Longitudinal MRI brain volume changes over one year in children with mucopolysaccharidosis types IIIA and IIIB

ObjectiveTo quantify changes in segmented brain volumes over 12 months in children with mucopolysaccharidosis types IIIA and IIIB (MPS IIIA and IIIB).MethodsIn order to establish suitable outcome measures for clinical trials, twenty-five children greater than 2 years of age were enrolled in a prospective natural history study of MPS IIIA and IIIB at Nationwide Children's Hospital. Data from sedated non-contrast brain 3 T MRIs and neuropsychological measures were reviewed from the baseline visit and at 12-month follow-up. No intervention beyond standard clinical care was provided. Age- and sex-matched controls were gathered from the National Institute of Mental Health Data Archive. Automated brain volume segmentation with longitudinal processing was performed using FreeSurfer.ResultsOf the 25 subjects enrolled with MPS III, 17 children (4 females, 13 males) completed at least one MRI with interpretable volumetric data. The ages ranged from 2.8 to 13.7 years old (average 7.2 years old) at enrollment, including 8 with MPS IIIA and 9 with MPS IIIB. At baseline, individuals with MPS III demonstrated reduced cerebral white matter and corpus callosum volumes, but greater volumes of the lateral ventricles, cerebellar cortex, and cerebellar white matter compared to controls. Among the 13 individuals with MPS III with two interpretable MRIs, there were annualized losses or plateaus in supratentorial brain tissue volumes (cerebral cortex ?42.10 ± 18.52 cm³/year [mean ± SD], cerebral white matter ?4.37 ± 11.82 cm³/year, subcortical gray matter ?6.54 ± 3.63 cm³/year, corpus callosum ?0.18 ± 0.62 cm³/yr) and in cerebellar cortex (?0.49 ± 12.57 cm³/year), with a compensatory increase in lateral ventricular volume (7.17 ± 6.79 cm³/year). Reductions in the cerebral cortex and subcortical gray matter were more striking in individuals younger than 8 years of age. Greater cerebral cortex volume was associated with higher fine and gross motor functioning on the Mullen Scales of Early Learning, while greater subcortical gray matter volume was associated with higher nonverbal functioning on the Leiter International Performance Scale. Larger cerebellar cortex was associated with higher receptive language performance on the Mullen, but greater cerebellar white matter correlated with worse adaptive functioning on the Vineland Adaptive Behavioral Scales and visual problem-solving on the Mullen.ConclusionsLoss or plateauing of supratentorial brain tissue volumes may serve as longitudinal biomarkers of MPS III age-related disease progression compared to age-related growth in typically developing controls. Abnormally increased cerebellar white matter in MPS III, and its association with worse performance on neuropsychological measures, suggest the possibility of pathophysiological mechanisms distinct from neurodegeneration-associated atrophy that warrant further investigation.     

Process Redesign to Improve First Case Surgical Starts in an Academic Institution

Purpose: On time start of the first surgical case improves operating room (OR) utilization, physician, and patient satisfaction and decreases delays in subsequent cases. The goal of our study was to evaluate the effect of a multidisciplinary initiative to improve first patient in the room (FPIR) and first case on time start (FCOTS) metrics in a tertiary care setting. Materials and Methods: A multidisciplinary committee focused on first case start data collection. Reasons for both anesthesia and surgical delays were analyzed. Improvement efforts focused on the timely completion of surgical consent, a requirement of a surgical, anesthesia, and nurse team member presence at the patient's bedside by specific time, and parallel processing in the OR. Results: Over 65,100 OR cases were analyzed between 2007 and 2014. There was a statistically significant improvement in FPIR (82.80% versus 69.60%, p < .0001) and FCOTS (66.60% versus 55.90%, p < .0001). Surgical consent completion rate increased from 35% baseline to 68%–100%, depending on the surgical subspecialty. Improvements appeared sustainable several years following process implementation for both FPIR (84.60% versus 69.60%, p < .0001) and FCOTS (67.60% versus 55.90%, p < .0001). Conclusions: Our study demonstrates a successful targeted, multidisciplinary initiative to improve first case surgical starts in an academic setting. Our approach was organizational rather than punitive or rewarding on an individual basis. Strategies included establishing concrete, time-specific goals and posting them visibly, empowering individuals to fulfill them, and ensuring no compromise in patient safety. In the complex environment of academic medicine including research protocols and teaching in the ORs, our organizational approach proved sustainable over several years.     

Pharmacokinetics of First-Line Antituberculosis Drugs in HIV-Infected Children with Tuberculosis Treated with Intermittent Regimens in India

The objective of this report was to study the pharmacokinetics of rifampin (RMP), isoniazid (INH), and pyrazinamide (PZA) in HIV-infected children with tuberculosis (TB) treated with a thrice-weekly anti-TB regimen in the government program in India. Seventy-seven HIV-infected children with TB aged 1 to 15 years from six hospitals in India were recruited. During the intensive phase of TB treatment with directly observed administration of the drugs, a complete pharmacokinetic study was performed. Drug concentrations were measured by high-performance liquid chromatography. A multivariable regression analysis was done to explore the factors impacting drug levels and treatment outcomes. The proportions of children with subnormal peak concentrations (C_max) of RMP, INH, and PZA were 97%, 28%, and 33%, respectively. Children less than 5 years old had a lower median C_max and lower exposure (area under the time-concentration curve from 0 to 8 h [AUC_0–8]) of INH (C_max, 2.5 versus 5.1 μg/ml, respectively [P = 0.016]; AUC_0–8, 11.1 versus 22.0 μg/ml · h, respectively [P = 0.047[) and PZA (C_max, 34.1 versus 42.3 μg/ml, respectively [P = 0.055]; AUC_0–8, 177.9 versus 221.7 μg/ml · h, respectively [P = 0.05]) than those more than 5 years old. In children with unfavorable versus favorable outcomes, the median C_max of RMP (1.0 versus 2.8 μg/ml, respectively; P = 0.002) and PZA (31.9 versus 44.4 μg/ml, respectively; P = 0.045) were significantly lower. Among all factors studied, the PZA C_max influenced TB treatment outcome (P = 0.011; adjusted odds ratio, 1.094; 95% confidence interval, 1.021 to 1.173). A high proportion of children with HIV and TB had a subnormal RMP C_max. The PZA C_max significantly influenced treatment outcome. These findings have important clinical implications and emphasize that drug doses in HIV-infected children with TB have to be optimized.     

Characterization of 14,15-epoxyeicosatrienoyl-sulfonamides as 14,15-epoxyeicosatrienoic acid agonists: use for studies of metabolism and ligand binding

Epoxyeicosatrienoic acids (EETs) are cytochrome P450 epoxygenase metabolites of arachidonic acid. EETs mediate numerous biological functions. In coronary arteries, they regulate vascular tone by the activation of smooth muscle large-conductance, calcium-activated potassium (BK(Ca)) channels to cause hyperpolarization and relaxation. We developed a series of 14,15-EET agonists, 14,15-EET-phenyliodosulfonamide (14,15-EET-PISA), 14,15-EET-biotinsulfonamide (14,15-EET-BSA), and 14,15-EET-benzoyldihydrocinnamide-sulfonamide (14,15-EET-BZDC-SA) as tools to characterize 14,15-EET metabolism and binding. Agonist activities of these analogs were characterized in precontraced bovine coronary arterial rings. All three analogs induced concentration-dependent relaxation and were equipotent with 14,15-EET. Relaxations to these analogs were inhibited by the BK(Ca) channel blocker iberiotoxin (100 nM), the 14,15-EET antagonist 14,15-epoxyeicosa-5(Z)-enoylmethylsulfonamide (10 muM), and abolished by 20 mM extracellular K(+). 14,15-EET-PISA is metabolized to 14,15-dihydroxyeicosatrienoyl-PISA by soluble epoxide hydrolase in bovine coronary arteries and U937 cells but not U937 cell membrane fractions. 14,15-EET-P(125)ISA binding to human U937 cell membranes was time-dependent, concentration-dependent, and saturable. The specific binding reached equilibrium by 15 min at 4 degrees C and remained unchanged up to 30 min. The estimated K(d) and B(max) were 148.3 +/- 36.4 nM and 3.3 +/- 0.5 pmol/mg protein, respectively. These data suggest that 14,15-EET-PISA, 14,15-EET-BSA, and 14,15-EET-BZDC-SA are full 14,15-EET agonists. 14,15-EET-P(125)ISA is a new radiolabeled tool to study EET metabolism and binding. Our results also provide preliminary evidence that EETs exert their biological effect through a membrane binding site/receptor.     

Mesoporous superacid catalysts for valorisation of refinery naphtha stream

In the current petroleum refining scenario, many refineries end up with surplus naphtha which is either absorbed into the gasoline pool or exported at unattractive prices. Therefore, several options for naphtha valorisation are currently being explored. The usage of Liquified Petroleum Gas (LPG) as a fuel in heating appliances, cooking equipment and automobiles is rapidly increasing. The high specific calorific value, high octane number, clean and efficient combustion of LPG distinguish it as an extremely promising fuel of the future. In the current work, tungstophosphoric acid (TPA) supported on four different mesoporous silica supports were investigated as mesoporous superacids for hydroconversion of refinery naphtha using n-heptane as a model feedstock. The varied levels of interactions of prepared mesoporous silica with tungstophosphoric acid catalysts were observed to have a prominent effect on the strength of the acid sites generated on silica surfaces and as a result affected heptane hydroconversion activity and selectivity of isomerized and cracked products. Interestingly, activity could be tuned towards selective cracking or isomerization-cracking by selection of a suitable topology of mesoporous silica. Hexagonal Mesoporous Silica (HMS) and plugged SBA-15 supported TPA catalysts demonstrated high n-heptane conversion activity and isomerization selectivity whereas KIT-6 and SBA-15 supported TPA catalysts demonstrated high cracking selectivity to LPG.

TPA silanol interactions in mesoporous TPA silica composites govern the strength of acid sites, activity and selectivity.     

Detailed Inspection of γ-ray,Fast and Thermal Neutrons Shielding Competence of Calcium Oxide or Strontium Oxide Comprising Bismuth Borate Glasses

For both the B₂O₃-Bi₂O₃-CaO and B₂O₃-Bi₂O₃-SrO glass systems, γ-ray and neutron attenuation qualities were evaluated. Utilizing the Phy-X/PSD program, within the 0.015–15 MeV energy range, linear attenuation coefficients (µ) and mass attenuation coefficients (μ/ρ) were calculated, and the attained μ/ρ quantities match well with respective simulation results computed by MCNPX, Geant4, and Penelope codes. Instead of B₂O₃/CaO or B₂O₃/SrO, the Bi₂O₃ addition causes improved γ-ray shielding competence, i.e., rise in effective atomic number (Z_eff) and a fall in half-value layer (HVL), tenth-value layer (TVL), and mean free path (MFP). Exposure buildup factors (EBFs) and energy absorption buildup factors (EABFs) were derived using a geometric progression (G–P) fitting approach at 1–40 mfp penetration depths (PDs), within the 0.015–15 MeV range. Computed radiation protection efficiency (RPE) values confirm their excellent capacity for lower energy photons shielding. Comparably greater density (7.59 g/cm³), larger μ, μ/ρ, Z_eff, equivalent atomic number (Z_eq), and RPE, with the lowest HVL, TVL, MFP, EBFs, and EABFs derived for 30B₂O₃-60Bi₂O₃-10SrO (mol%) glass suggest it as an excellent γ-ray attenuator. Additionally, 30B₂O₃-60Bi₂O₃-10SrO (mol%) glass holds a commensurably bigger macroscopic removal cross-section for fast neutrons (Σ_R) (=0.1199 cm⁻¹), obtained by applying Phy-X/PSD for fast neutrons shielding, owing to the presence of larger wt% of ‘Bi’ (80.6813 wt%) and moderate ‘B’ (2.0869 wt%) elements in it. 70B₂O₃-5Bi₂O₃-25CaO (mol%) sample (B: 17.5887 wt%, Bi: 24.2855 wt%, Ca: 11.6436 wt%, and O: 46.4821 wt%) shows high potentiality for thermal or slow neutrons and intermediate energy neutrons capture or absorption due to comprised high wt% of ‘B’ element in it.     

Pars plana modified Baerveldt implant versus neodymium:YAG cyclophotocoagulation in the management of neovascular glaucoma

OBJECTIVE: To determine the relative effectiveness of neodymium:YAG cyclophotocoagulation (NCYC) and pars plana modified Baerveldt implant (PPBI) surgery on intraocular pressure (IOP) control in eyes with neovascular glaucoma (NVG). PARTICIPANTS: In this retrospective comparative group study, 30 patients with NVG treated with contact NCYC were compared with 18 patients who underwent PPBI. Patients groups were not statistically dissimilar with respect to the underlying disorder-causing angle and iris neovascularization, intraocular pressure, and patient's age. RESULTS: During a follow up of 6 months, an IOP control of > or = 6 and < or = 21 mm Hg was achieved in 23 eyes (76.6%) treated with NCYC compared with 17 eyes (94.4%) receiving PPBI (P = 0.13). Among eyes that had unsuccessful outcome in both groups, the proportions with persistently high IOP or hypotony were greater in the NCYC group than in the PPBI group. Based on our criteria, the cumulative proportion of failure in the NCYC group was 23.3% at 6 months as compared to 5.6% in the PPBI group. Seven eyes (23.3%) in the NCYC group lost light perception versus 1 eye (5.6%) in the PPBI group. The incidence of postoperative choroidal effusion (36%) was higher in the PPBI group. CONCLUSIONS: This study suggests that in the management of NVG, PPBI surgery more frequently controls IOP in a medically acceptable range with less hypotony and greater preservation of visual acuity than NCYC.     

Anti-diabetic action of Punica granatum flower extract: activation of PPAR-gamma and identification of an active component

Peroxisome proliferator-activated receptor (PPAR)-gamma activators are widely used in the treatment of type 2 diabetes because they improve the sensitivity of insulin receptors. Punica granatum flower (PGF) has been used as an anti-diabetic medicine in Unani medicinal literature. The mechanism of actions is, however, unknown. In the current study, we demonstrated that 6-week oral administration of methanol extract from PGF (500 mg/kg, daily) inhibited glucose loading-induced increase of plasma glucose levels in Zucker diabetic fatty rats (ZDF), a genetic animal model for type 2 diabetes, whereas it did not inhibit the increase in Zucker lean rats (ZL). The treatment did not lower the plasma glucose levels in fasted ZDF and ZL rats. Furthermore, RT-PCR results demonstrated that the PGF extract treatment in ZDF rats enhanced cardiac PPAR-gamma mRNA expression and restored the down-regulated cardiac glucose transporter (GLUT)-4 (the insulin-dependent isoform of GLUTs) mRNA. These results suggest that the anti-diabetic activity of PGF extract may result from improved sensitivity of the insulin receptor. From the in vitro studies, we demonstrated that the PGF extract enhanced PPAR-gamma mRNA and protein expression and increased PPAR-gamma-dependent mRNA expression and activity of lipoprotein lipase in human THP-1-differentiated macrophage cells. Phytochemical investigation demonstrated that gallic acid in PGF extract is mostly responsible for this activity. Thus, our findings indicate that PPAR-gamma is a molecular target for PGF extract and its prominent component gallic acid, and provide a better understanding of the potential mechanism of the anti-diabetic action of PGF.     

Adeno-associated virus 2-mediated antiangiogenic cancer gene therapy: long-term efficacy of a vector encoding angiostatin and endostatin over vectors encoding a single factor

Angiogenesis is characteristic of solid tumor growth and a surrogate marker for metastasis in many human cancers. Inhibition of tumor angiogenesis using antiangiogenic drugs and gene transfer approaches has suggested the potential of this form of therapy in controlling tumor growth. However, for long-term tumor-free survival by antiangiogenic therapy, the factors controlling tumor neovasculature need to be systemically maintained at stable therapeutic levels. Here we show sustained expression of the antiangiogenic factors angiostatin and endostatin as secretory proteins by recombinant adeno-associated virus 2 (rAAV)-mediated gene transfer. Both vectors provided significant protective efficacy in a mouse tumor xenograft model. Stable transgene persistence and systemic levels of both angiostatin and endostatin were confirmed by in situ hybridization of the vector-injected tissues and by serum ELISA measurements, respectively. Whereas treatment with rAAV containing either endostatin or angiostatin alone resulted in moderate to significant protection, the combination of endostatin and angiostatin gene transfer from a single vector resulted in a complete protection. These data suggest that AAV-mediated long-term expression of both endostatin and angiostatin may have clinical utility against recurrence of cancers after primary therapies and may represent rational adjuvant therapies in combination with radiation or chemotherapy.