Nebulized Gadolinium‐Based Nanoparticles: A Theranostic Approach for Lung Tumor Imaging and Radiosensitization

Lung cancer is the most common and most fatal cancer worldwide. Thus, improving early diagnosis and therapy is necessary. Previously, gadolinium‐based ultra‐small rigid platforms (USRPs) were developed to serve as multimodal imaging probes and as radiosensitizing agents. In addition, it was demonstrated that USRPs can be detected in the lungs using ultrashort echo‐time magnetic resonance imaging (UTE‐MRI) and fluorescence imaging after intrapulmonary administration in healthy animals. The goal of the present study is to evaluate their theranostic properties in mice with bioluminescent orthotopic lung cancer, after intrapulmonary nebulization or conventional intravenous administration. It is found that lung tumors can be detected non‐invasively using fluorescence tomography or UTE‐MRI after nebulization of USRPs, and this is confirmed by histological analysis of the lung sections. The deposition of USRPs around the tumor nodules is sufficient to generate a radiosensitizing effect when the mice are subjected to a single dose of 10 Gy conventional radiation one day after inhalation (mean survival time of 112 days versus 77 days for irradiated mice without USRPs treatment). No apparent systemic toxicity or induction of inflammation is observed. These results demonstrate the theranostic properties of USRPs for the multimodal detection of lung tumors and improved radiotherapy after nebulization.     

Ultrasmall Nanoplatforms as Calcium‐Responsive Contrast Agents for Magnetic Resonance Imaging

The preparation of ultrasmall and rigid platforms (USRPs) that are covalently coupled to macrocycle‐based, calcium‐responsive/smart contrast agents (SCAs), and the initial in vitro and in vivo validation of the resulting nanosized probes (SCA‐USRPs) by means of magnetic resonance imaging (MRI) is reported. The synthetic procedure is robust, allowing preparation of the SCA‐USRPs on a multigram scale. The resulting platforms display the desired MRI activity—i.e., longitudinal relaxivity increases almost twice at 7 T magnetic field strength upon saturation with Ca²⁺. Cell viability is probed with the MTT assay using HEK‐293 cells, which show good tolerance for lower contrast agent concentrations over longer periods of time. On intravenous administration of SCA‐USRPs in living mice, MRI studies indicate their rapid accumulation in the renal pelvis and parenchyma. Importantly, the MRI signal increases in both kidney compartments when CaCl₂ is also administrated. Laser‐induced breakdown spectroscopy experiments confirm accumulation of SCA‐USRPs in the renal cortex. To the best of our knowledge, these are the first studies which demonstrate calcium‐sensitive MRI signal changes in vivo. Continuing contrast agent and MRI protocol optimizations should lead to wider application of these responsive probes and development of superior functional methods for monitoring calcium‐dependent physiological and pathological processes in a dynamic manner.     

One-step substrate nanofabrication and patterning of nanoparticles by lithographically controlled etching

We propose an integrated top-down and bottom-up approach to single-step nanofabrication of complex nanostructures made of different materials. The process, termed lithographically controlled etching (LCE), starts with a drop of an etching solution cast on the surface to be patterned. By placing a polymeric mold on the substrate, the stamp protrusions come into contact with the surface, thus protecting it, whereas the surface beneath the mold recesses is exposed to a thin layer of etching solution, allowing the surface to be etched. By dispersing nanoparticles into the etching solution, these can be deposited and self-organize in the recesses on the substrate as these are excavated. We demonstrate here the fabrication of complex structures and nanowires 30 nm wide. Moreover, by exploiting capillary forces, it is possible to deposit nanoparticles at precise positions with respect to optically addressable microstructures, thus realizing a multiscale functional pattern.     

Effectiveness of chlorine dioxide in disinfection on two soft denture liners

OBJECTIVE: The purpose of this study was to evaluate a hydroxylapatite-based material and calcium sulfate when each was used under a resin-modified glass ionomer cement to repair furcation perforations. STUDY DESIGN: Perforations of pulp chamber floors were made in 72 teeth of 9 dogs. Perforations were divided into 3 equal-sized groups and repaired with resin-modified glass ionomer either alone or over an artificial floor. The artificial floor was either a hydroxylapatite-based material or calcium sulfate. Three dogs were killed at each of 3 intervals (1, 3, and 6 months). The tissue response to the tested materials was evaluated clinically, radiographically, and histologically. RESULTS: The hydroxylapatite-based material showed the highest radiographic success; this was followed by calcium sulfate and glass ionomer. From histologic evaluation, the average success rate was found to be 67% for calcium sulfate, 62% for the hydroxylapatite-based material, and 59% for glass ionomer. However, there was no statistical significant difference with the resin-modified glass ionomer when it was used alone and when it was used over a barrier. There was also no significant difference between the hydroxylapatite-based material and the calcium sulfate when they were used as artificial floors. CONCLUSION: The use of an artificial floor may not be necessary when flowable resin-modified glass ionomer cements are used.     

Mometasone furoate decreases adhesion molecule expression in psoriasis

This study was performed to clarify the possibility of visualization and quantification with 99mTc-tetrofosmin (Tf) myocardial scintigraphy in cases with a large atrium demonstrated by trans-thoracic echocardiography (TTE). Myocardial SPECT was evaluated in 4 patients with mitral stenosis and 15 patients with mitral regurgitation. Left atrium was identified in 12 out of 19 cases from an antero-posterior projection. The Tf uptake ratio of the left atrium, which was defined as the ratio of ROI count of the left atrium divided by the ROI count of the left ventricle, showed a good correlation with the left atrial area obtained by both trans-thoracic and trans-esophageal echocardiography (r = 0.88 and 0.91, respectively), These data suggest that Tf myocardial SPECT is a useful method of evaluating left atrial enlargement.     

Role of the kdr and super-kdr sodium channel mutations in pyrethroid resistance: correlation of allelic frequency to resistance level in wild and laboratory populations of horn flies (Haematobia irritans)

The kdr and super-kdr point mutations found in the insect sodium channel gene are postulated to confer knockdown resistance (kdr) to pyrethroids. Using an allele-specific PCR assay to detect these mutations in individual horn flies, Haematobia irritans (L.), we determined the allelic frequency of the kdr and super-kdr mutations in several wild and laboratory populations. Wild populations with very similar allelic frequencies had resistance levels that ranged widely from 3- to 18-fold relative to a susceptible population. Conversely, the kdr allele frequency in a lab population with 17-fold resistance was nearly double that found in a heavily pressured wild population with 18-fold resistance. We conclude that, although the kdr mutation confers significant levels of pyrethroid resistance, a substantial component of resistance in insecticidally pressured populations is conferred by mechanisms that are PBO-suppressible. High super-kdr allele frequencies were detected in two resistant lab populations, but in wild populations with equivalent resistance the super-kdr allele frequency was very low. Interestingly, in over 1200 individuals assayed, the super-kdr mutation was never detected in the absence of the kdr mutation.     

''Dual positivity'' for neural tube defects and down syndrome at maternal serum screening: gestational outcome

The pattern of anatomical features of the brain revealed by magnetic resonance imaging (MRI) is described in six patients incidentally identified as having acallosal brains. The complex of morphological features associated with complete agenesis of the corpus callosum included lateral displacement of slitlike anterior horns of the lateral ventricles (bullhorn-like shape), dilatation of the posterior horns of the lateral ventricles, absence of the septum pellucidum, lateral displacement of the cingulate gyri, complete separation of fornices and the presence of the anterior commissure and longitudinal callosal bundles (Probst's bundles). No compensatory enlargement of the anterior commissure was seen in the patients. The planimetrically measured cross-sectional areas of the anterior commissures were between 2.0 and 4.2 mm2 (mean 3.1) (in ten normal subjects they were 4.5, SD 0.4; range 3.8-5.2 mm2) and were reduced in four and normal in two patients. Inconstant morphological features were an absence of the posterior commissure and a radial pattern of the sulci and gyri on the medial aspect of the hemispheres. Conventional clinical testing revealed no abnormalities except a slight impairment of walking heel-to-toe in two patients. None of the patients had subjective restrictions of activities of daily life, which shows the efficacy of unknown compensatory processes.     

Effects of age, breast density, ethnicity, and estrogen replacement therapy on screening mammographic sensitivity and cancer stage at diagnosis: review of 183,134 screening mammograms in Albuquerque, New Mexico

PURPOSE: To examine how common patient factors affect screening mammographic sensitivity and cancer stage at diagnosis. MATERIALS AND METHODS: The authors used a population-based database of 183,134 screening mammograms and a statewide tumor registry to identify 807 breast cancers detected at screening mammography. RESULTS: Sensitivity varied significantly with ethnicity, use of estrogen replacement therapy, mammographic breast density, and age. Sensitivity was 54% (13 of 24) in women younger than 40 years, 77% (121 of 157) in women aged 40-49 years, 78% (224 of 286) in women aged 50-64 years, and 81% (277 of 340) in women older than 64 years. Sensitivity was 68% (162 of 237) for dense breasts and 85% (302 of 356) for nondense breasts and 74% (180 of 244) in estrogen replacement therapy users and 81% (417 of 513) in nonusers. Sensitivity was most markedly reduced with the combination of dense breasts and estrogen replacement therapy use; there was little difference when only one factor was present. Median cancer size and the percentage of early cancers showed little change with any factors. CONCLUSION: Age is a minor determinant of mammographic sensitivity in women aged 40 years or older. Sensitivity is substantially decreased with the combination of higher breast density and estrogen replacement therapy use. There was not a notable shift in cancer outcomes in the groups with lower mammographic sensitivity. These data do not support different screening recommendations in women aged 40-49 years or in estrogen replacement therapy users.     

Inhibition of experimental autoimmune encephalomyelitis in Lewis rats by nasal administration of encephalitogenic MBP peptides: synergistic effects of MBP 68-86 and 87-99

Induction of mucosal tolerance by inhalation of soluble peptides with defined T cell epitopes is receiving much attention as a means of specifically down-regulating pathogenic T cell reactivities in autoimmune and allergic disorders. Experimental autoimmune encephalomyelitis (EAE) induced in the Lewis rat by immunization with myelin basic protein (MBP) and Freund's adjuvant (CFA) is mediated by CD4+ T cells specific for the MBP amino acid sequences 68-86 and 87-99. To further define the principles of nasal tolerance induction, we generated three different MBP peptides (MBP 68-86, 87-99 and the non-encephalitogenic peptide 110-128), and evaluated whether their nasal administration on day -11, -10, -9, -8 and -7 prior to immunization with guinea pig MBP (gp-MBP) + CFA confers protection to Lewis rat EAE. Protection was achieved with the encephalitogenic peptides MBP 68-86 and 87-99, MBP 68-86 being more potent, but not with MBP 110-128. Neither MBP 68-86 nor 87-99 at doses used conferred complete protection to gp-MBP-induced EAE. In contrast, nasal administration of a mixture of MBP 68-86 and 87-99 completely blocked gp-MBP-induced EAE even at lower dosage compared to that being used for individual peptides. Rats tolerized with MBP 68-86 + 87-99 nasally showed decreased T cell responses to MBP reflected by lymphocyte proliferation and IFN-gamma ELISPOT assays. Rats tolerized with MBP 68-86 + 87-99 also had abrogated MBP-reactive IFN-gamma and tumor necrosis factor-alpha mRNA expression in lymph node cells compared to rats receiving MBP 110-128 nasally, while similar low levels of MBP-reactive transforming growth factor-beta and IL-4 mRNA expressing cells were observed in the two groups. Nasal administration of MBP 68-86 + 87-99 only slightly inhibited guinea pig spinal cord homogenate-induced EAE, and passive transfer of spleen mononuclear cells from MBP 68-86 + 87-99-tolerized rats did not protect na?ve rats from EAE. Finally, we show that nasal administration of MBP 68-86 + 87-99 can reverse ongoing EAE induced with gp-MBP, although higher doses are required compared to the dosage needed for prevention. In conclusion, nasal administration of encephalitogenic MBP peptides can induce antigen-specific T cell tolerance and confer incomplete protection to gp-MBP-induced EAE, and MBP 68-86 and 87-99 have synergistic effects. Non-regulatory mechanisms are proposed to be responsible for tolerance development after nasal peptide administration.