Cell surface oligosaccharide modulation during differentiation: VI. The effect of biomodulation on the senescent and neoplastic cell phenotype.

These investigations test the hypothesis developed previously, that there are biomolecules which control and integrate cellular differentiation. Our specific interest in cellular differentiation lies in the area of what we refer to as basal or primitive cellular differentiation mechanisms. These mechanisms are common to all cells, and are required for simple recognition and growth regulation. We have investigated two models, the IMR-90 human fetal lung fibroblast model as a representative of normal growth control, and the CG model, canine glioma cells, a transplantable growth transformed cell line. These two models represent normal, and aberrant cellular differentiation control. In previous studies we have shown that the arrangement of the cell surface oligosaccharide structure on these cell types are predictive of phenotypic transition. We have developed, and partially characterized a series of BIOMODULATORS (BM) which delay the onset of display of neoplastic cells. Three classes of BIOMODULATOR have been explored; (1) a large molecular weight natural product (25-35 kDa), PokeWeed Mitogen (PWM); (2) a small molecular weight natural product (500 Da) Cellular Activator and Differentiator (CAD) and a number of natural and synthetic analogs; and (3) an indolizidine alkaloid natural product, Swainsonine (Sw) which has a known cellular target (oligosaccharide biosynthesis). Preliminary data is presented which structurally links some of these BIOMODULATORS in terms of their effective stereochemistry. These BIOMODULATORS, when used before PDL 38, prevent the cell surface oligosaccharide display changes typical of morphological senescence and delay their onset to PDL 100 or more. These BIOMODULATORS also appear to have regulatory effects on the neoplastic cell models. This re-regulation results in increases in generation time and an increase in the ability of these cells to be recognized by cytotoxic lymphocytes. Proton NMR linewidth measurements of the fraction of 'bound' water associated with the cellular surface of treated and untreated cell populations showed induced physical changes in the cell surface related to the use of the BIOMODULATOR and correlated to the oligosaccharide display changes. These data were interpreted as indicating an increase in the organizational level of these cells. The data for normal and neoplastic cell populations are compared and contrasted in an effort to form the basis for an analytical approach to the control and integration of differentiation mechanisms.     

Platelet and whole blood serotonin content in depressed inpatients: correlations with acute and life-time psychopathology.

Platelet or whole blood serotonin content did not differ significantly in patients with major depression compared to healthy controls, but within the patient group, platelet serotonin levels correlated negatively with severity of depression (r = -0.49, p = 0.007). Levels were 39% lower in patients who had made a suicide attempt compared to nonattempter patients (47.2 +/- 27.3 versus 77.6 +/- 41.7 ng/10(8) platelets, p = 0.04). Conversely, comorbid borderline personality disorder (85.3 +/- 41.5 ng/10(8) platelets) was associated with 31% greater platelet serotonin content than nonborderline patients (58.9 +/- 31.1 ng/10(8) platelets) and 27% greater than healthy controls (62.4 +/- 19.8 ng/10(8) platelets). A pronounced seasonal variation in whole blood and platelet serotonin content was found in both patients and controls, largely due to lower levels in summer. Excluding cases tested in the summer abolished the statistically significant differences in patients with and without comorbid borderline personality disorder (BPD). Nevertheless, BPD attempters had lower serotonin levels than BPD nonattempters but higher serotonin levels than non-BPD attempters. Current hostility and a life-time history of aggression were positively correlated with platelet serotonin content (r = 0.44, p = 0.04 and r = 0.41, p = 0.06). This study provides evidence for an association between lower platelet serotonin content and depression and suicidal behavior, and association of higher platelet serotonin content and comorbid borderline personality disorder and behavior traits such as aggressivity.     

Effect of FK-506 on xenografted human Graves' thyroid tissue in severe combined immunodeficient mice

OBJECTIVE We studied the macrolide antibiotic FK-506, an immunosuppressive agent, in an attempt to ameliorate the lesion of autoimmune thyroid disease in human thyroid tissue xenografted into severe combined immunodeficient (SCID) mice. It was not felt appropriate to employ this agent directly in patients with autoimmune thyroid disease because adequate therapeutic modalities are available and the introduction of new, experimental agents could not be justified. Moreover, the study of the tissue before and after treatment could not have been undertaken directly in patients. DESIGN Human thyroid xenografts from four patients with Graves' disease and two normal persons were xenografted into SCID mice. Two weeks after xenograft-ing, human immunoglobulin G (IgG) was detectable in all SCID mice xenografted with Graves' thyroid tissue. Mice were divided into two groups with human IgG levels similar to each other. Mice in the first group were treated with FK-506 daily for 6 weeks; mice in the second (similar) group were given phosphate-buffered saline (PBS) only (control group). MEASUREMENTS Blood samples were taken every 2 weeks from the tail veins for human IgG, thyroid stimulating antibody, thyroperoxidase antibodies, thyroglobulin antibodies, and interferon-gamma (IFN-7). After 8 weeks treatment, animals were sacrificed; thyroid tissue was examined histologically and for thyrocyte HLA-DR expression. FK-506 was also added to thyrocytes in in-vitro tissue culture conditions. RESULTS After 4–6 weeks of FK-506 therapy, human IgG, all thyroid antibodies and IFN-7 were suppressed, while the levels remained elevated in the control group. Lymphocytic infiltration virtually disappeared in the human thyroid tissue of the FK-506-treated mice and thyrocyte HLA-DR expression markedly declined; in the control mice, lymphocytic infiltration remained heavy and HLA-DR expression remained high. On the other hand, FK-506 added directly to thyrocytes in vitro (without lymphocytes) did not reduce thyrocyte HLA-DR expression. CONCLUSIONS FK-506 appears to suppress the activation of intrathyroidal lymphocytes, but not thyrocytes. From these observations, it is concluded that this agent, by its action on intrathyroidal lymphocytes, is able to ameliorate the immunologically mediated histological and serological disturbance in human autoimmune thyroid disease, at least under these circumstances.     

Role of the dopaminergic system in depression.

A hypothesis implicating dopamine in depression was proposed over 15 years ago (Randrup et al 1975). The identification of multiple new subtypes of dopamine receptors and evolving views regarding the function of the dopamine systems in the brain require a reexamination of this hypothesis. Results from studies in depression, Parkinson's disease, and animal models of depression suggest a deficiency of dopamine in depression. Dopamine precursors, dopamine agonists, and dopamine reuptake inhibitors show therapeutic efficacy in depression. Electroconvulsive therapy (ECT) and standard pharmacological antidepressants enhance dopamine function. Studies using receptor-specific drugs in clinical trials and neuroimaging studies are needed to further clarify the role of dopamine in depression.     

Short communication: treatment of relapsing-remitting multiple sclerosis 96 patients with IFN-beta1b: results of a 6-year follow-up.

The first pharmacon with proved efficacy for the treatment of patients with the relapsing-remitting or relapsing-progressive form of multiple sclerosis (MS) was interferon-beta1b (IFN-beta1b). In 1996, we started treating 34 relapsing-remitting (RRMS) and 2 relapsing-progressive MS (RPMS) patients with IFN-beta1b. Of these 36 patients, 28 received continuous medication for 6 years. The primary end point of the study was the effect of 6 years of continuous IFN-beta1b treatment on the annual relapse rate, the secondary end point was the change in the progression index during the 6 years, and the tertiary end point was the alteration in the expanded disability status scale (EDSS) score of the patients. Finally, we give the reasons for the dropouts. The relapse rate decreased by 80.62% (p < 0.001), the mean EDSS score increased significantly, by approximately 0.5 points, to 2.21 +/- 1.48 (p = 0.016), and the reduction in the mean progression index was 67.19% (p < 0.001). This increase of < 0.5 point in the EDSS score is appreciably different from the 3-point deterioration expected after 6 years for the natural course of the disease. The significant improvement in the progression index clearly demonstrates that 6 years of IFN-beta1b therapy slowed the progression of the disease, thereby improving the quality of life of these MS patients.     

Colonization with methicillin-resistant Staphylococcus aureus after liver transplantation.

Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of infection after orthotopic liver transplantation (OLT). Colonization with MRSA is associated with a higher risk of infection. Previous studies have shown a high prevalence of MRSA colonization among OLT candidates. However, the risk of colonization with MRSA after OLT is still unclear. The objective of this study was to estimate the incidence and the factors associated with colonization with MRSA after OLT. This was a prospective cohort study including patients submitted to OLT between the years 2000 and 2002. Surveillance cultures of nasal swab specimens were performed within the 1st 72 hours of hospital admission and, subsequently, on weeks 2, 6, 13, and 26. Patients whose baseline cultures revealed nasal carriage of MRSA were excluded. A total of 60 patients were included in the study. The median follow-up was 72 days. A total of 9 patients (15%) became colonized. In multiple logistic regression analyses, the use of a urinary catheter for > or =5 days (P = .006), postoperative bleeding at the surgical site (P = .009), and preoperative use of fluoroquinolones (P = .08) were associated with a higher risk of colonization. Patients without any of these risk factors did not become colonized. In conclusion, nasal carriage of MRSA is frequently acquired after OLT. Periodic postoperative screening for MRSA carriage should be an integral component in programs designed to reduce nosocomial MRSA transmission in these patients. Further studies are needed to set up and validate a predictive model that could allow targeting postoperative screening to high-risk OLT recipients.     

Heterogeneity of human bone

Matched samples of bone from the lumbar spine and tibia were obtained at autopsy from three adult males who had no known evidence of metabolic bone disease at the time of their demise. The soluble noncollagenous bone proteins were quantitatively extracted from these samples and assayed for the relative content of two bone-associated proteins, osteocalcin and osteonectin. When compared to trabecular bone, cortical bone had higher levels of osteocalcin and much lower levels of osteonectin. When concentration is expressed per gram of dried bone, the osteocalcin excess in cortical bone ranged from 30- to 32-fold, and the osteonectin excess in trabecular bone ranged from 21- to 47-fold. These differences were significant (P less than 0.01) using analysis of variance. We conclude that the human skeleton is not homogeneous with regard to these biochemical markers and that cortical and trabecular bone are biochemically quite distinct. This implies that these two types of bone may be subject to distinct regulatory mechanisms and that global assessments of skeletal function and bone quality based upon soluble markers should be applied with caution. The data also imply that a differential assessment of skeletal performance may be possible using biochemical serum markers.