Increased expression of decorin during the regeneration stage of mdx mouse

Satellite cells exist in postnatal muscle tissue and constitute the main source of muscle precursor cells for growth and repair. These cells carry out important roles for skeletal muscle formation postnatally during growth of muscle mass as well as damage-induced regenerative processes. Muscle regeneration supports muscle function in aging and has a role in the functional impairment caused by progressive neuromuscular diseases. Major substances controlling this process are growth factors and extracellular matrix. Myostatin, a member of TGF-β family, was mainly expressed in muscle tissue. Decorin, a member of the small leucine-rich proteoglycan gene family, is composed of a core protein and a dermatan/chondroitin sulfate chain. Recent studies have shown that decorin enhanced the proliferation and differentiation of myogenic cells by suppressing myostatin activity. Thus, decorin appears to be a new molecule in the myostatin signaling pathway and a promising target for treatment of progressive neuromuscular diseases. Therefore, in this study, we examined the localization of decorin as well as myostatin in a muscular dystrophy model in mdx mice and B10 Scott Snells mice as a control to elucidate the differences between decorin and myostatin messages as well as protein distribution. This study revealed increased expression of decorin protein as well as mRNA at the regenerative stage of mdx mice compared to early stages, while only weak expression of decorin was detected in the control mice. Our study contributes to identifying the relationship between decorin and myostatin as well as the development of a therapeutic strategy for progressive neuromuscular diseases.     

The importance and purpose of medical psychology in the study of medicine

Medical psychology is to be understood both as an interdisciplinary science, orientated to the bio-psychosocial concept of illness as well as a basic medical attitude that encompasses the whole of a doctor's activity. In the curriculum the students must be provided with a medico-psychological training that is specific to individual phases of study. This requires a didactic process that is centered on the student, both in the teaching of medical psychology as well as in medico-psychological hospital practice, which is to be achieved in close cooperation with other medical subjects. Medical psychology is mostly described as a newer scientific discipline. It does have a history, however, that has evolved over time. Although medical psychology has always been a building block in the thinking and actions of the medical profession, it is now explicitly anchored in the training (i.e. in the curriculum) of doctors.     

Epitope definition by proteomic similarity analysis: identification of the linear determinant of the anti-Dsg3 MAb 5H10

Cell-based bioassays have been suggested for screening of hormones and drug bioactivities. They are a plausible alternative to animal based methods. The technique used is called receptor/reporter system. Receptor/reporter system was initially developed as a research technique to understand gene function. Often reporter constructs containing viral promoters were used because they could be expressed with very 'high' magnitude in a variety of cell types in the laboratory. On the other hand mammalian genes are expressed in a cell/tissue specific manner, which makes them (i.e. cells/tissues) specialized for specific function in vivo. Therefore, if the receptor/reporter system is to be used as a cell-based screen for testing of hormones and drugs for human therapy then the choice of cell line as well as the promoter in the reporter module is of prime importance so as to get a realistic measure of the bioactivities of 'test' compounds. We evaluated two conventionally used viral promoters and a natural mammalian promoter, regulated by steroid hormone progesterone, in a cell-based receptor/reporter system. The promoters were spliced into vectors expressing enzyme CAT (chloramphenicol acetyl transferase), which served as a reporter of their magnitudes and consistencies in controlling gene expressions. They were introduced into breast cell lines T47D and MCF-7, which served as a cell-based source of progesterone receptors. The yardstick of their reliability was highest magnitude as well as consistency in CAT expression on induction by sequential doses of progesterone. All the promoters responded to induction by progesterone doses ranging from 10^-12 to 10^-6 molar by expressing CAT enzyme, albeit with varying magnitudes and consistencies. The natural mammalian promoter showed the most coherence in magnitude as well as dose dependent expression profile in both the cell lines. Our study casts doubts on use of viral promoters in a cell-based bioassay for measuring bioactivities of drugs and hormones for human therapy and suggests caution regardingtranslation in toto, of a research technique as a cell-based bioassay for drug screening.     

The puzzle of schizophrenia: tracking the core role of cognitive deficits

Cognitive deficits in schizophrenia are increasingly accepted as core features of this disorder that play a role as vulnerability indicators, as enduring abnormalities during clinical remission, and as critical rate-limiting factors in functional recovery. This article demonstrates the lasting influence of Norman Garmezy through his impact on one graduate student and then through his later collaborative research with colleagues. The promise of core cognitive deficits as vulnerability indicators or endophenotypes was demonstrated in research with children born to a parent with schizophrenia as well as with biological parents and siblings of individuals with schizophrenia. In studies of patients with a recent onset of schizophrenia, cognitive deficits were found to endure across psychotic and clinically remitted periods and to have a strong predictive influence on likelihood of returning successfully to work or school. Converging lines of evidence for the enduring core role of cognitive deficit in schizophrenia have led in recent years to a burgeoning interest in developing new interventions that target cognition as a means of improving functional recovery in this disorder.     

The generation of extracellular DNA in SLE: the role of death and sex

DNA is a large macromolecule that plays a central role in the pathogenesis of systemic lupus erythematosus (SLE), serving as a target antigen of autoantibodies as well as a major component of immune complexes. These complexes can both promote immune disturbances as well as deposit in the kidney to incite inflammation. While the origin of anti-DNA autoantibodies in SLE has received intense investigation, the mechanisms by which DNA exits cells to form immune complexes in the circulation is not well understood. To determine the origin of DNA circulating in the blood in SLE, our laboratory has been using a murine model system to track the in vivo fate of DNA from Jurkat T cells that have been made apoptotic or necrotic in vitro and then administered to mice. Results of these studies indicate that DNA from apoptotic and necrotic cells appears in the blood in a time- and dose-dependent manner. Irrespective of origin, this DNA has properties of nucleosomes as shown by its molecular weight. The process of release requires the presence of macrophages and can be modified by glucocorticoids as well as inflammation. In addition, sex may play a role in the generation of extracellular DNA from dead cells as male and female mice differ in their responses in this model. Together, these studies clarify the origin of extracellular DNA circulating in the blood in SLE and suggest steps in this process that can be interdicted by novel therapy.     

Coronary heart disease, chronic inflammation, and pathogenic social hierarchy: a biological limit to possible reductions in morbidity and mortality

We suggest that a particular form of social hierarchy, which we characterize as "pathogenic", can, from the earliest stages of life, exert a formal analog to evolutionary selection pressure, literally writing a permanent developmental image of itself upon immune function as chronic vascular inflammation and its consequences. The staged nature of resulting disease emerges "naturally" as a rough analog to punctuated equilibrium in evolutionary theory, although selection pressure is a passive filter rather than an active agent, like structured psychosocial stress. Exposure differs according to the social constructs of race, class, and ethnicity, accounting in large measure for observed population-level differences in rates of coronary heart disease across industrialized societies. American Apartheid, which enmeshes both majority and minority communities in a social construct of pathogenic hierarchy, appears to present a severe biological limit to continuing declines in coronary heart disease for powerful as well as subordinate subgroups: "Culture"--to use the words of the evolutionary anthropologist Robert Boyd--"is as much a part of human biology as the enamel on our teeth".     

Klotho: a novel regulator of calcium and phosphorus homeostasis

Klotho which was originally identified as an anti-aging protein is emerging as a substance with multiple effects on many systems including mineral homeostasis. In addition to its membrane-bound function as a co-receptor for fibroblast growth factor-23, soluble Klotho exerts effects as a circulating substance in plasma and urine. Novel features of this system include its autocrine–paracrine–endocrine glycan-modifying enzymatic function in the urinary lumen on calcium and phosphate transporters. Klotho induces phosphaturia by inhibiting the proximal tubule Na-coupled phosphate transporter. The action of Klotho is enzymatic in nature which includes alteration of transport activity and the more traditional means of regulation by trafficking. Klotho reduces calciuria by its distal as a sialidase directly on the apical calcium channel. Desialidation of the channel exposes glycan residues that promote binding to galectin-1, resulting in stabilization of residence on the plasma membrane. Through its systematic as well as renal actions, Klotho is emerging as a principal calciophosphoregulatory hormone.     

The effect of immunosuppressive and anti-inflammatory drugs on lymphocyte population and MIF in glomerulonephritis.

The effect of immunosuppressive and anti-inflammatory drugs on the T and B lymphocyte populations, as well as cellular hypersensitivity in relation to GBM antigens (measured by MIF activity) in 60 patients with different types of glomerulopathy has been tested. The results were compared with a control group of 47 untreated patients and 32 healthy subjects. The treatment was carried out using the following drugs: azathioprine, cyclophosphamide, prednisone, ibuprofen and indomethacin. In a sample of 14 patients receiving ibuprofen and in 7 receiving arathioprine, indomethacin and prednisone, the T and B lymphocyte kinetics as well as MIF activity were repeatedly tested before and during the treatment of 150 days. In the patients under this treatment, a decreased percentage of lymphocytes with receptors for a complement as well as, in some cases. MIF suppression was observed. A comparison of healthy subjects and untreated patients with a group of 39 subjects tested for T and B lymphocytes as well as MIF activity after several months of the above treatment was made. It was found that supportive therapy with azathioprine and prednisone led to a normalization of B lymphocytes (EA and EAC rosettes) and to a small increase of T lymphocytes number. On the other hand, treatment with indomethacin and ibuprofen led to an increased B lymphocyte count (EA and EAC rosettes). Cyclophosphamide given with azathioprine caused a decrease in the proportion of T lymphocytes and an increase in the number of null cells. In addition, it was found that immunosuppressive drugs as well as anti-inflammatory drugs, even when administered in supportive doses caused in some cases, the suppression of cellular immunity as measured by MIF activity.     

The pathology of the tuberculosis 100 years ago and its present role in mortality

On occasion of the centenary of the detection of the tubercle bacteria by Robert Koch we try to give a survey on the knowledge of pathology of tuberculosis 100 years ago. Besides mystic considerations since the antique medicine, the cause of the tuberculosis was seen in a phthisic habitus, as endogenous, not perceptible, the disease as not curable, its nature as a hereditary illness, as a metabolic disorder or, in the time of Robert Koch, mostly as a malignant neoplasia. Only few physicians considered the tuberculosis as an infectious disease with inflammatory properties. Since his discovery of the tubercle bacteria, Robert Koch was sure that the tuberculosis could be cured and eradicated like other infectious diseases. He believed that this aim could be attained in a short period. At the end of this paper, a brief review is given about the frequency and importance of the tuberculosis as a cause of death in the past and especially nowadays after the consequent fight against this disease.     

The Immunohistochemical Detection of Chorionic Gonadotropin in Experimental Rat Hepatomas

Using a peroxidase labelled antibody technique, the presence of chorionic gonadotropin or a substance closely related antigenically has been demonstrated in putative preneoplastic hepatocytes in the rat during carcinogenesis induced by diethylnitrosamine (DEN) as well as in hepatomas induced by DEN or by 2-acetylaminofluorene (2-AAF), a solid hepatoma derived from HTC cells and in the 5123 Morris hepatoma and two of its variants. Chorionic gonadotropin is a normal product of the syncytiotrophoblast. Consequently, its detection in an experimental hepatoma as well as in putative preneoplastic cells may represent a unique manifestation of the appearance in these experimental tumor models of gestational elements which may play a role as components of a programmed phenomenon early in the carcinogenic process.     

Decreased oral colonization of Streptococcus mutans during aging of Sprague-Dawley rats.

The colonization by streptomycin-resistant Streptococcus mutans strains of the teeth of conventional and ex-germfree Sprague-Dawley rats of various ages fed either a high-sucrose or a high-glucose diet was studied. Bacterial colonization occurred with increasingly greater difficulty as the rats became older. This was observed in studies of the implantation of the test organism after oral inoculation with different cell numbers as well as its transmission between infected and uninfected rats. With rat fed sucrose diet, the effect of age could not be demonstrated until they were age 3 months or older; the results from rats fed a glucose diet suggest that changes may already have occurred early after weaning. Changes in susceptibility to colonization during aging manifested themselves as a decrease in the proportions of rats which became infected as well as lower population levels in infected rats. The possible mechanism(s) involved as well as the possible significance of the findings was discussed.     

HMGB1 preconditioning: therapeutic application for a danger signal?

High mobility group box 1 (HMGB1) is a nuclear factor released extracellularly as a late mediator of lethality in sepsis and as an early mediator of inflammation following injury. In contrast to the proinflammatory role of HMGB1, recent evidence suggests beneficial applications of HMGB1 in injury states. One such application is the use of HMGB1 as a preconditioning stimulus. Preconditioning is a phenomenon whereby a low level of stressful stimuli confers protection against subsequent injury. Preconditioning has been demonstrated in multiple species, can be induced by various stimuli, and is applicable in different organ systems. Only with the recent introduction of the concept of endogenous molecules, such as HMGB1, as signals and mediators for inflammation during injury states has the use of endogenous molecules been investigated for this use. This review will focus on the use of endogenous molecules, specifically HMGB1, as a preconditioning stimulus and its mechanism of protection, as well as other protective applications for HMGB1.     

Mechanism of Tuberculostasis in Mammalian Serum III. Neutralization of Serum Tuberculostasis by Mycobactin

Tubercle bacilli exposed to an iron-poor medium multiplied at a slower rate but released more of the serum-tuberculostasis neutralizing factor (TNF) than the bacilli in an iron-rich medium. This growth-promoting factor found in spent medium exhibited characteristics which suggested its relationship to or identity with mycobactin. The identity of these two bacillary products was established by showing that both iron-free mycobactin and TNF promoted bacillary multiplication in tuberculostatic serum. This study resolved a long-standing controversy as to whether mycobactin serves as a growth factor or as a carrier of iron for tubercle bacilli. It was found that the tuberculostasis in mycobactin-neutralized serum was reconstituted by the addition of iron-free transferrin (Tr). The investigation of the interplay between mycobactin and Tr revealed that mycobactin does not serve as a growth factor but as a carrier of growth-essential iron which mycobactin (as contrasted to Tr) provides to tubercle bacilli in a utilizable form.     

Bony observations of some morphological variations and anomalies of the craniovertebral region

Human skeletons (214) belonging to a South African black and white cadaver population were pooled and examined for malformations of the craniovertebral region. Four crania, presenting with various manifestations of an occipital vertebra, such as a paracondylar process, epicondylar process, hypocondylar arch, and a third condyle were identified as well as two crania showing various degrees of assimilation of the atlas to the basicranium. Of particular interest was the identification of a cloverleaf-shaped foramen magnum in a cranium of an individual with achondroplasia as well as a cranium with marked asymmetry of both foramen magnum and occipital condyles. Due to the availability of both cranium and corresponding atlanto-axial components, the clinical significance of certain aspects of craniovertebral anomalies were vividly demonstrated, such as a pseudarthrosis formed by the meeting of a paracondylar process with an epitransverse process and a dens "riding high" in the foramen magnum as a result of assimilation of the atlas.     

Is beta-amyloid fibrillogenesis a strict process of deposition inherently interactive in molecular terms?

Amyloid fibrillogenesis as a process of interactive molecular processes of deposition in Alzheimer's disease might function as a phenomenon that transforms intracellular amyloid segregation to a state of equilibration with extracellular deposition. beta-Amyloidosis might dynamically implicate loss of viability of vascular tunica media myofibers as a strict reflection of loss of viability of neurons in such an overall system of equilibration between intracellular and extracellular amyloid fibrillogenesis. In terms beyond simple concepts of strict biophysical equilibration, deposition of beta-amyloid in Alzheimer's disease might constitute a phenomenon of congophilic angiopathy as a strict pathobiologic index of activity of the Alzheimer process; such a correlate would perhaps involve a quantitative index that would qualitatively characterize the Alzheimer process as an interactive series of reactions between the intracellular and extracellular microenvironment.     

Generation of fractal patterns for probing the visual memory.

The effective use of computer-generated pictures as a trial-unique probe for studying the visual memory is described. The shape of the pattern is determined by means of a fractal algorithm with pseudorandom parameters. This method enables us to easily obtain thousands of moderately complex and sufficiently diversified pictures in series from a given number which serves as the seed of a pseudorandom number generator. We can thereby create a new and unique set of pictures if a new seed is given, as well as retrieve exactly the same pictures in the same sequence as when the original seed is given. These properties eliminate the demand for the massive memory space in a computer otherwise needed to store the entire set of stimulus pictures.     

The light microscopic localization of substance P- and somatostatin-like immunoreactive cells in the larval tiger salamander retina

Summary Light microscopic immunocytochemistry was utilized to localize the populations of substance P (SP)- and somatostatin (SOM)-like immunoreactive cells in the larval tiger salamander retina. Of 104 SP-immunostained cells observed, 82% were Type 1 amacrine cells. Another 8% of the SP-cells were classified as Type 2 amacrine cells, while 10% of the SP-cells had their cell bodies located in the ganglion cell layer and were designated as displaced amacrine cells. Each type of SP-like immunoreactive cell was observed in the central and peripheral retina. SP-immunopositive processes were observed in the inner plexiform layer as a sparse plexus in sublamina 1 and as a denser network of fibers in sublamina 5. Seventy-eight percent of the 110 somatostatin-immunopositive cells observed were designated as Type 1 amacrine cells. Another 12% of SOM-cells were classified as displaced amacrine cells, while only two SOM-immunopositive Type 2 amacrine cells were observed. Nine percent of the SOM-cells were designated as interplexiform cells, based on their giving rise to processes distributing in the outer plexiform layer as well as processes ramifying in the inner plexiform layer. Each type of SOM-immunoreactive cell was observed in the central and peripheral retina, with the exception of the Type 2 amacrine cells, whose somas were only found in the central retina. Lastly, SOM-immunopositive processes in the inner plexiform layer appeared as a fine plexus in sublamina 1 and as a somewhat denser network of fibers in sublamina 5.     

Guanine nucleotide exchange factors of the cytohesin family and their roles in signal transduction

Summary:  Members of the cytohesin protein family, a group of guanine nucleotide exchange factors for adenosine diphosphate ribosylation factor (ARF) guanosine triphosphatases, have recently emerged as important regulators of signal transduction in vertebrate and invertebrate biology. These proteins share a modular domain structure, comprising carboxy-terminal membrane recruitment elements, a Sec7 homology effector domain, and an amino-terminal coiled-coil domain that serve as a platform for their integration into larger signaling complexes. Although these proteins have a highly similar overall build, their individual biological functions appear to be at least partly specific. Cytohesin-1 had been identified as a regulator of β2 integrin inside-out regulation in immune cells and was subsequently shown to be involved in mitogen-associated protein kinase signaling in tumor cell proliferation as well as in T-helper cell activation and differentiation. Cytohesin-3, which had been discovered to be strongly associated with T-cell anergy, was very recently described as an essential component of insulin signal transduction in Drosophila and in human and murine liver cells. Future work will aim to dissect the mechanistic details of the modes of action of the cytohesins as well as to define the precise roles of these versatile proteins in vertebrates at the genetic level.     

The clinical manifestations of Degos' syndrome

Pathologic mechanisms underlying Degos' syndrome are poorly characterized. Thrombosis, either as a consequence of a postulated vasculitis or as a primary defect, is often a clinical complication of this syndrome. We have studied multiple coagulation parameters, including potential defects in fibrin assembly and other adhesive proteins, in a patient with Degos' syndrome and found no specific abnormality to explain the pathologic features of this syndrome. An extensive literature review as well as detailed biochemical and biophysical coagulation studies are presented. The alternative possibility of Degos' syndrome as a mucinosis is discussed.