Showing papers in "Annals of the New York Academy of Sciences in 1987"

The pharmacology of monoclonal antibodies.

Abstract: We are entering an era in which biological macromolecules can be designed to order and genetically or synthetically produced. If the experience with classical low molecular weight drugs is any guide, it will be possible in fact, easy to produce many more such agents than can be tested for effect in animals, let alone in humans. Predictive criteria are required for the process of rational design, and these must be based on an understanding of fundamental physiological and pharmacological principles. Monoclonal antibodies illustrate the point. Hundreds of new monoclonal reagents with possible clinical use are being developed every year. Each of them could be administered as whole antibody, F(ab')*, or Fab. Each could be conjugated to a toxin, a drug, a radionuclide, or a liposome containing one of those agents. Each could be class-switched to change effector functions or could be mutated in its binding site. As noted previously,' the combinatorial aspects of trying every possibility are out of the question even before one has considered such current and likely future developments as ( I ) chimeric molecules combining mouse variable and human constant domains; (2) Fv (variable domain) fragments; (3) recombinants consisting of murine hypervariable segments and human variable domain framework; (4) conjugates formed by genetically grafting a linker peptide onto the molecule; and (5) enzyme-antibody or toxin-antibody chimeras. At the end of this developmental process will be ligand molecules consisting of antibody-derived binding sites grafted onto molecules designed de novo. A predictive pharmacology of biologicals must be based on theoretical and experimental information from several hierarchical levels: global (whole body), regional, local, cellular, and molecular. Here we will focus on one study of whole body pharmacokinetics, one development in regional delivery, and one issue at the local, or tissue, level.

Spatial localization in NMR spectroscopy in vivo.

Abstract: Spatial localization techniques are necessary for in vivo NMR spectroscopy involving heterogeneous organisms. Localization by surface coil NMR detection alone is generally inadequate for deep-lying organs due to contaminating signals from intervening surface tissues. However, localization to preselected planar volumes can be accomplished using a single selective excitation pulse in the presence of a pulsed magnetic field gradient, yielding depth-resolved surface coil spectra (DRESS). Within selected planes, DRESS are spatially restricted by the surface coil sensitivity profiles to disk-shaped volumes whose radii increase with depth, notwithstanding variations in the NMR signal density distribution. Nevertheless, DRESS is a simple and versatile localization procedure that is readily adaptable to spectral relaxation time measurements by adding inversion or spin-echo refocusing pulses or to in vivo solvent-suppressed spectroscopy of proton (1H) metabolites using a combination of chemical-selective RF pulses. Also, the spatial information gathering efficiency of the technique can be improved to provide simultaneous acquisition of spectra from multiple volumes by interleaving excitation of adjacent planes within the normal relaxation recovery period. The spatial selectivity can be improved by adding additional selective excitation spin-echo refocusing pulses to achieve full, three-dimensional point resolved spectroscopy (PRESS) in a single excitation sequence. Alternatively, for samples with short spin-spin relaxation times, DRESS can be combined with other localization schemes, such as image-selected in vivo spectroscopy (ISIS), to provide complete gradient controlled three-dimensional localization with a reduced number of sequence cycles.

A Nation At Risk

Abstract: With notable vision, members of the National Commission on Excellence in Education (NCEE) decided that their report, A Nation At Risk (hereafter called ANAR), should be short. They meant it to be read by people who would not ordinarily read such a thing the public at large and they composed it accordingly: ten thousand words of text on 36 pamphlet-size pages unimpeded by footnotes and references. Add a title page and 25 pages of appendices and you get a 7” x 9”, 63-page educational blockbuster that was set off on April 26, 1983; the reverberations of the explosion persist to this day. Initially 40,000 copies were printed for distribution by the Department of Education and 2,000 more for sale by the Government Printing Office. It was a slight underestimate. Just 5 months later, in October 1984, the report was in its fourth printing and over 120,000 copies had been distributed. It was the fastest seller in recent GPO experience; more than 65,000 copies had been sold through the mail or from their bookstores and demand remained heavy. That wasn’t all; indeed it was the smallest of the circulation statistics. Over 400,000 copies of the report were duplicated and distributed by various organizations. For example, the American Association of School Administrators sent copies to its entire 18,000-person membership, the Association for Computing Machinery blanketed 63,000 of its members with copies and the Iowa State Department of Education distributed copies to 60,000 Iowans. The trade press, the Congressional Record, and daily newspapers across the land have printed the piece in its entirety. By conservative estimate we calculated that the text of ANAR reached the offices and breakfast tables of at least 4 million citizens, with no telling how many more people shared the same copy. The report has sparked debate and discussion of educational matters to a degree unheard since Sputnik. Within a few months after the release of the

Transmission Modes and Evolution of the Parasitism-Mutualism Continuuma

Abstract: An analysis of fitness costs and benefits associated with pathogenicity suggests that modes of transmission are key determinants of evolution toward severely pathogenic, benign, or mutualistic symbioses. Specifically, this approach suggests that symbionts with mobile life history stages should evolve toward extremely severe parasitism, vector-borne symbionts should evolve toward severe parasitism in vertebrate hosts and benign parasitism in the vectors, waterborne symbionts should evolve toward severe parasitism, symbionts transmitted by predation should evolve toward severe parasitism in prey hosts and benign parasitism in predator hosts, and vertically transmitted symbionts should evolve toward benign parasitism and mutualism. Detailed reviews of the literature on human diseases support the hypothesized severity of vector-borne and waterborne transmission. Evaluation of the other associations is less detailed, but each association appears to be present. This framework draws attention to the need for detailed reviews of relationships between transmission modes and the nature of symbiotic interactions, and experimental manipulations of transmission.

Interaction of ascorbate and alpha-tocopherol.

Abstract: Vitamins C and E function as water-soluble and lipid-soluble chain-breaking antioxidants, respectively, and protect lipids, proteins, and membranes from oxidative damage. Vitamin C scavenges oxygen radicals in the aqueous phase, whereas vitamin E scavenges oxygen radicals within the membranes. Vitamin C regenerates vitamin E by reducing vitamin E radicals formed when vitamin E scavenges the oxygen radicals. This interaction between vitamin C and vitamin E radicals can take place not only in homogeneous solutions but also in liposomal membrane systems where vitamins C and E reside separately outside and within the membranes respectively, and vitamin C can act as a synergist.

The course of myasthenia gravis and therapies affecting outcome

Abstract: The course of 1,487 patients with myasthenia gravis followed between 1940 and 1985 for a mean of 18 years provides further evidence that the distribution, severity, and outcome of the disease are determined during the first 1 to 3 (occasionally 5) years after onset, suggesting that injury to acetylcholine receptors occurs mainly during this time. In 14%, the disease remained clinically localized to the extraocular muscles, and in the remaining 86% became generalized, in 87% within a year, with the disease reaching maximum severity within the first year after onset of symptoms in 55%, during the first 3 years in 70%, and during the first 5 years in 85%. Male patients tended to have more rapid progression of disease, higher mortality, and lower rates of remission and improvement than females. From 1940 to 1957, when management relied on anticholinesterase compounds, endotracheal intubation or tracheostomy and negative pressure assisted ventilation for respiratory failure, and thymectomy in 26% of patients and thymomectomy in 8%, 31% of patients with generalized myasthenia gravis died of the disease (29% of these during the first year after onset, 27% during the second and third years, and 17% during the fourth and fifth years), 32% improved, 23% remained unchanged, 10% went into remission, and only 5% were worse during the last year seen than during the worst of the first 3 years (or 5 years in the minority of patients who reached maximum weakness after 3 years). From 1958 to 1965, during which time the management of respiratory failure was improved by positive pressure and volume controlled ventilation and improved intensive care, mortality fell to 14% (p less than 0.005), and a higher proportion remained unchanged (p less than 0.005). From 1966 to 1985, when over half the patients received adrenal cortical steroids, mortality fell to 7% (p less than 0.005) and the proportion who improved rose to 47% (p less than 0.05). Even though the patients who received steroids usually had more severe myasthenia, they had a higher rate of improvement than those who received no steroid, 54% compared to 39% (p less than 0.005). Thymectomy was performed in one-fourth of patients with generalized myasthenia gravis, more frequently in young females and those with more severe weakness, and less often in older males and those with less severe weakness.(ABSTRACT TRUNCATED AT 400 WORDS)

The Origin of Eukaryote and Archaebacterial Cells

Abstract: Ultrastructural and molecular data have recently so rejuvenated the study of organismic diversity that we may soon have a clear understanding of the overall phylogeny of the living world, and even of the major steps in its diversification. Of these, the transition from the prokaryote to the eukaryote cell is certainly the most profound, ’ so much so that Prokaryota and Eukaryota are now generally ranked as superkingdoms (TABLE 1). To explain the origin of the eukaryote cell one has to determine the properties of the most primitive eukaryote, identify its likely prokaryotic ancestor, and explain in detail how the latter evolved into the former. That is the object of this paper. Identifying the most primitive eukaryote depends upon a proper understanding of the diversity and phylogenetic relationships within the most primitive eukaryote kingdom, the Protozoa. TABLE 2 indicates the protozoan classification and nomenclature that will be used in this paper: those protozoa recently separated as the subkingdom Archezoa are of special significance for early eukaryote evolution. All four archezoan phyla, though fully eukaryotic, completely lack any trace of mitochondria; the first three of them, especially, have a variety of other apparently primitive characters suggesting that they are living representatives of the earliest phases of eukaryote evolution. I argue that the most primitive eukaryote was a phagotrophic archezoan, with no chloroplasts, no mitochondria, no microbodies, and no stacked smooth cisternae forming a Golgi dictyosome, but possessing a single cilium with a sheaf of rootlet microtubules surrounding the single nucleus that divided by a closed mitosis in which the ciliary kinetosome was attached to the centrosome. The present day Mastigamoebea closely fit this description and may be “living fossils.” I suggest that this first eukaryote had a single chromosome and could form a resting cyst or spore in which (as in modem Anaxostylea) the ciliary axoneme and rootlets were not disassembled, and that with the origin of sexual syngamy allopolyploidy led to the formation of a cell with two chromosomes and two dissimilar (i.e., “anisokont”) cilia. This ancestral two-chromosomed anisokont perfected a primitive one-step meiosis and was the ancestor not only of the amitochondrial Metamonada and Parabasalia but also of all eukaryotes with mitochondria and chloroplasts, which it acquired by endosymbiosis of purple nonsulfur bacteria6 and cyanobacteria’ respectively. The

Plasma protein adsorption: the big twelve.

Abstract: We have discussed the general principles of protein adsorption at solid-liquid interfaces from single component and multicomponent solutions, based on qualitative kinetic models that include mass transport considerations, initial interaction energies, surface-dependent conformational changes, and possible desorption processes. We have surveyed plasma protein components greater than one milligram per milliliter in concentration, which we call "The Big Twelve." We considered their size, concentration, diffusion coefficient, structure and function, and methods of estimating their "surface denaturability" by using bulk solution measures of denaturation and conformational change. We have suggested that the role of the carbohydrate moieties in plasma proteins may have some bearing on their adsorption properties. We further suggest that lipoproteins, because of their lipid phase transition and conformational lability at body temperature, may tend to dominate the adsorption process, particularly on mobile elastomeric polymer surfaces. We suggest that detailed consideration of the structure and characteristics of each of the proteins involved is necessary in order to begin to understand plasma adsorption processes. Detailed characterization and understanding of the solid surface in the aqueous and protein environments are also required.

The Simultaneous Symbiotic Origin of Mitochondria, Chloroplasts, and Microbodies

Abstract: The purpose of this paper is not to discuss the continually growing evidence for the symbiotic origin of both chloroplasts and mitochondria.’ It is to argue that many uncritically accepted features of the conventional serial endosymbiosis theory’,’ are so seriously in error that they need to be replaced by a more realistic symbiotic theory. I shall first state and then justify the seven major changes needed:

Applications of Nonlinear Dynamics to Clinical Cardiology

Abstract: (1) Nonlinear mechanisms may apply both to the understanding of SA-AV node interactions and to bifurcations leading to certain types of AV block. (2) The fractal His-Purkinje system serves as the structural substrate for the generation of the broadband, inverse power-law spectrum of the stable ventricular depolarization (QRS) waveform. (3) Fractal anatomy is also seen in multiple other systems: pulmonary, hepatobiliary, renal, etc. Fractal morphogenesis may reflect a type of critical phenomenon that results in the generation of these irregular, but self-similar structures. (4) Self-similar (fractal) scaling may underlie the 1/f-like spectra seen in multiple systems (e.g., interbeat interval variability, daily neutrophil fluctuations). This fractal scaling may provide a mechanism for the "constrained randomness" that appears to underlie physiological variability and adaptability. (5) Behavior consistent with subharmonic bifurcations is seen in cardiac electrophysiology (e.g., sick sinus syndrome) and hemodynamic perturbations (e.g., swinging heart phenomenon in pericardial tamponade). (6) Ventricular tachyarrhythmias associated with sudden cardiac death (e.g., torsades de pointes, ventricular fibrillation) appear to reflect relatively periodic, not chaotic (turbulent) processes resulting from disruption of the physiologic fractal depolarization sequence. (7) Spectral analysis of Holter monitor data may help in the detection of patients at high risk for sudden death.

Clinical correlations of antibodies that bind, block, or modulate human acetylcholine receptors in myasthenia gravis.

Abstract: Acetylcholine receptor (AChR) binding and AChR modulating antibodies were found with approximately the same frequency (86%) in 349 patients with myasthenia gravis (MG). However, the total yield of positive serological results was significantly improved (90%) by assaying AChR modulating antibodies when AChR binding antibodies were not detected, because in 27 patients (8%) only one of the two tests was positive. The immunoprecipitation test for AChR blocking antibodies yielded fewer positive results (52%), but there was a significant correlation between the degree of AChR blockade and generalization of muscle weakness. In no patient was this the only positive test, because the test for AChR modulating antibodies in this study detected both AChR blocking and modulating antibodies. Human muscle AChR was used as antigen in all tests. False positive results were rare and were attributed to unexplained antibodies to 125I-alpha-Bgt (AChR binding antibody assay) and recent general anesthesia using muscle relaxants (AChR blocking and AChR modulating antibody assays). Unexplained positive results, documented previously in 5% of patients with the Lambert-Eaton myasthenic syndrome and amyotrophic lateral sclerosis (ALS), were found in this study in two of 22 patients with ALS, but in none of 427 patients with miscellaneous neurological diseases. Patients with severe generalized MG and/or thymoma tended to have higher titers of AChR binding antibodies and greater AChR modulating antibody activity. However, some patients with severe muscle weakness had low titers of antibodies, and some patients in remission or with only ocular manifestations had high titers. These seemingly paradoxical results reflect heterogeneity in the specificities, affinities, and isotypes of anti-AChR antibodies. To effect pathogenicity, antibodies must have access in vivo to extracellular antigenic sites on the AChR. One would anticipate that antibodies with greatest pathophysiological potential would be of an IgG with greatest pathophysiological potential would be of an IgG subclass that activates complement, or of a specificity that competes for acetylcholine's binding site on the receptor or readily cross-links two AChR molecules to trigger receptor modulation (e.g., by binding to sites on the duplicated alpha-subunit). In patients with suspected MG who lack serological evidence of anti-AChR antibodies, motor endplate biopsy is required for microelectrophysiological, immunochemical, and ultrastructural studies to establish with certainty whether or not the condition is acquired MG.

Bovine brain microvessel endothelial cell monolayers as a model system for the blood-brain barrier.

Abstract: Investigation of blood-brain barrier permeability and metabolic processes, and their regulation by endogenous or exogenous factors, will be important for development of efficient and selective delivery of therapeutic agents to the central nervous system. Primary cultures of brain microvessel endothelial cells offer a potentially powerful tool for studying at the cellular level the biochemical mechanisms regulating BBB function. Using this in vitro model, our studies are directed at characterization of the BBB processes that might be exploited as new schemes for drug delivery to the central nervous system.

Structural Diversity of Eukaryotic Small Subunit Ribosomal RNAsa

Abstract: The phylogenetic diversity of the eukaryotic kingdom was assessed by comparing the structural and evolutionary diversity of 18-20S ribosomal RNA genes. The coding regions for cytoplasmic small subunit ribosomal RNA genes vary in length from 1753 to 2305 nucleotides, and they appear to be evolutionary mosaics in which highly and partially conserved sequences are interspersed among regions that display very high rates of genetic drift. Structural similarities between these gene sequences were used to establish a phylogenetic framework for the eukaryotes. The extent of sequence variation within the eukaryotes exceeds that displayed within the eubacterial or archaebacterial lines of descent. The kinetoplastids and euglenoids represent the earliest branchings among the eukaryotes. These branchings preceded the divergence of lineages leading to the slime molds and apicomplexans and far antedate a radiative period that gave rise to the plants, animals, fungi, and other protists.

Lipid emulsions as drug delivery systems.

Abstract: Colloidal carriers used for the delivery of drugs take a variety of forms to include those that are solid-like in nature, such as microspheres and nanoparticles, and liquids in the form of emulsions, or vesicles (better known as liposomes). Natural colloidal particles (lipoproteins and chylomicrons present in circulating blood, for example) have also been investigated as potential carrier systems. The recent literature covering these different systems can be found in various detailed papers, review articles, and monographs.’4 This article will consider recent studies on the use of lipid emulsions as drug delivery systems and will concentrate on the intravenous route of administration. The earlier literature has been reviewed by Davis and others2

Safety of High‐level Vitamin C Ingestion

Abstract: Vitamin C is widely consumed as a dietary supplement, ingested either as a single nutrient or in combination with other vitamins and minerals. Stewart et al. reported that 35.1% of the adult U.S. population ingested a vitamin C supplement, with a median intake of 333% of the Recommended Dietary Allowance (RDA) and 28 times the RDA at the 95th percentile. Further, gram amounts of ascorbic acid are suggested for treatment and /or prevention of a wide array of health aberrations. Concern about the safety of these practices has been addressed in recent reviews.

The membrane attack complex of complement at the endplate in myasthenia gravis.

Abstract: The two major effector arms of the autoimmune response in acquired autoimmune myasthenia gravis ( M G ) are ( 1) modulation of AChR by antibody and (2) complement-mediated lysis of the postsynaptic membrane. The relative significance of these mechanisms has been debated (for reviews, see REFS. 1 and 2). The lytic C9 complement component was previously localized at the M G endplate by light and electron microscopy. ',' Those endplates showing the greatest structural injury showed the heaviest C9 deposits. The deposits were predominantly on remnants of the junctional folds that had been shed into the synaptic space. Reaction for C9 also occurred at highly degenerate postsynaptic regions denuded of their nerve terminal, and near existing endplates on debris positioned between layers of basal lamina. Thus, the C9 deposits are evidence for complement-mediated lysis of the junctional folds and can also represent tombstones of preexisting folds.'\" In the present study we further investigated the frequency of complement-mediated damage at the MG endplate by paired fluorescence localization in the same sections of the neoantigenic determinants of the C5b-9 complement membrane attack complex (MAC) and AChR. This allowed us to evaluate the frequency of MG endplates damaged by complement and to compare the relative reactivities for AChR and MAC at the same endplates.

Clinical and Laboratory Evidence of Autoimmunity in Acute Schizophrenia

Abstract: A number of assays were performed to assess immunologic function in 28 patients with clinically well-defined schizophrenia. Our data provide laboratory evidence that patients with schizophrenia have characteristics consistent with an autoimmune process, directed to components of the brain, which may participate in either the pathogenesis or etiology of schizophrenia. One-third of our patients had a clinically evident autoimmune syndrome unrelated to their psychiatric illness. Of the nine patients with an autoimmune disease, two had one autoantibody in their serum and five had more than one autoantibodies. Twelve of eighteen patients without clinical evidence of autoimmune disease had no detectable autoantibodies. Mitogenic responses to PHA and PWM were significantly reduced in the patient population when compared to controls. Fifty percent of the patients had an increased percentage (greater than 5%) of blood-borne HLA-DR (+) OKT4 (+) T-helper lymphocytes. Immune reactivity toward brain antigens was sought by measuring lymphocyte transformation to a saline extract of frontal lobe, and by immunoblotting of antigens extracted from frontal lobe, cingulate gyrus, interventricular septum, and hippocampus. Lymphocyte transformation did not reveal differences between patient and control groups. Normal sera were found to contain antibody to some of these brain antigens. However, patients with schizophrenia had antibody to antigens of the hippocampus, septal region and cingulate gyrus which were not encountered during analysis of normal sera.

Characterization of corticosterone feedback regulation of ACTH secretion.

Abstract: Adrenalectomy-induced increases in ACTH secretion in rats are returned to normal by an action of corticosterone on the brain, not on the pituitary. Five days after adrenalectomy with constant steroid replacement, the concentration of free corticosterone in plasma which reduces plasma ACTH by 50% is approximately 0.8 nM. By contrast, the concentration of free plasma corticosterone required for 50% reduction of thymus wet weight or plasma transcortin concentration (both targets for glucocorticoid action) is about 4.5 nM. These results suggested that the inhibition of ACTH by corticosterone might be mediated by association of the steroid with high affinity, type I corticosteroid receptors, whereas the inhibition of thymus weight and transcortin might be mediated by association of the steroid with lower affinity, type II receptors. The results of studies comparing the ability of corticosterone, dexamethasone and aldosterone to inhibit adrenalectomy-induced ACTH secretion support the hypothesis that basal ACTH secretion in rats is mediated by association of corticosterone with type I receptors.

Enzyme‐Catalyzed Processes in Organic Solvents

Abstract: Three different lipases (porcine pancreatic, yeast, and mold) can vigorously act as catalysts in a number of nearly anhydrous organic solvents. Various transesterification reactions catalyzed by porcine pancreatic lipase in hexane obey Michaelis-Menten kinetics. The dependence of the catalytic activity of the enzyme in organic media on the pH of the aqueous solution from which it was recovered is bell-shaped, with the maximum coinciding with the pH optimum of the enzymatic activity in water. The catalytic power exhibited by the lipases in organic solvents is comparable to that displayed in water. In addition to transesterification, lipases can catalyze several other processes in organic media including esterification, aminolysis, acyl exchange, thiotransesterification, and oximolysis; some of these reactions proceed to an appreciable extent only in nonaqueous solvents.

The role of adrenal nerves in the regulation of adrenocortical functions.

Abstract: There is now convincing evidence for the distribution of several nerve plexuses in the outer zone of the adrenal cortex. At the ultrastructural level, the close proximity of nerve boutons to cortical cells establishes the anatomical substrate for a direct neural effect on adrenal cortical cell functions. Of those neurotransmitters and neuropeptides identified to date, catecholamine, VIP, and NPY appear to be most prevalent. Importantly, the amounts of morphologically identifiable catecholamine, VIP and NPY are differentially sensitive to alteration of several physiological conditions. Furthermore, the VIP plexus appears to be intrinsic to the adrenal while the catecholamine and NPY nerve fibers enter the adrenal along blood vessels. Together, these results suggest that these multiple nerve plexuses might exert control on several adrenocortical cellular processes in addition to the regulation of adrenal blood flow. Compensatory adrenal growth, a rapid proliferative response to unilateral adrenalectomy, was previously shown to be neurally mediated. The role of the catecholamine innervation in the mediation of this process has now been demonstrated. The elimination of the sympathetic nervous system by neonatal sympathectomy inhibited the proliferative response as measured by DNA synthesis. In vivo administration of beta-adrenergic receptor blockers did not inhibit the compensatory growth response. Furthermore, the beta-adrenergic agonist isoproterenol, inhibited the rate of DNA synthesis both in vivo and in vitro. The direct action of the beta-adrenergic agonist on the adrenocortical cell DNA synthesis rate suggests that the catecholaminergic nerves tonically inhibit cell proliferation associated with compensatory growth and that the release from the beta-adrenergic inhibition is necessary for compensatory growth. Whether inhibition of the beta-adrenergic innervation is the trigger for compensatory growth or whether it is permissive to the action of a still unidentified mitogenic substance, is not yet known. The direct role of VIP and catecholamines in the regulation of steroidogenesis has been investigated in vitro using the perifused capsule-glomerulosa preparation which is representative of a normal outer zone of the adrenal and is the site of the neural plexuses and identified receptors. Both VIP and isoproterenol stimulate steroidogenesis and specifically cause a greater increase in secretion of aldosterone than corticosterone. Although the concentrations of VIP and isoproterenol required to stimulate steroidogenesis are greater than reported circulating levels, release from resident nerves could provide high local concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)

Neuropeptide modulation of leukocyte function.

Abstract: Neuropeptides released from peripheral nerve endings in mammals, including substance P (SP), somatostatin (SOM), vasoactive intestinal peptide (VIP), and calcitonin gene-related peptide (CGRP), are potent mediators of smooth muscle contraction and relaxation, vasodilatation, secretion by exocrine glands, and leukocyte function.' The potent effects of these peptides on mast cells, lymphocytes, and other types of leukocytes and the generation by leukocytes of neuropeptide-like factors suggest the possibility of important bidirectional modulatory influences between the nervous system and leukocytes in immunologic and inflammatory responses.

Corticotropin-releasing factor receptors: distribution and regulation in brain, pituitary, and peripheral tissues.

Abstract: Since the characterization of corticotropin releasing factor (CRF) in 198 1, evidence has accumulated to indicate that the hypothalamic peptide plays an important role in the regulation of ACTH secretion as well as in mediating visceral and behavioral responses to stress.’.’ The initial event in the action of peptide hormones is their binding to a plasma membrane receptor, and labeled ligands were rapidly developed in order to investigate the mode of interaction of C R F with its cellular binding site. Receptors for C R F were first identified in rat pituitary membranes using radioiodinated Tyr-oCRF, and subsequently studied by radioassays in autoradiographic p r o c e d ~ r e s , ~ ~ ~ and cytochernical techniques using biotinylated or fluorescein-conjugated C R F The use of autoradiography facilitated the identification and characterization of C R F receptors in the central and peripheral nervous system, which has contributed to our understanding of the physiological actions of CRF. The most common ligand used for C R F receptor studies is the radiolabeled ovine C R F derivative, Tyr-oCRF, but similar receptor properties have been described using iodinated [NLe”, Tyr3’]oCRFS. Analogues of rat/human C R F have given tracers with reduced biological action and lower binding activity due to peptide damage during the iodination procedure. Since ovine and human C R F bind to the C R F receptor in different species with equal affinities, oCRF can be used for studies in rat and primates. The purpose of this review is to discuss current knowledge of the C R F receptor, including its binding properties, regulation, and distribution in the pituitary, and nervous system.

Cell-cell interactions in the testis.

Abstract: In conclusion, the information available indicates that the interactions between different cell types in the testis play an important role in the control and maintenance of testicular functions. Further characterization of these interactions will clearly provide insight into the cell biology of the testis and into the regulation of cellular differentiation, function, and growth. It is apparent that no testicular cell type is autonomous, but that there is communication and cooperation between all cell types in the testis.

Androgen Receptors in Human Thymocytes

Abstract: On the basis of a variety of evidence androgenic hormones are thought to exert modulatory effects on immune function. Because specific actions of these hormones are exerted through receptor-mediated mechanisms, we have examined the human thymus gland for the presence of specific high-affinity androgen receptors. Cytosolic extracts of whole human thymus were found to contain 6.5 (+/- 2.6) fmol of specific [3H]methyltrienolone binding per mg protein. The receptor sedimented at 8s on sucrose density gradient centrifugation analysis. Thymic fibroblast lines derived from these glands did not express sufficient receptor content to account for the findings in whole thymus cytosolic extracts. Purified thymocyte preparations (greater than 99.3% pure as assessed by flow cytometry with monoclonal anti-thymocyte marker OKT11) contained 3.34 (+/- 1.2) fmol receptor per mg cytosolic protein. Mature peripheral blood lymphocytes, human T cells obtained from thoracic duct drainage, and the human T cell line Jurkat were not found to contain these receptors. These studies demonstrate for the first time that a high affinity androgen receptor is present in maturing human thymocytes. A functional role for these receptors is suggested by dihydrotestosterone-mediated decreases in interleukin 2-like activity produced by cultured human thymocytes.

The role of the thymus in myasthenia gravis: immunohistological and immunological studies in 115 cases.

Abstract: The thymus and its cellular products, the T cells, are involved in many aspects of autoimmune diseases. T cells may act as effector cells, as is suspected in chronic active hepatitis and in type I diabetes. They may also operate as helper T cells for autoantibody formation. Last, suppressor T cells are known to regulate negatively humoral and cell-mediated autoimmune responses, and their deficiency has been incriminated in the pathogenesis of several experimental and clinical autoimmune diseases. These contrasting actions explain why thymectomy may show diverse effects on the course of experimental autoimmune diseases. Neonatal thymectomy prevents the onset of lupus in MRL/l mice, of diabetes in NOD mice, and of most experimentally induced autoimmune diseases. Conversely, it aggravates the lupus of NZB (NZB X NZW) F1 and B X SB mice and the thyroiditis of obese strain chickens.’.’ Myasthenia gravis (MG) is an autoimmune disease associated with antibodies against acetylcholine receptor ( AChR). Several arguments suggest the existence of a close relationship between disease pathogenesis and thymus function. The disease is frequently associated with morphological abnormalities of the thymus gland (hyperplasia or thym~ma);~.‘ thymectomy has been reported to improve the symptoms of the disease; 5*6 thymocytes from myasthenics produce anti-AChR antibodies;’.’ and their epithelial cells synthesize increased amounts of thymic hormone^,^ one of which has been reported to depress neuromuscular conduction. lo Last, the presence of AChR in extracts of myasthenic thymuses can be demonstrated both by its function (abungarotoxin binding) and its antigenicity (cross-immunoreactivity with muscle AChR).”.’’ It is the purpose of this article to review the data in the literature and

Flow patterns in vessels of simple and complex geometries.

Abstract: Disturbed flows associated with the particular geometry of vessels are considered not only to play an important role in the focal deposition of platelets and white cells on artificial surfaces and the localization of thrombosis and atherosclerosis in vivo, but also to exert some detrimental effects on both the circulating blood cells and the vessel wall, resulting in hemolysis of red cells, activation and aggregation of platelets and white cells, and formation of aneurysms and dilatation of the vessel wall in regions of disturbed flow. Ideally, therefore, it is desirable to avoid creating any flow disturbance, but if this is inevitable, to minimize the size and intensity of the disturbed flows that may form in living vessels as the result of vascular surgery or in channels of artificial organs and vascular prostheses. Except for the case of very high flow rates (or high Reynolds numbers well over 2000), turbulent flow either in the straight parts of arteries in vivo, or in any artificial conduit having a circular cross section, is not likely to be seen. Therefore, in the context of the present paper, we will limit our description and discussion only to the phenomena that occur at Reynolds numbers smaller than 2000 and in steady flow. During the past 10 years or so we have been carrying on a series of investigations on the role of fluid mechanical factors in the localization of thrombosis and atherosclerosis in man, and studying the flow patterns in various vessels of simple and complex geometries by means of flow visualization and cinemicrographic techniques. In this paper we will summarize our findings on the detailed three-dimensional structures of disturbed flows formed in glass models of stenoses and T-junctions, compare them with those observed in isolated transparent natural arteries and veins prepared from dogs and humans postmortem, and then identify the differences in geometrical structures and flow patterns between the artificial vessels and the natural blood vessels in order to find out the optimum conditions to eliminate or minimize the region of disturbed flow that may form in vivo as well as in any channel of artificial vessels.

Effect of ascorbic acid on male fertility.

Abstract: Lindsay and Medes showed in 1926 that a diet deficient in ascorbic acid (AA) for one month caused a massive degeneration of the germinal epithelium with desquamation into the lumina of the tubules in the testes of guinea pigs.' In 1941, it was reported that the seminal plasma of normal man contains 12.8 2 1.6 mg/dl of AA, which is actively concentrated and secreted by the seminal vesicles during ejaculation.24 This level is many times the 0.2-1.40 mg/dl level normally found in serum, and suggests a vital metabolic role for AA in the seminal plasma. In 1960, Lindahl and Kihlstrom described a proteinaceous substance in seminal plasma, which appears in two forms (oxidized or reduced), and which is reversibly transformed from one form to the other.5 The reduced form has antiagglutinic activity-that is, it prevents clumping and immotility of sperm in seminal plasma. This form is attached to the surface of the sperm and loses its ability to be fixed to the cell surface when oxidized. Ascorbic acid, a biological reducing agent, has been shown to reduce the oxidized protein in several in vitro studies6 In 1986, the studies of Lindsay and Medes were duplicated when male guinea pigs with proven fertility were placed on an avitaminotic C diet for 3 weeks and sacrificed. The most severe histological damage was observed in the testicular tissue. The most pronounced damage was in the cauda epididymus, wherein sperm undergo maturation, with thickened peritubular muscle layer and connective tissue, decreased tubular diameter and epithelial cell height, and nuclear pycnosis. Similarly affected was the vas deferens and accessory sex glands, although to a lesser degree. Sperm analysis of semen samples collected from testis, cauda epididymus, and vas deferens showed decline in total sperm count and sperm motility, as well as an increase in the number of abnormal sperm.' Over a decade ago, the obstetricians of our clinical service commenced prescribing AA to husbands when it was apparent from fertility testing of both husband and wife that infertility was possibly due to sperm agglutination in excess of 25%. The practice is to prescribe 1 g per day for 10 days and then 500 mg per day through two menstrual cycles (60 days). This practice has proved successful. Subsequently, we reported a comparison of the differences in sperm qualities between a group of 20 men with sperm agglutination over 25% who followed the AA supplementation protocol and

Fractal Time and 1/f Noise in Complex Systems

Abstract: The later part of the twentieth century seemed to be a period when science and mathematics were becoming more and more specialized. Remarkably, in the last decade, this trend has been reversed due to two major themes: nonlinear dynamics and fractals. The former has involved the discovery of generic universal behavior of nonlinear deterministic equations of motion, and the latter has involved a geometry (and dynamics on that geometry) of self-similar and self-afine objects. Both themes have been applied to an impressive array of interdisciplinary problems. A key to the success of these approaches has been their global rather than specific nature. Physicists, mathematicians, chemists, engineers, biologists, etc., have all by now constructed phase-space plots and calculated fractal dimensions. This paper is concerned with fractal behavior in time rather than in space. This concept has met with much success in the physics of amorphous materials and is just beginning to be introduced into the biological sciences. We will begin by discussing the notion of scaling that underlies fractal time. We then will define fractal time and mention its applications to transport, reaction, and relaxation in disordered materials. Finally, we will show how a limiting case of fractal time is related to the famous problem of l/f noise.