Medullary thyroid carcinoma and biomarkers: past, present and future.

The clinical management of patients with persistent or recurrent medullary thyroid carcinoma (MTC) is still under debate, because these patients either have a long-term survival, due to an indolent course of the disease, or develop rapidly progressing disease leading to death from distant metastases. At this moment, it cannot be predicted what will happen within most individual cases. Biomarkers, indicators which can be measured objectively, can be helpful in MTC diagnosis, molecular imaging and treatment, and/or identification of MTC progression. Several MTC biomarkers are already implemented in the daily management of MTC patients. More research is being aimed at the improvement of molecular imaging techniques and the development of molecular systemic therapies. Recent discoveries, like the prognostic value of plasma calcitonin and carcino-embryonic antigen doubling-time and the presence of somatic RET mutations in MTC tissue, may be useful tools in clinical decision making in the future. In this review, we provide an overview of different MTC biomarkers and their applications in the clinical management of MTC patients.

Intestinal carriage of Staphylococcus aureus: how does its frequency compare with that of nasal carriage and what is its clinical impact?

The bacterial species Staphylococcus aureus, including its methicillin-resistant variant (MRSA), finds its primary ecological niche in the human nose, but is also able to colonize the intestines and the perineal region. Intestinal carriage has not been widely investigated despite its potential clinical impact. This review summarizes literature on the topic and sketches the current state of affairs from a microbiological and infectious diseases' perspective. Major findings are that the average reported detection rate of intestinal carriage in healthy individuals and patients is 20% for S. aureus and 9% for MRSA, which is approximately half of that for nasal carriage. Nasal carriage seems to predispose to intestinal carriage, but sole intestinal carriage occurs relatively frequently and is observed in 1 out of 3 intestinal carriers, which provides a rationale to include intestinal screening for surveillance or in outbreak settings. Colonization of the intestinal tract with S. aureus at a young age occurs at a high frequency and may affect the host's immune system. The frequency of intestinal carriage is generally underestimated and may significantly contribute to bacterial dissemination and subsequent risk of infections. Whether intestinal rather than nasal S. aureus carriage is a primary predictor for infections is still ill-defined.

Multiple endocrine neoplasia type 2B mutation in human RET oncogene induces medullary thyroid carcinoma in transgenic mice.

Multiple endocrine neoplasia type 2B (MEN 2B) is a familial cancer syndrome, in which the cardinal feature is medullary thyroid carcinoma (MTC), a malignant tumor arising from the calcitonin producing thyroid C-cells. MEN 2B is associated with a germline point mutation in the RET proto-oncogene, leading to a Met-->Thr substitution at codon 918 in the kinase domain, which alters the substrate specificity of the protein. We used the human calcitonin gene (CALC-I) promoter to generate transgenic mice expressing either the human RET oncogene with the MEN2B-specific 918 Met-->Thr mutation (CALC-MEN2B-RET) or the human non-mutated RET proto-oncogene (CALC-WT-RET) in the C-cells. At 20 - 22 months of age three out of eight CALC-MEN2B-RET transgenic founders presented with macroscopic bilateral MTC. In two founders nodular C-cell hyperplasia (CCH) was observed. Thyroid abnormalities were never observed in CALC-WT-RET transgenic mice or control non-transgenic mice analysed at this age. In some mice from established CALC-MEN2B-RET transgenic lines nodular CCH was observed from 8 months on whereas MTC was detected in 13% of mice from one CALC-MEN2B-RET line, from the age of 11 months on. These results show for the first time that the MEN2B mutation in the RET oncogene predisposes mice for MTC.

Simultaneous daytime measurements of the atmospheric coherence diameter r(0) with three different methods.

The most common parameter used in characterizing atmospheric turbulence (seeing) is the atmospheric coherence diameter, or r(0). r(0) can be measured in many ways. Three such techniques that are useful when one is making daytime seeing measurements by observing the Sun are described. Results from an experiment in which r(0) was measured with all three methods are presented.

Correction of static optical errors in a segmented adaptive optical system.

Adaptive optical systems are designed to compensate for wave-front errors caused by atmospheric turbulence. In addition, they may also correct for wave-front errors associated with fixed optical aberrations in the host telescope. In general, however, adaptive optical systems cannot sense wave-front errors caused by imperfections in their own internal optical components. Consequently, these fixed internal errors will remain uncorrected. The problem of fixed internal aberrations has been noted in a segmented adaptive optics system designed for solar astronomy. This problem has been eliminated by measurement of the fixed errors, off line, through the use of a simple adaptation of a Hartmann test. Results from a recent experiment demonstrating the correction of the errors are presented.

Phase-diversity wave-front sensor for imaging systems.

A phase-diversity wave-front sensor has been developed and tested at the Lockheed Palo Alto Research Labs (LPARL). The sensor consists of two CCD-array focal planes that record the best-focus image of an adaptive imaging system and an image that is defocused. This information is used to generate an object-independent function that is the input to a LPARL-developed neural network algorithm known as the General Regression Neural Network (GRNN). The GRNN algorithm calculates the wave-front errors that are present in the adaptive optics system. A control algorithm uses the calculated values to correct the errors in the optical system. Simulation studies and closed-loop experimental results are presented.

Solar imaging with a segmented adaptive mirror.

A 19-segment adaptive-mirror system is currently being used on the Sacramento Peak 76-cm Tower Telescope to remove wave-front distortions resulting from atmospheric turbulence. The system has proven to be capable of substantially improving the quality of an image, at times achieving 0.33-arcsec resolution in visible wavelengths under 1-3-arcsec seeing conditions. An improvement in resolution seems to occur across a large field of view that is, at times, 30 arcsec in diameter.

Wave-front tilt power spectral density from the image motion of solar pores.

We have constructed an image-stabilization system that measures wave-front tilt over a telescope aperture that is due to atmospheric turbulence. This system uses small features on the Sun as point sources. The wave-front tilt power spectral density has been measured with this system out to more than 500 Hz. The spectra show three distinct asymptotic slopes that do not, in general, agree with theoretical predictions based on the Kolmogorov model.

Internalization of antithrombin III by cultured human endothelial cells and its subcellular localization.

The presence of antithrombin III was demonstrated in cultured human endothelial cells derived from the umbilical cord by using immunofluorescence, immunoelectron microscopy studies, and an enzyme-linked immunosorbent assay (ELISA) specific for antithrombin III. Immunofluorescence studies indicated the presence of antithrombin III in granule-like structures in the endothelial cell. Immunoelectron microscopy studies performed with ultrathin cryosections of endothelial cells showed a colocalization of antithrombin III and a lysosomal marker protein in low electron dense organelles, indicating a lysosomal localization of antithrombin III. By using the ELISA, 77 +/- 40 ng (n = 8) antithrombin III was quantitated in 10(6) endothelial cells. Immunoprecipitation studies performed with metabolically labeled cultured human endothelial cells indicated that antithrombin III was not synthesized by the cells. Endothelial cells cultured in antithrombin III-depleted human serum did not contain antithrombin III, as was measured by ELISA. Internalization studies performed with radiolabeled purified antithrombin III and antithrombin III-thrombin complexes indicated that endothelial cells internalize antithrombin III when it is complexed to thrombin. Antithrombin III alone was not internalized by the endothelial cells.