1.Simultaneous Bilateral Proximal Humeri Anterior Fracture Dislocations in a Patient with 1st Onset Seizure. A Case Report and Review of the Literature
Kelvin G Tan ; Sathappan SS ; Ganesan N R
Malaysian Orthopaedic Journal 2011;5(2):37-40
Bilateral anterior fracture-dislocations of humeral neck in a patient with seizure are extremely rare. We describe a rare case of a 33 -year-old Chinese gentleman who presented post seizure secondary to subdural gliosis, sequelae from a previous subdural haematoma. Following physical examination and radiographic assessment, including a Computed Tomography scan (CT scan), Rarely fracturedislocation of bilateral proximal humeri were diagnosed; similar fracture patterns were noted. Open reduction and internal fixation with PHILOS proximal humeral locking plate allowed early shoulder rehabilitation.
2.The anti-malarial chloroquine modulated cytokine levels and increased animal survivability via Akt-mediated inhibition of GSK3β in Burkholderia pseudomalleiinfected mice
Ganesan, N., Embi, N. and Hasidah, M.S.
Tropical Biomedicine 2018;35(3):709-723
Melioidosis is a common cause of fatal community-acquired septicaemia and
pneumonia in endemic regions even with appropriate antibiotic treatments. The involvement
of inflammatory cytokines in the manifestation of melioidosis is well-documented. Antibacterial
and anti-inflammatory therapies may prove more efficacious against melioidosis
rather than just anti-bacterial therapy alone. The phosphatidylinositol 3-kinase (PI3K)/Akt
pathway has a central role in regulating the host inflammatory response; and glycogen
synthase kinase-3β (GSK3β), a downstream effector molecule within this axis, plays a pivotal
role in regulating the production of pro- and anti-inflammatory cytokines. The anti-malarial
drug, chloroquine is a novel activator of Akt, and can elicit inhibition of GSK3β via PI3K/Akt
signalling. LiCl, a GSK3 inhibitor is reported to increase survivability and modulate cytokine
production in B. pseudomallei-infected mice. Here we determined the effects of chloroquine
administration on animal survivability, cytokine levels and phosphorylation states of GSK3β
(Ser9), Akt (Ser473) and NF-κB p65 (Ser536) in a murine model of acute melioidosis infection.
Administration of 50 mg/kg b w chloroquine improved survivability (mean 67.0 ± 6.3%) of
mice infected with 3 X LD50 B. pseudomallei compared to controls. Bacterial loads in spleen,
liver, lung and blood of infected mice administered with chloroquine were significantly lower
than controls. Western blot analysis revealed that the intensities of pAkt (Ser473) and pGSK3β
(Ser9) in liver samples of mice administered with chloroquine were significantly (P<0.05)
higher (2.3- and 4.4-fold respectively) compared to controls. On the other hand, chloroquine
treatment signicantly decreased (P<0.05) phosphorylation of NF-κB p65 (Ser536) by 0.7-fold
compared to control. Chloroquine administration also resulted in significantly reduced levels
of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β and IL-18) but increased levels of antiinflammatory
cytokines (IL-4 and IL-10) in sera and liver of B. pseudomallei-infected mice.
Findings from this study demonstrate that the increased survivability of B. pseudomalleiinfected
mice after chloroquine administration is at least in part due to its cytokine-modulating
effects elicited via Akt-mediated inhibition of GSK3β that resulted in inhibition of NF-κB
activation. This study represents laboratory evidence of the use of chloroquine for cytokine
modulation and a plausible effective adjunctive therapeutic for B. pseudomallei infection.
3.A Longitudinal Study of Relation between Side-effects and Clinical Improvement in Schizophrenia: Is There a Neuro-metabolic Threshold for Second Generation Antipsychotics?.
Ganesan VENKATASUBRAMANIAN ; Naren P RAO ; Rashmi ARASAPPA ; Sunil V KALMADY ; Bangalore N GANGADHAR
Clinical Psychopharmacology and Neuroscience 2013;11(1):24-27
OBJECTIVE: Classical studies demonstrated Neuroleptic Induced Extrapyramidal Side-effects (NIES; Neuroleptic threshold) to correlate with the efficacy of first generation antipsychotics. Second generation antipsychotics (SGAs), in addition to the extrapyramidal side effects, are also associated with metabolic side effects. This prospective study on antipsychotic-naive schizophrenia patients, for the first-time, examined concurrently the relationship between clinical improvement and these side-effects NIES and Neuroleptic Induced Metabolic Side-effects. METHODS: Thirty six-antipsychotic-naive schizophrenia (DSM-IV) patients were examined at baseline and after 5 weeks of treatment with antipsychotics. At baseline and follow-up, we recorded the body mass index (BMI) and assessed psychopathology using Scale for Assessment of Positive-symptoms (SAPS) and Scale for Assessment of Negative-symptoms (SANS), extrapyramidal symptoms using Simpson-Angus Extra Pyramidal Scale (SAEPS) and improvement using Clinical Global Impression Improvement (CGI). RESULTS: After treatment, patients showed significant reduction in SAPS (baseline, 27.97+/-14.47; follow-up, 14.63+/-13.25; p<0.001) and SANS total scores (baseline, 63.77+/-28.96; follow-up, 49.30+/-28.77; p=0.001) and a significant increase in BMI (baseline, 18.5+/-3.37; follow-up, 19.13+/-3.17; p<0.001). At follow-up CGI-Improvement score was (2.55+/-0.65) and SAEPS score was (0.8+/-1.32). CGI-Improvement score had a significant negative correlation with magnitude of increase in BMI (rs=-0.39; p=0.01) and SAEPS symptom score at follow-up (rs=-0.58; p<0.001). In addition, magnitude of increase in BMI showed positive correlation with the magnitude of reduction in SAPS total score (rs=0.33; p=0.04). CONCLUSION: The study findings suggest a possible relation between clinical improvement and antipsychotic-induced neuroleptic as well as metabolic side-effects in schizophrenia. Though the mechanism of this relation is yet to be elucidated, insulin signaling pathways and lipid homeostasis are potential mechanisms in addition to the established neurotransmitter hypothesis. Theoretically findings support the novel hypothetical construct of 'Neuro-Metabolic threshold' in the treatment of schizophrenia.
Antipsychotic Agents
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Body Mass Index
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Follow-Up Studies
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Homeostasis
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Humans
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Insulin
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Longitudinal Studies
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Neurotransmitter Agents
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Prospective Studies
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Psychopathology
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Schizophrenia
4.A Functional Domain Based Approach in Neurocognitive Rehabilitation with Transcranial Direct Current Stimulation: A Case Report
Vanteemar S SREERAJ ; Venkataram SHIVAKUMAR ; Anushree BOSE ; Purohit N ABHIRAM ; Sri Mahavir AGARWAL ; Harleen CHHABRA ; Janardhanan C NARAYANASWAMY ; Ganesan VENKATASUBRAMANIAN
Clinical Psychopharmacology and Neuroscience 2019;17(1):125-129
Transcranial direct current stimulation (tDCS) is a novel brain stimulation technique which has kindled hope in alleviating motor, language as well as cognitive deficits in neuronal injury. Current case report describes application of tDCS in two phases using two different protocols in a patient with hypoxic injury. In the first phase anodal stimulation of dorsolateral prefrontal cortex improved the language fluency. Subsequently, after 6 months second phase application of anodal stimulation over posterior parietal region targeted arithmetic and working memory deficits. Individualising the treatment protocols of brain stimulation, based on the lesion and the functional deficits, for neuro-rehabilitation is emphasised.
Brain
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Clinical Protocols
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Cognition Disorders
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Dyscalculia
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Hope
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Humans
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Hypoxia-Ischemia, Brain
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Memory, Short-Term
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Neurons
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Parietal Lobe
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Prefrontal Cortex
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Rehabilitation
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Transcranial Direct Current Stimulation
5.Potential of repurposing chloroquine as an adjunct therapy for melioidosis based on a murine model of Burkholderia pseudomallei infection
Ganesan, N. ; Embi, N. ; Hasidah, M.S.
Tropical Biomedicine 2020;37(No.2):303-317
Burkholderia pseudomallei is the etiologic agent of melioidosis, a major cause of community-acquired pneumonia and sepsis in the endemic areas. The overall mortality of patients with severe melioidosis remains high due to severe sepsis attributed to overwhelming inflammatory cytokine response in spite of recommended antibiotic therapy. It is crucial that therapeutic approaches beyond just effective antibiotic treatment such as adjunct therapy be considered to mitigate the dysregulated inflammatory signaling and augment host defenses. In an acute B. pseudomallei infection model, we have previously demonstrated that treatment with anti-malarial drug, chloroquine, modulated inflammatory cytokine levels and increased animal survivability via Akt-mediated inhibition of glycogen synthase kinase-3β (GSK3β). GSK3β is a downstream effector molecule within the phosphatidylinositol 3-kinase (PI3K)/ Akt axis which plays a pivotal role in regulating the production of pro- and anti-inflammatory cytokines. Here we evaluate the effect of chloroquine treatment in combination with a subtherapeutic dose of the antibiotic doxycycline on animal survivability, cytokine levels and phosphorylation states of GSK3β (Ser9) in a murine model of acute melioidosis infection to investigate whether chloroquine could be used as an adjunct therapy along with doxycycline for the treatment of melioidosis. Our findings revealed that 50 mg/kg b.w. chloroquine treatment together with a dose of 20 mg/kg b.w. doxycycline improved survivability (100%) of mice infected with 3 X LD50 of B. pseudomallei and significantly (P<0.05) lowered the bacterial loads in spleen, liver and blood compared to controls. B. pseudomallei-infected mice subjected to adjunct treatment with chloroquine and doxycycline significantly (P<0.05) reduced serum levels of pro-inflammatory cytokines (TNF-α, IFN-γ and IL-6) but increased levels of antiinflammatory cytokines (IL-4 and IL-10). Western blot analysis demonstrated that the intensities of pGSK3β (Ser9) in liver samples from mice treated with chloroquine and doxycycline combination were significantly (P<0.05) higher suggesting that the adjunct treatment resulted in significant inhibition of GSK3β. Taken together the bacteriostatic action of doxycycline coupled with the cytokine-modulating effect of chloroquine gave full protection to B. pseudomallei-infected mice and involved inhibition of GSK3β. Findings from the present study using B. pseudomallei-infected BALB/c mice suggest that chloroquine is a plausible candidate for repurposing as adjunct therapy to treat acute B. pseudomallei infection.
6.GSK3β: A plausible molecular target in the cytokinemodulating effect of exogenous insulin in a murine model of malarial infection
Aizuddin, N.N.F. ; Ganesan, N. ; Ng, W.C. ; Ali, A.H. ; Ibrahim, I. ; Basir, R. ; Embi, N. ; Hasidah, M.S.
Tropical Biomedicine 2020;37(No.4):1105-1116
Malaria is a life-threatening disease caused by the Plasmodium sp. parasite.
Infection results in heightened pro-inflammatory response which contributes to the
pathophysiology of the disease. To mitigate the overwhelming cytokine response, host-directed
therapy is a plausible approach. Glycogen synthase kinase-3β (GSK3β), a serine/threonine
kinase plays a pivotal role in the regulation of inflammatory response during pathogenic
infections. The present study was conducted to investigate the chemo-suppressive and
cytokine-modulating effects of insulin administration in malaria-infected mice and the
involvement of GSK3β. Intraperitoneal administrations of 0.3 and 0.5 U/kg body weight
insulin each for four consecutive days into Plasmodium berghei NK65 (PbN)-infected mice
resulted in chemo-suppression exceeding 60% and improved median survival time of infected
mice (20.5 days and 19 days respectively compared to 15.5 days for non-treated control).
Western analysis revealed that pGSK3β (Ser9) intensity in brain samples from insulin-treated
(0.3 and 0.5 U/kg body weight) infected mice each were 0.6 and 2.2 times respectively than
that in control. In liver samples, pGSK3β (Ser9) intensity from insulin-treated infected mice
were significantly higher (4.8 and 16.1 fold for 0.3 and 0.5 U/kg bw respectively) than that in
control. Insulin administration decreased both brain and liver pNF-κB p65 (Ser536) intensities
(to 0.8 and 0.6 times for 0.3 U/kg bw insulin; and to 0.2 and 0.1 times for 0.5 U/kg bw insulin
respectively compared to control). Insulin treatment (0.5 U/kg bw) also significantly decreased
the serum levels of pro-inflammatory cytokines (TNF-α (3.3 times) and IFN-γ (4.9 times))
whilst significantly increasing the levels of anti-inflammatory cytokines (IL-4 (4.9 fold) and
IL-10 (2.1 fold)) in PbN-infected mice. Results from this study demonstrated that the cytokinemodulating effects of insulin at least in part involve inhibition of GSK3β and consequent
inhibition of the activation of NF-κB p65 suggesting insulin as a potential adjunctive therapeutic
for malaria.