Blood-brain barrier and peptides.

The brain is both the source and the recipient of peptide signals. The question is: Do endogenous, blood-borne peptide molecules influence brain function? Brain regions with the tight capillaries of the blood-brain barrier (BBB) extract low but measurable amounts of labeled peptide molecules from an intracarotid bolus injection. In the rat, the extraction fractions of beta-casomorphin-5, DesGlyNH2-arginine-vasopressin, arginine-vasopressin, lysine-vasopressin, oxytocin, gonadoliberin, substance P, and beta-endorphin, studied in this laboratory, range from 0.5% (substance P) to 2.4% (arginine-vasopressin). Extraction varies little among the 15 examined brain regions. As shown for arginine-vasopressin, the extracted peptides may be bound in part to specific binding sites located on the luminal membrane of the tight endothelial cells. Transport of peptide molecules across the BBB cannot be ruled out, but it is unlikely that endogenous peptides pass the BBB in physiologically significant amounts. In contrast, in brain regions with leaky capillaries, e.g., selected circumventricular organs including the pineal gland, neurohypophysis, and choroid plexus, the peptide fraction extracted approaches that of water. Within the circumventricular organs, the peptide molecules actually reach the cellular elements of the tissue. However, no studies definitively show that peptides reach neurons in the deeper layers of the brain. On the other hand, blood-borne peptides influence the BBB permeability by altering the transport of essential substances. The effect may be mediated by specific peptide binding sites located at the luminal membrane of the endothelium. It is possible that the effect of peptides on the BBB is necessary for proper brain function.(ABSTRACT TRUNCATED AT 250 WORDS)

Age-related pathophysiology of the blood-brain barrier in heat stress.

The possibility that the blood-brain barrier (BBB) might play an important role in the pathophysiology of heat stress (HS) has been examined in young (age 8-9 weeks) and adult (age 24-32 weeks) rats. Exposure of young rats to 4 h HS at 38 degrees C in a biological oxygen demand (BOD) incubator (relative humidity 47-50%, wind velocity 20-26 cm/sec, simulating the environmental conditions of Varanasi, India, during the month of June) resulted in a marked hyperthermia (41.7 +/- 0.23 degrees C) and behavioral symptoms. In these animals there was a profound increase in the permeability of the BBB to Evans blue-albumin (EBA) (464%) and to 131I-sodium iodide (515%), accompanied by a marked increase in the brain water content (4%), of the levels of serotonin (5-hydroxytryptamine, 5-HT) in plasma (687%) and in brain (267%) and a pronounced reduction (30%) in cerebral blood flow (CBF). Morphological examination using light- and electron-microscopy revealed profound neuronal changes associated with a marked increase in glial fibrillary acidic protein (GFAP) and in vimentin immunoreactivities, together with a substantial reduction in myelin basic protein (MBP) immunostaining in the brain. These changes were more pronounced in the brain-stem reticular formation, pons and medulla region. On the other hand, exposure of adult animals to the same intensity of HS resulted in mild or no changes in BBB permeability, content of brain water and 5-HT in the plasma and brain, CBF or other cellular changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Transfer of [3H]leucine across the blood-brain barrier at high blood-side oxytocin concentrations in normal and morphine-dependent rats.

The effects of circulating oxytocin on permeability of the blood-brain barrier (BBB) to L-[3H]leucine were studied in anaesthetized rats using the intracarotid, single pass, bolus injection technique. After bolus intracarotid oxytocin injection (10(-9) M), there were no differences in [3H]leucine uptake, compared with controls, in any of eight brain regions with a 'tight' BBB (olfactory bulb, frontal cortex, visual cortex, corpus striatum, hippocampus, thalamus, hypothalamus and colliculi) or in BBB-free, 'leaky' structures (pineal gland, choroid plexus, neuro-intermediate pituitary, anterior pituitary). [3H]leucine uptake by the 'leaky' structures was 2.4x and 2.6x uptake by 'tight' regions in the oxytocin and control groups respectively. In morphine-dependent rats, naloxone increased oxytocin secretion 28-fold within 5 min, but did not affect [3H]leucine uptake for any BBB-protected brain region or BBB-free 'leaky' structure. Accumulation of [3H]leucine was 8.3x and 7.0x greater in the 'leaky' structures than in the 'tight' regions in the naloxone and control groups respectively; [14C]inulin accumulation by each 'tight' region (measured simultaneously with [3H]leucine to determine the vascular space) was not affected by naloxone. It is concluded that even very high blood plasma concentrations of oxytocin do not affect BBB permeability for leucine. It is unlikely that altered BBB permeability, at least for amino acids, contributes to CNS changes during naloxone-provoked morphine withdrawal.

On the blood-brain barrier to peptides: specific binding of atrial natriuretic peptide in vivo and in vitro.

Using the intracarotid bolus injection technique, a saturable binding of [125I]atrial natriuretic peptide (ANP) was found in 8 blood-brain barrier (BBB)-protected rat brain regions as well as in the pineal gland, choroid plexus, neurointermediate and anterior lobes of the pituitary, i.e. structures lacking a BBB. The presence of specific ANP binding on the BBB, here shown for the first time by an in vivo approach, was evidenced concomitantly in vitro by incubation of isolated microvessels. A single-class high affinity binding without regional differences was obtained with Kd = 0.23 nM and Bmax = 120 fmol/mg protein. From that a density of 1,400 binding sites per endothelial cell was calculated, thought to be localized predominantly in the luminal membranes. In the in vivo study, the portion of the extracted peptide that, under the conditions used, may have crossed the BBB by passive diffusion amounted to less than 0.4% of the labeled ANP administered. ANP itself did not change the tightness of the BBB to the non-diffusible reference molecule [14C]inulin. In the BBB-free areas, ANP enhanced the inulin space by nearly 50%.

[Selective percutaneous transluminal thrombolytic therapy with rt-PA in central retinal artery occlusion]. / Selektive perkutane transluminale Lysetherapie mit RTPA bei retinalem Zentralarterienverschluss.

UNLABELLED: In central retinal arterial occlusion systemic fibrinolytic therapy can involve a variety of serious complications. The local application of a fibrinolytic agent close to the embolus by means of a femoral catheter should reduce the rate of complications. We therefore present the results of a preliminary study of nine consecutive patients treated with rt-PA via transcutaneous femoral catheter. PATIENTS: From October 1993 to January 1994, nine patients ranging in age from 50 to 83 years who had central retinal occlusion were treated with rt-PA. The latency from the onset of the symptoms to the beginning of the therapy was 10-37 h. A catheter was placed via the femoral artery, the tip being located either at the common carotid artery or at the internal carotid artery or at the internal carotid artery. A continuous infusion containing 10 micrograms (ACTILYSE (rt-PA) was given over 2 h. Thereafter, each patient received 7000 IU heparin sulfate 4 times daily for 3 days and 1200 micrograms pentoxifylline i.v. daily for 10 days. On discharge, permanent therapy with salicylic acid (100 micrograms) was prescribed. The patients have been followed up for up to 18 months so far. RESULTS: In five of eight patients an improvement of central visual acuity was observed. It changed from perception of hand movement only to 12/20 in three patients. In two of these patients visual acuity had continued to improve after 6-9 months, to 16/20 and 20/20. In one patient visual acuity fell to 6/20 because of progression of ischemic ophthalmopathy. In our patients visual acuity could still be improved even 27 h after arterial occlusion. CONCLUSION: A low incidence of complications and the good effect on thrombolysis support the local rt-PA therapy. Good interdisciplinary cooperation is required. Patients must be referred for this therapy as early as possible.

A water-cooled spherical niobium target for the production of [18F]fluoride.

A new automated target system for the routine production of [18F]fluoride from (18)O-enriched water has been constructed. It consists of a small spherical niobium target chamber mounted into a special holder, which provides rapid cooling by water flow around the sphere. The target is irradiated with 21 MeV protons; the incident energy in the target chamber is 13 MeV. The system is operated without external over-pressure and has been tested for beam currents up to 50 microA. 95% of the theoretical yield of [18F]fluoride has been extracted and used for the synthesis of [18F]2-fluoro-2-deoxy-D-glucose.

Prevalence of Chlamydia specific antibodies among obstetric and gynecological outpatients in Gondar, north-west Ethiopia.

A total of 533 obstetric and gynecological outpatients who visited the dedicated clinics in Gondar, Ethiopia, between April and August 1995 were investigated for Chlamydia-specific antibodies. Relevant epidemiological and clinical data were collected using a pretested questionnaire, clinical examinations and laboratory tests. Earlier, using an antigen specific ELISA technique, we had reported that only 33 (6%) of these women were positive for C. trachomatis in cervical swabs. In this study, we evaluated the prevalence of C. trachomatis-specific antibodies in serum samples of the same patients collected at the time the cervical swabs were taken. Employing a genus-specific ELISA for the detection of chlamydial LPS antibodies, 90% of the sera were found to be positive for IgG, while 49% of the sera contained IgA and 28% IgM antibodies. For 436 of the positive sera, species specificity of the antibodies was determined by means of a micro-immunofluorescence assay. Antibodies against C. trachomatics were present in 75% and antibodies against C. pneumoniae in 69% of these sera. Forty-nine percent of the patients carried antibodies against both species. The antibody based assay estimated that 13.9% of the patients had acute genital chlamydial infection (antigen specific IgM and the simultaneous presence of C. trachomatis specific IgG, IgM and IgA). C. trachomatis antigen detection in cervical swabs apparently underestimated the real frequency of acute infections. Seroprevalence of C. pneumoniae antibodies in the Ethiopian patients was similar to that in industrialized countries.

[40 years breast carcinoma treatment in the Neubrandenburg region.Can an increase in prognostically more favorable stages be detected?]. / 40 Jahre Mammakarzinombehandlung in der Region Neubrandenburg. Lässt sich eine Verschiebung zu prognostisch günstigeren Stadien nachweisen?

The data of clinical presentation for women suffering from breast carcinoma were analysed for a period of 4 decades retrospectively. The authors have found a significant decrease in the duration of the history and an increase of early stages of the breast carcinoma. This increase was caused by the introduction of mammography. The mammography is the most important method for the diagnosis of breast carcinoma in asymptomatic women.

[3H-leucine incorporation into the secretory cells of the murine mammary gland under the action of adrenomimetics]. / Vkliuchenie 3H-leitsina v sekretornye kletki molochnoi zhelezy myshei pri deistvii adrenomimetikov.

Although there is some evidence suggesting the involvement of the sympathoadrenal system in the mammary gland function, the precise mechanism by which adrenergic agents may influence galactopoietic processes is largely unknown. The aim of this study was to investigate whether the reported decrease in milk and organic substance content after catecholamine administration might be due to the inhibition of protein synthesis. For that purpose, the incorporation of 3H-leucine into the secretory cells of the mammary gland of lactating mice under the influence of the alpha-adrenoceptor agonist phenylephrine and the beta-adrenoceptor agonist isoproterenol, respectively, was studied by light microscopic autoradiography. Tissue radioactivity as a whole was measured by liquid scintillation counting. It was shown that neither the alpha- nor the beta-agonist simultaneously given with the labeled amino acid were able to change the amount of radioactivity taken up by the mammary gland. From this result it is concluded that a transitory increase in catecholamine concentration in the blood has no effect on mammary gland protein synthesis.

[The Harderian gland--target for cyclic nonapeptide neurohypophyseal hormones. Autoradiographic studies on the rat (author's transl)]. / Die Hardersche Drüse--ein Zielorgan für Neurohypophysenhormone. Autoradiographische Untersuchungen an der Ratte.

Among autoradiograms of different tissues prepared after intravenous injection of 3H-tyrosine oxytocin into male white rats, only those of the kidney and the Harderian gland, an exocrine gland in the orbit of most terrestrial vertebrates, displayed a saturable labelling, i.e., pretreatment of the rats with an excess of unlabelled oxytocin led to a significantly lowered tissue content of radioactivity. Liquid scintillation analysis confirmed this result. Moreover, besides the kidney only the Harderian gland proved to be labelled in autoradiograms prepared after intracarotid injection of 125I-lysine vasopressin into male white rats. The intensity of this label is enhanced in Brattleboro rats. The results strongly suggest that the Harderian gland represents a hitherto not recognized target for posterior pituitary cyclic nonapeptide hormones. Concerning the physiological role these hormones may play in the gland, the speculation is put forward that oxytocin like its role in the mammary gland might be involved in the regulation of Harderian gland secretory processes.

[Hyperthyreosis and gravidity (author's transl)]. / Hyperthyreose und Gravidität.

An account is given of incidence, diagnosis, therapy, and clinical peculiarities of hyperthyreosis in gravidity, with reference being made to literature as well as to the authors' own experience. It is strongly suggested that thyreostatic treatment may yield good success even under the conditions of gravidity, provided that certain peculiarities are taken into due consideration. Conclusions then are drawn for efficient organisation of medical attention to pregnant patients with thyroid diseases.

[Detection of special radionuclides in waste water from nuclear power plants]. / Erfassung spezieller Radionuklide im Abwasser aus Kernkraftwerken.

For the nuclear power stations in the Federal Republic of Germany, the emissions of the radionuclides C 14, P 32, Fe 55 and Ni 63 in liquid effluents were investigated for several years. For the seven nuclear power stations, for which C 14 was measured for years, the releases in liquid effluents were in the range of 1 to 67 mCi. Yearly releases of P 32 generally do not exceed 0,5 mCi. Exceptions are boiling water reactors during the first two or three years after starting operation. Yearly releases up to 30 mCi were measured. The releases of Fe 55 and Ni 63 are in the range of 1 to 20 mCi per year and thus, in general, low compared to the releases of other activated corrosion products. As a consequence of decontamination measures especially during long shut down of a facility, yearly releases up to 68 mCi of Fe 55 and 190 mCi of Ni 63 occurred. The hypothetical radiation exposure of the public, resulting from these releases is low. The dose is below 1 mrem/a.

The influence of exogenous oxytoxin on labelling of secretory epithelium of mouse mammary gland by [3H]leucine, evidenced by autoradiography.

It has been suggested that oxytocin, besides its milk-ejecting activity, is also involved in the hormonal regulation of the mammary gland secretory cells. The available data, however, are conflicting. In this study two independent experiments, separated by a certain time interval show that oxytocin intravenously administered to mice at days 10-14 of lactation diminished the incorporation of [3H]leucine into the mammary gland tissue by 32 and 53 per cent, respectively. The neurohormone was co-injected with the tracer amino acid. The radioactivity taken up by the secretory cells was estimated by light microscopic autoradiography. The autoradiograms were evaluated by visual silver grain counting. Tissue radioactivity was measured by liquid scintillation counting. A milk stasis in the mammary gland induced by depriving the mice of suckling two hours before tracer injection had no influence on the secretory activity of the glandular cells. It is assumed that oxytocin has a direct effect on the milk-producing cells, and that the reduction in measurable radioactivity caused by the neurohormone may be due to an accelerated intracellular passage of labelled milk proteins.

[Hyperprolactinemia in malignant lymphomas]. / Hyperprolactinämie bei malignen Lymphomen.

Serum prolactin levels at the time of confirmed diagnosis and of remission were determined prospectively in 36 patients (22 males, 14 females; mean age 54.2 [18-77] years), 12 with Hodgkin and 24 with non-Hodgkin lymphoma. Basal prolactin levels were elevated to a mean of 1900 (720- greater than 4000) mU/l in 12 patients. Eight of these had extranodal manifestations of lymphoma. At the time of remission the elevated prolactin levels had returned to normal in six patients. The cortisol concentrations of the 36 patients did not correlate with the prolactin levels so that stress-induced increase in secretion seems unlikely. These results point to prolactin possibly playing a role as a nonspecific tumour marker. In addition, lymphomas should be included in the differential diagnosis of hyperprolactinaemia.

[Changing of therapeutic habits in the drug therapy of high blood pressure]. / Zur Anderung der Therapiegewohnheiten in der medikamentösen Therapie des Bluthochdruckes.

The evaluation of special literature shows that in recent years a considerable change took place in the recommendations concerning the medicamentous therapy of high blood pressure. According to this the beta-receptor blockers took the first place, whereas the Rauwolfia-preparations increasingly receded into the background. An analysis of the consumption of antihypertensive drugs in the County of Leipzig resulted in the fact that the newer scientific knowledge is only very slowly followed in practice; thus the Rauwolfia-preparations are still at the top in the prescription of antihypertensive drugs. The results show that increased troubles are necessary to transfer scientific knowledge more quickly into practice. The ways to this are shown.

On the blood-brain barrier to peptides: [3H]gonadotropin-releasing hormone accumulation by eighteen regions of the rat brain and by anterior pituitary.

After intracarotid injection of [3H]gonadotropin-releasing hormone ([3H]GnRH) the mean accumulation of radioactivity per unit wet weight of 18 investigated brain samples and the anterior pituitary was 0.38 +/- 0.11% g-1 of the injected tracer dose. This indicates a low but measurable brain uptake of the peptide. The brain uptake of [3H]GnRH in blood-brain barrier (BBB)-protected regions is 5% of that of separately investigated [3H]OH. In BBB-free regions the accumulation of radioactivity was more than 25-fold higher than in BBB-protected regions. The accumulation of [3H]GnRH among regions with BBB varies less than among regions with leaky endothelia. The data presented for [3H]GnRH are similar to those for other peptides so far investigated.

The presence of steroids in larval and mature brook lampreys (Lampetra planeri Bloch).

The presence of steroids was investigated by radioimmunoassay - mass spectrometry in serum and homogenates of gonads and presumed adrenocortical (pro- and opisthonephric) tissue of larval and mature brook lampreys (Lampetra planeri Bloch) of both sexes. Pregnenolone was detected in all tissue samples studied whereas androstenedione could be identified only in presumed adrenocortical tissue from male and female mature animals as well as in testis. Testosterone was present in testis of adult lampreys and in sera of larval and adult animals.