Notwithstanding remarkable progress in vascular network engineering, implanted bioengineered microvessels largely fail to form anastomoses with the host vasculature. Here, we demonstrate that implants containing assembled human vascular networks (A-Grafts) fail to engraft due to their inability to engage non-inflammatory host neutrophils upon implantation into mice. In contrast, unassembled vascular cells (U-Grafts) readily engage alternatively polarized neutrophils, which in turn serve as indispensable mediators of vascular assembly and anastomosis. The depletion of host neutrophils abrogated vascularization in U-Grafts, whereas an adoptive transfer of neutrophils fully restored vascularization in myeloid-depleted mice. Neutrophil engagement was regulated by secreted factors and was progressively silenced as the vasculature matured. Exogenous addition of factors from U-Grafts reengaged neutrophils and enhanced revascularization in A-Grafts, a process that was recapitulated by blocking Notch signaling. Our data suggest that the pro-vascularization potential of neutrophils can be harnessed to improve the engraftment of bioengineered tissues.

The above-mentioned findings support performance of prospective controlled studies of quinidine efficacy in children with KCNT1 gain-of-function mutations that control for age as a possible variable affecting response.

Summary:Purpose: A focal cortical-subcortical calcification (FCSC) is a common finding on computed tomography (CT) in individuals with focal or generalized seizures in the Indian subcontinent. We sought to determine the relation of FCSCs to epilepsy by comparing the lobe of seizure origin by electroclinical and CT evaluations and to study the nature and severity of epilepsy associated with FCSCs.Methods: The relation of these FCSCs to epilepsy/seizures was studied in 40 patients, seen for the first time to the neurology outpatient department of a tertiary care hospital. An attempt was made to classify seizures and determine their lobe of origin based on clinical-electroencephalographic (EEG) criteria of the International League Against Epilepsy (ILAE). The clinical lobe of origin was compared with the location of the FCSC on CT scan. In addition, records of the CT unit of the same hospital were reviewed retrospecitvely, to identify cases with an FCSC and their referral diagnoses.Results: Thirty-one (77.5%) patients with FCSCs were considered to have localization-related epilepsy (frontal lobe epilepsy, 20; temporal lobe epilepsy, three; parietal lobe epilepsy, one; occipital lobe epilepsy, three; and definitely localization related but having ambiguous localization features, four) based on ictal semiology and EEG studies. Other ILAE categories in the cohort included epilepsy without unequivocal focal or generalized features (four patients; 1 0%), isolated seizures (one patient; 2.5%), juvenile absence epilepsy (one patient; 2.5%), and insufficient data to classify epilepsy (three patients; 7.5%). Radiologic sites for FCSCs included frontal (20; 50%), temporal (six; 15%), parietal (seven; 17.5%), and occipital (seven; 17.5%). Electroclinical and radiologic data were congruent in localizing and lateralizing seizures in 22 (55%) patients. The FCSC was truly incidental in one patient with juvenile absence epilepsy. Discordance between the clinical and radiologic localizations was noted in five (12.5%) instances. Magnetic resonance imaging (MRI) did not reveal additional lesions corresponding to lobes of origin as determined by electroclinical analysis. Discordance was surmised to be a result of seizure spread from a silent region to symptomatic cortex. In 12 (30%) patients, electroclinical and radiologic congruence could not be ascertained because ictal descriptions were either inadequate or ambiguous, and EEG findings were noncontributory. Review of 4,452 CT scans of brain performed in the CT unit revealed 29 (0.65%) cases with FCSCs in individuals with nonseizure disorders, that could be labeled as incidental.Conclusiunh: An FCSC is an important radiologic finding in localization-related epilepsy in the Indian subcontinent. The severity of epilepsy ranges from asymptomatic cases to daily seizures. Key Words: Focal cortical-subcortical calcifications (FCSCs)-Epilepsy-Classification-Computed tomography-Cysticercosis.Computed tomography (CT) often reveals a single, small (

Although the early diagnosis of gastric cancer provides the opportunity for curative endoscopic resection, comprehensive screening endoscopy would be invasive and expensive. To date, there is a complete absence of clinically useful gastric cancer biomarkers. With the goal of discovering noninvasive biomarkers for the early diagnosis of gastric cancer, we have conducted a case-control study using urine samples from individuals with gastric cancer versus healthy control samples. Of the enrolled 106 patients from September, 2012 to April, 2013, a cohort of 70 patients composed of 35 patients with gastric cancer and 35 age-and sex-matched healthy controls was analyzed. The gastric cancer group was composed of stage IA of 62.9% (22/35). The urinary levels of MMP-9/NGAL complex (uMMP-9/NGAL) and ADAM12 (uADAM12) were significantly higher in the gastric cancer group compared with the healthy control group as determined by monospecific ELISAs (uMMP-9/NGAL: median, 85 pg/mL vs. 0 pg/mL; P ¼ 0.020; uADAM12: median, 3.35 ng/mL vs. 1.44 ng/mL; P < 0.001). Multivariate analysis demonstrated that both uMMP-9/NGAL and uADAM12 were significant, independent diagnostic biomarkers for gastric cancer. Moreover, MMP-9/NGAL activity was significantly elevated as determined by gelatin zymography. The combination of uMMP-9/NGAL with uADAM12 distinguished between control samples and gastric cancer samples with an AUC of 0.825 (P < 0.001) in an ROC analysis. Significantly, immunohistochemical analyses demonstrated a high coexpression of MMP-9 and NGAL (P < 0.001) and high expression of ADAM12 (P < 0.001) in gastric cancer tissues compared with adjacent normal tissues (N ¼ 35). In summary, uMMP-9/NGAL and uADAM12 are potential noninvasive biomarkers for gastric cancer, including early-stage disease. Cancer Prev Res; 8(3); 240-8. Ó2015 AACR.

ObjectiveTo report our experience and investigate 5 original hypotheses: (1) multiple types of epileptic seizures occur in alternating hemiplegia of childhood (AHC), and these can be the initial presentation; (2) epileptiform abnormalities often appear well after clinical seizures; (3) nonepileptic reduced awareness spells (RAS) occur frequently; (4) epilepsy is commonly drug resistant but may respond to vagal nerve stimulation (VNS); and (5) status epilepticus (SE) is common and is usually refractory and recurrent.MethodsWe analyzed a cohort of 51 consecutive patients with AHC.ResultsThirty-two of 51 patients had epilepsy: 18 focal seizures, frontal more frequently than temporal, and then posterior. Eleven had primary generalized seizures (tonic-clonic, myoclonic, and/or absence). Epileptic seizures preceded other AHC paroxysmal events in 8 (lag 5.63 ± 6.55 months; p = 0.0365). In 7 of 32, initial EEGs were normal, with the first epileptiform EEG lagging behind by 3.53 ± 4.65 years (p = 0.0484). RAS occurred equally in patients with epilepsy (16 of 32) and patients without epilepsy (10 of 19, p = 1.0). Twenty-eight patients had video-EEG; captured RAS showed no concomitant EEG changes. Nineteen patients (59%) were drug resistant. VNS resulted in >50% reduction in seizures in 5 of 6 (p < 0.04). Twelve patients (38%) had SE (9 of 12 multiple episodes), refractory/superrefractory in all (p < 0.001), and 4 of 12 had regression after SE.ConclusionsEpilepsy in AHC can be focal or generalized. Epileptic seizures may be the first paroxysmal symptom. EEG may become epileptiform only on follow-up. Epilepsy, although frequently drug resistant, can respond to VNS. RAS are frequent and nonepileptic. SE often recurs and is usually refractory/superrefractory. Our observations are consistent with current data on AHC-ATP1A3 pathophysiology.

Objective To examine a series of candidate markers for urological chronic pelvic pain syndrome (UCPPS), selected based on their proposed involvement in underlying biological processes so as to provide new insights into pathophysiology and suggest targets for expanded clinical and mechanistic studies. Methods Baseline urine samples from Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study participants with UCPPS (n = 259), positive controls (PCs; chronic pain without pelvic pain, n = 107) and healthy controls (HCs, n = 125) were analysed for the presence of proteins that are suggested in the literature to be associated with UCPPS. Matrix metalloproteinase (MMP)‐2, MMP‐9, MMP‐9/neutrophil gelatinase‐associated lipocalin (NGAL) complex (also known as Lipocalin 2), vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGF‐R1) and NGAL were assayed and quantitated using mono‐specific enzyme‐linked immunosorbent assays for each protein. Log‐transformed concentration (pg/mL or ng/mL) and concentration normalized to total protein (pg/μg) values were compared among the UCPPS, PC and HC groups within sex using the Student's t‐test, with P values adjusted for multiple comparisons. Multivariable logistic regression and receiver‐operating characteristic curves assessed the utility of the biomarkers in distinguishing participants with UCPPS and control participants. Associations of protein with symptom severity were assessed by linear regression. Results Significantly higher normalized concentrations (pg/μg) of VEGF, VEGF‐R1 and MMP‐9 in men and VEGF concentration (pg/mL) in women were associated with UCPPS vs HC. These proteins provided only marginal discrimination between UCPPS participants and HCs. In men with UCCPS, pain severity was significantly positively associated with concentrations of MMP‐9 and MMP‐9/NGAL complex, and urinary severity was significantly positively associated with MMP‐9, MMP‐9/NGAL complex and VEGF‐R1. In women with UCPPS, pain and urinary symptom severity were associated with increased normalized concentrations of MMP‐9/NGAL complex, while pain severity alone was associated with increased normalized concentrations of VEGF, and urinary severity alone was associated with increased normalized concentrations of MMP‐2. Pain severity in women with UCPPS was significantly positively associated with concentrations of all biomarkers except NGAL, and urinary severity with all concentrations except VEGF‐R1. Conclusion Altered levels of MMP‐9, MMP‐9/NGAL complex and VEGF‐R1 in men, and all biomarkers in women, were associated with clinical symptoms of UCPPS. None of the evaluated candidate markers usefully discriminated UCPPS patients from controls. Elevated VEGF, MMP‐9 and VEGF‐R1 levels in men and VEGF levels in women may provide potential new insights into the pathophysiology of UCPPS.

Aim To determine the neuropsychological abnormalities that occur in alternating hemiplegia of childhood (AHC) and report on our experience in managing them. Method Patients underwent evaluations according to our standardized AHC pathway. Data were entered into our prospective AHC database and then analyzed. Results Of the cohort of 25 consecutive patients (ages 15mo–42y), eight had initial chief complaints about cognition, 14 language, five attention, and 11 behavior. As compared to population norms means, neuropsychological and behavioral assessment tools (including Child Behavior Checklist, Vineland Adaptive Behavior Scales, Peabody Picture Vocabulary, and Wechsler Intelligence Quotient tests) showed significant impairments in multiple domains: cognition, expressive and receptive language, executive function/attention, and behavior (p<0.05 in all comparisons). Evaluations generated management recommendations in all patients. Twenty had neuropsychiatric diagnoses: 10 attention‐deficit/hyperactivity disorder (ADHD), seven disruptive behavior, and three anxiety disorder. Eight out of nine patients with ADHD who were prescribed medications responded to pharmacotherapy. Interpretation Patients with AHC have developmental difficulties related to impairments in multiple neuropsychological domains. This supports the hypothesis that the underlying AHC pathophysiology involves diffuse neuronal dysfunction. Testing generated recommendations to help manage these difficulties. Patients with AHC also have a range of neuropsychiatric diagnoses, the most common being ADHD which responds to pharmacotherapy. What this paper adds Patients with alternating hemiplegia of childhood (AHC) have developmental difficulties with underlying neuropsychological impairments. The findings in this study are consistent with an underlying AHC pathophysiology which involves diffuse neuronal, probably largely GABAergic, dysfunction. Patients with AHC have a range of neuropsychiatric diagnoses, the most common being attention‐deficit/hyperactivity disorder.

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