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Background Microscopic transsphenoidal excision of pituitary gland, though considered safe from neurosurgical point of view, produces marked cardiovascular and stress responses despite adequate depth of anesthesia. The aim of this study was to evaluate the effect of dexmedetomidine bolus and infusion in microscopic transsphenoidal pituitary surgery on hemodynamics, bleeding in surgical field, and recovery parameters. Materials and Methods A prospective randomized double-blind study was conducted in 40 American Society of Anesthesiologists (ASA) I-II patients between 18 and 65 years, who underwent elective transsphenoidal excision of pituitary tumor. Two groups were constituted: one group received dexmedetomidine 1 μg/kg loading dose followed by 0.5 μg/kg/h infusion, the other received placebo bolus and infusion. A standard anesthesia protocol including isoflurane and fentanyl was used in both groups. The hemodynamic profile, intraoperative bleeding, and recovery profile were studied. Results The heart rate (HR) did not vary significantly from the baseline during surgery and recovery in the dexmedetomidine group. The systolic, diastolic, and mean blood pressures decreased significantly with dexmedetomidine in statistical terms, though they were within the clinically acceptable range and did not require intervention. On comparing the groups, dexmedetomidine group had better perioperative blood pressure profile and decreased isoflurane requirement. Bleeding scores during surgery and recovery were similar in both groups. Conclusions Intraoperative use of dexmedetomidine in transsphenoidal pituitary surgery provided stable perioperative hemodynamics comprising reduced cardiovascular response to intubation and surgical noxious stimuli along with a similar recovery compared with the control group. Therefore, dexmedetomidine appears as a useful adjunct to control hemodynamics in neurosurgical patients undergoing transsphenoidal surgery.

Seismic Microzonation comprising study of site specific seismic Microtremor (H/V ratio) is deployed to generate seismological parameters (Peak Frequency, Peak Amplification, Site Vulnerability Index) that may help estimate requisite factors for sound building design codes that can be used to construct risk resilient infrastructures. In this paper the site of Pakyong, Sikkim, India has been investigated by dividing it into three differed zones (Zone 1, Zone II, Zone III). The study area is associated with site amplification factor varying from 1.47 to 11.49 with corresponding frequency variations from 0.5 Hz - 12.5 Hz in which site vulnerability index found varied from 0.2 to 220.6. The anomalous subsurface formation with its high amplification corresponds to the centre of the Pakyong sites having conspicuous trend in NW-SE direction suggesting the existence of geological formations of Chlorite, Phyllite with intercalations of Quartzite beneath the centre of Pakyong site. The risk associated with vulnerability index for different zones maintains its variability as Zone I > Zone II > Zone III, indicating the low vulnerability index values are attributed to compact parts of the sub-surface materials with less amplifications whilst high vulnerability index of the site corresponds to relatively lower strength of the sub-surface materials and soft sediments underlying the Pakyong site which can be used for constructing risk resilient structure by enhancing the stiffness coefficient of the sub-surface by providing plausible engineering solutions for the purpose.

PurposeNon-functioning pituitary adenomas (NFPAs) exhibit high recurrence rates after surgery. However, the determinants of recurrence are inconsistent in the available literature. The present study sought to investigate the association between nuclear phosphorylated EGFR (pEGFR) levels and recurrence of NFPAs.MethodsTissue microarrays from patients undergoing adenomectomy for NFPAs at our tertiary care center from 2003 to 2015 and having a minimum of 60 months of follow-up (n=102) were accessed. Immunohistochemical analysis (IHC) was performed to determine the expression of nuclear pEGFR T693. h-score was calculated as the product of staining intensity and the number of positively staining cells. Radiological surveillance (MRI) was performed to categorize NFPAs as recurrent or non-recurrent on follow-up.ResultsThe mean age of the cohort was 50 ± 11 years with a male preponderance (61.1%). Recurrence was observed in 46.1% of the patients at a median of 123 months (IQR 72-159) of follow-up. pEGFR T693 positivity was higher in a significantly greater number of recurrent NFPAs as compared to non-recurrent NFPAs (95.7%vs81%, p=0.02). h-scores were also significantly higher in recurrent NFPAs (122.1 ± 6vs81.54 ± 3.3, pConclusionpEGFR T693 was expressed in significantly higher number of recurrent NFPAs. The h-scores were also higher in recurrent NFPAs. Nuclear pEGFR T693 may serve as a predictor of recurrence in NFPAs.

Germinomas are highly immunogenic tumors eliciting a strong peri-tumoral immune response that can spillover into the surrounding healthy tissues. This phenomenon can also occur in intracranial germinomas, manifesting as secondary hypophysitis. Herein, we report a case of 12-year-old-girl presenting with polyuria and polydispsia. She had central diabetes insipidus (CDI) and panhypopituitarism. Imaging revealed a sellar-suprasellar mass with infundibular stalk thickening. Transphenoidal biopsy revealed epithelioid granulomas with immunostaining negative for germinomatous cells. Other causes of hypophysitis were ruled out. Accordingly, she was diagnosed as primary granulomatous hypophysitis and treated with high-dose corticosteroids. Three years later she again presented with headache, vomiting and diminution of vision. Imaging showed a heterogeneous, solid-cystic peripheral rim-enhancing lesion at the same location with involvement of hypothalamus, ependyma and pineal gland. Cerebrospinal fluid beta-human chorionic gonadotropin was markedly elevated, confirming the diagnosis of an intracranial germ cell tumor. She was started on chemotherapy; however, she succumbed to febrile neutropenia. We performed a literature search and found 18 anecdotal cases of secondary hypophysitis associated with intracranial germinomas. There was a slight male preponderance (male:female 5:4). Two-thirds of the cases were below 18 years of age. Polyuria was the most common presenting manifestation (83%). CDI and panhypopituitarism were seen in 89 and 78% cases, respectively. Imaging evidence of pituitary stalk thickening was seen in 12 cases (67%), while pituitary enlargement and/or sellar mass were reported in 11 cases (61%). Pineal involvement was extremely rare, being reported in only 1 case, implying the predilection of suprasellar (rather than pineal) germinomas in causing secondary hypophysitis. Histologically, 82% had lymphocytic hypophysitis, while 18% had granulomatous hypophysitis. Initially, the diagnosis of germinoma was missed in 60% of the cases who were wrongly treated with corticosteroids. To conclude, physicians should make it a dictum that all children and adolescents presenting with CDI and pituitary stalk thickening should be rigorously screened for an underlying intracranial germinoma before labeling them as primary hypophysitis.

Introduction: Prolactin-adjusted adrenocorticotropic hormone (ACTH) ratio is used to improve the diagnostic accuracy of bilateral inferior petrosal sinus sampling (BIPSS) for lateralization of pituitary adenoma. Objective: To study the use of prolactin for successful catheterization during BIPSS, the role of prolactin-normalized ACTH ratio for confirmation of Cushing's disease (CD) and prolactin-adjusted ACTH ratio in predicting the lateralization. Patients and Methods: BIPSS was done in patients with CD; prolactin-adjusted ACTH ratio was compared with intersinus ACTH ratio, magnetic resonance imaging, and intraoperative findings for localization of pituitary adenoma. Histopathology was taken as “gold standard” for the diagnosis of CD. Results: Eight patients underwent BIPSS. All the patients underwent transsphenoidal surgery. All these patients had proper venous sampling during BIPSS as determined by inferior petrosal sinus (IPS):Peripheral prolactin ratio of ≥1.8. Prolactin-normalized ACTH ratio of ≥1.3 was achieved in all the eight patients, which was consistent with the diagnosis of CD. Concordance of intersinus ACTH ratio ≥1.4 with the intraoperative findings was found in five of eight (62.5%) patients depicting correct lateralization. Concordance of prolactin-adjusted ACTH ratio with intraoperative findings was found in four of eight (50%) patients. Seven of eight patients had concordance of intersinus ACTH ratio with prolactin-adjusted ACTH ratio. Conclusion: Prolactin is a useful marker for successful catheterization, confirming the diagnosis of CD during BIPSS, and prolactin-adjusted ACTH ratio does not add to the accuracy of lateralization of pituitary adenoma compared with intersinus ACTH ratio.

Purpose The transsphenoidal approach presents unique challenges in young, with scanty literature. This study compares the outcome of pituitary tumors among young in our center between endoscopic(EES) and microscopic(MTS) transsphenoidal surgery, with a meta-analysis. Methods Patients within 20 years were studied for their surgical approach to a favorable outcome of endocrine remission (ER) (functioning) or Gross/Near-Total resection (nonfunctioning), besides the need for retreatment. Relevant studies were pooled and analyzed according to PRISMA guidelines. Results Out of 64 young patients with pituitary tumors, 48 underwent transsphenoidal surgery using MTS(33) or EES(15). Of these, 21, 14, 5, and 8 had Cushing's, somatotropinomas, prolactinomas, and non-secreting tumors, respectively. Mean symptom duration was 28months, with weight gain(50 %) and visual complaints(29 %) most prevalent. Hypogonadism(21 %) was the most frequent endocrinopathy. The mean tumor volume was 3.8 cm3. Over mean follow-up of 4.4years, favorable outcome was significantly higher after EES than MTS(78.6 % vs. 46.7 %)(odds ratio 4.18, p = 0.05). EES's better outcome was homogeneous across subgroups of age and tumor type, with no significant subgroup difference. Symptom duration was significantly higher among those who required retreatment(p = 0.05), while ER had a non-significant association with tumor volume(p = 0.07). Overall, 40 %, 27 %, 17 %, and 8% were on hydrocortisone, thyroxine, sex hormone, and desmopressin, respectively, at follow-up with no significant difference between EES and MTS. In pooled analysis of literature, both favorable outcome(74 % vs. 48 %,p = 0.02) and retreatment rate(8% vs. 37 %,p = 0.004) were significantly better with EES than MTS. Conclusion Among young patients with pituitary tumors, the favorable outcome and retreatment rates are better with endonasal endoscopy and associated with symptom duration and tumor volume.

The scientific basis of intracranial aneurysm (IA) formation, its rupture and further development of cerebral vasospasm is incompletely understood. Aberrant protein expression may drive structural alterations of vasculature found in IA. Deciphering the molecular mechanisms underlying these events will lead to identification of early detection biomarkers and in turn, improved treatment outcomes. To unravel differential protein expression in three clinical subgroups of IA patients: (1) unruptured aneurysm, (2) ruptured aneurysm without vasospasm, (3) ruptured aneurysm who developed vasospasm, we performed untargeted quantitative proteomic analysis of aneurysm tissue and serum samples from three subgroups of IA patients and control subjects. Candidate molecules were then validated in a larger cohort of patients using enzyme-linked immunosorbent assay. A total of 937 and 294 proteins were identified from aneurysm tissue and serum samples, respectively. Several proteins that are known to maintain structural integrity of vasculature were found to be dysregulated in the context of aneurysm.

Here we describe data of a comprehensive phosphoproteomic evaluation of 20 non-functioning pituitary adenomas (NFPAs). Peptides from 20 tumor samples were enriched with TiO 2 beads and fractioned using bRPLC and subjected to high throughput LC-MS/MS-Orbitrap Fusion™ Tribrid™ Mass Spectrometer for analysis. Upto 5 precursor ions were selected for MS/MS analysis. Data was analyzed using MASCOT and SEQUEST. Bioinformatics tools Phosphosite Plus, Gene Ontology, DAVID, and KEGG were used to determine the biological significance of identified phosphoproteins. In this study, 2508 phosphopeptides corresponding to 1345 phosphoprotein were identified. The phospho EGFR, MEK, and STAT1/3, β-Catenin, BRAF, and HSPB1 were significantly hyperphosphorylated in the recurrent group as compared to the non-recurrent NFPA. Identification of these phosphoproteins provides a roadmap for patient stratification, prognostication for recurrence and trials for targeted therapy.

Context Bilateral inferior petrosal sinus sampling (BIPSS) using hCRH is currently considered the ‘gold standard’ test for the differential diagnosis of ACTH-dependent Cushing’s syndrome (CS). Vasopressin is more potent than CRH to stimulate ACTH secretion as shown in animal studies; however, no comparative data of its use are available during BIPSS. Objective To study the diagnostic accuracy and comparison of hCRH and lysine vasopressin (LVP) stimulation during BIPSS. Patients and methods 29 patients (27-Cushing’s disease, 2-ectopic CS; confirmed on histopathology) underwent BIPSS and were included for the study. Patients were randomized to receive hCRH, 5 U LVP or 10 U LVP during BIPSS for ACTH stimulation. BIPSS and contrast-enhanced magnetic resonance imaging (CEMRI) were compared with intra-operative findings of trans-sphenoidal surgery (TSS) for localization and lateralization of the ACTH source. Results BIPSS correctly localized the source of ACTH excess in 29/29 of the patients with accuracy of 26/26 patients, using any of the agent, whereas sensitivity and PPV for lateralization with hCRH, 5 U LVP and 10 U LVP was seen in 10/10, 6/10; 10/10,8/10 and 7/7,6/7 patients respectively. Concordance of BIPSS with TSS was seen in 20/27, CEMRI with BIPSS in 16/24 and CEMRI with TSS in 18/24 of patients for lateralizing the adenoma. Most of the side effects were transient and were comparable in all the three groups. Conclusion BIPSS using either hCRH or LVP (5 U or 10 U) confirmed the source of ACTH excess in all the patients, while 10 U LVP correctly lateralized the pituitary adenoma in three fourth of the patients.

IntroductionThe present study aimed to evaluate the accuracy of time-resolved-computed tomographic angiography (TR-CTA) on a 128-slice CT scanner vis-à-vis cerebral digital subtraction angiography (DSA) in defining the morphological and haemodynamic characteristics of cerebral arteriovenous malformation (AVM).MethodsTwenty-one patients (age range 10–46, mean 24.8 years) with clinical suspicion of AVM and three patients (age range 23–35, mean 24.3 years) with diagnosed AVM who were on follow-up underwent DSA and TR-CTA, on average 1.5 days apart. Three independent neuroradiologists analysed both studies in a blinded fashion based on the following parameters: AVM location, arterial feeder territories, venous drainage pattern, nidus flow characteristics, venous outflow obstruction, arterial feeder enlargement, external carotid artery feeder, location of aneurysm if any, leptomeningeal and transdural recruitment, neoangiogenesis, and pseudophlebitic pattern.ResultsThe TR-CTA correctly demonstrated AVM in all 21 positive cases. It concordantly detected location (21/21), venous drainage pattern (21/21), nidus flow characteristics (21/21), and the venous outflow obstruction (9/9). However, discordance was seen in the demonstration of the arterial feeder (2/45) ( p = 0.49), arterial enlargement (13/17) ( p = 0.103), external carotid artery feeder (0/1), aneurysmal location (3/5) ( p = 0.40), leptomeningeal recruitment (1/3) ( p = 0.40), neoangiogenesis (0/4) ( p = 0.028) and in the pseudophlebitic pattern (2/5) ( p = 0.167) demonstration.ConclusionsThe results suggest that TR-CTA can provide the important features of cerebral AVM which are required in patient management.

Tuberculosis (TB) remains one of the leading causes of morbidity and mortality worldwide. Extrapulmonary tuberculosis (EPTB) constitutes around 15–20% of TB cases in immunocompetent individuals. Extrapulmonary sites that are affected by TB include bones, lymph nodes, meningitis, pleura, and genitourinary tract. Whole genome sequencing has emerged as a powerful tool to map genetic diversity among Mycobacterium tuberculosis (MTB) isolates and identify the genomic signatures associated with drug resistance, pathogenesis, and disease transmission. Several pulmonary isolates of MTB have been sequenced over the years. However, availability of whole genome sequences of MTB isolates from extrapulmonary sites is limited. Some studies suggest that genetic variations in MTB might contribute to disease presentation in extrapulmonary sites. This can be addressed if whole genome sequence data from large number of extrapulmonary isolates becomes available. In this study, we have performed whole genome sequencing of five MTB clinical isolates derived from EPTB sites using next-generation sequencing platform. We identified 1434 nonsynonymous single nucleotide variations (SNVs), 143 insertions and 105 deletions. This includes 279 SNVs that were not reported before in publicly available datasets. We found several mutations that are known to confer resistance to drugs. All the five isolates belonged to East-African-Indian lineage (lineage 3). We identified 9 putative prophage DNA integrations and 14 predicted clustered regularly interspaced short palindromic repeats (CRISPR) in MTB genome. Our analysis indicates that more work is needed to map the genetic diversity of MTB. Whole genome sequencing in conjunction with comprehensive drug susceptibility testing can reveal clinically relevant mutations associated with drug resistance.

Purpose Dural arteriovenous fistula (DAVF) of the anterior cranial fossa with cortical venous reflux is an aggressive neurovascular entity with a high rate of intracranial bleeding. Only two cases of anterior cranial fossa DAVF presenting with epistaxis alone have been reported. Endovascular approaches have emerged as the primary and safer treatment modality for most DAVFs. Certain fistulas are better treated with open surgical approaches and disconnection. Case description A 55 years old male presented with the history of multiple episodes of severe epistaxis. Cerebral angiography revealed an anterior cranial fossa DAVF of the cribriform plate with cortical venous reflux and a venous varix. The patient was successfully managed with a bifrontal craniotomy and disconnection from the arterial side. Conclusion Atypical or severe epistaxis may arise from a DAVF. Surgical arterial disconnection my be a curative treatment option.

The natural history of glucose intolerance (GI) in patients with acromegaly undergoing surgical treatment has not been fully understood. This study was aimed to unravel the prevalence and predictors of recovery from GI in these patients in a prospective multivariate model.Patients with acromegaly treated between 2007 and 2016 were prospectively studied with respect to demographics, clinicoradiological features, comorbidities, and hormonal investigations before surgery and at regular follow-up. The independent predictors of recovery from diabetes were analyzed.There were a total of 151 patients with active acromegaly included in the study. The median baseline growth hormone (GH) and insulin-like growth factor (IGF)-1 levels were 25 and 811 ng/mL, respectively. Diabetes mellitus (DM) and pre-diabetes were noted in 93 (61.6%) and 20 (13.2%) patients, respectively. Following surgical treatment, the median HbA1c decreased significantly from 6.4% to 5.5% (P0.001), with 46.8% having complete recovery from DM or pre-diabetes. This glycemic recovery had significant association with both biochemical (P = 0.001) and radiological remission (P = 0.01). The recovery from DM had a greater association with post-operative IGF-1 than GH, especially among those with discordant GH and IGF-1 levels (60% in normal IGF-1 and high GH vs. 20% in high IGF-1 and normal GH). Post-operative IGF-1 had a significant impact on recovery from DM (P = 0.01) independent of age, body mass index, duration of DM, and pre-operative HbA1c.Nearly half of the patients with acromegaly with DM or pre-diabetes had glycemic recovery, influenced by biochemical and radiologic remission. Post-operative IGF-1 appears to be the strongest independent determinant of recovery from DM.

Impaired insulin sensitivity (IS) and β-cell dysfunction result in hyperglycaemia in patients of acromegaly. However, alterations in incretins and their impact on glucose-insulin homeostasis in these patients still remain elusive. Twenty patients of active acromegaly (10 each, with and without diabetes) underwent hyperinsulinemic euglycaemic clamp and mixed meal test, before and after surgery, to measure indices of IS, β-cell function, GIP, GLP-1 and glucagon response. Immunohistochemistry (IHC) for GIP and GLP-1 was also done on intestinal biopsies of all acromegalics and healthy controls. Patients of acromegaly, irrespective of presence or absence of hyperglycaemia, had similar degree of insulin resistance, however patients with diabetes exhibited hyperglucagonemia, and compromised β-cell function despite significantly higher GIP levels. After surgery, indices of IS improved, GIP and glucagon levels decreased significantly in both the groups, while there was no significant change in indices of β-cell function in those with hyperglycaemia. IHC positivity for GIP, but not GLP-1, staining cells in duodenum and colon was significantly lower in acromegalics with diabetes as compared to healthy controls possibly because of high K-cell turnover. Chronic GH excess induces an equipoise insulin resistance in patients of acromegaly irrespective of their glycaemic status. Dysglycaemia in these patients is an outcome of β-cell dysfunction consequent to GIP resistance and hyperglucagonemia.

The aryl hydrocarbon receptor (AHR) is a multi-domain cytosolic protein that belongs to the basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) family of transcription factors. Ligand binding induces a conformational change in AHR and promotes nuclear translocation of the receptor (Kewley et al. 2004). AHR can either bind to exogenous (polycyclic aromatic hydrocarbons, dioxins, cigarette smoke) or endogenous ligands (arachidonic acid and leukotrienes, heme metabolites, UV photoproducts of tryptophan) within the cytoplasm. Exogenous ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene are known to activate AHR and mediate cellular toxic response. AHR is also activated by dietary compounds including indole-3-carbinol and flavonoids that mediate various physiological activities in the body (Nguyen and Bradfield 2008; Marconett et al. 2010). AHR ligands are classified as agonists and antagonists depending on the ability of ligands to activate or inhibit AHR induced activity. Previous reports indicate that ligands such as kaempferol, resveratrol, galangin, chrysin and quercetin act either as agonists or antagonists based on the ligand concentration and type of cells induced (Zhang et al. 2003). Thus, diversity of ligands makes AHR signaling a very dynamic and complex. AHR in its inactive state is located in the cytoplasm and forms a complex with molecular chaperones, such as heat shock protein 90 (HSP90) and co-chaperons such as p23 and AHR-interacting protein (AIP) (Trivellin and Korbonits 2011). In presence of ligand, AHR undergoes nuclear translocation where it interacts with AHR nuclear transporter (ARNT) or AHR repressor (AHRR) through the PAS domain. It has been reported that nucleocytoplasmic transport mechanism of AHR varies between humans and mice. In humans, AHR both in stimulated or unstimulated state can undergo nuclear translocation complexed with AIP. In contrast, association of AIP prevents nucleocytoplasmic shuttling of AHR in mice in both stimulated and unstimulated states (Ramadoss et al. 2004). Once AHR is translocated to the nucleus it forms a heterodimer complex with ARNT and binds to xenobiotic response elements located in the promoter region of the target genes. This complex induces coordinated transcription of detoxifying enzymes for efficient absorption, distribution and elimination of xenobiotics from the body (Abel and Haarmann-Stemmann 2010). Apart from this, AHR is known to exhibit endogenous functions such as cell proliferation, cell differentiation and apoptosis. It also acts as an endogenous regulator in several developmental and physiological processes including neurogenesis, hematopoietic stem cell regulation, cellular stress response, immunoregulation and reproductive health (Lindsey and Papoutsakis 2012; Kadow et al. 2011; Hansen et al. 2014). AHR is associated with various pathological and physiological disorders in the body including autoimmune diseases (Veldhoen et al. 2008), inflammation (Podechard et al. 2008; Ovrevik et al. 2014), cardiovascular diseases (Kerley-Hamilton et al. 2012; Savouret et al. 2003) and cancer. Activation of AHR in presence of cigarette smoke has been well documented in lung cancer (Martey et al. 2005; Tsay et al. 2013). Cigarette smoke induced AHR is also known to mediate immune signaling mechanism in chronic obstructive pulmonary disease (COPD) (Chen et al. 2011). Apart from playing an essential role in COPD and lung cancer, AHR expression has been reported in other cancers and adenomas. AHR is reported to be downregulated in growth hormone secreting pituitary adenomas (Jaffrain-Rea et al. 2009), while, increased expression levels of AHR are associated with tumorigenesis in medulloblastoma (Dever and Opanashuk 2012). The enhancement of AHR levels under ligand stimulation induced cell cycle arrest has been reported in pancreatic and gastric cancer (Koliopanos et al. 2002; Peng et al. 2009). Depending upon the type of ligand stimulation, AHR is either known to promote or inhibit tumor progression. Stimulation of AHR with TCDD, 2,3,7,8-tetrachlorodibenzofuran and 3,3′-diindolylmethane inhibits invasiveness and cell growth in breast cancer (Hall et al. 2010). In contrast, stimulation of AHR with n-butyl benzyl phthalate and dibutyl phthalate ligands enhances tumorigenic properties in breast cancer cells (Hsieh et al. 2012). Therefore, AHR could serve as a potential therapeutic target in several cancers (Murray et al. 2014) and hence it is important to develop AHR signaling pathway to understand the mechanism of AHR mediated tumor progression and regression. Although, the diverse role of AHR is documented in literature however a detailed network of AHR signaling is lacking. In this study, we have curated literature information pertaining to AHR induced signaling and developed a pathway map to facilitate better understanding of this receptor.

Spinal radiosurgery is not considered in the domain of traditional Gamma Knife radiosurgery (GKRS) setup. The major obstacles in GKRS for upper cervical spine lesions remain in difficulty of frame fixation, avoiding collision and maintaining the integrity of the relative position of the lesion from image acquisition to treatment. The supraorbital margin remains the standard lowest fixation point for Leksell stereotactic frame. We describe fixation at the maxilla to target and treat upper cervical spine lesions (up to C3 vertebra) with measures to ensure cervical immobilisation and precision of the GKRS treatment. We have treated two patients at the upper cervical spine up to C3 vertebra by fixing anterior pillars of the Leksell stereotactic frame at the maxilla. To ensure cervical immobilisation and precision of treatment, the neck was immobilised with a Philadelphia collar. The relative position between the head and sternum with the couch from image acquisition to the radiation delivery was kept constant. Docking angle was kept neutral (90 degrees) throughout the treatment (from image acquisition to actual treatment). The maxilla is a potential alternative for stereotactic frame fixation. Measures to ensure cervical immobilisation with lower-down frame position permits treatment of lesions as low as C3 vertebra.

Little is known about the natural history of skull base fungal lesions in immunocompetent individuals and the effect of high-dose radiation on fungal lesions.We report a case where radiosurgery was given to a skull base aspergilloma, mistaking it to be a trigeminal schwannoma. There was dramatic spread of the lesion to periventricular region with significant increase in the skull base lesion. The patient never received steroids. A stereotactic biopsy established the diagnosis, and treatment with voriconazole helped.It is possible that radiosurgery decreases local immunity due to vascular sclerosis and aids in spread of the fungal lesion, though it is only speculative. This again highlights the importance of establishing the diagnosis prior to radiosurgery.

Background and Purpose- Though reports suggest decreasing fatality rates of subarachnoid hemorrhage with time, trends in outcome are not reported much especially from developing countries. This study was to analyze changes in outcome across 2 decades and elucidate probable factors. Methods- Prospective databases during 1996 to 2015 were reviewed for neurological outcome at 3 months in relation to demographics, Hunt and Hess grade, Fisher grade, and definitive treatment; and compared between 2 decades, contrasted by establishment of intensive care unit with continuous monitoring and other advancements. Univariate and multivariate analyses were performed. Results- Of the total 2039 patients, 1035 were managed in the former and 1004 in the recent decades. Compared with the former decade, there is delayed age at presentation (46 versus 49 years, P0.001), poorer Fisher grades (81% versus 87%, P0.001), and more patients with Hunt and Hess grade 2 (24% versus 39%, P0.001) in the recent decade. While all patients in databases of the former decade had undergone clipping, 6% in the recent decade underwent coiling. 11% in the recent decade could not undergo definitive treatment. Despite this, there was significantly higher overall favorable outcome (50% versus 60%; odds ratio, 1.5; P0.001) in recent decade. Favorable outcome of surgical clipping per se improved significantly from 50% to 67% (odds ratio 2.0; P0.001). Though the improvement was across subgroups, it was more marked among Hunt and Hess grade 3 and Fisher grades 3 and 4. In multivariate analyses, both overall outcome (adjusted odds ratio, 1.7; 95% CI, 1.4-2.1; P0.001) and surgical outcome (adjusted odds ratio, 1.8; 95% CI, 1.5-2.2; P0.001) were significantly better in recent decade, independent of known prognostic factors. Conclusions- This is probably the first report to show independent improvement in outcome of subarachnoid hemorrhage with betterment in neurosurgical services from developing country. Dedicated intensive care unit care and focused management protocols could be the likely causes for improvement. Resource-constrained institutions may target patients in Hunt and Hess grade 3 and Fisher grades 3 and 4 for optimal intensive care unit utilization.

Background: Imatinib, a tyrosine kinase inhibitor, causes growth failure in children with chronic myeloid leukemia probably by targeting the growth hormone (GH)/insulin like growth factor-1 (IGF-1) axis. We aim to explore the imatinib targets expression in pituitary adenomas and study the effect of imatinib on GH secretion in somatotropinoma cells and GH3 cell line.Materials and Methods: The expression pattern of imatinib's targets (c-kit, VEGF, and PDGFR-α/β) was studied using immunohistochemistry and immunoblotting 157 giant (≥4 cm) pituitary adenomas (121 non-functioning pituitary adenomas, 32 somatotropinomas, and four prolactinomas) and compared to normal pituitary (n = 4) obtained at autopsy. The effect imatinib on GH secretion, cell viability, immunohistochemistry, electron microscopy, and apoptosis was studied in primary culture of human somatotropinomas (n = 20) and in rat somato-mammotroph GH3 cell-line. A receptor tyrosine kinase array was applied to human samples to identify altered pathways.Results: Somatotropinomas showed significantly higher immunopositivity for c-kit and platelet-derived growth factor receptor-β (PDGFR-β; P < 0.009 and P < 0.001, respectively), while staining for platelet-derived growth factor receptor-α (PDGFR-α) and vascular endothelial growth factor (VEGF) revealed a weaker expression (P < 0.001) compared to normal pituitary. Imatinib inhibited GH secretion from both primary culture (P < 0.01) and GH3 cells (P < 0.001), while it did not affect cell viability and apoptosis. The receptor tyrosine kinase array showed that imatinib inhibits GH signaling via PDGFR-β pathway.Conclusion: Imatinib inhibits GH secretion in somatotropinoma cells without affecting cell viability and may be used as an adjunct therapy for treating GH secreting pituitary adenomas.

Methylenetetrahydrofolate reductase (MTHFR) polymorphism (C677T, A1298C) has been implicated in increased plasma homocysteine (Hcy) levels. The present study was designed to investigate the association between MTHFR polymorphism and increased Hcy levels in subarachnoid haemorrhage (SAH) patients. A total of 150 subjects from North India were included in the study, comprising of 100 SAH patients and 50 healthy controls. Plasma Hcy levels was determined and MTHFR polymorphism (C677T, A1298C) was screened by High resolution melting (HRM) analysis. Plasma Hcy levels were found to be significantly higher (p

At times we encounter clinical problems for which there are no directly applicable evidence-based solutions, but we are compelled by circumstances to act. When doing so we rely on related evidence, general principles of best medical practice, and our experience. Each “Current Clinical Practice” feature article in Seminars in Oncology describes such a challenging presentation and offers treatment approaches from selected specialists. We invite readers' comments and questions, which, with your approval, will be published in subsequent issues of the Journal. It is hoped that sharing our views and experiences will better inform our management decisions when we next encounter similar challenging patients. Please send your comments on the articles, your challenging cases, and your treatment successes to me at dr.gjmor ris@gmail.com. I look forward to a lively discussion. Gloria J. Morris, MD, PhD Current Clinical Practice Feature Editor

The effectiveness and short-term safety of recombinant human GH (r-hGH) in acromegaly patients with GH deficiency (GHD) after treatment are not well established. The study includes ten subjects with acromegaly who had GHD treated with r-hGH for 6 months. Control groups consisted of ten age-, gender-, and BMI-matched healthy subjects and ten active acromegaly patients who were treatment naïve. Body composition, quality of life (QoL), muscle strength, lipid profile, and cardiovascular risk factors were assessed in all subjects at baseline, and the same parameters were reassessed after 6 months of therapy with r-hGH in acromegaly with GHD. Repeat magnetic resonance imaging of the sella was performed in treated subjects. Optical colonoscopy was done and biopsies were taken from multiple sites for proliferation indices (Ki67). The median duration of GHD was 17.8 months and dose of r-hGH administered was 5.7±1.5 μg/kg per day. There was improvement in bone mineral content (P=0.01), bone mineral density (P=0.04), muscle strength (PP=0.003), high-density cholesterol (PP=0.005), and reduction in low-density cholesterol (P=0.003) and triglyceride (P=0.004) after treatment. There was no change in lean body mass, total body fat, hsCRP, lipoprotein (a), and fibrinogen levels. There was a modest increase in plasminogen activator inhibitor 1 (P=0.002), but it was lower compared with healthy controls and treatment naïve acromegalics (P=0.007). Six month-r-hGH therapy improves body composition, atherogenic lipid profile, QoL, and muscle strength in GHD patients who had acromegaly. Long-term prospective studies are needed to evaluate the effect of r-hGH therapy in these patients.

To evaluate the diagnostic efficacy of various screening tests for the diagnosis of Cushing syndrome (CS).Thirty-five patients with CS and 16 patients of pseudo-CS were enrolled. Assessment of 24-h urinary free cortisol (UFC), late-night salivary cortisol (LNSC), overnight dexamethasone suppression test (ONDST), late-night plasma cortisol (LNPC), and adrenocorticotropic hormone (ACTH) on outpatient basis, and during sleep as well as in awake state after 48 hours of hospital admission.We found that 24-h UFC performed the best among the screening tests with sensitivity, specificity and areas under the curve (AUCs) of 96.0%, 99%, and 0.988, respectively, at a cut-off of 144.6 μg/24 h. A cut-off of 10.5 nmol/L for LNSC had sensitivity 85.7%, specificity 88.2%, and an AUC of 0.897. A cut-off of 412.4 nmol/L for LNPC on outpatient basis had sensitivity 88.2%, specificity 91.2%, and an AUC of 0.957. Cut-offs of 215 and 243.3 nmol/L for LNPC during sleep and awake states after acclimatization had sensitivity, specificity, and an AUC of 94.1%, 88.2%, and 0.958, respectively. An ONDST cut-off of 94.6 nmol/L provided sensitivity, specificity, and an AUC of 96.0%, 99.03% and 0.995, respectively. A cut-off of 30.3 pg/mL for late-night ACTH on outpatient basis had sensitivity 67.6%, specificity 99.9%, and an AUC 0.796.A cut-off of 22.6 pg/mL for ACTH during sleep state after acclimatization had sensitivity, specificity, and an AUC of 73.5%, 99.2%, and 0.827, respectively.UFC is the best screening test for CS. Furthermore, single measurements of LNPC and ACTH help to establish the diagnosis and ACTH dependency of CS in the majority of patients with CS.ACTH = adrenocorticotropic hormone AUC = area under the curve CRH = corticotropin-releasing hormone CS = Cushing syndrome ECLIA = electrochemiluminescence immuno-assay LDDST = low-dose dexamethasone suppression test LNPC = late-night plasma cortisol LNSC = late-night salivary cortisol ONDST = overnight dexamethasone suppression test RIA = radio-immuno assay UFC = urinary free cortisol.

Background: To evaluate the feasibility, safety and efficacy of dose fractionated gamma knife radiosurgery (DFGKRS) on a daily schedule beyond the linear quadratic (LQ) model, for large volume arteriovenous malformations (AVMs). Material and Methods: Between 2012-16, 14 patients of large AVMs (median volume 26.5 cc) unsuitable for surgery or embolization were treated in 2-3 of DFGKRS sessions. The Leksell G frame was kept in situ during the whole procedure. 86% (n = 12) patients had radiologic evidence of bleed, and 43% (n = 6) had presented with a history of seizures. 57% (n = 8) patients received a daily treatment for 3 days and 43% (n = 6) were on an alternate day (2 fractions) regimen. The marginal dose was split into 2 or 3 fractions of the ideal prescription dose of a single fraction of 23-25 Gy. Results: The median follow up period was 35.6 months (8-57 months). In the three-fraction scheme, the marginal dose ranged from 8.9-11.5 Gy, while in the two-fraction scheme, the marginal dose ranged from 11.3-15 Gy at 50% per fraction. Headache (43%, n = 6) was the most common early postoperative complication, which was controlled with short course steroids. Follow up evaluation of at least three years was achieved in seven patients, who have shown complete nidus obliteration in 43% patients while the obliteration has been in the range of 50-99% in rest of the patients. Overall, there was a 67.8% reduction in the AVM volume at 3 years. Nidus obliteration at 3 years showed a significant rank order correlation with the cumulative prescription dose (p 0.95, P value 0.01), with attainment of near-total (more than 95%) obliteration rates beyond 29 Gy of the cumulative prescription dose. No patient receiving a cumulative prescription dose of less than 31 Gy had any severe adverse reaction. In co-variate adjusted ordinal regression, only the cumulative prescription dose had a significant correlation with common terminology criteria for adverse events (CTCAE) severity (P value 0.04), independent of age, AVM volume, number of fractions and volume of brain receiving atleast 8 Gy of radiation. Conclusion: DFGKRS is feasible for large AVMs with a fair nidus obliteration rate and acceptable toxicity. Cumulative prescription dose seems to be the most significant independent predictor for outcome following DFGKRS with 29-30 Gy resulting in a fair nidus obliteration with least adverse events.

The role of nutritional markers on outcome following subarachnoid hemorrhage (SAH) has been scarcely described.This is a prospective study of 273 patients with SAH, in which haemoglobin, serum protein and albumin were measured within 24 hours and again at one week following ictus, and analysed with respect to other variables. New neurologic deficits (NND), infarct, mortality and Glasgow outcome scale (GOS) at 3 months were assessed.The values of haemoglobin, total protein and albumin showed significant (p .001) decline over the first week of SAH. Patients who developed NND had significantly lower serum albumin levels at admission compared to others (median 3.6 vs 3.9 g/dL, p .001). Patients having lower albumin (≤3.5 gm/dL) levels at admission had significantly higher rates of NND (52% vs 20%), infarct (35% vs 23%), mortality (28% vs 16%) and unfavourable GOS (38% vs 25%). HuntHess (HH) grade and Fisher grade also affected all the outcome parameters significantly. Percentage decrease in albumin levels at one week following ictus significantly affected mortality and unfavourable GOS. On multivariate analyses, Fisher grade and lower admission albumin levels had significant impact on NND, while percentage decrease in albumin levels had significant impact on mortality and unfavourable GOS, independent of other nutritional markers and known prognostic variables.Serum albumin levels following SAH can be useful to predict development of NND, while its further weekly decrease correlates independently with unfavourable outcome at 3 months. Albumin assessment being readily available may serve as more than a mere nutritional parameter in SAH.

Background: Extraskeletal mesenchymal chondrosarcoma (ESMCS) is an unusual pathologic variant of chondrosarcoma. There are no specific clinicoradiographic parameters to distinguish it from other intracranial pathologies. The diagnosis can be established only on the basis of histopathology, which may pose significant challenges in certain unusual locations. Purpose: In this case, we discuss the pitfalls in diagnosis, management, and major characteristics of ESMCS with a review of current literature. Methods and Results: A 47-year-old female patient presented with a jugular foramen tumor which was misdiagnosed as glomus jugulare tumor for which she received primary gamma knife radiosurgery at 2 instances. But unfortunately, the patient died because of the increase in size of the lesion associated with necrosis. Autopsy analysis revealed a highly cellular tumor, rich in sarcomatous cells, and well-differentiated cartilages consistent with ESMCS. Conclusion: A definite preoperative diagnosis of ESMCS is crucial though difficult especially when located at complex sites like jugular foramen and clinicoradiological mimicry. The most crucial step in the management of ESMCS is accurate diagnosis with critical evaluation of clinical, radiological, and histopathological parameters and realization of highly variable clinical course of the disease.

Esophageal perforation is a dreaded complication of anterior cervical spinal surgery. A 52-year-old diabetic man had undergone a surgery for a C6-C7 disc prolapse and developed spiking fever with chills and rigor on the 7th postoperative day. No cause could be found out but a CT scan of thorax done in the course of investigations revealed pneumomediastimum. The patient succumbed on the 10th day after surgery. Autopsy revealed the cause of death to be mediastinitis following iatrogenic esophageal perforation. A second patient, 53 years of age, following surgery for C5-C6 disc prolapse and developed intractable dysphagia. Later, fever and purulent discharge from the wound prompted an MRI showing prevertebral collection extending to the superior mediastinum. Presuming only wound infection, debridement and implant removal was done. However persistent serous discharge from the wound revealed an esophageal injury. Late diagnosis precluded primary repair. With conservative treatment, the fistula finally closed after 42 days. Postoperative dysphagia, a common complaint following surgery, may not always be present in cases of esophageal injury. A high index of suspicion is required for diagnosing and initiating treatment for esophageal perforation before complications set in.

Introduction: Ishikawa and Jefferson are the two most commonly used systems used for the classification of cavernous sinus syndrome (CSS). However, relative utilities of these two classification systems have not been evaluated in detail in developing countries. In this study, we compared relative utilities of these two classification schemes in the evaluation of CSS. Objective: To compare the utility of Jefferson and Ishikawa classifications in the evaluation of CSS. Patients and Methods: A total of 73 consecutive patients of CSS were prospectively classified using either Ishikawa or Jefferson classification and relative utility of these two classification schemes in determining etiology of CSS was compared. Results: While only 46.6% of patients could be classified using Jefferson classification, 95.5% of patients could be classified using Ishikawa scheme. CSS was classified as anterior, middle, and posterior in 17.8%, 21.9%, and 8.2% of patients, respectively, as per the Jefferson classification. As per the Ishikawa classification, 37% of patients each showed anterior and posterior CSS, 16.4% showed middle CSS, whereas 4.1% had whole CSS. Middle CSS was significantly associated with the presence of fungal infections (P = 0.045) as per Jefferson classifications, and anterior CSS was significantly associated with a vascular etiology (P = 0.005) as per Ishikawa classification. Overall, inflammatory causes were the most common cause for anterior CSS, while tumors accounted for maximum cases of posterior CSS. Conclusion: Although more number of patients could be classified using Ishikawa classification, there was no advantage of Ishikawa classification over Jefferson with regard to determination of etiology of CSS.

The Department of Neurosurgery started functioning at the Postgraduate Institute of Medical Education and Research, Chandigarh in 1962 with the joining of Dr. Gulati. The department provides neurosurgical services primarily to the people of Chandigarh, Punjab, Haryana, Himachal Pradesh, Jammu and Kashmir as well as the neighbouring areas of Rajasthan, Uttar Pradesh and Uttarakhand. The infrastructure and subspecialties have been developed over the last 5 decades by the dedicated and tireless efforts of the faculty and residents. We attempt to chronicle the contributions of those who have served the department in the past.

Homocysteine (tHcy) has been known over the last few decades for its putative impact on vascular diseases, but has not been evaluated much in patients with subarachnoid hemorrhage (SAH). This study was carried out to assess its prognostic impact on the neurological outcome following SAH. Admission plasma tHcy was evaluated in 90 SAH patients and prospectively studied in relation to various factors and the Glasgow Outcome Scale (GOS) at 3 months. Univariate and multivariate analyses were performed using SPSS 21. tHcy was significantly higher following SAH compared to matched controls [median (IQR): 25.7 (17.3–35.9) vs. 14.0 (9.8–17.6) μmol/l, p

Background: Parachordomas are rare soft tissue tumors commonly occurring in limbs, chest, Abdomen, and back. The World Health Organization (WHO) classification includes parachordomas in the same group as mixed tumors and myoepitheliomas. Exact histogenesis of this tumor is unclear. Case Description: A 52‑year‑old male presented with headache and blurring of vision since one month. Preoperative computed tomography (CT) scan of brain revealed left parieto‑occipital tumor extending up to the trigone. Total excision of the tumor was done. Histopathologically, the tumor was composed of relatively uniform cells with eosinophilic cytoplasm in a myxoid stroma and with cartilaginous and osseous metaplasia. The tumoral cells were immunoreactive for cytokeratin, epithelial membrane antigen (EMA), S‑100, and vimentin. The constellation of findings revealed the tumor to be parachordoma. Magnetic resonance imaging (MRI) brain during follow‑up at one year showed no recurrent tumor. No adjuvant therapy was given to this patient. Conclusion: This is the first reported case of primary intracranial parachordoma. It is difficult to diagnose the lesion preoperatively by imaging alone. Long‑term follow‑up is necessary in view of few reports in literature of recurrence and metastasis, of parachordomas in other anatomical locations.

Posttraumatic true irreducible C1–2 lateral dislocation is rare. The mechanism of injury is likely to be different for this kind of dislocation. The management of such an injury and the technique for direct posterior reduction remain unclear because of its rarity. The authors describe the case of a 34-year-old man who sustained injury in a vehicular accident, leading to neck pain. Radiological studies revealed fixed right lateral and posterior C1–2 dislocation. Direct posterior open reduction was achieved by distracting the facets and rotating them in a counterclockwise direction. Care was taken to avoid direct or indirect injury to the vertebral arteries. Segmental C1–2 fusion was performed. Distraction with lateral extension injury possibly gives rise to this unique fracture dislocation. Preoperative imaging including angiography for vertebral arteries helps in defining the cause of fixity and in surgical planning. Direct posterior reduction is possible in such fixed C1–2 lateral dislocation, circumventing transoral surgery—provided the facets are preserved.

The availability of human genome sequence has transformed biomedical research over the past decade. However, an equivalent map for the human proteome with direct measurements of proteins and peptides does not exist yet. Here we present a draft map of the human proteome using high-resolution Fourier-transform mass spectrometry. In-depth proteomic profiling of 30 histologically normal human samples, including 17 adult tissues, 7 fetal tissues and 6 purified primary haematopoietic cells, resulted in identification of proteins encoded by 17,294 genes accounting for approximately 84% of the total annotated protein-coding genes in humans. A unique and comprehensive strategy for proteogenomic analysis enabled us to discover a number of novel protein-coding regions, which includes translated pseudogenes, non-coding RNAs and upstream open reading frames. This large human proteome catalogue (available as an interactive web-based resource at http://www.humanproteomemap.org) will complement available human genome and transcriptome data to accelerate biomedical research in health and disease.

Introduction Introduction:Non-functioning pituitary adenomas (NFPA) usually present as macroadenomas and 42% shows invasion of the adjacent structures, such as cavernous sinus, sphenoid bone or nasopharynx and some recur locally. The incomplete surgery section of invasive non-functional pituitary adenomas (NFPAs) carries the increased risks of recurrence and requires adjuvant radiotherapy and surgeries. It is necessary to clarify the molecular mechanisms and markers of invasiveness to guide the management of NFPA patients. Here we describe a comprehensive phosphoproteomic evaluation of 20 NFPAs followed by validation in a larger set of samples. Material and methods Peptides from 20 tumours were enriched with TiO2 beads, fractionated using bRPLC and subjected to high-throughput LC-MS/MS-Orbitrap Fusion Tribrid Mass Spectrometer. Upto 5 precursor ions were chosen for MS/MS analysis. Following MASCOT and SEQUEST analysis our bioinformatics pipeline (PhosphositePlus, Gene Ontology, DAVID, and KEGG) identified 1345 phosphoprotein groups and 2233 unique phosphopeptides. Eight candidate phosphoproteins involved in cell proliferation and growth were selected for validation using immunohistochemistry(tissue microarray containing 200 NFPA samples) and immunoblotting (n=18). Results and discussions Hsp27 phospho-Ser82 was found 2.1 fold upregulated in invasive and 7.8 fold hyperphosphorylated in recurrent group while Hsp phospho-Ser15 was found 2.1 fold upregulated in invasive and 7.8 fold hyperphosphorylated in recurrent group in our mass spectrometry experiment. Immunohistochemistry for Ser82 revealed 2.1-fold upregulation (p Conclusion Hsp27 phosphorylated at Ser82 is significantly associated with NFPA invasion and recurrence. It Provides a roadmap for patient stratification, and prognostication for recurrence and trials for targeted therapy.

Introduction Yellow-colored cerebrospinal fluid (CSF) suggestive of xanthochromia can be due to elevated CSF protein and can be one of the causes of papilledema. Observation We observed a 55-year-old lady with papilledema with yellow-colored CSF which was hypercoagulable along with elevated CSF protein and no cells. Her systemic and nervous system examination was unremarkable except for the eye findings. Her contrast-enhanced brain magnetic resonance imaging (MRI) showed multiple meningiomas, and on imaging of the spine, she had multiple contrast-enchancing intradural, extramedullary lesions. Her eye findings were attributed to Froin syndrome found in patients with spinal tumors. Conclusion Our case stresses the need to keep the possibility of Froin syndrome in mind while evaluating patients with papilledema and it may be pertinent to perform a spinal imaging, especially when no apparent cause for papilledema is found. How to cite this article Choudhary A, Goyal MK, Modi M, Mukherjee KK, Ahuja CK, Lal V. Froin Syndrome. J Postgrad Med Edu Res 2018;52(1):34-35.

Background: Radiation-induced brain edema (RIBE) is a serious complication of radiation therapy. It may result in dramatic clinico-radiological deterioration. At present, there are no definite guidelines for management of the complication. Corticosteroids are the usual first line of treatment, which frequently fails to provide long-term efficacy in view of its adverse complication profile. Bevacizumab has been reported to show improvement in cases of steroid-resistant radiation injury. The objective of this study is to evaluate the role of Bevacizumab in post-radiosurgery RIBE. Material and Methods: Since 2012, 189 out of 1241 patients who underwent radiosurgery at our institution developed post-radiosurgery RIBE, 17 of which did not respond to high-dose corticosteroids. We systematically reviewed these 17 patients of various intracranial pathologies with clinic-radiological evidence of RIBE following gamma knife radiosurgery (GKRS). All patients received protocol-based Bevacizumab therapy. The peer-reviewed literature was evaluated. Results: 82 percent of the patients showed improvement after starting Bevacizumab. The majority began to improve after the third cycle started improvement after the third cycle of Bevacizumab. Clinical improvement preceded radiological improvement by an average of eight weeks. The first dose was 5 mg/kg followed by 7.5–10 mg/kg at with two-week intervals. Bevacizumab needs to be administered for an average of seven cycles (range 5–27, median 7) for best response. Steroid therapy could be tapered in most patients by the first follow-up. One patient did not respond to Bevacizumab and needed surgical decompression for palliative care. One noncompliant patient died due to radiation injury. Conclusion: Bevacizumab is a effective and safe for treatment of RIBE after GKRS. A protocol-based dose schedule in addition to frequent clinical and radiological evaluations are required. Bevacizumab should be considered as an early treatment option for RIBE.

Background context Computed tomography (CT) has become the sole modality of screening for cervical injury in polytrauma because of the high sensitivity, speed, and convenience, thereby eliminating the need for plain radiographs. Purpose We report two cases of misleading artifactual fracture-subluxation of cervical spine in CT, which could have resulted in needless treatment, and describe its characteristics. Study design Case report and review. Methods Two patients who were initially diagnosed with fracture-subluxation on screening CT cervical spine were later noted to have motion artifacts and were reviewed. Results The artifactual nature of the supposed fracture-subluxation was unmasked by the soft-tissue findings of obscuration in sagittal reconstruction and duplication in axial images, along with the presence of double bony margins. Conclusions Motion artifact in cervical CT screening can lead to a misdiagnosis of fracture subluxation. Duplication of soft tissue is highly suggestive of this motion artifact, and an additional single lateral plain radiograph may avert this pitfall.

Neurotrophic factors are growth factors, which play an essential role in the development and maintenance of nervous system. These include members of the nerve growth factor (NGF) family, known as neurotrophins. Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), neurotrophin 4 (NT4/5) and neurotrophin 6 (NT-6) constitute the family of neurotrophins (Barbacid 1995). The identification of neurotrophic factors began from the search for target-derived molecules, which act on neurons and promote their survival (Lindsay 1996). BDNF is one such essential survival factor. BDNF was first isolated and purified from pig brain (Barde et al. 1982). BDNF, encoded by the BDNF gene, is the second member of the neurotrophin family after NGF (Timmusk et al. 1993). BDNF, like other neurotrophins, exists as a homodimer. It is synthesized as a precursor molecule, proBDNF (32 kDa), which is cleaved to form the mature and biologically active form of BDNF (∼13 kDa) (Negro et al. 1994). It is expressed throughout the central nervous system (Leibrock et al. 1989) and also in peripheral tissues including muscle, liver, pancreas, colon, duodenum, lung, kidney and bladder (Lommatzsch et al. 1999). The dimerized BDNF binds to the tyrosine kinase receptor, tropomyosin-related kinase B (TrkB), leading to activation of various signaling modules. Trk was first identified as an oncoprotein in human tumors (Martin-Zanca et al. 1986). The Trk family of receptors includes TrkA, which binds to NGF (Kaplan et al. 1991); TrkB, which is the receptor for BDNF and NT-4 (Klein et al. 1989); and TrkC, the receptor for NT-3 (Lamballe et al. 1991). TrkB is an 821 amino acid long glycoprotein, encoded by the NTRK2 gene. It comprises of a signal peptide followed by an extracellular domain, a transmembrane domain and a cytoplasmic region consisting of the tyrosine kinase domain (Nakagawara et al. 1995). TrkB is expressed in the central and peripheral nervous system (Allen et al. 1994). Like other neurotrophins, BDNF also binds to nerve growth factor receptor (NGFR), also known as p75 neurotrophin receptor (p75NTR), albeit with a low-affinity (Chao et al. 1986). Binding of BDNF to TrkB results in the dimerization of the receptor and activation of its cytoplasmic kinase domain (Ohira et al. 2001; Wu et al. 1996), which results in the recruitment of adaptor proteins to the receptor, which in turn leads to the activation of intracellular signaling cascades including RAS/ERK pathway, PI3K/AKT pathway, PLC/PKC pathway and NFκB pathway. BDNF/TrkB signaling is essential for growth, differentiation and survival of neurons. It is also important for neuronal morphogenesis and synaptic plasticity (Binder and Scharfman 2004). BDNF also plays a major role in other processes such as energy metabolism (Matthews et al. 2009), behavior, learning, memory (Hall et al. 2000), pain (Pezet et al. 2002) and apoptosis (Yeiser et al. 2004). BDNF is implicated in Alzheimer’s disease (Ferrer et al. 1999), Huntington’s disease (Zuccato et al. 2001), epilepsy (Takahashi et al. 1999) and bipolar disorder (Neves-Pereira et al. 2002). However, despite its biological significance, molecular events induced by either BDNF/TrkB or BDNF/p75NTR interactions, were not organized into a signaling network. As a part of the ongoing NetPath project, which aims at the development of a centralized resource for human signaling pathways (Kandasamy et al. 2010; Raju et al. 2011b), we have documented molecular reactions induced by several signaling systems by systematically reviewing published reports and assembled them in the form of signaling pathways. We have previously published molecular networks of signaling induced by prolactin (Radhakrishnan et al. 2012), oncostatin M (Dey et al. 2012); corticotropin releasing hormone (Subbannayya et al. 2013) and advanced glycation end-products (Soman et al. 2013). Similarly, as BDNF signaling pathway is of immense biomedical interest, we analyzed literature pertaining to BDNF-induced signaling events and developed a graphical network map of BDNF/TrkB and BDNF/p75NTR signaling pathways.