Millimeter wave silicon micromachined waveguide probe as an aid for skin diagnosis--results of measurements on phantom material with varied water content.

BACKGROUND: More than 2 million cases of skin cancer are diagnosed annually in the United States, which makes it the most common form of cancer in that country. Early detection of cancer usually results in less extensive treatment and better outcome for the patient. Millimeter wave silicon micromachined waveguide probe is foreseen as an aid for skin diagnosis, which is currently based on visual inspection followed by biopsy, in cases where the macroscopical picture raises suspicion of malignancy. AIMS: Demonstration of the discrimination potential of tissues of different water content using a novel micromachined silicon waveguide probe. Secondarily, the silicon probe miniaturization till an inspection area of 600 × 200 µm2, representing a drastic reduction by 96.3% of the probing area, in comparison with a conventional WR-10 waveguide. The high planar resolution is required for histology and early-state skin-cancer detection. MATERIAL AND METHODS: To evaluate the probe three phantoms with different water contents, i.e. 50%, 75% and 95%, mimicking dielectric properties of human skin were characterized in the frequency range of 95-105 GHz. The complex permittivity values of the skin are obtained from the variation in frequency and amplitude of the reflection coefficient (S11), measured with a Vector Network Analyzer (VNA), by comparison with finite elements simulations of the measurement set-up, using the commercially available software, HFSS. The expected frequency variation is calculated with HFSS and is based on extrapolated complex permittivities, using one relaxation Debye model from permittivity measurements obtained using the Agilent probe. RESULTS: Millimeter wave reflection measurements were performed using the probe in the frequency range of 95-105 GHz with three phantoms materials and air. Intermediate measurement results are in good agreement with HFSS simulations, based on the extrapolated complex permittivity. The resonance frequency lowers, from the idle situation when it is probing air, respectively by 0.7, 1.2 and 4.26 GHz when a phantom material of 50%, 75% and 95% water content is measured. DISCUSSION: The results of the measurements in our laboratory set-up with three different phantoms indicate that the probe may be able to discriminate between normal and pathological skin tissue, improving the spatial resolution in histology and on skin measurements, due to the highly reduced area of probing. CONCLUSION: The probe has the potential to discriminate between normal and pathological skin tissue. Further, improved information, compared to the optical histological inspection can be obtained, i.e. the complex permittivity characterization is obtained with a high resolution, due to the highly reduced measurement area of the probe tip.

Identification of a human-specific epitope in a conserved region of the La/SS-B autoantigen.

Human anti-La/SS-B autoantibodies are known to react with highly conserved epitopes suggested to be functional or active sites on the La/SS-B polypeptide. This study was designed to determine whether the autoantibodies also react with poorly conserved regions of La/SS-B as predicted by an antigen-driven autoimmune response. Binding of human autoantibodies to purified human, mouse, and bovine recombinant fragments representing immunodominant regions of the La/SS-B polypeptide was compared using Western blotting and ELISA. A cross-reactive epitope was located in the highly conserved NH2-terminal region of La/SS-B. Significantly, human-specific epitopes were identified in both the conserved RNA-recognition motif and a poorly conserved COOH-terminal fragment, providing direct evidence for an autoantigen-driven response. The lack of autoantibody cross-reactivity with a conserved domain of mouse and bovine La/SS-B implies that a small number of residues in human autoepitopes may be critical for autoimmunogenicity.

Restoration of mitochondrial energy-linked reactions following dexamethasone treatment of rats infected with the liver fluke Fasciola hepatica.

Mitochondria isolated from male Wistar rats experimentally infected with the common liver fluke, Fasciola hepatica, exhibit loss of respiratory control from 2 weeks post-infection (Rule, et al. (1989) Biochem. J. 260, 517-523). We now report that subcutaneous injections of the anti-inflammatory drug, dexamethasone, during the final week of infection prevented the mitochondrial uncoupling and restored respiratory control almost to the levels of uninfected controls. Further investigations have shown that mitochondria from infected rat livers are unable to synthesize ATP and that abnormal respiration is also evident in hepatocytes isolated from infected rats. These abnormalities were absent when infected rats were treated with dexamethasone. In addition, liver mitochondrial function in infected, congenitally athymic, nude rats (CBH/R nu/nu) was not significantly different from that in uninfected nude or Wistar controls. These results provide evidence that the mitochondrial dysfunction in fascioliasis is host-mediated and that T lymphocytes in particular may be involved.

Importance of T-cell-dependent inflammatory reactions in the decline of microsomal cytochrome P450 concentration in the livers of rats infected with Fasciola hepatica.

The concentration of cytochrome P450, measured spectrophotometrically in microsomal preparations from the livers of rats infected with 30 metacercariae of Fasciola hepatica, declined by approximately 50% at 3 weeks post-infection. Treatment of infected rats with the anti-inflammatory agent dexamethasone (2 mg/kg at 48 h intervals for 8 days prior to assay) abolished the decline in P450 content. Assay of P450 in infected congenitally athymic (nude) rats showed normal levels. These results demonstrate that the T-cell-dependent inflammatory response in the liver of the host is a necessary factor in the development of the decline in hepatic P450, which is known to compromise the metabolism of certain drugs in infected hosts.

How does autoimmunity to La and Ro initiate and spread?

Autoimmunity to La(SS-B) and Ro(SS-A) is a paradigm for understanding the normal mechanisms of B cell and T cell tolerance and development of autoimmunity to clinically important sequestered autoantigens. Epitope mapping experiments have indicated that the autoantibody response is largely self antigen-driven but have failed to elucidate why these particular autoantigens are selected. Abnormal trafficking of La or Ro peptides in polarised epithelial cells and their presentation to autoreactive T cells, or selective release of ribonucleoproteins by injured epithelial cells, could explain the targeting of salivary and lacrimal epithelium in Sjogren's syndrome. There appears to be little, if any, immune tolerance to La in the T helper and B cell compartments. Both intra-and inter-molecular spreading of the autoimmune response have been observed for La. We present a model of recruited autoimmunity whereby capture and internalisation of La/Ro ribonucleoproteins by B cells and subsequent presentation of La or Ro determinants to autoreactive T cells could lead to inter-molecular spreading of the response.

The medical theory of Richard Koch I: theory of science and ethics.

Richard Koch first made his appearance in the 1920s with works published on the foundations of medicine. These publications describe the character of medicine as an action and the status of medicine within the theory of science. One of his conclusions is that medicine is not a science in the original sense of the word, but a practical discipline. It serves a practical purpose: to heal the sick. All medical knowledge is oriented towards this purpose, which also defines the physician's role. One kind of knowledge is diagnosis, which is strictly understood in relation to therapy, and is at the core of medical thinking. Diagnosis is not the assignment of a term of a species to a patient's disease: this would not do justice to the individuality of a clinical manifestation and would fail to provide a reason for individual therapy. Nevertheless, the terms assigned to diseases, although fictitious, are not useless, but assist in differentiating various phenomena. These conclusions carry ethical consequences. Because the task of helping the sick constitutes medicine, morals not only set ethical limits: medicine originates in a moral decision. If there are no diseases but only individual sick people, disease can not be defined as an abnormality. The individual benefit to the patient must not necessarily be the complete restoration of health. With its object being incalculable, medicine cannot guarantee its own success. Here the physician has to develop principles that allow for the best possible response to the challenges faced in varying situations of conduct.

The medical theory of Richard Koch II: natural philosophy and history.

Richard Koch(1) became known in the 1920s with works on basic medical theory. Among these publications, the character of medical action and its status within the theory of science was presented as the most important theme. While science is inherently driven by the pursuit of knowledge for its own sake, medicine pursues the practical purpose of helping the sick. Therefore, medicine must be seen as an active relationship between a helping and a suffering person. While elucidating this relationship, Koch discusses the fundamental elements of medicine found in natural philosophy and the relationship of medicine to its own history. One of his aims is to unite natural history and the history of ideas without reducing intellectual processes to biological ones. Koch considers free will as something intuitively certain. It must serve as an axiom which will capture human as well as non-human reality. Based on the fact that human free will, considered a psychic quality, evolved out of inanimate matter, Koch grants matter (proto-) psychic qualities. They are evoked through specific constellations of matter. - With regard to history, Koch rejects the notion of constant progress. The history of medicine has provided insights that cannot be surpassed but can be obscured. Historical self-contemplation serves as a means for avoiding any deviations which may prevent medicine from fulfilling its ultimate purpose. Koch connects nature and history through the concept of a unity between natural history and the historical development of medicine. Medicine is considered an especially complex development of a purposive reaction to harmful stimuli, a reaction which can already be encountered in unicellular organisms. Without intending to reduce historical and mental processes to biological ones, Koch sets for himself the aim of gathering different phenomena and presenting them in one encapsulating unity.

Characterization of the mouse autoantigen La (SS-B). Identification of conserved RNA-binding motifs, a putative ATP binding site and reactivity of recombinant protein with poly(U) and human autoantibodies.

To facilitate the study of autoimmunity to the nuclear Ag La (SS-B) we have isolated and characterized cDNA encoding the mouse La (SS-B) protein. Mouse La (SS-B) protein has 76.7% identity to both human and bovine La (SS-B) proteins and the previously recognized RNP-binding motifs were noted to be highly conserved across the three species. Examination of the primary sequence of human and bovine La (SS-B) newly identifies the site of a potential ATP-binding motif G/AXXXXGK which is preserved in mouse La (SS-B) despite a unique 16 amino acid insertion present in this region of the mouse protein. Analysis of mouse genomic DNA suggests a single gene encodes mouse La (SS-B) and no restriction fragment polymorphisms were identified in the three mouse strains investigated. Two alternate 5' untranslated regions were identified in mouse La (SS-B) cDNA and La (SS-B) mRNA was identified in a wide range of murine tissues consistent with its ubiquitous expression. Recombinant mouse La (SS-B) protein purified from Escherichia coli was shown to bind to poly(U) agarose and to react with sera containing anti-La (SS-B) antibodies obtained from patients with Sjögren's syndrome. The ability to produce recombinant mouse La (SS-B) should provide a valuable reagent for the study of the cellular autoimmune response as well as immunologic tolerance to La (SS-B) Ag in mice.

Intra- and intermolecular spreading of autoimmunity involving the nuclear self-antigens La (SS-B) and Ro (SS-A).

We have tested the extent of immune self-tolerance to the ubiquitously expressed nuclear/cytoplasmic autoantigens La (SS-B) and Ro (SS-A) in healthy, nonautoimmune mice. Immunization of mice with recombinant mouse La resulted in a specific, isotype-switched autoantibody response, which was initially directed toward the La C subfragment (aa 111-242) but rapidly spread to involve the La A (aa 1-107) and La F (aa 243-345) regions of the La antigen. Intramolecular spreading of the anti-La antibody response was further demonstrated by the appearance of autoantibodies to multiple, nonoverlapping antigenic regions of La, after immunization of mice with the 107-aa La A subfragment. Moreover, immunization of mice with recombinant mouse or human La also elicited specific anti-60-kDa Ro IgG antibodies in all strains tested. Mice immunized with 60-kDa Ro produced a high titer anti-Ro antibody response, which was also associated with intermolecular spreading, resulting in the specific appearance of anti-La autoantibodies. These findings show that the development of autoantibodies to multiple components of the La/Ro ribonucleoprotein complex may follow initiation of immunity to a single component. In addition, the data reveal the incomplete nature of immune tolerance to La and Ro despite their endogenous expression in all nucleated cells. These observations are likely to account for the coexistence of anti-La/Ro antibodies in autoimmune disease and suggest a general explanation for the appearance of mixed autoantibody patterns in systemic autoimmune disorders.