12(S)-Hydroxyeicosatetraenoic acid (12-HETE) is one of the metabolites of arachidonic acid involved in pathological conditions associated with mitochondria and oxidative stress. The present study tested effects of 12-HETE on mitochondrial functions. In isolated rat heart mitochondria, 12-HETE increases intramitochondrial ionized calcium concentration that stimulates mitochondrial nitric oxide (NO) synthase (mtNOS) activity. mtNOS-derived NO causes mitochondrial dysfunctions by decreasing mitochondrial respiration and transmembrane potential. mtNOS-derived NO also produces peroxynitrite that induces release of cytochrome c and stimulates aggregation of mitochondria. Similarly, in HL-1 cardiac myocytes, 12-HETE increases intramitochondrial calcium and mitochondrial NO, and induces apoptosis. The present study suggests a novel mechanism for 12-HETE toxicity.

The antitumor effects of therapeutic mAbs may depend on immune effector cells that express FcRs for IgG. IL-12 is a cytokine that stimulates IFN-γ production from NK cells and T cells. We hypothesized that coadministration of IL-12 with a murine anti-HER2/neu mAb (4D5) would enhance the FcR-dependent immune mechanisms that contribute to its antitumor activity. Thrice-weekly therapy with IL-12 (1 μg) and 4D5 (1 mg/kg) significantly suppressed the growth of a murine colon adenocarcinoma that was engineered to express human HER2 (CT-26HER2/neu) in BALB/c mice compared with the result of therapy with IL-12, 4D5, or PBS alone. Combination therapy was associated with increased circulating levels of IFN-γ, monokine induced by IFN-γ, and RANTES. Experiments with IFN-γ–deficient mice demonstrated that this cytokine was necessary for the observed antitumor effects of therapy with IL-12 plus 4D5. Immune cell depletion experiments showed that NK cells (but not CD4+ or CD8+ T cells) mediated the antitumor effects of this treatment combination. Therapy of HER2/neu-positive tumors with trastuzumab plus IL-12 induced tumor necrosis but did not affect tumor proliferation, apoptosis, vascularity, or lymphocyte infiltration. In vitro experiments with CT-26HER2/neu tumor cells revealed that IFN-γ induced an intracellular signal but did not inhibit cellular proliferation or induce apoptosis. Taken together, these data suggest that tumor regression in response to trastuzumab plus IL-12 is mediated through NK cell IFN-γ production and provide a rationale for the coadministration of NK cell-activating cytokines with therapeutic mAbs.

Imaging plays an important role in detection, diagnosis as well as pre and post operative management of patients with soft tissue sarcomas. Soft tissue sarcomas are generally a diagnostic dilemma needing the complimentary use of both radiology and pathology for their accurate diagnosis. In this review article, we have tried to highlight the important facts about the various imaging modalities available as well as the recent advances in the field of radiology.

Introduction:

Configuration and size of the foramen magnum and posterior fossa plays an important role in the pathophysiology of the posterior fossa and craniovertebral junction disorders. This study is aimed to find out various dimensions of the foramen magnum and posterior fossa.

Materials and Methods:

This is a prospective study of 100 consecutive normal computerized tomography (CT) scans of posterior fossa and 100 dry adult skulls without any bony abnormality. The posterior fossa volume was calculated by abc/2 in method 1 and by advanced work station of CT scan in method 2. Various dimensions of posterior fossa and foramen magnum were also studied.

Results:

Age ranged from 16 to 89 years with a mean of 51.3 years. Mean height of posterior fossa were 3.01 cm (±0.22) and 3.52 (±0.43) cm in dry skull and CT scan group, respectively (P < 0.0001). Mean volume of posterior fossa were 157.88 (±27.94) cm3 and 159.58 (±25.73) cm3 by method 1 and method 2, respectively (P > 0.05). All the dimensions of posterior fossa and foramen magnum were larger in male as compared to female. Mean anteroposterior (AP), transverse diameter and surface area of the foramen magnum were 3.31 (±0.35) cm, 2.76 (±0.31) cm, and 729.15 (±124.87) mm2, respectively, in CT scan group as compared to 3.41 (±0.29) cm, 2.75 (±0.25) cm, and 747.67 (±108.60) mm2, respectively, in dry skull group.

Conclusion:

Normal values of posterior fossa and foramen magnum could serve as a future reference. Dry skull dimensions could be different from CT scan measurement. More studies are needed as there could be variations in dimensions in different regions in India

Endoscopic endonasal trans-sphenoid surgery (EETS) is increasingly used for pituitary lesions. Pre-operative CT and MRI scans and peroperative endoscopic visualization can provide useful anatomical information. EETS is indicated in sellar, suprasellar, intraventricular, retro-infundibular, and invasive tumors. Recurrent and residual lesions, pituitary apoplexy and empty sella syndrome can be managed by EETS. Modern neuronavigation techniques, ultrasonic aspirators, ultrasonic bone curette can add to the safety. The binostril approach provides a wider working area. High definition camera is much superior to three-chip camera. Most of the recent reports favor EETS in terms of safety, quality of life and tumor resection, hospital stay, better endocrinological, and visual outcome as compared to the microscopic technique. Nasal symptoms, blood loss, operating time are less in EETS. Various naso-septal flaps and other techniques of CSF leak repair could help reduce complications. Complications can be further reduced after achieving the learning curve, good understanding of limitations with proper patient selection. Use of neuronavigation, proper post-operative care of endocrine function, establishing pituitary center of excellence and more focused residency and endoscopic fellowship training could improve results. The faster and safe transition from microscopic to EETS can be done by the team concept of neurosurgeon/otolaryngologist, attending hands on cadaveric dissection, practice on models, and observation of live surgeries. Conversion to a microscopic or endoscopic-assisted approach may be required in selected patients. Multi-modality treatment could be required in giant and invasive tumors. EETS appears to be a better surgical option in most pituitary adenoma.

Orbital tuberculosis is an extremely rare, potentially devastating state, when not effectively treated, can lead to grave sequelae. Proptosis can be the result of primary orbital pathology or systemic disease processes. (1, 2) Thyroid ophthalmopathy being commonest cause of proptosis .It can also be a manifestation of, diseases involving various structures of orbit and of superior orbital fissure or cavernous sinus. A case of orbital tubercular abscess presenting with proptosis and blindness in a young male 27 years is reported. Clinicians should suspect rare causes in an immuno- compromised host .(2, 3) The failure to diagnose these conditions can lead to unintended sequelae.

Key Message: The patient who presents with proptosis must be evaluated to ascertain the causation. Preservation of vision is of paramount importance. On follow-up patients should be monitored for complications and remedied.

Introduction

Spontaneous pathological fractures of the cervical spine due to tuberculosis are rare. But with escalating incidences of atypical presentations of tubercular disease, clinicians should exercise a high index of suspicion for early diagnosis of such cases.

Case presentation

We present a case of a 50-year-old Hindu man from northern India, who complained of pain and stiffness in his neck. His radiographs showed a fracture in his second cervical vertebral body. But further investigations raised the suspicion of an infective pathology, which was corroborated by magnetic resonance imaging and fine needle aspiration cytology. His symptoms improved and the fracture healed following antitubercular chemotherapy and immobilization.

Conclusion

In endemic regions like India, clinicians should be on the lookout for atypical presentations of tuberculosis. Any suspicious lesion should be evaluated with care for clinical, radiological and laboratory evidences of the infection. The affected spine should be protected and appropriate chemotherapy should be instituted at the earliest opportunity.

Endoscopic third ventriculostomy (ETV) is considered as a treatment of choice for obstructive hydrocephalus. It is indicated in hydrocephalus secondary to congenital aqueductal stenosis, posterior third ventricle tumor, cerebellar infarct, Dandy-Walker malformation, vein of Galen aneurism, syringomyelia with or without Chiari malformation type I, intraventricular hematoma, post infective, normal pressure hydrocephalus, myelomeningocele, multiloculated hydrocephalus, encephalocele, posterior fossa tumor and craniosynostosis. It is also indicated in block shunt or slit ventricle syndrome. Proper Pre-operative imaging for detailed assessment of the posterior communicating arteries distance from mid line, presence or absence of Liliequist membrane or other membranes, located in the prepontine cistern is useful. Measurement of lumbar elastance and resistance can predict patency of cranial subarachnoid space and complex hydrocephalus, which decides an ultimate outcome. Water jet dissection is an effective technique of ETV in thick floor. Ultrasonic contact probe can be useful in selected patients. Intra-operative ventriculo-stomography could help in confirming the adequacy of endoscopic procedure, thereby facilitating the need for shunt. Intraoperative observations of the patent aqueduct and prepontine cistern scarring are predictors of the risk of ETV failure. Such patients may be considered for shunt surgery. Magnetic resonance ventriculography and cine phase contrast magnetic resonance imaging are effective in assessing subarachnoid space and stoma patency after ETV. Proper case selection, post-operative care including monitoring of ICP and need for external ventricular drain, repeated lumbar puncture and CSF drainage, Ommaya reservoir in selected patients could help to increase success rate and reduce complications. Most of the complications develop in an early post-operative, but fatal complications can develop late which indicate an importance of long term follow up.

Differences in CD8+CD57− and CD8+CD57+ lymphocyte lifespan have been documented. Lower numbers and shorter lifespan are characteristic of CD8+CD57+ in normal individuals. However, CD8+CD57+ are expanded in certain disease states including T cell large granular leukemia and other hematologic malignancies. The mechanisms responsible for the differences in CD8+CD57− and CD8+CD57+ lifespan remain elusive. In this study, we demonstrate that the small heat shock protein (Hsp) 27 is a key regulator of CD8+CD57+ lymphocyte lifespan. We found that Hsp27 expression is significantly lower in CD8+CD57+ than in CD8+CD57− lymphocytes. In contrast, Hsp60 and Hsp70 are expressed at comparable levels. Unlike other antiapoptotic Bcl-2–like molecules, the expression of Hsp27 tightly correlates with CD8+CD57+ and CD8+CD57−lifespan. We demonstrate that Hsp27 overexpression in CD8+CD57+ lymphocytes to levels found normally in CD8+CD57− lymphocytes decreased apoptosis. Accordingly, silencing of Hsp27 in CD8+CD57− lymphocytes increased apoptosis. Collectively these results demonstrate that Hsp27 is a critical regulator of normal CD8+CD57+ lifespan supporting its use as a marker of lifespan in this lineage, and suggest a mechanism responsible for the decreased apoptosis and clonal expansion characteristic of certain disease states.

Congenital double lip is a rare developmental anomaly which usually involves the upper lip. It may occur in isolation or as a part of Ascher's syndrome. The occurrence of double lip may result in facial deformity especially when patient attempts to talk, smile, or even try to show the teeth. It affects esthetics and also interferes with speech and mastication. Although surgery may be undertaken to facilitate speech and mastication, majority of cases are operated for cosmetic reasons. A case of congenital double upper lip which was surgically treated for cosmetic reason is reported.

Acute seizure (AS) activity in old age has an increased predisposition for evolving into temporal lobe epilepsy (TLE). Furthermore, spontaneous seizures and cognitive dysfunction after AS activity are often intense in the aged population than in young adults. This could be due to an increased vulnerability of inhibitory interneurons in the aged hippocampus to AS activity. We investigated this issue by comparing the survival of hippocampal GABA-ergic interneurons that contain the neuropeptide Y (NPY) or the calcium binding protein parvalbumin (PV) between young adult (5-months old) and aged (22-months old) F344 rats at 12 days after three-hours of AS activity. Graded intraperitoneal injections of the kainic acid (KA) induced AS activity and a diazepam injection at 3 hours after the onset terminated AS-activity. Measurement of interneuron numbers in different hippocampal subfields revealed that NPY+ interneurons were relatively resistant to AS activity in the aged hippocampus in comparison to the young adult hippocampus. Whereas, PV+ interneurons were highly susceptible to AS activity in both age groups. However, as aging alone substantially depleted these populations, the aged hippocampus after three-hours of AS activity exhibited 48% reductions in NPY+ interneurons and 70% reductions in PV+ interneurons, in comparison to the young hippocampus after similar AS activity. Thus, AS activity-induced TLE in old age is associated with far fewer hippocampal NPY+ and PV+ interneuron numbers than AS-induced TLE in the young adult age. This discrepancy likely underlies the severe spontaneous seizures and cognitive dysfunction observed in the aged people after AS activity.

INTRODUCTION

The objective of this prospective audit was to compare two methods of anticoagulation reversal in the pre-oper-ative period for hip fracture patients.

PATIENTS AND METHODS

In the first part of the audit, our current practice was analysed. Data relating to the number of days from admission to surgery and the reasons for delay to surgery were collected. Also, data concerning common reasons for which the patients were started on warfarin and the time required for INR to drop to 1.5 or below were collected. In the second part of the audit, 45 patients with INR above 1.5 were given a single dose of vitamin K (1 mg i.v.) in addition to stopping warfarin.

RESULTS

The mean difference in the time for INR < 1.5 in the two groups was 2 days (52 h; P < 0.05). The mean difference in wait for surgery since admission between the two groups was 4 days (91 h; P < 0.05). There was no significant difference between the two groups as regards the average number of co-morbidities in the patient groups.

CONCLUSIONS

A single 1 mg intravenous dose of vitamin K significantly reduces the time for the reversal of INR and the pre-operative delay to surgery, in patients on long-term warfarin. We conclude that 1 mg of intravenous vitamin K on admission is a safe and effective treatment to avoid delay in the treatment in this group of patients.

Maintenance of neurogenesis in the adult hippocampus is important for functions such as mood and memory. As exposure to unpredictable chronic stress (UCS) results in decreased hippocampal neurogenesis, enhanced depressive- and anxiety-like behaviors and memory dysfunction, it is believed that declined hippocampal neurogenesis mainly underlies the behavioral and cognitive abnormalities after UCS. However, the effects of predictable chronic mild stress (PCMS) such as the routine stress experienced in day-to-day life on functions such as mood, memory, hippocampal neurogenesis are unknown. Using forced swim and elevated plus maze tests in a prototype of adult rats, we demonstrate that PCMS (comprising 5 minutes of daily restraint stress for 28 days) decreases depressive- and anxiety-like behaviors for prolonged periods. Moreover, we illustrate that decreased depression and anxiety scores after PCMS are associated with ~1.8 fold increase in the production and growth of new neurons in the hippocampus. Additionally, we found that PCMS leads to enhanced memory function in water maze as well as novel object recognition tests. Collectively, these findings reveal that PCMS is beneficial to the adult brain function, which is exemplified by an increased hippocampal neurogenesis and an improved mood and cognitive function.

Alzheimer’s disease is associated with synapse loss, memory dysfunction and pathological accumulation of amyloid beta in plaques. However, an exclusively pathological role for amyloid beta is being challenged by new evidence for an essential function of amyloid beta at the synapse. Amyloid beta protein exists in different assembly states in the central nervous system and plays distinct roles ranging from synapse and memory formation to memory loss and neuronal cell death. Amyloid beta is present in the brain of symptom-free people where it likely performs important physiological roles. New evidence indicates that synaptic activity directly evokes the release of amyloid beta at the synapse. At physiological levels, amyloid beta is a normal, soluble product of neuronal metabolism that regulates synaptic function beginning early in life. Monomeric amyloid beta 40 and 42 are the predominant forms required for synaptic plasticity and neuronal survival. With age, some assemblies of amyloid beta are associated with synaptic failure and Alzheimer’s disease pathology, possibly targeting the N-methyl-D-aspartic acid (NMDA) receptor through the α7-nicotinic acetylcholine receptor (α7-nAChR), mitochondrial amyloid-β alcohol dehydrogenase (ABAD) and cyclophilin D. But emerging data suggests a distinction between age effects on the target response in contrast to the assembly state or the accumulation of the peptide. Both aging and beta amyloid independently decrease neuronal plasticity. Our laboratory has reported that amyloid beta, glutamate and lactic acid are each increasingly toxic with neuron age. The basis of the age-related toxicity partly resides in age-related mitochondrial dysfunction and an oxidative shift in mitochondrial and cytoplasmic redox potential. In turn, signaling through phosphorylated extracellular signal-regulated protein kinases (pERK) is affected along with an age-independent increase in phosphorylated cAMP response element-binding protein (pCREB) This review examines the long-awaited functional impact of amyloid beta on synaptic plasticity.

Monocytes and macrophages are central cells of the innate immune system, responsible for defending against diverse pathogens. While they originate from a common myeloid precursor and share functions in innate immunity, each has a very distinct life span finely tuned by the apoptotic caspases. Normally, circulating monocytes are short-lived and undergo spontaneous apoptosis on a daily basis. Macrophages, however, have a longer life span. In chronic inflammatory diseases and, as recently recognized, in the tumor microenvironment, the inhibition of the apoptotic program promotes monocyte survival contributing to the accumulation of macrophages and the persistence of an inflammatory milieu. A complex network of differentiation factors and inflammatory stimuli determine monocyte/macrophage life span by blocking the apoptotic pathway and activating a myriad of survival pathways. Our understanding of apoptosis has flourished over the last decade, and its relevance in the regulation of the immune system is now indisputable. Nevertheless, how the complicated networks of survival and apoptotic regulators are integrated to determine cellular life span remains elusive. This review summarizes the contribution of the caspases and their regulators in monocyte/macrophage cell fate and discusses how these molecules orchestrate the initiation, maintenance, and resolution of inflammation. More provocatively, we discuss possible strategies to control inflammation by manipulating leukocyte life span.

BCG has been administered globally for more than 75 years, yet tuberculosis (TB) continues to kill more than 2 million people annually. Further, BCG protects childhood TB but is quite inefficient in adults. This indicates that BCG fails to induce long-term protection. Hence there is a need to explore alternative vaccination strategies that can stimulate enduring T cell memory response. Dendritic cell based vaccination has attained extensive popularity following their success in various malignancies. In our previous study, we have established a novel and unique vaccination strategy against Mycobacterium tuberculosis (M. tb) and Salmonella typhimurium by utilizing infected macrophages (IM). In short-term experiments (30 days), substantial degree of protection was observed. However, remarkable difference was not observed in long-term studies (240 days) due to failure of the vaccine to generate long-lasting memory T cells. Hence, in the present study we employed T cell memory augmenting cytokines IL-1+IL-6+TNF-α and IL-7+IL-15 for the induction of the enhancement of long-term protection by the vaccine. We co-administered the M. tb infected macrophages vaccine with IL-1+IL-6+TNF-α (IM-1.6.α) and IL-7+IL-15 (IM-7.15). The mice were then rested for a reasonably large period (240 days) to study the bona fide T cell memory response before exposing them to aerosolized M. tb. IM-1.6.α but not IM-7.15 significantly improved memory T cell response against M. tb, as evidenced by recall responses of memory T cells, expansion of both central as well as effector memory CD4 and CD8 T cell pools, elicitation of mainly Th1 memory response, reduction in the mycobacterial load and alleviated lung pathology. Importantly, the protection induced by IM-1.6.α was significantly better than BCG. Thus, this study demonstrates that not only antigen-pulsed DCs can be successfully employed as vaccines against cancer and infectious diseases but also macrophages infected with M. tb can be utilized with great efficacy especially in protection against TB.

Aims and objectives:

To evaluate the role of magnetic resonance imaging (MRI) as a non-invasive diagnostic tool in patients with acute and chronic spinal trauma and to compare and correlate the MRI findings with those of patients’ clinical profile and neurological outcome according to ASIA impairment scale to assess prognostic and clinical value of MRI.

Materials and Methods:

Sixty two patients of spinal trauma formed the study group in a prospective fashion. The patients undergoing MR imaging and magnetic resonance images were analyzed and correlated with findings on neurological examination according to American Spinal Injury Association (ASIA) impairment scale (AIS) at the time of MRI examination and subsequently at sub-acute interval to assess neurological outcome.

Statistical Analysis:

Sample profile was described in terms of 95% confidence limit and proportion. To describe strength of association between extent of spinal cord injury and outcome, odd's ratio, bivariate and multi variant analysis, was used. Pearson's chi square (χ) 2 statistics was applied to test the association between two categorical variables. Data were analyzed using statistical software package, STATA 9.2 and the difference was considered to be significant if ‘P’ value was <0.05.

Observation and Results:

The cord edema without hemorrhage was the most common MR finding (41.5%). The others were sizable focus of hemorrhage within the cord (33%), epidural hematoma (5.0%), and normal cord (26%). Majority of MR findings correlated well with clinical profile of the patient according to ASIA impairment scale. This study demonstrated that patients with presence of sizable focus of haemorrhage had larger cord edema and more severe grade of initial ASIA impairment scale( AIS) with poor recovery at follow up (P=0.032).Improvement in upper extremity was more than lower extremity. Severe cord compression was also associated with poor neurological outcome; however it was not statistically significant (P=0.149).

Conclusions:

With this study the authors concluded that various MRI findings in acute spinal cord injury correlated well with the initial clinical findings and on follow-up according to ASIA impairment scale. MRI is useful for initial diagnosis of acute spinal cord injury and its prognostication for predicting neurological recovery.

Summary

Cerebral mycotic aneurysms (MAs) also called infective aneurysms, are uncommon and are usually encountered in patients with infective endocarditis. These aneurysms often present with intracranial hemorrhage. MAs may resolve on treatment with antibiotics alone. However prognosis with medical management alone is unpredictable. Good prognosis with surgery has been reported for single accessible ruptured MAs. However surgery is associated with significant morbidity. Endovascular treatment of MAs along with appropriate antibiotics is emerging as an acceptable option for these patients.

We describe two cases of infective endocarditis complicated by ruptured MA treated successfully by liquid embolic glue material.

CONTEXT:

The enzymes encoded by the polymorphic genes NAD (P) H: quinone oxidoreductase 1 (NQO1) play an important role in the activation and inactivation of xenobiotics. This enzyme has been associated with xenobiotic related diseases, such as cancer, therapeutic failure and abnormal effects of drugs.

AIM:

The aim of the present study was to determine the allelic and genotypic frequencies of NQO Hinf I polymorphisms in a Hindu population of Central India.

SETTINGS AND DESIGN:

Polymorphisms of NQO1 were determined in 311 unrelated Hindu individuals.

MATERIALS AND METHODS:

Polymerase chain reaction- Restriction Fragment Length Polymorphism (PCR-RFLP) analysis in peripheral blood DNA for NQO1 Hinf I polymorphism was used in 311 unrelated Hindu individuals.

STATISTICAL ANALYSIS:

Allele frequencies were calculated by direct counting. Hardy Weinberg Equilibrium was evaluated using a Chi-square goodness of fit test.

RESULTS:

The observed allelic frequency was 81% for C (wild) and 19% for T (mutant) in the total sample.

CONCLUSIONS:

The allelic frequency of “C” was higher than in other Asians (57%), but similar to Caucasians (81%). The genotype distributions for Hinf I polymorphisms were in Hardy-Weinberg equilibrium.

We report a case of a 13-year-old girl with Hallervorden-Spatz disease (HSD) or pantothenate kinase-2 associated neurodegeneration (PKAN). HSD is a rare neurodegenerative disorder, which is characterized by a rapidly progressive extrapyramidal syndrome, dementia with optic atrophy, and retinal degeneration. It is associated with accumulation of cysteine-iron complex in the globus pallidi and substantia nigra. The MRI “eye of the tiger” sign is the characteristic. MRI spectroscopy is also characteristic. It shows markedly decreased NAA/Cr values in the globus pallidi and substantia nigra with increased mI/Cr values that suggest of gliosis.

Swyer James syndrome is a rare syndrome which occurs due to viral illness in early childhood. The post infective obliterative bronchiolitis results in arrest of lung growth and alveolarization with reduced vascularity resulting in classical radiological features. We describe two cases of patients fulfilling all the criteria of the syndrome - 1) Unilateral hyperlucent small lung in chest radiograph with air trapping on expiration, small ipsilateral hila and pulmonary artery. 2) Diffuse decrease in attenuation of lung parenchyma with bronchiectasis and reduction in vascularity. 3) Unilateral pruned tree appearance on angiography (MRA). The clinical presentation was recurrent chest infection in a child and infrequent bouts of hemoptysis in a middle aged female. The study demonstrates the role of magnetic resonance angiography in diagnosing the condition.