Biophysical changes in normal-appearing white matter and subcortical nuclei in late-life major depression detected using magnetization transfer

Neuroanatomical changes have been identified in patients diagnosed with late-life major depressive disorder (MDD) compared with controls. These primarily comprise a decrease in focal brain volumes and an increase in MRI-determined high intensity lesions that are largely confined to the white matter. The physiological status of normal-appearing white matter in patients with MDD remains unknown. Magnetization transfer (MT) is a relatively new neuroimaging technique that permits us to examine the biophysical characteristics of specific brain regions. Using MT, we studied eight patients with late-life MDD and eight non-depressed controls. MT ratios (MTR), which reflect the integrity of the macromolecular protein pool, were ascertained in normal-appearing white matter and subcortical nuclei. Patients had significantly lower MTRs in the genu and splenium of the corpus callosum, the right caudate nucleus and putamen, and the occipital white matter compared with controls. The findings indicate that the structure of the macromolecular protein matrix may be compromised in normal-appearing white matter and critical subcortical nuclei in patients with late-life major depression. These changes may provide important substrates to mood disorders and have implications for neuronal connectivity and its role in the pathophysiology of late-life depression.     

Characterization of Suspension-Based Metered Dose Inhaler Formulations Composed of Spray-Dried Budesonide Microcrystals Dispersed in HFA-134a

PURPOSE: To assess the physicochemical characteristics and aerosol properties of suspensions of lipid-coated budesonide microcrystals dispersed in HFA-134a. METHODS: Lipid-coated budesonide microcrystals were prepared by spray-drying an emulsion-based feedstock. Physicochemical characteristics of spray-dried particles were assessed by electron microscopy, laser diffraction, and differential scanning calorimetry. Purity and content were determined by reverse-phase HPLC. Particle aggregation and suspension stability were assessed visually, and aerosol performance was assessed by Andersen cascade impaction and dose content uniformity. RESULTS: Spray-drying of micronized budesonide microcrystals in the presence of phospholipid-coated emulsion droplets results in the production of low-density lipid-coated microcrystals with low surface energy. These spray-dried particles form stable suspensions in HFA-134a. This translates into good uniformity in the metered dose across the contents of the inhaler and acceptable aerodynamic particle size distributions (MMAD = 3.2 to 3.4 microm). The formulation was observed to maintain its performance over 6 months at 40 degrees C/75% RH and 16 months at 25 degrees C/60% RH. No effect of storage orientation was observed on the content of first sprays following storage (i.e., no Cyr effect). The fine particle dose was found to be linear out to suspension concentrations of about 2% wt/vol, and FPD(4.7 microm) values approaching 400 microg can be delivered in a single inhalation. CONCLUSIONS: Engineered particles comprised of lipid-coated microcrystals may provide an acceptable alternative formulation technology for metered dose inhalers in the new hydrofluoroalkane propellants.     

The effects of tetrathiomolybdate (TTM, NSC-714598) and copper supplementation on fertility and early embryonic development in rats

Based on its ability to chelate copper, TTM is being studied as an antiangiogenic agent for cancer therapy. The purpose of this study was to evaluate the toxicity of TTM and the protection of copper supplementation on the reproductive capability of male and female CD rats. Doses of 0, 1, 4, and 12 mg/kg/day with copper supplementation (110 mg/kg of diet) were given by gavage. There were no effects on the estrous cycle or reproductive indices, or maternal toxicity in any female dose group. Male rats given 12 mg/kg/day showed significant decreases in body weight gains and food consumption, and anemia. Serum ceruloplasmin levels were dose-dependently decreased in all male dose groups. Reduced epididymal weights, sperm counts, and sperm motility, sperm morphologic abnormalities and histopathologic changes in testis and epididymis occurred only at 12 mg/kg/day. Dietary copper supplementation prevented the adverse sperm effects produced by 12 mg/kg/day of TTM.     

Radiometals as payloads for radioimmunotherapy for lymphoma

Because of their remarkable effectiveness in radioimmunotherapy (RIT), 2 anti-CD20 monoclonal antibody (MAb) drugs, one labeled with indium 111 for imaging or yttrium 90 for therapy, and another labeled with iodine I 131 for imaging and therapy, have been approved for use in patients with non-Hodgkin's lymphoma (NHL). Successful RIT for lymphomas is due in large part to the rapid and efficient binding of the targeted MAb to lymphoma cells. Carcinomas are more difficult to access, necessitating novel strategies matched with radionuclides with specific physical properties. Because there are many radionuclides from which to choose, a systematic approach is required to select those preferred for a specific application. Thus far, radionuclides with g emissions for imaging and particulate emissions for therapy have been investigated. Radionuclides of iodine were the first to be used for RIT. Many conventionally radioiodinated MAbs are degraded after endocytosis by target cells, releasing radioiodinated peptides and amino acids. In contrast, radiometals have been shown to have residualizing properties, advantageous when the MAb is localized in malignant tissue. b-emitting lanthanides like those of 90Y, lutetium 177, etc. have attractive combinations of biologic, physical, radiochemical, production, economic, and radiation safety characteristics. Other radiometals, such as copper-67 and copper-64, are also of interest. a-emitters, including actinium-225 and bismuth-213, have been used for therapy in selected applications. Evidence for the impact of the radionuclide is provided by data from the randomized pivotal phase III trial of 90Y ibritumomab tiuxetan (Zevalin) in patients with NHL; responses were about 2 times greater in the 90Y ibritumomab tiuxetan arm than in the rituximab arm. It is clear that RIT has emerged as a safe and efficient method for treatment of NHL, especially in specific settings.     

Drug insight: Cancer cell immortality-telomerase as a target for novel cancer gene therapies

Rapid advances in our understanding of the molecular basis of cancer development and progression over the past three decades have led to the design of new potential cancer therapies. High throughput target validation and expression studies are expected to yield a powerful arsenal of new cancer treatments, but untangling the complex pathways underlying the major cancer phenotypes remains a significant challenge. A considerable body of evidence in recent years implicates deregulated expression of a single multi-component enzyme, telomerase, as a causative factor at the heart of immortalization in the vast majority of human tumors. This review highlights the potential of telomerase as a target for novel cancer therapies. The potential of exploiting the selectivity of the telomerase family of genes within cancer cells to develop gene therapy strategies is discussed, and the progress towards translating these novel therapeutics from the laboratory to the clinic is reviewed.     

Comparison of genotypic-based microbial source tracking methods requiring a host origin database

Microbial source tracking (MST) results, obtained using identical sample sets and pulsed field gel electrophoresis (PFGE), repetitive element PCR (rep-PCR) and ribotyping techniques were compared. These methods were performed by six investigators in analysis of duplicate, blind sets of water samples spiked with feces from five possible sources (sewage, human, dog, cow and seagull). Investigators were provided with samples of the fecal material used to inoculate the water samples for host origin database construction. All methods correctly identified the dominant source in the majority of the samples. Modifications of some of these methods correctly identified the dominant sources in over 90% of the samples; however, false positive rates were as high as 57%. The high false positive rates appeared to be indirectly proportional to the levels of stringency applied in pattern analysis. All the methods produced useful data but the results highlighted the need to modify and optimize these methods in order to minimize sources of error.     

Risk assessment dosimetry model for inhaled particulate matter: I. Human subjects

Pollutant particulate matter (PM) is a serious global problem, presenting a threat to the health and well being of human subjects. Inhalation exposures tests with surrogate animals can be performed to estimate the threat. However, it is difficult to extrapolate the findings of animal tests to human conditions. In this two-part series, interspecies dosimetry models especially designed for implementation with risk assessment protocols are presented. In Part I, the mathematical integrity of the source model per se was tested with data from human subjects, and theoretical predictions agreed well with experimental measurements. In Part II, for surrogate (rat) simulations, appropriate algorithms for morphologies and ventilatory parameters were used as subroutines in the validated model. We conducted a comprehensive series of computer simulations describing the behavior of a representative air pollutant, secondary cigarette smoke. For risk assessment interests, a range of states from rest to exercise was considered. PM hygroscopicity had a pronounced effect on deposition in a complex but systematic manner, in humans and rats: deposition was increased for particles larger than about 1 microm, but was decreased for particles smaller than about 0.1 microm. The results clearly indicate that dosimetry models can be effectively used to a priori determine the laboratory conditions necessary for animals tests to accurately mimic human conditions. Moreover, the use of interspecies models is very cost effective. We propose, therefore, that mathematical models be used in a complementary manner with inhalation exposure experiments and be actively integrated into PM risk assessment protocols.     

The temporomandibular joint: clinical and surgical aspects

Advances in imaging techniques have greatly enhanced the ability to visualize the internal anatomy of the temporomandibular joint and have increased understanding of the etiology of many temporomandibular disorders. When used together with careful history and physical examination, this knowledge can contribute to better treatment outcomes.     

Physical models and dose factors for use in internal dose assessment

Internal dose assessment depends on the use of mathematical formulas for dose calculation and models of the human body and its organs. A simple, unified method for internal dose calculations is described, which brings together and simplifies concepts used in nuclear medicine and occupational internal dose systems previously described. Using the best current decay data and phantoms for internal dose calculations, dose factors for internal dose assessment are provided. Decay data for over 800 radionuclides from the data service at Brookhaven National Laboratory were combined with absorbed fraction data from a number of currently available mathematical whole body and organ models to provide the dose factors. This represents the first published update on nuclear medicine dose factors since MIRD Pamphlet No. 11 in 1975; in this paper, dose factors for many more nuclides are given (816 vs. 117 in MIRD 11), including some alpha emitters. New models are also employed, and dose factors for bone and marrow have been updated with recently suggested corrections. The good agreement of the new dose factors with previously published values for several of the models gives good confidence in their accuracy. This article gives an overview of the technical basis for these dose factors and some example tables of data, but the bulk of the data files will be distributed electronically. The use of an "electronic publishing" approach permits the publication of this kind of voluminous information in mainstream journals while facilitating rapid access and use without the need to purchase often expensive and bulky paper documents.     

Bone mineral density and fracture in postmenopausal women

Summary This retrospective study examined bone mineral density (BMD) for discrimination of female patients with fractures. Bone densitometry was done in 146 patients over the age of 50 years at radius, lumbar spine, and proximal femur sites using single and dual photon absorptiometry. The patients were divided into three groups: (A) no osteoporotic fractures (n=92); (B) mild spine fractures with >15% compression (n=38); and (C) hip fractures (n=16). Groups B and C did not differ significantly from each other in BMD, but these groups differed significantly from group A for spine and femur BMD. No significant differences between groups were found for the radius. Receiver operating characteristic (ROC) analysis showed that the BMD of the proximal femur had the highest diagnostic sensitivity for both spine and femur fractures; the radius had the lowest overall sensitivity, and the spine was intermediate.