PURPOSE: To gain insight into the mechanisms underlying the transforming growth factor-beta induced (TGFBI)-related corneal dystrophies and the influence of the Arg555Trp and Thr538Pro, TGFBI mutations on C-terminal cleavage and cell endoplasmic reticulum (ER) stress were investigated. METHODS: The Arg555Trp and Thr538Pro mutations known to be associated with corneal dystrophy granular type I and lattice corneal dystrophy, respectively, were introduced with the two-sequential PCR site-directed mutagenesis technique. Wild-type and mutant TGFBI DNAs were cloned into the pcDNA3.1(-)/myc-his expression vector and overexpressed in HeLa and human corneal epithelial cells (HCE) with transient transfection. Transfection efficiency was measured by the expression of green fluorescent protein. Expression of the fusion proteins was measured with western blot analysis with anti-c-myc-tag and anti-TGFBI antibodies. For cell ER stress studies, the expression levels of GRP78/BiP in HeLa cells were analyzed with western blot analysis using an anti-GRP78 monoclonal antibody at 12, 24, and 48 h after either the wild-type or mutant plasmid was transfected. RESULTS: Arg555Trp and Thr538Pro mutant TGFBIp were detected with the anti-c-myc and anti-TGFBI antibodies, while wild-type TGFBIp was detected only with the anti-TGFBI antibody, indicating that the Arg555Trp and Thr538Pro mutations prevent the C-terminal cleavage of TGFBIp. Moreover, no significant differences were seen in the expression levels of GRP78/BiP between the mutant and wild-type TGFBIp groups, suggesting that mutations in TGFBIp are unlikely to disrupt protein folding or induce cell ER stress. CONCLUSIONS: This is the first time that the influence of TGFBI mutants on C-terminal cleavage and cell ER stress has been illustrated. Corneal dystrophy-related mutations are more likely to disrupt the interaction of TGFBI with critical binding proteins than affect the whole protein structure.

RATIONALE AND OBJECTIVES: To retrospectively evaluate effectiveness and safety of radiofrequency (RF) ablation with retroperitoneal metastatic lymph nodes from hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Thirty-two patients with retroperitoneal metastatic lymph node recurrence from HCC were enrolled in our study and the patients stratified into two groups based on the treatment. Nineteen patients in Group A were percutaneously treated and each metastatic lymph node was ablated with computed tomographic (CT) guidance. Thirteen patients in Group B only underwent RF ablation for hematogenous metastases, but did not undergo RF ablation or any other treatment for metastatic lymph nodes. Follow-up contrast material-enhanced CT or positron emission tomographic scans were reviewed and Kaplan-Meier survival estimates were analyzed. RESULTS: There were no significant differences between characteristics of the two groups. Kaplan-Meier analysis indicated the patients of Group A had an overall survival of 26.3% at 1 year compared with 7.7% for those of Group B. Mantel-Cox log rank test showed the 1-year survival rate of Group A was significantly higher than that of Group B (P =.029). In Group A, the local control rate of 3, 6, 10, and 15 months was 78.9%, 73.3%, 41.7%, and 25.0%, respectively. Sixteen, 12, 6, and 2 patients showed no evidence of local progression for 3, 6, 10, and 15 months, respectively. There was no thermal injury of gastrointestinal tract or bile duct during RF ablation in all the 19 patients of Group A. CONCLUSION: RF ablation is effective and may be safely applied to retroperitoneal metastatic lymph nodes from HCC.

Background:  The clinical utility of increasing to weekly adalimumab therapy in psoriasis patients with inadequate response to every other week (eow) dosing is unknown. Objectives:  Determine effectiveness of escalating adalimumab dosage from 40 mg eow to weekly in patients with <PASI 50 response following ≥24 weeks treatment. Identify characteristics of patients likely to benefit from dose escalation retrospectively using classification and regression tree analysis. Assess cost implications for allowing dose escalation from the private payers' perspective. Methods:  Patients with moderate-to-severe psoriasis who received blinded adalimumab 40 mg eow or placebo in antecedent phase II/III studies could enroll in OLE and initially receive open-label adalimumab 40 mg eow (EOW population). On/after Week-24 (OLE), patients with <PASI 50 response relative to baseline of antecedent study could increase to 40 mg weekly. Dosage escalation population continued on weekly dosing until achieving PASI 75 response, then resumed eow dosing. Study visits were 6/12 weeks after dosage escalation, and every 12 weeks thereafter. Percentage of patients who achieved PASI 75 response following dosage escalation was determined (missing PASI scores imputed as nonresponse). Safety was assessed for dosage escalation population and for all adalimumab exposure that did not follow dosage escalation in the EOW set. Results:  349/1256 (27.8%) patients underwent dosage escalation (OLE). 12/24 weeks after dosage escalation, 26.6%(93/349)/38.1%(133/349) were PASI 75 responders or resumed eow dosing. Secondary nonresponders, patients weighing ≤102 kg, with disease duration <8.3 years were most likely to benefit from dose escalation. Rates of serious/serious infectious/malignant (excluding non-melanoma skin cancers or lymphoma) AEs were 6.8/0.9/1.4 events/100 patient-years (dosage escalation population); comparable rates in the EOW set were 6.5/1.2/0.5 events/100 patient-years. Conclusions:  Most patients did not require dose escalation. By 12 weeks after dose escalation, one-quarter achieved substantial clinical improvement. Safety results were similar between patients who dosage-escalated and those who did not.

We have explored a method to reduce turbulence-induced scintillation by using an incoherent beam array composed of beamlets with nonuniform polarization. It is shown that significant scintillation reduction of such an incoherent beam array can be obtained by using nonuniformly polarized beamlets whose scintillation properties are optimized.

OBJECTIVE:The widely reported associations between various nutrients and cognition may occur through many biologic pathways including those of β-amyloid (Aβ). However, little is known about the possible associations of dietary factors with plasma Aβ40 or Aβ42. The aim of the current study was to evaluate the association between nutrient intake and plasma Aβ levels. METHODS:In this cross-sectional study, plasma Aβ40 and Aβ42 and dietary data were obtained from 1,219 cognitively healthy elderly (age >65 years), who were participants in a community-based multiethnic cohort. Information on dietary intake was obtained 1.2 years, on average, before Aβ assay. The associations of plasma Aβ40 and Aβ42 levels and dietary intake of 10 nutrients were examined using linear regression models, adjusted for age, gender, ethnicity, education, caloric intake, apolipoprotein E genotype, and recruitment wave. Nutrients examined included saturated fatty acid, monounsaturated fatty acid, ω-3 polyunsaturated fatty acid (PUFA), ω-6 PUFA, vitamin E, vitamin C, β-carotene, vitamin B(12), folate, and vitamin D. RESULTS:In unadjusted models that simultaneously included all nutrients, higher intake of ω-3 PUFA was associated with lower levels of Aβ40 (β =-24.7, p < 0.001) and lower levels of Aβ42 (β =-12.3, p < 0.001). In adjusted models, ω-3 PUFA remained a strong predictor of Aβ42 (β =-7.31, p = 0.02), whereas its association with Aβ40 was attenuated (β =-11.96, p = 0.06). Other nutrients were not associated with plasma Aβ levels. CONCLUSIONS:Our data suggest that higher dietary intake of ω-3 PUFA is associated with lower plasma levels of Aβ42, a profile linked with reduced risk of incident AD and slower cognitive decline in our cohort.

Objective: The objective of this study was to explore the association between coronary artery disease and genetic polymorphisms of the renin-angiotensin-aldosterone system (RAAS) pathway. In addition, we examined the interactions between demographic and lifestyle risk factors (environmental factors including age, sex, smoking status, alcohol intake) and RAAS polymorphisms on disease risk. Methods: A total of 1089 subjects who underwent coronary angiography were enrolled in this study. Eight RAAS polymorphisms were genotyped in this population: the G2350A (rs4343) polymorphism in exon 17 of the angiotensin converting enzyme (ACE) gene, 1166A→C (rs5186) and 573C/T (rs5182) in the angiotensin II type 1 receptor (AGTR1) gene, the -344C→T transversion (rs1799998) in the aldosterone synthase (CYP11B2) gene, and the G-217A (rs5049), G-6A (rs5051), M235T (rs699; T4072C), and T174M (rs4762; C3889T) polymorphisms in the angiotensinogen (AGT) gene. Subjects with coronary heart disease were defined as those with at least 50% stenosis in at least one major coronary artery, and, the severity of coronary atherosclerosis was defined by the Gensini scoring system. Results: Compared to the subjects with AA genotype, the subjects with AG + GG genotype of rs1799998 had significant lower gensini score (p=0.029). After adjusting for age, gender, cigarette smoking, and alcohol intake status, the AG genotype (OR 0.717 95%CI 0.541-0.950, p=0.021) and the AG + GG genotype (OR 0.730 95%CI 0.559-0.954, p=0.021) distributions of rs1799998 were significantly different between the cases and controls compare to the AA genotype. Subjects with three at-risk loci had increased risk of coronary artery disease compared to subjects carrying 0 or 1 risk-associated polymorphism (OR [95% CI]:1.579 [1.077-2.316], p=0. 019), and the significance of the association was not reduced after adjusting for age, sex, cigarette smoking, or alcohol intake (adjusted OR [95% CI]: 1.673 [1.116-2.507], p=0.013). The results of multifactor-dimensionality reduction analysis revealed an interaction effect of CYP11B2 -344C→T, age, and smoking status on the risk of coronary heart disease (training OR [95% CI]: 3.7685 [2.8463-4.9895], p<0.0001; testing OR [95% CI]: 2.7583 [1.2038-6.3203], p=0.015). Conclusions: Subjects who carried the G allele of the rs1799998 polymorphism significantly associated with coronary heart disease and severity of coronary atherosclerosis estimated by the Gensini score in the whole population of the study. And, multiple RAAS gene polymorphisms are associated with coronary artery disease. The interaction of the CYP11B2 -344C→T polymorphism (rs1799998), age, and smoking status is also associated with enhanced risk of coronary artery disease.

Hewson, J., Johnson, R., Arroyo, L. G., Diaz-Mendez, A., Ruiz-López, J. A., Gu, Y., del Castillo, J. R. E. Comparison of continuous infusion with intermittent bolus administration of cefotaxime on blood and cavity fluid drug concentrations in neonatal foals. J. vet. Pharmacol. Therap. doi: 10.1111/j.1365-2885.2012.01394.x. Healthy neonatal foals were treated with cefotaxime by bolus (40 mg/kg IV q6h for 12 doses; n = 10) or by infusion (loading dose of 40 mg/kg IV followed by continuous infusion of a total daily dose of 160 mg/kg per 24 h for 3 days; n = 5). Population pharmacokinetics was determined, and concentrations in cavity fluids were measured at steady state (72 h). Highest measured serum drug concentration in the bolus group was 88.09 μg/mL and minimum drug concentration (C(min)) was 0.78 μg/mL at 6-h postadministration (immediately before each next dose), whereas infusion resulted in a steady-state concentration of 16.10 μg/mL in the infusion group. Mean cefotaxime concentration in joint fluid at 72 h was higher (P = 0.051) in the infusion group (5.02 μg/mL) compared to the bolus group (0.78 μg/mL). Drug concentration in CSF at 72 h was not different between groups (P = 0.243) and was substantially lower than serum concentrations in either group. Insufficient data on pulmonary epithelial lining fluid were available to compare the methods of administration for cefotaxime in this cavity fluid. Results support continuous drug infusion over bolus dosing in the treatment for neonatal foal septicemia to optimize time that cefotaxime concentration exceeds the minimum inhibitory concentration of common equine pathogens.

A previously derived condition for the complete destructive interference of partially coherent light emerging from a trio of pinholes in an opaque screen is generalized to the case when the coherence properties of the field are asymmetric. It is shown by example that the interference condition is necessary, but not sufficient, and that the existence of complete destructive interference also depends on the intensity of light emerging from the pinholes and the system geometry; more general conditions for such interference are derived. The phase of the wave field exhibits both phase singularities and correlation singularities, and a number of nonintuitive situations in which complete destructive interference occurs are described and explained.

Guillain-Barré syndrome (GBS) is an autoimmune-mediated disease triggered by a preceding infection. A substantial body of evidence implicates antibodies to various gangliosides in subtypes of GBS. A significant proportion of patients with acute demyelinating subset of GBS have IgG antibodies against peripheral nervous system myelin specific neolactogangliosides such as LM1 and Hex-LM1. Although anti-neolactoganglioside antibodies in GBS were described more than two decades ago, their pathogenic role in neuropathy remains unknown due to the lack of suitable experimental models. In this study, we immunized ten guinea pigs with purified LM1 ganglioside mixed with keyhole limpet hemocyanin (KLH) and emulsified in complete Freund's adjuvant (CFA). Control guinea pigs were injected with KLH emulsified in CFA only. The animals were bled every four week intervals. The animals were boosted 3 times every four weeks. Experiments were terminated four months after initial immunization. Nine of 10 guinea pigs immunized with LM1 exhibited antibody responses to LM1. Anti-LM1 IgG titers in nine guinea pigs ranged from 1:400 to 1:12,800 at 16-weeks after initial immunization. Anti-LM1 antibodies were predominantly of IgG2 subclass. One guinea pig with the highest levels of IgG antibodies exhibited mild signs of neuropathy. There was no evidence of demyelination or inflammation in the sciatic nerves of LM1-immunized guinea pigs. Anti-LM1 antibodies bound to rat sciatic nerve myelin and to isolated rat Schwann cells. In summary, our findings suggest that relatively high levels of anti-LM1 IgG antibodies can be induced in guinea pigs and that LM1 is localized in peripheral nerve myelin and in Schwann cells. Further studies are needed to determine the pathogenic potential of anti-neolactoganglioside antibodies in neuropathy.

We introduce a precise three-dimensional (3D) localization method of spherical gold nanoparticle probes using model-based correlation coefficient mapping. To accomplish this, a stack of sample images at different z-positions are acquired and a 3D intensity profile of the probe serving as the model is used to map out the positions of nanoparticles in the sample. By using this model-based correlation imaging method, precise localization can be achieved in imaging techniques with complicated point spread functions (PSF) such as differential interference contrast (DIC) microscopy. We demonstrated the localization precision of 4-7 nm laterally and 16 nm axially for 40-nm gold nanospheres at an imaging rate of 10 frames per second. The 3D super-localization method was applied to tracking gold nanospheres during live endocytosis events.