α-Hemolysin promotes uropathogenic E. coli persistence in bladder epithelial cells via abrogating bacteria-harboring lysosome acidification.

There is a growing consensus that a significant proportion of recurrent urinary tract infections are linked to the persistence of uropathogens within the urinary tract and their re-emergence upon the conclusion of antibiotic treatment. Studies in mice and human have revealed that uropathogenic Escherichia coli (UPEC) can persist in bladder epithelial cells (BECs) even after the apparent resolution of the infection. Here, we found that, following the entry of UPEC into RAB27b+ fusiform vesicles in BECs, some bacteria escaped into the cytoplasmic compartment via a mechanism involving hemolysin A (HlyA). However, these UPEC were immediately recaptured within LC3A/B+ autophagosomes that matured into LAMP1+ autolysosomes. Thereafter, HlyA+ UPEC-containing lysosomes failed to acidify, which is an essential step for bacterial elimination. This lack of acidification was related to the inability of bacteria-harboring compartments to recruit V-ATPase proton pumps, which was attributed to the defragmentation of cytosolic microtubules by HlyA. The persistence of UPEC within LAMP1+ compartments in BECs appears to be directly linked to HlyA. Thus, through intravesicular instillation of microtubule stabilizer, this host defense response can be co-opted to reduce intracellular bacterial burden following UTIs in the bladder potentially preventing recurrence.

Lactobacillus crispatus Limits Bladder Uropathogenic E. coli Infection by Triggering a Host Type I Interferon Response.

Many urinary tract infections (UTIs) are recurrent because uropathogens persist within the bladder epithelial cells (BECs) for extended periods between bouts of infection. Because persistent uropathogens are intracellular, they are often refractive to antibiotic treatment. The recent discovery of endogenous Lactobacillus spp. in the bladders of healthy humans raised the question of whether these endogenous bacteria directly or indirectly impact intracellular bacterial burden in the bladder. Here, we report that in contrast to healthy women, female patients experiencing recurrent UTIs have a bladder population of Lactobacilli that is markedly reduced. Exposing infected human BECs to L. crispatus in vitro markedly reduced the intracellular uropathogenic Escherichia coli (UPEC) load. The adherence of Lactobacilli to BECs was found to result in increased type I interferon (IFN) production, which in turn enhanced the expression of cathepsin D within lysosomes harboring UPECs. This lysosomal cathepsin D-mediated UPEC killing was diminished in germ-free mice and type I IFN receptor-deficient mice. Secreted metabolites of L. crispatus seemed to be responsible for the increased expression of type I IFN in human BECs. Intravesicular administration of Lactobacilli into UPEC-infected murine bladders markedly reduced their intracellular bacterial load suggesting that components of the endogenous microflora can have therapeutic effects against UTIs.

Injectable liposome-containing click hydrogel microparticles for release of macromolecular cargos.

Hydrogel microparticles ranging from 0.1-100 µm, referred to as microgels, are attractive for biological applications afforded by their injectability and modularity, which allows facile delivery of mixed populations for tailored combinations of therapeutics. Significant efforts have been made to broaden methods for microgel production including via the materials and chemistries by which they are made. Via droplet-based-microfluidics we have established a method for producing click poly-(ethylene)-glycol (PEG)-based microgels with or without chemically crosslinked liposomes (lipo-microgels) through the Michael-type addition reaction between thiol and either vinyl-sulfone or maleimide groups. Unifom spherical microgels and lipo-microgels were generated with sizes of 74 ± 16 µm and 82 ± 25 µm, respectively, suggesting injectability that was further supported by rheological analyses. Super-resolution confocal microscopy was used to further verify the presence of liposomes within the lipo-microgels and determine their distribution. Atomic force microscopy (AFM) was conducted to compare the mechanical properties and network architecture of bulk hydrogels, microgels, and lipo-microgels. Further, encapsulation and release of model cargo (FITC-Dextran 5 kDa) and protein (equine myoglobin) showed sustained release for up to 3 weeks and retention of protein composition and secondary structure, indicating their ability to both protect and release cargos of interest.

Is intraoperative electrocorticography (ECoG) for long-term epilepsy-associated tumors (LEATs) more useful in children?-A Randomized Controlled Trial.

OBJECTIVES: The utility of intraoperative electrocorticography (ECoG)-guided resective surgery for pediatric long-term epilepsy-associated tumors (LEATs) with antiseizure medication (ASM) resistant epilepsy is not supported by robust evidence. As epilepsy networks and their ramifications are different in children from those in adults, the impact of intraoperative ECoG-based tailored resections in predicting prognosis and influencing outcomes may also differ. We evaluated this hypothesis by comparing the outcomes of resections with and without the use of ECoG in children and adults by a randomized study. METHODS: From June 2020 to January 2022, 42 patients (17 children and 25 adults) with LEATs and antiseizure medication (ASM)-resistant epilepsy were randomly assigned to one of the 2 groups (ECoG or no ECoG), prior to surgical resection. The 'no ECoG' arm underwent gross total lesion resection (GTR) without ECoG guidance and the ECoG arm underwent GTR with ECoG guidance and further additional tailored resections, as necessary. Factors evaluated were tumor location, size, lateralization, seizure duration, preoperative antiepileptic drug therapy, pre- and postresection ECoG patterns and tumor histology. Postoperative Engel score and adverse event rates were compared in the pediatric and adult groups of both arms. Eloquent cortex lesions and re-explorations were excluded to avoid confounders. RESULTS: Forty-two patients were included in the study of which 17 patients were in the pediatric cohort (age < 18 years) and 25 in the adult cohort. The mean age in the pediatric group was 11.11 years (SD 4.72) and in the adult group was 29.56 years (SD 9.29). The mean duration of epilepsy was 9.7 years (SD 4.8) in the pediatric group and 10.96 (SD 8.8) in the adult group. The ECoG arm of LEAT resections had 23 patients (9 children and 14 adults) and the non-ECoG arm had 19 patients (8 children and 11 adults). Three children and 3 adults from the ECoG group further underwent ECoG-guided tailored resections (average 1.33 additional tailored resections/per patient.).The histology of the tailored resection specimen was unremarkable in 3/6 (50%).Overall, the commonest histology in both groups was ganglioglioma and the temporal lobe, the commonest site of the lesion. 88.23% of pediatric cases (n = 15/17) had an excellent outcome (Engel Ia) following resection, compared to 84% of adult cases (n = 21/25) at a mean duration of follow-up of 25.76 months in children and 26.72 months in adults (p = 0.405).There was no significant difference in seizure outcomes between the ECoG and no ECoG groups both in children and adults, respectively (p > 0.05). Additional tailored resection did not offer any seizure outcome benefit when compared to the non-tailored resections. CONCLUSIONS: The use of intraoperative electrocorticography in LEATs did not contribute to postoperative seizure outcome benefit in children and adults. No additional advantage or utility was offered by ECoG in children when compared to its use in adults. ECoG-guided additional tailored resections did not offer any additional seizure outcome benefit both in children and adults.

EUS-guided Gastroenterostomy: A Multicenter International Study Comparing Benign and Malignant Diseases.

BACKGROUND: Endoscopic ultrasound (EUS)-guided gastroenterostomy (EUS-GE) is a minimally invasive therapy for patients with gastric outlet obstruction without the risks of surgical bypass and the limited long-term efficacy of enteral self-expanding metal stent placement. However, due to its novelty, there is a lack of significant data comparing long-term outcomes of patients with EUS-GE, based on the underlying disease. In this study, we compare outcomes of EUS-GE on benign versus malignant indications. METHODS: Consecutive patients from 12 international, tertiary care centers who underwent EUS-GE over 3 years were extracted in a retrospective registry. Demographic characteristics, procedure-related information and follow-up data was collected. Primary outcome was the rate of adverse events associated with EUS-GE and the comparison of the rate of adverse events in benign versus malignant diseases. Secondary outcomes included technical and clinical success as well as hospitalization admission. RESULTS: A total of 103 patients were included: 72 malignant and 31 benign. The characteristics of the patients undergoing EUS-GE is shown in Table 1. The mean age of the cohort was 68 years and 58 years for malignant and benign etiology. Gender distribution was 57% and 39% being females in malignant and benign etiology group, respectively. Clinical success, technical success, average procedure time, and hospital length of stay were similar in both groups. Patients with benign underlying etiology had significantly higher number of surgically altered midgut anatomy (P=0.0379). CONCLUSION: EUS-GE is equally efficient regardless of the underlying etiology (malignant vs. benign), and the adverse events both groups were comparable.

Oscillatory shear stress modulates Notch-mediated endothelial mesenchymal plasticity in cerebral arteriovenous malformations.

BACKGROUND: Cerebral arteriovenous malformations (cAVM) are a significant cause of intracranial hemorrhagic stroke and brain damage. The arteriovenous junctions in AVM nidus are known to have hemodynamic disturbances such as altered shear stress, which could lead to endothelial dysfunction. The molecular mechanisms coupling shear stress and endothelial dysfunction in cAVMs are poorly understood. We speculated that disturbed blood flow in artery-vein junctions activates Notch receptors and promotes endothelial mesenchymal plasticity during cAVM formation. METHODS: We investigated the expression profile of endothelial mesenchymal transition (EndMT) and cell adhesion markers, as well as activated Notch receptors, in 18 human cAVM samples and 15 control brain tissues, by quantitative real-time PCR (qRT-PCR) and immunohistochemical evaluation. Employing a combination of a microfluidic system, qRT-PCR, immunofluorescence, as well as invasion and inhibitor assays, the effects of various shear stress conditions on Notch-induced EndMT and invasive potential of human cerebral microvascular endothelial cells (hCMEC/d3) were analyzed. RESULTS: We found evidence for EndMT and enhanced expression of activated Notch intracellular domain (NICD3 and NICD4) in human AVM nidus samples. The expression of transmembrane adhesion receptor integrin α9/ß1 is significantly reduced in cAVM nidal vessels. Cell-cell adhesion proteins such as VE-cadherin and N-cadherin were differentially expressed in AVM nidus compared with control brain tissues. Using well-characterized hCMECs, we show that altered fluid shear stress steers Notch3 nuclear translocation and promotes SNAI1/2 expression and nuclear localization. Oscillatory flow downregulates integrin α9/ß1 and VE-cadherin expression, while N-cadherin expression and endothelial cell invasiveness are augmented. Gamma-secretase inhibitor RO4929097, and to a lesser level DAPT, prevent the mesenchymal transition and invasiveness of cerebral microvascular endothelial cells exposed to oscillatory fluid flow. CONCLUSIONS: Our study provides, for the first time, evidence for the role of oscillatory shear stress in mediating the EndMT process and dysregulated expression of cell adhesion molecules, especially multifunctional integrin α9/ß1 in human cAVM nidus. Concomitantly, our findings indicate the potential use of small-molecular inhibitors such as RO4929097 in the less-invasive therapeutic management of cAVMs.

Evaluation of a New Viral Vaccine Vector in Mice and Rhesus Macaques: J Paramyxovirus Expressing Hemagglutinin of Influenza A Virus H5N1.

H5N1, an avian influenza virus, is known to circulate in many Asian countries, such as Bangladesh, China, Cambodia, Indonesia, and Vietnam. The current FDA-approved H5N1 vaccine has a moderate level of efficacy. A safe and effective vaccine is needed to prevent outbreaks of highly pathogenic avian influenza (HPAI) H5N1 in humans. Nonsegmented negative-sense single-stranded viruses (NNSVs) are widely used as a vector to develop vaccines for humans, animals, and poultry. NNSVs stably express foreign genes without integrating with the host genome. J paramyxovirus (JPV) is a nonsegmented negative-strand RNA virus and a member of the proposed genus Jeilongvirus in the family Paramyxoviridae. JPV-specific antibodies have been detected in rodents, bats, humans, and pigs, but the virus is not associated with disease in any species other than mice. JPV replicates in the respiratory tract of mice and efficiently expresses the virus-vectored foreign genes in tissue culture cells. In this work, we explored JPV as a vector for developing an H5N1 vaccine using intranasal delivery. We incorporated hemagglutinin (HA) of H5N1 into the JPV genome by replacing the small hydrophobic (SH) gene to generate a recombinant JPV expressing HA (rJPV-ΔSH-H5). A single intranasal administration of rJPV-ΔSH-H5 protected mice from a lethal HPAI H5N1 challenge. Intranasal vaccination of rJPV-ΔSH-H5 in rhesus macaques elicited antigen-specific humoral and cell-mediated immune responses. This work demonstrates that JPV is a promising vaccine vector. IMPORTANCE A highly pathogenic avian influenza (HPAI) H5N1 outbreak in Southeast Asia destroyed millions of birds. Transmission of H5N1 into humans resulted in deaths in many countries. In this work, we developed a novel H5N1 vaccine candidate using J paramyxovirus (JPV) as a vector and demonstrated that JPV is an efficacious vaccine vector in animals. Nonsegmented negative-sense single-stranded viruses (NNSVs) stably express foreign genes without integrating into the host genome. JPV, an NNSV, replicates efficiently in the respiratory tract and induces robust immune responses.

Aberrant regulation of retinoic acid signaling genes in cerebral arterio venous malformation nidus and neighboring astrocytes.

BACKGROUND: Cerebral arterio venous malformations (AVM) are a major causal factor for intracranial hemorrhage, which result in permanent disability or death. The molecular mechanisms of AVM are complex, and their pathogenesis remains an enigma. Current research on cerebral AVM is focused on characterizing the molecular features of AVM nidus to elucidate the aberrant signaling pathways. The initial stimuli that lead to the development of AVM nidus structures between a dilated artery and a vein are however not known. METHODS: In order to understand the molecular basis of development of cerebral AVM, we used in-depth RNA sequencing with the total RNA isolated from cerebral AVM nidus. Immunoblot and qRT-PCR assays were used to study the differential gene expression in AVM nidus, and immunofluorescence staining was used to study the expression pattern of aberrant proteins in AVM nidus and control tissues. Immunohistochemistry was used to study the expression pattern of aberrant proteins in AVM nidus and control tissues. RESULTS: The transcriptome study has identified 38 differentially expressed genes in cerebral AVM nidus, of which 35 genes were upregulated and 3 genes were downregulated. A final modular analysis identified an upregulation of ALDH1A2, a key rate-limiting enzyme of retinoic acid signaling pathway. Further analysis revealed that CYR61, a regulator of angiogenesis, and the target gene for retinoic acid signaling is upregulated in AVM nidus. We observed that astrocytes associated with AVM nidus are abnormal with increased expression of GFAP and Vimentin. Triple immunofluorescence staining of the AVM nidus revealed that CYR61 was also overexpressed in the abnormal astrocytes associated with AVM tissue. CONCLUSION: Using high-throughput RNA sequencing analysis and immunostaining, we report deregulated expression of retinoic acid signaling genes in AVM nidus and its associated astrocytes and speculate that this might trigger the abnormal angiogenesis and the development of cerebral AVM in humans.

Women with drug-resistant epilepsy: Surgery or pregnancy first?

OBJECTIVE: We compared women with drug-resistant focal epilepsy who had undergone surgery (WWE-S) with those who were managed medically (WWE-M) for maternal and fetal outcomes of their pregnancies. METHODS: We classified all WWE-S who were enrolled in a prospective registry of epilepsy and pregnancy (1998-2015) as those who underwent the surgery before pregnancy (WWE-SF) or after pregnancy (WWE-PF). The comparator group (WWE-M) was twice that number of age-matched women with focal epilepsy in this registry. Their clinical profile, anti-epileptic drug (AED) use, and pregnancy outcomes were extracted from the records of the registry. RESULTS: The number of completed pregnancies with known outcome was 74 for WWE-S (67 WWE-SF and 7 WWE-PF) and 134 for WWE-M. Seizures increased during pregnancy for fewer WWE-SF than for WWE-M (14.9% vs 39.6%, P = .001). Compared to WWE-M, fewer WWE-SF had dose escalation during pregnancy (28.4% vs 14.9%, P = .025). Preterm deliveries were more frequent in WWE-SF than WWE-M (24.6% vs 12.2%, P = .029). The differences between the WWE-SF and WWE-M regarding the rates of fetal loss (10.4% vs 6.7%, P = .255), major congenital malformations (8.5% vs. 11.1%, P = .395), and development quotient at 1 year of age <85 (42.5% vs 42.3%, P = .569) were not statistically significant. Compared to WWE-PF, fewer WWE-SF had AED dose escalation (14.9% vs 85.7%, P = .001) or increase in seizures (14.9% vs 100%, P = .001) during pregnancy. WWE-SF had fewer infants with development quotient <85 (41.0% vs 100%, P = .005). SIGNIFICANCE: WWE-SF can expect better control of seizures and decreased AED burden during pregnancy than WWE with focal epilepsies managed with medicines only. WWE who undergo surgery for epilepsy before their pregnancies can expect fewer seizures and lower AED burden during pregnancy.

The implication of giant tumor size on surgical resection, oncological, and functional outcomes in craniopharyngioma.

OBJECTIVE: Implication of the tumor size on oncological and functional outcomes of craniopharyngioma is inconsistently reported. The aim of this study is to assess the postoperative outcome of giant craniopharyngiomas (> 4 cm in diameter) and to elucidate the impact of tumor size on various outcome parameters and survival. MATERIAL AND METHODS: Forty-four patients (children aged ≤ 18 years: 25; adults: 16) with giant craniopharyngioma, operated between January 2001 and December 2015, were included in this study. Various outcomes, progression-free survival (PFS) and overall survival (OS) were calculated. RESULTS: Gross total resection (GTR) was achieved in 17 (39%) and subtotal resection (STR) in 27 (61%) patients. Eleven patients (25%) received radiotherapy (RT) after STR. Postoperatively, new cranial nerve and motor deficits were noted in 12 (27%) and 9 (20%) patients, respectively. Tumor recurrence following GTR and STR without adjuvant RT was diagnosed in 3 (17%), and 5 (38%) patients, respectively. Following STR with RT, one (9%) experienced recurrence. PFS at 5-, and 10- year following GTR, STR, and STR + RT was 80.8%, 45.4%, and 90%, respectively. At 5- and 10- year, OS was 86.5%, 77.9% and 100% following GTR, STR, and STR + RT, respectively. The rate of GTR was significantly lower in patients with giant tumors (39% vs. 62%; Chi-square test, p value 0.008). Postoperatively, neurological deficit (20%), hypopituitarism (95%) and hypothalamic dysfunction (26%) were significantly higher for giant craniopharyngiomas. Hazards of recurrence were not significant between giant and non-giant tumors (hazard ratio 1.86; 95% CI 0.94-3.68; p 0.07). There was no significant difference in OS between the patients with giant and non-giant tumors (log-rank test 2.1; p value 0.14). CONCLUSION: Tumor size should be considered as an important predictor of the postoperative functional outcome. Although the rate of GTR is less than that of small tumors, the recurrence rate, progression-free survival, and overall survival of the patients with giant tumor are comparable to non-giant tumors.

Meningioma with rosettes: A rare morphologic pattern.

We describe a case of WHO grade I transitional meningioma with rosettes in a 68-year-old woman. The rosettes were composed of meningothelial cells arranged around dense collagenous cores. Even though the presence of rosettes in tumors of the brain and spinal cord is an indication of neuronal or ependymal differentiation, they are also known to occur in tumors of other lineages. Rosette is an uncommon morphological pattern in meningiomas, with only few cases reported in the literature.

Spinal angiolipoma-a rare but reversible cause of paraplegia in a child.

PURPOSE: Spinal angiolipomas are benign spinal epidural tumors consisting of mature fat cells with angiomatous components. These tumors are rare in children and there are no definite management guidelines. METHOD: To the best of our knowledge, only five cases of spinal angiolipomas have been reported in children below 12 years. This article discusses the presentation, diagnostics, and surgical tips for the management of a case of spinal angiolipoma. RESULT: In this paper, we present a one and half-year-old child presenting with a spontaneous spinal epidural hematoma from a spinal angiolipoma and underscore the importance of early surgery in a benign disease for a good outcome. CONCLUSION: Overall neurological recovery and prognosis following timely intervention for spinal angiolipomas are good.

Long-term outcome and prognostic factors of intramedullary spinal hemangioblastomas.

Spinal hemangioblastomas constitute 1.6-5.8% of all spinal cord tumors. Microsurgical excision of these tumors is challenging. The purpose of this study is to analyze the neurological improvement and long-term functional outcome of spinal hemangioblastomas. This retrospective study included 15 patients who underwent surgery for intramedullary spinal hemangioblastoma at the Department of Neurosurgery of Sri Chitra Tirunal Institute for Medical Sciences and Technology from January 2001 to June 2014. Eight patients (53%) were diagnosed to have von Hippel-Lindau (vHL) disease. Eight (53%) of them were females, and seven were males (47%). Mean age was 33.8 years (16-55 years). Duration of illness ranged from 2 weeks to 4 years, and average duration was 10.5 months. Most common symptom was motor weakness followed by sensory disturbances, pain, and bladder incontinence. Six (85.7%) sporadic spinal hemangioblastomas were in McCormick grade I; whereas, 7 (87.5%) of vHL spinal hemangioblastomas were in grade II or above. In the immediate postoperative period, three patients noticed improvement in their motor weakness. Six patients (40%) experienced deterioration of preoperative neurological status in the immediate postoperative period. Three of them were sporadic tumors, and others had vHL syndrome. Favorable long-term outcome was achieved in 80% of cases. Though neurological deterioration is common after surgical resection of spinal hemangioblastomas, majority of them are reversible. Long-term functional outcome is favorable with minimal postoperative morbidities. Both sporadic- and vHL-associated tumors share common clinical and radiological features, and neurological outcome is equally good in both.

Role of Small Hydrophobic Protein of J Paramyxovirus in Virulence.

J paramyxovirus (JPV) was first isolated from moribund mice with hemorrhagic lung lesions in Australia in 1972. It is a paramyxovirus classified under the newly proposed genus Jeilongvirus JPV has a genome of 18,954 nucleotides, consisting of eight genes in the order 3'-N-P/V/C-M-F-SH-TM-G-L-5'. JPV causes little cytopathic effect (CPE) in tissue culture cells but severe disease in mice. The small hydrophobic (SH) protein is an integral membrane protein encoded by many paramyxoviruses, such as mumps virus (MuV) and respiratory syncytial virus (RSV). However, the function of SH has not been defined in a suitable animal model. In this work, the functions of SH of JPV, MuV, and RSV have been examined by generating recombinant JPV lacking the SH protein (rJPV-ΔSH) or replacing SH of JPV with MuV SH (rJPV-MuVSH) or RSV SH (rJPV-RSVSH). rJPV-ΔSH, rJPV-MuVSH, and rJPV-RSVSH were viable and had no growth defect in tissue culture cells. However, more tumor necrosis factor alpha (TNF-α) was produced during rJPV-ΔSH infection, confirming the role of SH in inhibiting TNF-α production. rJPV-ΔSH induced more apoptosis in tissue culture cells than rJPV, rJPV-MuVSH, and rJPV-RSVSH, suggesting that SH plays a role in blocking apoptosis. Furthermore, rJPV-ΔSH was attenuated in mice compared to rJPV, rJPV-MuVSH, and rJPV-RSVSH, indicating that the SH protein plays an essential role in virulence. The results indicate that the functions of MuV SH and RSV SH are similar to that of JPV SH even though they have no sequence homology.IMPORTANCE Paramyxoviruses are associated with many devastating diseases in animals and humans. J paramyxovirus (JPV) was isolated from moribund mice in Australia in 1972. Newly isolated viruses, such as Beilong virus (BeiPV) and Tailam virus (TlmPV), have genome structures similar to that of JPV. A new paramyxovirus genus, Jeilongvirus, which contains JPV, BeiPV, and TlmPV, has been proposed. Small hydrophobic (SH) protein is present in many paramyxoviruses. Our present study investigates the role of SH protein of JPV in pathogenesis in its natural host. Understanding the pathogenic mechanism of Jeilongvirus is important to control and prevent potential diseases that may emerge from this group of viruses.

Seizure outcome and its predictors after frontal lobe epilepsy surgery.

OBJECTIVES: Frontal lobe epilepsy (FLE) surgery is the second most common focal resective surgery for drug-resistant epilepsy. Not many studies are available regarding the long-term surgical outcome of FLE. We studied the longitudinal outcome and predictors of seizure outcome following FLE surgery in a sizeable cohort of patients. MATERIALS & METHODS: A total of 73 consecutive patients who underwent FLE surgery between January 1997 and May 2015 with a minimum follow-up of 1 year (range 1-16 years) were studied. Primary outcome was seizure freedom at last follow-up (Engel Class IA). "Seizure freedom" separately was defined as absence of seizures till last follow-up. Outcome predictors were subjected to multivariate analysis. Using Kaplan-Meier curve, we assessed the post-operative seizure freedom over time. RESULTS: Twenty-five patients (34%) were seizure-free till last follow-up. The seizure freedom was 45%, 34%, 26%, 20% and 14% at the end of 1st, 2nd, 3rd, 4th and 5th post-operative year, respectively. Engel class I outcomes were 48%, 41%, 56%, 57% and 53% at end of 1st, 2nd, 3rd, 4th and 5th post-operative year, respectively. Predictors of seizure recurrence on multivariate analysis were older age at surgery (P = 0.032), longer duration of epilepsy (P = 0.031), presence of interictal epileptiform discharges in post-operative EEG on 7th day (P = 0.005), 3 months (P = 0.005) and 1 year (P = 0.0179). In subgroup analysis, duration of epilepsy of less than 2 years before surgery was a significant predictor for achieving seizure freedom (P = 0.029). CONCLUSIONS: These results emphasize early surgery for better outcome in frontal lobe epilepsy. Post-operative EEG remained a good predictor for long-term outcome.

Multicenter Evaluation of Clinical Efficacy and Safety of Per-oral Endoscopic Myotomy in Children.

OBJECTIVES: Per-oral endoscopic myotomy (POEM) is a recommended treatment modality for achalasia, but there is little published data for its use in children. The objective of the present study was to evaluate whether POEM is clinically effective and safe for children. METHODS: International multicenter retrospective study conducted in 14 tertiary centers that included consecutive children who underwent POEM between January 2012 and August 2018. Outcomes, such as clinical response were assessed whenever available. Adverse events and factors associated with clinical failure were also investigated. RESULTS: A total of 117 patients (mean ±â€ŠSD age: 14.2 ±â€Š3.7 years) underwent POEM for achalasia (type I, n = 36; type II n=66; type III, n=8). Among these, 30 (26%) were pretreated (botulinum injection and/or pneumatic dilatation). Mean ±â€ŠSD baseline Eckardt score was 7.5 ±â€Š2.0. Clinical success was achieved in 90.6% of cases (95%CI [83.8%;95.2%]) in the intention-to-treat analysis. The mean ±â€ŠSD Eckardt score post-POEM was 0.9 ±â€Š1.2 (P < 0.001). The mean duration of follow-up time 545 days (range: 100-1612). A total of 7 adverse events occurred (4 mucosotomies, 2 subcutaneous emphysema, 1 esopleural fistula). Gastroesophageal reflux symptoms were seen in 17 patients (15%); missing data for 10 patients (9%). There was a trend towards more frequent clinical failure in achalasia associated with genetic disorders (40% vs 8%, P = 0.069). CONCLUSIONS: POEM in pediatric patients appears to be effective and safe, although there was a trend towards more frequent clinical failure achalasia associated with genetic disorders. Further studies are needed to assess the long-term outcomes, especially the consequences of GERD.

Cerebrospinal fluid rhinorrhea from the lateral recess of sphenoid sinus: More to it than meets the eye.

BACKGROUND: Cerebrospinal fluid (CSF) leak from the lateral recess of the sphenoid sinus is rare when compared to leaks from other sites. The extended endonasal approach along with a transpterygoid extension provides adequate exposure for repair of these defects. MATERIALS AND METHODS: We retrospectively analyzed a series of seven patients who underwent eight transpterygoid approaches for repair of the CSF leak from the lateral recess of the sphenoid sinus. We analyzed the patient characteristics, site of leaks, type of repair done, and presence of increased intracranial pressure (ICP) in these individuals. RESULTS: Seven patients underwent eight transpterygoid approaches for CSF leaks from the lateral recess of the sphenoid sinus. The leak was bilateral in one patient. The materials used for repair consisted of fat, fascia lata, free mucosal flap or a vascularised nasoseptal flap, and fibrin glue. Evidence of increased ICP was found in five of the seven patients. CSF diversion was needed in three of the seven patients (two ventriculoperitoneal shunt and one thecoperitoneal shunt). CONCLUSION: Endoscopic endonasal transpterygoid approach provides an excellent visualization of the skull-base defect and facilitates adequate instrument manipulation within the corridor, allowing successful repair of the defect with low rates of recurrence. Increased ICP can have a role in causing spontaneous CSF rhinorrhea from this location.

"Time is Brain"-How early should surgery be done in drug-resistant TLE?

OBJECTIVES: To explore the effect of duration of epilepsy and delay in surgery on seizure outcome in patients operated for drug-resistant temporal lobe epilepsy (TLE). MATERIALS & METHODS: A total of 664 consecutive patients who underwent anterior temporal lobectomy (ATL) for TLE from 1995 to 2008 formed the study cohort. We divided them into two, one as seizure-free with or without antiepileptic drugs after ATL as "good outcome" (Engel class I a) and seizures of any type, any time after surgery as "poor outcome." The probability of seizure freedom/seizure recurrence based on the duration of epilepsy was compared using Kaplan-Meier curves, univariate Cox regression survival analysis, and multivariate Cox proportional hazards regression model. RESULTS: A total of 136 children and 528 adults underwent ATL during this period. Mean duration of epilepsy pre-ATL was 17.1 + 9.4 years. At mean follow-up of 8.5 years, 331 patients (49.8%) had good outcome and 333 (50.2%) had poor outcome. The hazard of seizure recurrence linearly increased with duration of epilepsy pre-ATL, from 1.5 (duration of epilepsy, 5-10 years) to 1.9 (duration of epilepsy, 10-15 years) to 2 (duration of epilepsy over 15 years). In addition, encephalitis as antecedent, bilateral mesial temporal sclerosis in MRI, normal histopathology, and spikes in postoperative EEG at 3 months and 1 year predicted poor seizure outcome. CONCLUSIONS: "Epilepsy duration" independently predicted both short- and long-term seizure outcome after surgery in TLE. "Lost years" translate into poor seizure outcome after ATL. Therefore, all cases of drug-resistant TLE should be referred to a surgical center at the earliest.

Is 'burned-out hippocampus' syndrome a distinct electro-clinical variant of MTLE-HS syndrome?

AIM: To study the clinical, electrophysiological and imaging characteristics of patients with unilateral mesial temporal lobe epilepsy (MTLE) with contralateral ictal onset on scalp EEG, viz. 'burned-out hippocampus' syndrome (MTLE-BHS). METHODS: MTLE-BHS was defined as TLE with unilateral hippocampal sclerosis (HS) without any dual pathology on MRI and contralateral ictal onset on scalp EEG, unlike in classical hippocampal sclerosis (HS). Consecutive "MTLE-BHS" patients evaluated at our Centre for Comprehensive Epilepsy Care from January 2005 to July 2014 were studied. Twenty-five cases of classic MTLE-HS operated during the same period were also analyzed for comparison. RESULTS: Seventeen patients were diagnosed to have MTLE-BHS. Mean age of seizure onset was 9.5±7.7years and the mean duration of epilepsy was18.2±7.3years. Epigastric aura was more common in MTLE-HS and fear, secondary generalized seizures and temporal polar changes on MRI were more prevalent in the MTLE-BHS subgroup. In the latter group, five (29%) exhibited seizure semiology and 2 (12%) had interictal discharges discordant to the side of MTS. Eight (47%) patients in the MTLE-BHS sub-group had normal medial temporal volume on Scheltens scale. Eight patients among MTLE-BHS underwent surgery (4 following intracranial monitoring that localized to the side of HS) with Engel class I outcome at 1year follow-up in 6 and Engel class II outcome in 2. CONCLUSION: Attenuation of ipsilateral fast ictal rhythms on scalp EEG as well as neocortical changes are likely to be deterministic factors for MTLE-BHS as opposed to the severity of hippocampal atrophy. Considering good post-operative outcomes, intracranial monitoring for surgical selection is not mandatory in MTLE-BHS despite discordant semiology and ictal onset, in the presence of inter-ictal, functional imaging and neuropsychology data concordant to the side of HS.

Preoperative determination of tibial nail length: An anthropometric study.

OBJECTIVE: To assess the correlation between five anthropometric parameters and the distance from tibial tuberosity to medial malleolus in 100 volunteers. METHODS: Six anthropometric parameters were measured in 50 male and 50 female medical students using a metallic scale: medial knee joint line to ankle joint line (K-A), medial knee joint line to medial malleolus (K-MM), tibial tuberosity to ankle joint (TT-A), tibial tuberosity to medial malleolus (TT- MM), olecranon to 5th metacarpal head (O-MH) and body height (BH). Nail size predicted based upon TT-MM measurement was chosen as ideal nail size. A constant was derived for each of the six anthropometric parameters which was either added or subtracted to each measurement to derive nail size. A regression equation was applied to BH measurements. Nail sizes calculated were compared with that obtained from TT-MM measurement and accuracy was evaluated. Accuracy of O-MH and BH regression equations recommended by other authors were calculated in our data. RESULTS: Adding 11 mm to TT-A distance had highest accuracy (81%) and correlation (0.966) in predicting nails correctly. Subtracting 33 mm from K-MM measurement and 25 mm from K-A distance derived accurate sizes in 69% and 76% respectively. Adding 6 mm to O-MH distance had a poor accuracy of 51%. Nail size prediction based upon body height regression equation derived correct nail sizes in only 34% of the cases. Regression equation analysis by other authors based on O-MH and BH distances yielded correct sizes in 11% and 5% of the cases respectively. CONCLUSION: TT-A, K-A and K-MM measurements can be used simultaneously to increase accuracy of nail size prediction. This method would be helpful in determining nail size preoperatively especially when one anatomic landmark is difficult to palpate.