Evaluation of growth and histology of human tumor xenografts implanted under the renal capsule of immunocompetent and immunodeficient mice

Fresh surgical explants of human carcinomas were implanted as first transplant generation xenografts under the kidney capsule of mice. Immunocompetent and immune-deficient mice were compared for their ability to support the persistence and growth of these xenografts. Consistent growth of tumor xenografts could not be demonstrated following implantation under the kidney capsule of immunocompetent mice. Immunological infiltration and rejection of the xenografts began 3 days postimplantation, and tumors were largely eliminated from the subcapsular space by 6 days postimplantation. In contrast human tumors consistently grew under the kidney capsule of nude mice. Significant growth became apparent by 9 days postimplantation with most human carcinomas and continued thereafter. Growth was always accompanied by neovascularization of tumor xenografts which was visible by examination of tumor-bearing kidneys under a dissecting microscope (X 6). There was no histological evidence of immunological interference with the persistence and growth of xenografts in nude mice. Thymectomized, irradiated, bone marrow-reconstituted conventional mice, as well as conventional mice, treated daily with 60 mg of cyclosporine A/kg were comparable to nude mice as hosts which supported the long-term persistence and growth of subrenal capsule implants of human tumors. Such mice could provide an alternative to nude mice as hosts in which chemosensitivity assays could be carried out against growing human tumors at a considerable saving in cost and convenience.     

Influence of food on the bioavailability of diltiazem and two of its metabolites following the administration of conventional tablets and slow-release capsules

The influence of food on the bioavailability of a conventional tablet and of a slow-release capsule of diltiazem was investigated in two separate groups of 24 healthy volunteers in two open crossover studies. Diltiazem, as a conventional tablet (2 x 30 mg, first group) or as a slow-release capsule (120 mg SR, second group), was administered in a fasting condition and 30 min after a breakfast of 784 kcal (23 per cent proteins, 55 per cent lipids, and 22 per cent of carbohydrates). Multiple blood samples were withdrawn during the next 24 h and diltiazem, desmethyldiltiazem, and deacetyldiltiazem were assayed by HPLC. Neither the rate of absorption, assessed by the rate constant of absorption, the peak plasma concentration, and the time required to reach the peak, nor the amount of drug reaching the systemic circulation, assessed by the area under the plasma concentration time curve (AUC infinity) were influenced by food, and that independently of the formulation. Compared to the fasting experiment, food did not affect either the rate of formation or the AUC infinity of desmethyldiltiazem or deacetyldiltiazem. The results of the present study show that the relative bioavailability of the single dose of diltiazem administered as a slow-release capsule is significantly higher (69 per cent) than that estimated after the administration of diltiazem in a conventional tablet. It was concluded that food does not influence the bioavailability of diltiazem administered as a conventional tablet or as a slow-release formulation.     

Extraocular muscle insertions relative to the fovea and optic nerve: humans and rhesus macaque

PURPOSE: To identify extraocular anatomic relationships of muscle insertions relative to the fovea and the optic nerve. METHODS: Thirty-eight human eye bank eyes and 10 rhesus macaque (Macaca mulatta) eyes were measured. Ten human volunteers were used to determine the horizontal rectus muscle-to-globe apposition in primary, left, and right gaze. RESULTS: External globe measurements (human/rhesus; mm +/- SD) from the temporal border of the optic nerve (ON) to the center of the fovea (F) were 3.7 +/- 0.6 and 2.6 +/- 0.2; F to the posterior border of the inferior oblique (IO) insertion, 2.5 +/- 0.8 and 0.5 +/- 0.4; ON to the posterior border of the IO, 5.6 +/- 0.9 and 2.8 +/- 0.3; horizontal axial plane (H) of the eye, defined by the long posterior ciliary artery, to the IO, 2.0 +/- 0.8 and 0.5 +/- 0.4; and H to F, 1.0 +/- 0.6 and 0.4 +/- 0.3, respectively. The IO insertion formed an arc, inferior to H, with an anterior-to-posterior cord insertion width of 9.2 +/- 0.7 and 7.7 +/- 0.3. The IO angle of insertion (theta) was 30 degrees in 84% (32/38) and 0 degrees in 16% (6/38) of human eyes and 25 to 30 degrees in all rhesus. In 20 human volunteers, from the ON to the apex of lateral rectus globe apposition was 13.9 +/- 1.1 in primary, 17.2 +/- 1.9 in lateral, and 9.3 +/- 1.7 in medial gaze. CONCLUSIONS: The fovea is located mostly superior and slightly posterior to the posterior border of the IO insertion. Topographic relationships of the extraocular muscles relative to the fovea are essential for the design of extraocular drug delivery systems.     

Development of Caenorhabditis elegans pharynx, with emphasis on its nervous system

The Caenorhabditis elegans pharynx is a neuromuscular tube of which the function is to pump and crush bacteria, and inject them into the intestine. The 80-cell pharynx develops via the morphogenesis and differentiation of the cells that compose its semi-spherical primordium, and requires the activity of several evolutionarily conserved genes, such as pha-4 (the homolog to the Drosophilaforkhead and vertebrate FoxA), ceh-22 (the homolog to the Drosophila tinman and vertebrate Nkx2.5), and pha-2 (the homolog to the vertebrate Hex). There are 20 neurons in the pharynx, each with a reproducible unique trajectory. Developmental genetic analysis of axon guidance in the pharynx indicates that some axon trajectories are in part established without growth cones, whereas other parts necessitate growth cone function and guidance. Here we provide an overview of the developmental genetics of the Caenorhabditis elegans pharynx, with an emphasis on its nervous system.     

Evidence of recombination producing allelic diversity in MHC class I Mafa-B and -A alleles in cynomolgus macaques

The MHC class I-A and -B genes of cynomolgus macaques are highly polymorphic. These genes encode proteins presenting peptides to CD8+ T cells to initiate adaptive immune response. Recombination events are one way the diversity of these alleles can be increased. Such events have been well characterized in humans, but have not been as well characterized in macaques. In order to identify and examine recombinations that create new alleles, it is important to analyze intron sequences. Intron sequences have been shown to be important to understand the evolutionary mechanisms involved in the generation of major histocompatibility complex (MHC) alleles and loci. Thus far, there have been relatively few intron sequences reported for MHC class I alleles in macaques, and this has hampered the understanding of MHC organization and evolution in macaques. In this study, we present evidence of a gene conversion event generating the Mafa-B*099 allele lineage by the combination of Mafa-B*054 and Mafa-B*095 allele lineages. A potential recombination between the Mafa-A3*13 and Mafa-A4:14 lineages was also observed, but it is less clear due to lack of intron 2 sequence. This report stresses the role that recombination can play in MHC class I diversity in cynomologus macaques, and the importance of introns in identifying and analyzing such events.     

Increased serum resistin in nonalcoholic fatty liver disease is related to liver disease severity and not to insulin resistance

CONTEXT: The recently discovered hormone resistin is linked to the development of insulin resistance, but direct evidence of resistin levels in humans with nonalcoholic fatty liver disease (NAFLD) is lacking. METHODS: We conducted this study to assess the relationship between serum resistin and NAFLD. We measured serum resistin and biochemical, hormonal, and histological correlates in 28 NAFLD patients, 33 controls, and 30 obese patients [body mass index (BMI), >30 kg/m2] without NAFLD. RESULTS: Resistin and adiponectin expression were measured in sc adipose tissue by quantitative RT-PCR. Resistin was higher in NAFLD patients compared with controls (5.87 +/- 0.49 vs. 4.30 +/- 0.20 ng/ml; P = 0.002) and obese patients (4.37 +/- 0.27 ng/ml; P = 0.002). Increased resistin mRNA was also found in the adipose tissue of NAFLD patients compared with controls and obese subjects. CONCLUSIONS: Both NAFLD and obese patients had lower adiponectin levels, whereas leptin was increased only in the obese group. No correlation was found between resistin and high-sensitivity C-reactive protein, BMI, homeostasis model assessment, insulin, glucose, transaminases, and lipid values. A positive correlation was found between resistin and histological inflammatory score. These data report increased resistin in NAFLD patients that is related to the histological severity of the disease, but do not support a link between resistin and insulin resistance or BMI in these patients.     

Autobiographical memory in mild cognitive impairment and Alzheimer's disease: A comparison between the Levine and Kopelman interview methodologies

Previous studies have produced inconsistent results concerning the two components of autobiographical memory—personal semantic memory and episodic memory. Results in subjects with mild cognitive impairment (MCI) and dementia of Alzheimer's type (DAT) have varied concerning the existence of a temporal gradient in retrograde amnesia. These results have important theoretical implications regarding multiple trace theory versus standard consolidation models of long‐term memory (LTM). We investigated whether this variability arises from differences in the methods used in assessing autobiographical memory. We examined patterns of memory impairment in 20 healthy elderly controls, 20 MCI subjects, and 10 DAT subjects using the Autobiographical Memory Interview (AMI) of Kopelman and the Autobiographical Interview (AI) of Levine. Both the AMI and AI were modified to allow for the test scores to be derived from a single interview without fatiguing the subjects. On the AMI, DAT subjects were significantly impaired on both components of autobiographical memory—episodic memory and personal semantics—with episodic memory showing a significant though gentle temporal gradient sparing childhood memories. Using the AI test, subjects with DAT showed impaired recall of episodic details (but not personal semantics), again with a gentle temporal gradient. Differences between the two interview methods (fewer epochs in the AMI; fewer memories per epoch in the AI) were found to have a significant impact on the pattern of findings; fewer epochs in the AMI brought out the temporal gradient, and fewer memories per epoch (in the AI) diminished it. These data show the importance of technical details of the different tests in favouring one versus another LTM theory. The data are not purely compatible with either theory. © 2012 Wiley Periodicals, Inc.