The protein hormone, prolactin, has been of great interest to endocrinologists ever since the demonstration of its presence in the anterior pituitary by Stricker and Grueter in 1929. The action of this hormone was shown to be exerted on the fully developed mammary gland, causing the induction and maintenance of lactation (Nelson, 1936). This role of the hormone has even been of economic interest since prolactin for a time was used in Britian to prevent the decline in the spring in milk production of cows. More recently, there have been reports that prolactin may have other effects in the body besides its function in lactation. It is thought to induce the secretion of hormones from the corpus luteum; but here again, only when the gland is fully developed and ready to function. In 1947 when the present problem was undertaken, almost nothing was known about the behavior of the hormone in the animal body. Questions such as “where does it go, and what does it do?” could not have been answered. The search for answers to questions like this are a proper responsibility of modern endocrinology. As tools for investigations of this nature, radioactive isotopes are proving indispensible, because use of them allows study of the behavior of the hormones in minute doses, and these potent biological entities exert widespread effects when present in almost infinitisimal amounts.[...]

The function of the central nervous system cannot be understood from inspection of a single region, for each cell and fiber has discrete connections. Therefore, a study of the nervous system requires distinct approaches. One fundamental approach has been the study of comparative neuroanatomy. In a comparative study of the evolution of the primates and subsequently man, the investigator is confronted with a variety of animal forms. Each form represents an end product of a long vertical line of evolutionary development. The problem is to try to reconstruct the vertical line (ancestral forms) from the horizontal end products (extant forms). The order Primates has two suborders: (1) the Prosimii - composed of six families - Tupaiidae, Lemuridae, Indriidae, Daubentoniidae, Lorisidae, and Tarsiidae and (2) the Anthropoidea - also composed of six families including the Old and New World monkeys, the great apes and man. One group of the suborder Prosimii is the family Lorisidae. The living members of the family are represented by the lorises of India and Southeast Asia and the galagoes and pottos of Africa. Characters these animals share with the higher anthropoid primates are seen in the osteology of the middle ear and the medial wall of the orbit (Le Gros Clark, 1959). They also have orbits encircled by bone, three kinds of teeth, a well developed caecum, true nails and a pseudo-opposable thumb. In habit, these animals are omnivorous, nocturnal and arboreal. In progression, the lorisoids are less tied to the quadrupedalism of many lemurs (Osman Hill, 1953). The lorises have a slow deliberate mode of hand-over-hand locomotion, their limbs are subequal in length. In contrast, the galagos locomote by a rapid, saltatory behavior and have pelvic limbs much longer than pectoral limbs. Both of these means of progression effect an orthograde (erect or semi-erect) posture of the trunk and a tendency for a different mode of balancing the head on the spine. Some authors regard the vertical clinging and leaping of galagos as the earliest locomotor specialization of primates (Napier and Walker, 1967; Napier, 1967). From the post-cranial osteology of early Miocene Lorisidae (Walker, 1970) and from a comparative osteological, behavioral and paleontological study (Napier and Walker, 1967), it appears that this locomotor pattern was present in early Eocene and subsequent Miocene prosimians. These authors conclude that vertical clinging and leaping is the earliest known primate locomotor specialization and preadaptive to some or possibly all subsequent patterns of primate progression—quadrupedalism, brachiation and bipedalism. Although comparative neuroanatomical investigations have utilized the anthropoid primates, (mainly Macaca) rodents and carnivores (chiefly the cat), the prosimian primates have been relatively ignored. Yet their locomotor behavior and their propensity toward bipedalism make them an interesting model for a study of central nervous pathways related to locomotion.

Cultures of human umbilical vein endothelial cells were treated with heparin-corticosteroid combinations to determine effects on cellular growth. Standard proliferation assays, colony formation assays, and cytoflourometric analysis were the methods employed. Dexamethasone (DEX) and hydrocortisone (HC) were inhibitory to growth of HUVEC when EtOH was used as a solvent and fully supplemented medium (20% serum) was employed. When DMSO was the solvent, growth enhancement sometimes occurred when (DEX) was the test steroid; growth inhibition occurred with this steroid when a reduced (1%) serum component was used. Since significant inhibition of cell colony formation in response to DEX administration was observed, the results suggest that low density growth of HUVEC was inhibited by steroid treatment, while higher density growth was facilitated. Cytoflourometric analysis of HUVEC treated with DEX-heparin combinations indicated that this treatment increased cellular size and possibly increased the number of endothelial cells in the S and/or G2-M phases of the cell cycle in early passage HUVEC. Senescent expression was studied in HUVEC using a cell counting method to determine the percentage of senescent cells in these cultures. The effects of culture gender and passage number on senescent expression were determined for various plating densities and passage split ratios. When primary cultures of HUVEC were passed at a 1:10 split ratio and subsequently passed at a 1:5 split ratio, male cultures expressed a greater degree of cellular senescence than to female cultures. When differences in confluent cell density between male and female primary cultures were corrected for by plating at standard density (1.25 x 105 cells/flask), there were no significant differences in total cells, total senescent cells, or percentages of senescent cells between male and female cultures, a phenomenon which was true in both five and seven day assessments. When cultures of both male and female HUVEC were passed at high density (1:4 split ratio), significantly greater senescent expression occurred in later passages vs. earlier passages, an effect not seen when the cultures were passed at a lower density (1:16 split ratio). There was a trend for both male and female cultures passed at a lower density to express less senescence when contrasted with male and female cultures passed at a higher density. The results suggest that cellular density at passage may be more important than gender in the expression of senescence in HUVEC.

In recent years renal homotransplantation has become more frequently used in the treatment of terminal renal disease in man. By carefully selecting donors with the aid of tissue compatibility tests and employing immunosuppressive drugs, these transplants have become increasingly more successful. It is true, however, that even with good tissue match-up and drug treatment rejection episodes occur, frequently within the first two-postsurgical weeks. The majority of these rejection crises may be reversed by increasing drug dosages and occasionally applying x-irradiation to the area of the transplant. In other cases rejection by the recipient is responsible for cessation of function of the transplanted kidney, terminating in its ultimate removal. Millard et al. (1970) suggested that light microscopic studies of biopsy tissue Obtained from transplanted kidneys at various intervals postoperatively would be useful in early clinical management of the patients. The primary purpose cf the present study is to determine if electron microscopic studies of renal tabules in tissue obtained one hour postoperatively would also be useful in indicating subsequent graft rejection or dysfunction. Light (Dempster, 1952; Simonsen et al., 1952; Porter et al., 1964; and Shorter et al., 1964) and electron microscopic (Darmady et al., 1955; Kountz et al., 1963; Porter et al., 1964; and Williams et al., 1964) observations of canine homotransplanted kidneys are numerous but none of the biopsies studied were obtained prior to six hours post-transplantation. Ultrastructure of normal human kidney has been described (Rhodin, 1958; Flume et al., 1963; Brewer, 1965; Myers et al., 1966; Tisher et al., 1966; Bulger et al., 1967; and Tisher et al., 1968) as has the ultrastructure of normal monkey renal tubules (Tisher et al., 1969). Electron microscopic studies of human renal homotransplanted tissue including the glomerulus, tubules and vasculature have also been reported. However, the majority of the biopsies described were Obtained one week or more following transplantation (Hamburger et al., 1965; Porter et al., 1966; Shimamura et al., 1966; and Busch et al., 1971). Hume et al. (1970) included one hour biopsies in their studies of glomerulonephritis. Weymouth et al. (1970) described the ultrastructure of the glomerulus one hour post-transplantation and.were able to correlate changes in the glomerulus with future function of the transplant. Electron.microscopic studies of the tubules, vasculature or interstitium one hour after transplantation have not been previously reported. Therefore, it seemed pertinent to study these tissues, correlating structure with clinical function in an effort to determine if this information could be used to postulate the future of the individual renal transplant.

The pineal gland secretes the hormone melatonin (n-acetyl-5-methoxytryptamine) with a circadian rhythm. This secretion's rhythm becomes disrupted with age. When melatonin secretion is decreased with advanced age, the immune, endocrine and reproductive systems fail to function optimally. Melatonin possesses lipophilic and anti-oxidant properties, providing it with access to nuclei. Melatonin protects the DNA, preventing cancerous mutation. Hippocampal degeneration and age increase and prolong the adrenocortical responses to stress. Melatonin supplementation reduces the prolonged exposure to harmful hormones.

Oculomotor deficits are now recognized as being present in several neurological diseases of the basal ganglia. The present report will focus primarily on those observed in Huntington's and Parkinson's diseases. Neuronal cell loss in the pars compacta of the substantia nigra, degeneration of the nigrostriatal pathway, and consequent depletion of the neurotransmitter dopamine is the most obvious etiological abnormality in Parkinson's disease. Huntington's disease, on the other hand, involves the selective genetically-driven atrophy of the striatum (caudate and putamen). In order to attempt to understand oculomotor dysfunction, as a component of basal ganglia disease, it is necessary to first establish a definition of the basal ganglia, its relevant connections, and their associated neurotransmitters and functions.

The nucleus raphe magnus (NRM) is known to play an important role in a descending antinociceptive system through its projections to the spinal cord dorsal horn and trigeminal subnucleus caudalis. Identifying those nuclei which project to NRM is essential in determining other CNS cell groups which could influence analgesic mechanisms by virtue of their connections with NRM. In an attempt to define NRM afferents, 19 adult Sprague-Dawley rats were stereotaxically implanted with a pellet of HRP gel within NRM and in adjacent areas. A transcannula technique was specifically developed for the subcortical placement of HRP in a gel form. Use of a preimplanted stainless steel cannula for delivery of the gel to its target site, prevented contamination along the implantation tract, a factor which has compromised previous studies of this area. Employing tetramethylbenzidine neurohistochemistry, large numbers of retrogradely labelled cells were consistently found in the zona incerta, n. parafascicularis prerubralis (pPfPr), pretectum, dorsal and lateral periaqueductal gray, n. cuneiformis (nC), deep superior colliculus (dSC), and n. of Bechterew. Smaller numbers of cells were seen in the preoptic area, and the dorsomedial n. of the hypothalamus. Confirmational anterograde autoradiographic studies were done by injecting tritiated leucine into the nPfPr and into the area of the dSC and nC. The HRP results are compared and contrasted with control HRP implants in the inferior olive, n. reticularis paragigantocellulais, medial facial n., spinal cord, and the dorsolateral funiculus. Comments are also made concerning the parcellation of the ventromedial medulla and the possible role of both NRM and its afferents in central analgesic mechanisms.

The following review of the p53 tumor suppressor gene will be discussed with particular attention to its role in human gliomas, as well as the various advances that have brought this molecule to the forefront of cancer research. A review of tumorigenesis focuses on the molecular mechanisms that convey neoplastic characteristics upon a normal cell. It is discussed how the coordinate advances in chromosome analysis and molecular techniques enabled the p53 gene to be categorized as a "tumor suppressor gene" and applied to various forms of cancer, including colorectal and lung carcinoma. The focus of the review will be on the involvement of p53 in gliomas, as the p53 mutation rate in gliomas is quite different from that in other cancers. It is also noted how cellular characteristics. contribute to the function of p53, and how p53 expression indicates grades of tumor malignancy, thereby aiding in diagnosis and prognosis. In conclusion, future applications of p53 in areas such as gene therapy are examined, as well as alternative mechanisms of tumor suppression that circumvent direct p53 mutations in gliomas.

A number of recent studies suggest that expression of mutant p53 with mutations in certain codons show a gain of function and some of the characteristics of an oncoprotein. In order to study gain of function mutation and eliminate the potential of a dominant negative interaction with endogenous wild type p53 protein, p53 knockout mouse astrocytes were used. A retrovirus system was used to introduce mutant p53 genes into these p53-null astrocytes. Immunohistochemical staining and western blot experiments showed the expression of mutant p53 protein in these cells after infection with the mutant p53 retroviruses. Cell growth experiment did not suggest growth advantages for mutant p53 expressing astrocytes over vector control cells. Data from clonogenic survival assays following exposure to etoposide or cisplatin suggested that mutant p53 expressing cells with a point mutation at codon 273 may be resistant to apoptosis induced by etoposide. In contrast, p53 with a point mutation at codon 248 may sensitize cells to the apoptotic effects of etoposide and cisplatin.

The blood-brain barrier (BBB) selectively restricts the blood-to-brain passage of many solutes owing to unique properties of cerebrovascular endothelial cell membranes. This selective blood/brain interface participates in the maintenance of brain homeostasis by controlling nutrient, gas, and fluid exchange necessary for brain function. Normal BBB function can be altered under various pathological and experimental conditions, allowing the transfer into brain parenchyma of blood-borne solutes normally excluded. To date, experimental study of the BBB has been accomplished primarily through the use of two different methodological approaches. Some investigators have focused on the barrier's morphological correlates and its morphopathological alteration under various pathological conditions. Other investigators have attempted to define the physiological transport properties of the BBB. Morphological studies have employed, for the most part, large molecular weight (MW) tracers to detect morphological alterations underlying increased permeability. Physiological studies, employing smaller, more physiologic tracers have been successful in describing, quantitatively, certain functional aspects of blood-to-brain transfer. The current work attempts to merge these two approaches and to consider barrier function/dysfunction from both a morphological and a functional perspective. Specifically, the study compares in rats, following acute hypertension (a condition well-known to elicit BBB alteration), the cerebrovascular passage of C-alpha-aminois obutyric acid (AIB), a small MW tracer employed in quantitative physiologic barrier studies, and that of horseradish peroxidase (HRP), a large MW protein tracer traditionally employed in morphological barrier studies. The blood-to-brain passage of AIB and HRP were compared, following acute hypertension, with regard to both the topographical distributions of the tracer extravasation patterns and the magnitude of tracer extravasation at two different levels of hypertension. Quantitative measures of cerebrovascular AIB transfer were obtained through macroautoradiography and computerized image analysis. The data, both qualitative and quantitative, revealed dramatic focal permeability increases to AIB in some brain loci which also showed permeability increases to HRP. Such loci included the cerebral cortices and the thalamus. However, many brain regions, such as the caudate-putamen, cerebellum, and brainstem, showed more subtly-elevated AIB passage where no corresponding HRP passage was observed. Linear regression analysis of the physiologic data showed that the rate of cerebrovascular AIB transfer was positively related to the abruptness of the onset of hypertension and not related to other physiologic parameters of the hypertensive insult. The qualitative and quantitative results of this study suggest that traditional morphological barrier studies a lone do not reveal all aspects of altered barrier status and that multiple mechanisms underlying increased BBB permeability may operate simultaneously during BBB dysfunction.