

Protein thiol oxidation by haloperidol results in inhibition of mitochondrial complex I in brain regions: comparison with atypical antipsychotics.

Usage of 'typical' but not 'atypical' antipsychotic drugs is associated with severe side effects involving extrapyramidal tract (EPT). Single dose of haloperidol caused selective inhibition of complex I in frontal cortex, striatum and midbrain (41 and 26%, respectively) which was abolished by pretreatment of mice with thiol antioxidants, alpha-lipoic acid and glutathione isopropyl ester, and reversed, in vitro, by disulfide reductant, dithiothreitol. Prolonged administration of haloperidol to mice resulted in complex I loss in frontal cortex, hippocampus, striatum and midbrain, while chronic dosing with clozapine affected only hippocampus and frontal cortex. Risperidone caused complex I loss in frontal cortex, hippocampus and striatum but not in midbrain from which extrapyramidal tract emanates. Inhibition of the electron transport chain component, complex I by haloperidol is mediated through oxidation of essential thiol groups to disulfides, in vivo. Further, loss of complex I in extrapyramidal brain regions by anti-psychotics correlated with their known propensity to generate side-effects involving extra-pyramidal tract.

Characterization and localization of cytochrome P450 mediated metabolism of MPTP to nor-MPTP in mouse brain: relevance to Parkinson's disease.

1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) is a dopaminergic toxin which produces Parkinson's disease-like symptoms in primates and dopaminergic cell loss in mice. MPTP is bioactivated through monoamine oxidase to MPP(+) and detoxified by cytochrome P450 to nor-MPTP. We have examined metabolisms of MPTP to nor-MPTP by mouse brain microsomes and compared it with corresponding activity in liver. In brain, but not in liver, this biotransformation was completely abolished by quinidine, an inhibitor of P4502D. Northern blotting experiments demonstrated constitutive expression of cytochrome P4502D mRNA predominantly in neuronal cells within the cortex, hippocampus, thalamus, Purkinje and granule cell layers of the cerebellum and in the reticular neurons of midbrain. Striatal neurons were sparsely stained indicating a relative paucity of expression. These studies demonstrate for the first time that detoxification of MPTP to nor-MPTP occurs in mouse brain through cytochrome P4502D which is primarily localized in neuronal cells. Cytochrome P4502D6 is known to exhibit genetic polymorphism in humans, and a defect in this isoform could potentially lead to decreased detoxification of neurotoxins in certain neuronal sub-population, which in turn may have implications in pathogenesis of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced complex I inhibition is reversed by disulfide reductant, dithiothreitol in mouse brain.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes dopaminergic cell loss in mice by inhibiting mitochondrial complex-I through its metabolite, MPP+, which binds to specific sites on complex-I. Since complex-I is highly vulnerable to oxidative stress, we have examined the nature of inhibition of complex-I by MPTP. Both MPTP and MPP+ inhibited complex-I activity, in vitro, in mouse brain slices, which was abolished by prior exposure of brain slices to glutathione. Further, the inhibited complex-I activity rebounded after incubation with disulfide reductant, dithiothreitol. Systemic administration of MPTP to mice resulted in inhibition of complex-I in striatum and midbrain which was also reversed by treatment of mitochondria with dithiothreitol. Inhibition of complex I activity by MPTP may be due to oxidation of thiol group(s) in complex-I, which may be reversed by thiol antioxidants.

Multiple forms of cytochrome P450 and associated monooxygenase activities in human brain mitochondria.

We have investigated cytochrome P450 (P450) and associated monooxygenase activities in human brain mitochondria isolated from eight regions of four human brain samples obtained at autopsy. P450-associated monooxygenase activities including aminopyrine N-demethylase (APD), 7-ethoxycoumarin O-deethylase (ECD), p-nitrophenol hydroxylase (PNPH), and N-nitrosodimethylamine N-demethylase (ND-MAD) were detectable in the mitochondria from human brain regions. Immunoblot experiments using antisera to purified rat liver microsomal P450, namely P4502B1/2, P4501A1/2, and P4502E1, revealed immunoreactive bands in isolated mitochondria from different regions of the human brain. The antibody to P4502B1/2 and P4501A1/2 inhibited the human brain mitochondrial APD and ECD activities, respectively. The addition of antiserum to microsomal NADPH cytochrome P450 reductase did not affect the mitochondrial P450-associated monooxygenase activities, although it completely inhibited the corresponding activities in brain microsomes. Overall, the present study demonstrates, in human brain mitochondria, the presence of multiple forms of P450 belonging to the 1A, 2B, and 2E subfamilies that are involved in xenobiotic metabolism.

Cytochrome P4502E (CYP2E) in brain: constitutive expression, induction by ethanol and localization by fluorescence in situ hybridization.

Cytochrome P4502E (P4502E), the major ethanol-inducible P450 metabolizes ethanol to acetaldehyde and bioactivates procarcinogens to ultimate carcinogens. Metabolism of ethanol to acetaldehyde in the brain could be deleterious since it can react with cytoskeletal proteins, forming adducts. In the present study, rats were administered ethanol chronically to evaluate its effect on chlorzoxazone hydroxylation in rat brain regions. Chlorzoxazone hydroxylation in brains from the treated rats was induced in hippocampus and cortex, downregulated in brainstem, and unchanged in cerebellum, striatum, and thalamus. The presence of functionally active P4502E was also seen in human brain regions obtained at autopsy from traffic accident victims. Northern blot analysis of rat and human brain poly(A)(+) RNA hybridized with cDNA to rat CYP2E1 revealed the constitutive presence of a corresponding transcript in rat and human brain. Localization of CYP2E by fluorescence in situ hybridization demonstrated the constitutive expression of CYP2E preferentially in the neuronal cells in rat and human brain. CYP2E expression was seen in neurons within the cerebral cortex, Purkinje and granule cell layers of cerebellum, granule cell layer of dentate gyrus, and pyramidal neurons of CA1, CA2, and CA3 subfields of hippocampus in both rat and human brain. The present studies demonstrate constitutive expression of P4502E1 in brain, its differential induction in rat brain regions by chronic ethanol treatment, and its topographic distribution in rat and human brain.

Human brain thioltransferase: constitutive expression and localization by fluorescence in situ hybridization.

Thioltransferase (glutaredoxin) is a member of the family of thiol-disulfide oxido-reductases that maintain the sulfhydryl homeostasis in cells by catalyzing thiol-disulfide interchange reactions. One of the major consequences of oxidative stress in brain is formation of protein-glutathione mixed disulfide (through oxidation of protein thiols) which can be reversed by thioltransferase during recovery of brain from oxidative stress. Here we have visualized the location of thioltransferase in brain regions from seven human tissues obtained at autopsy. Constitutively expressed thioltransferase activity was detectable in all human brains examined although inter-individual variations were seen. The enzyme activity was significantly higher in hippocampus and cerebellum as compared to other regions. Constitutive expression of thioltransferase mRNA was detectable by Northern blot analysis. Localization of thioltransferase mRNA by fluorescence in situ hybridization revealed its presence predominantly in neurons in the cerebral cortex, Purkinje and granule cell layers of the cerebellum, granule cell layer of the dentate gyrus and in the pyramidal neurons of CA1, CA2 and CA3 subfields of hippocampus. These discrete neuronal concentrations of thioltransferase would be consistent with an essential role in modulating recovery of protein thiols from mixed disulfides formed during oxidative stress.

Effect of thiol modification on brain mitochondrial complex I activity.

We have studied the effect of altered thiol status on brain mitochondrial complex I activity. Exposure of mouse brain slices to diethyl maleate resulted in significant loss in complex I activity with concomitant loss of thiol antioxidant, glutathione. However, incubation of mitochondria isolated from diethyl maleate treated slices with dithiothreitol completely regenerated activity of complex I. Incubation of mouse brain slices with iodoacetic acid, a thiol modifier, also resulted in inhibition of complex I activity, which was reversed by glutathione. The present study demonstrates sensitivity of complex I to thiol modifying agents. Reversal of this inhibition by thiol reductants indicates that secondary oxidation of thiol groups in complex I as a consequence of thiol modification is responsible for the loss in activity.