Kabuki make-up (Niikawa-Kuroki) syndrome: a study of 16 non-Japanese cases.

Kabuki make-up (Niikawa-Kuroki) syndrome has been described mainly in Japanese patients. In this paper we report sixteen new cases from Europe and North America, suggesting that Kabuki make-up syndrome may be more common outside of Japan than supposed. Their features are compared with those of the Japanese patients and most of our findings are similar to those previously reported. The facial phenotype is specific and easily recognizable, regardless of ethnic origin. Postnatal growth retardation and mild mental retardation are confirmed to be cardinal manifestations of the syndrome. Skeletal anomalies were present in all cases but most of the radiological changes were non-specific. The specificity of metacarpophalangeal pattern profile is not confirmed. Conversely, dermatoglyphic analysis is helpful in the diagnosis of this condition. Two differences have emerged between the Japanese patients and those in this study. Firstly, two-thirds of the patients in this series had significant neurological dysfunction other than mental retardation. Secondly, joint hypermobility appears more common in non-Japanese patients. Confirmation of these findings requires further studies.


[Chromo-colposcopic images during oral contraception].

The Authors report chromocolposcopic pictures with AZEA (Azure 2 + alcohol-soluble eosine + ethanol) and related histologic pictures in six women under oral contraception. Columnar epithelium develops violet or blue-violet areas histologically corresponding to endocervicitis. Aceto-white epithelium develops reddish color in case of medium-mature metaplasia, brown-violet in case of mature metaplasia, lilac in case of superficial koilocytosis on metaplasia. Native epithelium appears dark brown, or yellow-brown in case of koilocytosis.


[Effect of acute and chronic administration of L- thyroxine and methimazole on blood levels of tryptophane, serotonin and 5-hydroxyindoleacetic acid in plasma of rats].

The effects of hyperthyreosis induced by the administration of thyroxine and hypothyreosis induced by the administration of methimazole on the levels of tryptophane, serotonin and 5-hydroxyindoleacetic acid in low-platelet blood plasma have been studied in Wistar rats. Thyroxine administration (120 micrograms/kg/24 h, intraperitoneally) lasting 7 days caused a decrease in serotonin concentration by 38 per cent. The level of this amine in rats receiving thyroxine during three months was elevated by almost three times. Tryptophane concentration did not change following thyroxine administration. Methimazole administration lasting 14 days (oral dose 15 mg/kg/24 h) caused an increase in tryptophane concentration by 34 per cent and in serotonin concentration by 24 per cent. Long-term hypothyreosis induced by methimazole administration lasting three months caused an 39 per cent increase in tryptophane and 38 per cent increase in serotonin concentration. Neither hyperthyreosis induced by thyroxine administration nor hypothyreosis induced by methimazole++ caused any changes in the concentration of 5-hydroxyindoleacetic acid. The importance of serotonin in pathogenesis of clinical symptoms accompanying the states of deficit or excess of thyroid hormones needs further elucidation.


Clinical applications of radioimmunoassay of the alpha-subunit of glycoprotein hormones.

The radioimmunoassay of alpha-subunit adapted in our laboratory was widely evaluated. Three different antisera (anti-pituitary alpha-subunit, anti-alpha-TSH and anti-alpha-hCG), the labelled preparations of pituitary alpha-subunit and alpha-hCG, and cross-reactivity with intact glycoprotein hormones (MRC standards of LH, FSH, hCG and TSH) were tested for their potential influence on the results of the assay. The basal levels of alpha-subunit were measured in 48 healthy young men, 48 normally menstruating women, 33 menopausal women, 37 pregnant women and 70 patients with pituitary adenoma. In addition a possibility of pulsatile secretion of alpha-subunit was investigated in 9 healthy young women, the ranges of alpha-subunit concentrations found were as follow (means +/- SD): 1.2 +/- 0.4 micrograms/l--in young men, 1.1 +/- 0.4 micrograms/l--in young women, 3.2 +/- 0.7 micrograms/l--in postmenopausal women, 1-54 micrograms/l--in pregnant women, and between 2.6 and 44.0 micrograms/l in 14 of 70 patients with pituitary adenoma. There were good correlations of results for 3 different antisera and their cross-reactivity with LH, FSH, hCG and TSH were just as low. In conclusion, the alpha-subunit assay appears clinically useful and should be widely applied in routine endocrinological diagnostics.


[Alcohol decreases the alpha subunit, LH and testosterone secretion in response to LH-RH].

In our previous study we showed that alcohol disturbed the circadian rhythms of LH, testosterone and its conversion to DHT. To determine the effect of LH-RH on pituitary-gonadal function before and after alcohol, 11 male volunteers aged 24-29 years (mean 25.5) were investigated. Blood for hormonal estimations was withdrawn before and 20, 30, 60, and 120 min after LH-RH. In every case, the LH-RH test was performed twice: 6 hours after placebo and, a week later, 6 hours after alcohol administered orally, in dose of 1.0 g/kg bw. The LH, FSH, alpha-subunit and testosterone concentrations were measured with radioimmunological methods. It was shown that alcohol significantly inhibited LH (p < 0.05), alpha-subunit (p < 0.02) and testosterone (p < 0.001) response to LH-RH stimulation, but not that of FSH.


Recent advances in the mechanism of action of cyclosporine and FK506.

The immunosuppressants cyclosporine and FK506 (tacrolimus) are extremely potent inhibitors of T-lymphocyte activation. Recent studies have shown that these agents are actually prodrugs that become active only when bound to specific members of the cyclophilin or FK506 binding protein receptor gene families. The cyclosporine-cyclophilin or FK506-FK506 binding protein receptor complexes interact with a key component of the T-cell antigen receptor signal transduction pathway, the calcium-calmodulin-dependent phosphoprotein phosphatase calcineurin. The drug-receptor complexes inhibit the phosphatase activity of calcineurin and thereby prevent transcriptional activation of the interleukin-2 gene.


Peripheral blood stem cell mobilization by chemotherapy with and without recombinant human granulocyte colony-stimulating factor.

Chemotherapy can serve as a stimulus for mobilizing hematopoietic progenitor cells to the peripheral blood for harvest via leukapheresis. Mobilized peripheral blood stem cells (PBSC) support rapid hematologic reconstitution after bone marrow aplasia induced by intensive myelosuppressive treatments. Our purpose was to develop effective mobilization regimens allowing collection of large quantities of PBSC. We administered high-dose cyclophosphamide (HDC, 4 gm/m2) or cyclophosphamide (4 gm/m2) plus etoposide (600 mg/m2) (HDCE) in a nonrandomized, sequential fashion to 94 patients with breast cancer, lymphoma, and other malignancies with collection of PBSC via leukapheresis during white blood cell (WBC) recovery from nadir counts. Each apheresis product was analyzed for total nucleated cell number, granulocyte-macrophage colony-forming units (CFU-GM) and CD34+ cells. Twenty-four additional patients with comparable pretreatment characteristics received HDCE plus recombinant human granulocyte colony-stimulating factor (HDCE+G) after chemotherapy through the end of apheresis. Patients receiving HDC were matched for age, sex, and disease but were more heavily pretreated. HDCE was superior to HDC in mean daily CFU-GM and CD34+ yield (p < 0.05), even when groups were adjusted for performance status and amount of prior therapy. HDCE+G led to 3.7 times more CFU-GM and 4.7 times more CD34+ cells than HDCE. Target PBSC yield, defined as > 20 x 10(4) CFU-GM/kg and >4 x 10(8) cells/kg, was achieved by 92% of HDCE+G patients after a median of three aphereses, 56% of HDCE patients after five aphereses, and 16% of HDC patients after six apheresis (p < 0.0001). Prior chemotherapy inversely correlated with the quantity of PBSC harvested regardless of regimen utilized. Our results demonstrate effective chemotherapy regimens for harvesting hematopoietic progenitors in a diverse patient population. HDCE+G produced the highest number of progenitors, suggesting that increasing dose intensity and adding rhG-CSF enhances mobilization. Correlation between cumulative CD34+ and CFU-GM allows real-time flow cytometric analysis of the number of aphereses required to harvest target numbers of PBSC.


Defining a therapeutic dose of peripheral blood stem cells.

Peripheral blood stem cells (PBSC) are now used extensively to provide rapid and durable hematopoietic reconstitution following supralethal myeloablative therapies. A major clinical issue is the quantitation of the cells responsible for reconstitution. We review here published reports of transplants using the measurement of mononuclear cells and granulocyte-macrophage colony-forming units (CFU-GM) to quantitate PBSC. In addition, we present data from three institutions where hematopoietic recovery is correlated with doses of CFU-GM or CD34+ cells. These data suggest doses of 20 x 10(4) CFU-GM or 2 x 10(6) CD34+ cells/kg body weight that provide rapid engraftment of neutrophils and platelets.


On the immunopathology of multiple sclerosis lesions.

Active chronic multiple sclerosis (MS) lesions contain numerous T-200 and leukocyte function associated antigen (LFA)-1-positive infiltrating cells. Macrophages at the lesion edge are stained for immunoglobulins (Ig), Class I and Class II major histocompatibility complex (MHC) antigens, for interferon (IFN)-alpha and for the beta-2 integrin adhesion molecule gp 150/95. In the periplaque area, numerous CD2, CD4, and CD8 positive T cells and cells reactive for the CD45RO phenotype of memory cells and for gamma/delta T cell receptors are located between MHC-positive glial cells. White matter at the edge is diffusely stained for intercellular adhesion molecule (ICAM)-1 and LFA-3. Remote from lesions, labeling for Class II MHC, ICAM-1 and LFA-3 was enhanced on some endothelial and glial cells. These findings indicate that adhesion molecules are involved in the formation and possibly also in the reactivation of MS lesions.


Reduced CD4-CD8 T cell ratios in patients with Wegener's granulomatosis.

All of the patients with Wegener's granulomatosis (WG), whom we studied, exhibited abnormalities in lymphocyte subsets. We used two-color immunofluorescence flow cytometry to examine the lymphocyte subset alterations. WG group showed a decrease in the percentage of CD4+ cells and an increase of CD8+ cells. Within the NK cell family, functionally unidentified CD8+57+ cells were markedly increased in number. The disproportion of these lymphocyte subsets (CD4+ decreases, CD8+57+ increases) was similar to that seen in Acquired Immunodeficiency Syndrome (AIDS) and AIDS related complex (ARC).


Protein folding pathways determined using disulphide bonds.

The best-characterized model pathway of protein folding, that of disulphide bond formation in the small protein BPTI, has been questioned recently. A reinvestigation of that pathway, using alternative methods, concluded that the intermediates with non-native disulphide bonds accumulated to lower levels than previously had been observed. On this basis, a revised pathway was proposed that simply omitted those intermediates. Even if totally correct, however, the new observations are not inconsistent with the important characteristics of the original pathway and even confirmed many of them. Certain crucial observations that were the experimental basis for the original pathway were ignored, and these observations invalidate the revised pathway.


[Chlormadinone Acetate Reference Standard (Control 881) of National Institute of Hygienic Sciences].

Chlormadinone acetate was tested for the preparation of the "Chlormadinone Acetate Reference Standard (Control 881)". Analytical data obtained were as follows: loss on drying, 0.00%; infrared spectrum, 1740, 1715, 1658, 1604, 1587, 1256, 1244 cm-1; ultraviolet spectrum, lambda max = 284 nm; absorbance, E1cm1% (284 nm) = 539-549; optical rotation, [alpha]D20: -12.1 degrees; melting point, 214.6 degrees C; thin-layer chromatography, contaminants were not detected until 300 micrograms; high-performance liquid chromatography, one contaminant was detected. On the basis of the above results, this material was authorized as the National Institute of Hygienic Sciences Reference Standard (Control 881).


[Lectin reactivity in the kidney of newborn rat compared to adult rat].

The distribution of binding sites for 13 lectins with different specificities was studied in adult and new-born rat kidney tissue by staining paraffin sections with the ABC method. Various segments of the uriniferous tubule in both rats showed differential affinity for lectins. None of these lectins showed any reactivity with the immature developmental components of kidney like S-shaped bodies and mesonephric blastema. In the new-born rat kidney, the reactivity of 4 lectins (DBA, PNA, SBA and WGA) on the proximal tubules was very weak compared with the adult rat. Seven lectins (RCA-I, BSL-I, WGA, UEA-I, PHA-E, PSA, LCA), which stained the glomerulus of adult rats, failed to react with glomerular turf in new-born rat kidneys. On the contrary, 4 lectins (RCA-I, WGA, UEA-I and PHA-E) out of these 7 lectins stained the surface of podocyte in the new-born kidney. Colloidal iron stained glomerular turf in adult rats also showed less reactivity in immature glomerulus. These results suggested that changes in lectin binding reactivity are associated with the development and the differentiation of the rat kidney.


MHC class II determinants on peripheral blood monocytes from newly diagnosed IDDM patients.

The expression of MHC class II determinants (HLA-DR, HLA-DP and Ia7) on peripheral blood monocytes (OKM1+ cells) was studied in 20 children with newly diagnosed IDDM. Monocytes of 10 children with IDDM and familial predisposition showed a statistically significant increase of HLA-DR expression when compared to control group (10 healthy children). There were no significant differences concerning Ia7 expression. HLA-DP expression was similar in all studied groups.


[The correlation between the level of prostate-specific antigen and prostate gland volume in the early diagnosis of prostatic cancer].

One hundred and eighty six patients (Pts) presenting with either an abnormal per rectum examination (P.R. suggestive of prostatic cancer (P.Ca) (excluding stage T3) or a prostatic specific antigen (P.S.A.) level greater than or equal to 2.5 ng/ml (radioimmunoassay) were submitted to transrectal ultrasonography (T.R.U.) using a 7 MHz transducer. The prostatic volume (Vol.P) was systematically calculated during T.R.U. and correlated with the P.S.A. level. Six systematic multiple ultrasound-guided biopsies (S.M.U.B.) were performed in the 2 prostatic lobes (3 per lobe) regardless of the result of T.R.U. In the 111 patients in whom the S.M.U.B. were negative, a highly significant correlation (p < 0.001) was observed between the serum P.S.A. level (y) and the prostatic volume (Vol.P): y = (4.13 +/- 0.15 Vol.P) +/- 8.43. In the 75 Pts with P.Ca, the P.S.A./Vol.P correlation was significantly different (p < 0.05) from the straight line of regression with the previous standard deviation. A similar difference in correlation (p < 0.05) was observed in the sub-group of 14 Pts with P.Ca despite normal P.R. and T.R.U. These results suggest: 1) that there is a correlation between the Vol.P measured by T.R.U. and the P.S.A. level in patients with negative S.M.U.B. 2) that the absence of correlation is highly suspicious of P.Ca and requires S.M.U.B. 3) that there is a 15% incidence of P.Ca in the sub-group of Pts with normal P.R. and T.R.U. which are only detected by the raised P.S.A. not correlated with the volume of the prostate.


[Focused extracorporeal pyrotherapy. Initial experimental results].

The objective of this study was to develop an apparatus allowing the generation of a high temperature (exceeding 80 degrees C) in a precise focus (20 mm x 2 mm) by means of extracorporeal elastic waves. The treatment time at high temperatures is brief and administered in sequences of 4 to 7 seconds. In vitro studies on blocks of polyurethane demonstrated melting of the plastic at the focal point. Studies on plastic spheres introduced into the bladder of the pig demonstrated melting of the sphere without any alteration in the tissues in the wave path. Studies of cellular viability of bladder carcinoma cultures demonstrated a significant difference after 48 hours between the non-treated control group and the group of cells submitted to high temperatures. This technique, called Pyrotherapy, should be promising if the preliminary results are confirmed.


Differences in the K(+)-channels opened by cromakalim, acetylcholine and substance P in rat aorta and porcine coronary artery.

1. The effects of acetylcholine and substance P on the efflux of 86Rb+ and 42K+ from rat aorta and pig coronary artery, respectively, were compared with those of the K+ channel opening agent, cromakalim. 2. In rat aorta preloaded with 86Rb+ and/or 42K+, acetylcholine produced transient, concentration-dependent increases in the efflux rate coefficients of these tracers (maximum approximately 35%). These effects were abolished by endothelial cell removal. 3. Donor/acceptor experiments with rat aorta suggested that at least some of the efflux of 86Rb+ seen in the presence of acetylcholine was not derived from the endothelium, but came from the smooth muscle itself. 4. Acetylcholine (10 microM)-induced 86Rb+ efflux was reduced by tetraethylammonium (TEA, 10 mM) to 33% and ouabain (300 microM) to 54% of control. Preincubation with Ba2+ (100 microM) did not significantly inhibit acetylcholine-induced efflux. 5. Acetylcholine-induced 42K+/86Rb+ efflux was unaffected by preincubation with glibenclamide (10 microM). In contrast, the 42K+/86Rb+ efflux induced by cromakalim was inhibited by glibenclamide (50 nM) by 50%. 6. Acetylcholine (0.3-10 microM)-induced inhibition of phenylephrine (1 microM)-induced tone was abolished by endothelial cell removal but unaffected by glibenclamide. Cromakalim-induced relaxations were endothelium-independent and were inhibited by glibenclamide in a concentration-dependent manner. 7. LG-monomethyl L-arginine (L-NMMA, 250 microM) produced a significant (37 +/- 14%) inhibition of acetylcholine-induced 86Rb+ efflux whereas DG-monomethyl L-arginine was without effect. In the tissue bath L-NMMA inhibited relaxations produced by acetylcholine (0.3-10 microM), but was without effect on responses to cromakalim. 8. In the pig coronary artery, substance P induced an endothelium-dependent efflux of 86Rb+ and 42K+, which was unaffected by preincubation with glibenclamide (10 microM) or L-NMMA (250 microM). 9. The present study shows that acetylcholine and substance P each open K(+)-channels in arterial smooth muscle. However, the insensitivity of the stimulated 86Rb/42K+ efflux to inhibition by glibenclamide suggests that the K(+)-channel opened by these agents is different from the K(+)-channel opened by cromakalim. In addition, the inability of L-NMMA to inhibit fully the acetylcholine- and substance P-stimulated 86Rb+ efflux suggests that in rat aorta and pig coronary artery the endothelium-derived hyperpolarizing factor(s) (EDHF) is different from endothelium-derived relaxing factor (EDRF).


Interference of BN 52021, an antagonist of PAF, with different forms of active anaphylaxis in the guinea-pig: importance of the booster injection.

1. BN 52021, an antagonist of platelet activating factor (PAF), was inactive against bronchoconstriction in guinea-pigs sensitized with low amounts of ovalbumin (OA) injected twice, at a 14 day interval and challenged i.v. 7 days later. 2. Serum IgG titers increased for 7 weeks after the booster injection at day 14 and returned to low levels at day 96. 3. Administered by the intratracheal (i.t.) route at 1 mg, BN 52021 failed to inhibit bronchoconstriction induced by the i.t. administration of OA to guinea-pigs tested 7, 28, 56 and 84 days after the booster injection, even when the titers of circulating IgG had declined with time. BN 52021 was also inactive against bronchoconstriction in guinea-pigs boosted at day 98 and tested 7 days later and against contractions and thromboxane (Tx) B2 and histamine release induced by OA-challenged parenchymal lung strips from the boosted guinea-pigs. 4. Sensitized unboosted guinea-pigs displayed reduced IgG serum titers. Used 21 or 70 days after the sensitizing injection, they did develop bronchoconstriction upon the i.t. instillation of OA, which was blocked by BN 52021. The latter also inhibited OA-induced contractions of lung parenchymal strips from these unboosted guinea-pigs. 5. When boosted and non-boosted guinea-pigs received OA i.t. and bronchoalveolar lavage fluid was collected 10 min later, the number of eosinophils increased markedly in boosted, but not in non-boosted guinea-pigs. 6. The booster injection of antigen thus modifies the response of the lung and PAF appears to be relevant for antigen-induced bronchoconstriction in unboosted animals, but loses its major role following the booster injection.


Selectivity of Ca2+ channel blockers in inhibiting muscular and nerve activities in isolated colon.

1. Potency and efficacy of nifedipine, verapamil and diltiazem and of Bay K 8644 in modifying propulsion and nerve or smooth muscle activities have been compared in the guinea-pig isolated distal colon. Both the neuronal and muscular effects of Ca2+ channel blockers seem to develop at concentrations that are devoid of any significant effect apart from that on Ca2+ channels. 2. Nifedipine, verapamil and diltiazem were all able to impair propulsion, resting and stimulated acetylcholine (ACh) release and smooth muscle contractility in a concentration-dependent way. However, some degree of selectivity for neuronal and muscular effects could be observed. Nifedipine was more than 500 fold more potent than verapamil in relaxing musculature but less than twice as potent in reducing ACh release. On the other hand, verapamil was the most efficacious Ca2+ channel blocker tested in inhibiting ACh release, its effects being inversely correlated to the external Ca2+ concentration, and completely abolished by Bay K 8644. 3. By comparing the potencies exhibited by each drug against peristaltic reflex, smooth muscle contractility and ACh release, verapamil proved to be almost as potent in slowing the peristaltic reflex as in reducing ACh release, while nifedipine was about 100 fold more potent against the peristaltic reflex than against ACh release, but nearly equal against the peristaltic reflex and smooth muscle tone. Therefore, interference with cholinergic neurotransmission is likely to play a major role in the antipropulsive effect of verapamil, while peristaltic reflex impairment by nifedipine is likely to be dependent on inhibition of smooth muscle. 4. A facilitatory effect of Bay K 8644 on both the efficiency of the peristaltic reflex and the nonadrenergic, non-cholinergic (NANC) nerve-mediated relaxation could be observed at concentrations at least 10 fold lower than those required to affect ACh release or smooth muscle. 5. It is concluded that the effects of Ca2+ channel blockers on neurotransmitter release may be relevant to their effects on the gastrointestinal motor function.


In vitro characterization of prostanoid EP-receptors in the non-pregnant human myometrium.

1. Prostaglandin receptors of the PGE type have been characterized in the non-pregnant human myometrium in vitro according to the scheme of Coleman et al. (1984) by use of the agonists PGE2, sulprostone, rioprostil, AY23626, butaprost, misoprostol, 16,16-dimethylprostaglandin E2, enprostil and iloprost, and, the antagonist AH6809. 2. All prostanoids tested were active in non-pregnant human myometrium either as stimulators and/or inhibitors of spontaneous activity or both. Biphasic responses to PGE2 indicate that at least two receptor types of the EP-receptor exist, one mediating relaxation and the other mediating contraction. 3. Further evidence for the EP-receptor mediating excitation and relaxation was provided by the action of the EP2-/EP3-receptor selective prostanoids rioprostil, AY23626 and misoprostol, and the EP1-/EP2-receptor selective agonist 16,16-dimethylprostaglandin E2. 4. Butaprost, an EP2-receptor selective agonist, produced potent inhibition of spontaneous activity in the tissue which was generally longer-lasting than that evoked by the natural prostanoid PGE2. 5. The EP1-/EP3-receptor selective agonist sulprostone and the EP3-receptor agonist enprostil produced potent contractile responses supporting the presence of contractile EP3-receptors in the non-pregnant human myometrium in vitro. 6. The EP1-/IP-receptor selective agonist, iloprost, produced mixed responses in non-pregnant human myometrium. The contractile response was inhibited by the EP1-receptor antagonist AH6809. However, responses to the EP1-/EP3-receptor selective agonist sulprostone were unaffected by AH6809 which may indicate that only a small population of EP1-receptors is present. 7. Therefore it would seem that a heterogeneous population of EP-receptors is present in the non-pregnant human myometrium.


[Evaluation of the consequences of hepatic artery embolization under experimental conditions].

The experiments were performed in the healthy mongrel dogs aged 5 to 8 years whose body weight ranged from 10-20 kg. Just after the coeliac arteriography the hepatic artery was embolized. The dogs were divided into 2 groups because of the application of two different embolizing materials. Spongostan was used as the embolizing material in group I consisting of 7 dogs. In group II consisting of 5 dogs the embolizing material was absolute ethyl alcohol with urogranic acid. The symptoms of the postembolization syndrome were observed in all dogs after the embolization for 1-5 days. In most dogs the transient increase of the aminotransferase activity was observed while the results of thymol turbidity test and bilirubin levels in serum were not significantly changed. In dogs of group II the clinical picture after the embolization was clearly more severe. The anatomo- and histopathological examinations in dogs after the hepatic artery embolization were carried out. In group I no hepatic changes were found macroscopically. In the histopathological studies of liver the numerous, tiny foci of coagulative necrosis with the resorptive reactions were noticed. In group II multifocal deliquescent necrosis in the liver, numerous, small perivascular and extravascular foci of coagulative-deliquescent necrosis with the inflammatory and the resorptive reactions were noted.


Mobilized blood stem cells: immunophenotyping and functional characteristics.

High levels of peripheral blood stem cells (PBSC) can be collected from patients with hematopoietic malignancies or solid tumors after high-dose chemotherapy and/or growth factors. Rapid, complete, and durable hematopoietic reconstitution has been observed in patients who have been transplanted with PBSC after conditioning with supralethal myeloablative therapy. We will review the recent data concerning the immunophenotype and functional capacities of mobilized blood stem cells. PBSC seem to be comprised of a mixture of primitive and committed hematopoietic progenitors and are not that different from bone marrow-derived stem cells.


Use of lectins for characterization and purification of human bone marrow cells that express CD34.

The binding of lectins to nucleated cells from human bone marrow was studied in a search for markers that can be used to subdivide further immature hemopoietic cells that are characterized by their expression of CD34. Low-density bone marrow cells were indirectly labeled with biotinylated lectins and streptavidin-R-phycoerythrin (SA-RPE) together with FITC-labeled monoclonal anti-CD34. Four-parameter flow cytometric analysis was then performed and list mode data analyzed. Of the 21 lectins tested, only a few showed differential staining of CD34+ versus CD34- cells. These include soybean agglutinin (SBA) and Ulex europaeus agglutinin I (UE). Lycopersicon esculentum (LE) and Erythrina cristigalli (EC) reacted preferentially with, respectively, CD34+ and CD34- cells, suggesting their usefulness in some method to enrich for CD34+ cells. This possibility was tested by passing cells labeled with biotinylated lectins over a column containing streptavidin-coated beads. CD34+ cells could be enriched > 10-fold by competitive (sugar) elution of LE-labeled cells from the column. Similarly, depletion of biotinylated EC-labeled cells by passage through the streptavidin column enriched CD34+ cells several fold. The results of these studies document the reactivity of a large panel of lectins with subpopulations of nucleated bone marrow cells and indicate that certain lectins could possibly be used for development of cell separation procedures aimed at the selective enrichment of cells that express CD34.


The CD34 antigen: structure, biology, and potential clinical applications.

The diversity of function of mature circulating blood cells is reflected in their respective complements of cell-surface molecules and receptors. Although monoclonal antibodies have been instrumental in the identification and characterization of many cell-surface molecules on mature hematopoietic cells, the CD34 antigen represents to date, the only molecule, similarly identified, whose expression within the blood system is restricted to a small number of primitive progenitor cells in the bone marrow. Although its precise function remains unknown, the pattern of expression of the CD34 structure suggests that it plays an important role in early hematopoiesis. The availability of CD34 antibodies has greatly aided the development of techniques for the enrichment of primitive progenitor cells for studies of hematopoiesis in vitro. Additionally, the use of CD34 antibodies for the 'positive selection' of hematopoietic stem/progenitor cells represents and alternative strategy to 'negative selection' or purging for the large-scale manipulation of bone marrow cells prior to transplantation. The availability of pure populations of the most primitive hematopoietic progenitor cells may also facilitate the development of genetic techniques for the repair of specific blood cell disorders. In this article, we review the biology of the CD34 molecule and assess some of the roles for CD34 antibodies in immunopathology and for progenitor/stem cell purification in clinical applications.


Substance P levels are decreased in lesional skin of atopic dermatitis.

There is increasing evidence that neuropeptides (NP) such as substance P (SP) and vasoactive intestinal polypeptide (VIP) are involved in the pathogenesis of atopic dermatitis (AD). Vasoactive intestinal polypeptide levels were found to be significantly elevated in lesional skin of AD as compared to controls. We evaluated by radioimmunoassay the SP content in whole skin homogenates from chronic lichenified lesions of patients with AD. The levels of SP were significantly decreased in lesional skin from AD patients as compared to control skin (0.25 +/- 0.03 vs. 0.97 +/- 0.24 pmol/g tissue, p < 0.01). The diminished SP levels as opposed to increased VIP concentrations could be consistent with different roles of these NP as modulatory agents in the mechanisms associated with AD.


Evidence that filopodia outgrowth is a common final pathway for fibroblast growth inhibition in vitro.

To identify events associated with fibroblast growth inhibition, the effect of two known inhibitors, interferon-alpha and all-trans retinoic acid, on the growth and surface morphology of cultured fibroblasts was examined. Interferon-alpha administered at seeding reduced both growth rate and saturation density; all-trans retinoic acid reduced only saturation density. However, both negative growth modulators were associated with an increase in filopodia outgrowth and an increase in intracellular filamentous actin in a time course corresponding to onset of growth inhibition by these agents. In combination with earlier findings, these data suggested that, regardless of etiology, cultured fibroblast growth restriction is mediated in part by an actin-dependent outgrowth of filopodia that augment intercellular contact.


Increased expression of ICAM-1, E-selectin, and VCAM-1 by cultured human endothelial cells upon exposure to haptens.

Contact allergens induce several accessory signals which promote the activation of antigen-specific T cells. One of these signals is the increased expression of adhesion molecules on antigen-presenting cells and endothelial cells. Epicutaneous application of non-toxic doses of 2,4-dinitrofluorobenzene (DNFB) onto the skin of non-sensitized individuals elicited progressive staining for ICAM-1 on dermal microvascular endothelial cells. To elucidate the question of whether contact allergens can act directly on endothelial cells to elevate their expression of surface structures that bind leukocytes, confluent monolayers of human umbilical vein endothelial cells were incubated with the contact allergens NiSO4, CoSO4 or DNFB. The ICAM-1, E-selectin and HLA-DR expression were quantified by immunofluorescence flow cytometric analysis. Furthermore VCAM-1, E-selectin and ICAM-1 transcription were demonstrated by Northern blot hybridization. Constitutive ICAM-1 expression on HUVEC increased similarly to that obtained after LPS (20 micrograms/ml) stimulation after 4 and 24 hours of incubation with 1 or 2 mM NiSO4 or CoSO4, respectively. Pulse-stimulation with 100 or 500 nM DNFB resulted in a modest but significant increase of ICAM-1-positive cells. E-selectin and VCAM-1 were not expressed on untreated HUVEC; 4 to 6 hours exposure to nickel sulfate and LPS resulted in a potent induction of E-selectin and VCAM-1 expression. DNFB and PMA had no significant influence on VCAM-1 expression. None of the tested contact allergens was capable of inducing HLA-DR expression on EC at 48 to 72 hours. Enhanced expression of adhesion molecules may be an important early unspecific mechanism for induction and elicitation of a contact dermatitis.


Diet-induced dermatitis response of hairless rats to systemic treatment with cyclosporin A (Sandimmun), cyclosporin H and FK506.

Weaned hairless rats were fed a diet deficient in fat, magnesium and folacin. After approximately 1 week, an erythematous dermatitis developed which was associated with extreme generalized pruritus. Scratching led to excoriations and hemorrhagic crusting. The acute stage (pruritic rash) resolved after several days and was followed by sporadic non-itching relapses. Subsequent to the onset of symptoms, rats were treated orally, once daily for 3 days with CyA, CyH or FK506. The immunosuppressants CyA and FK506 caused a dose-dependent inhibition of symptoms in contrast to CyH. The immediate clinical response was associated with changes in blood histamine, white blood cell counts and histological parameters. Since CyH is known to lack immunosuppressive activity, these results may indicate that the cutaneous changes induced by the nutritional deficiency are associated with immunological abnormalities. The results may also indicate mechanisms influenced by CyA and FK506 but not by CyH; for example, release of chemical mediators from inflammatory cells.


The ELAM-1 ligand sialosyl-Le(X) is present on Langerhans cells isolated from stratified epithelium.

In this study we show the expression of the newly identified carbohydrate ligand, sialosyl-Le(X) on Langerhans cells. The receptor for sialosyl-Le(X) is the endothelial leukocyte adhesion molecule-1 (ELAM-1) present on activated endothelial cells. Using flow cytometry, Langerhans cells were selected due to positivity for an antibody against CD1a and low orthogonal light scatter. The CD1a antigen stained by the OKT6 antibody is considered a maturational marker of Langerhans cells in agreement with the specific labeling of dendritic cells in the epithelium only. Double immunostaining (OKT6/anti-sialosyl-Le(X)) using flow cytometry and immunohistochemistry demonstrated that almost all OKT6-positive cells in normal stratified epithelium expressed sialosyl-Le(X). Conversely, by immunohistochemistry of oral epithelium with acute inflammation, additional dendritic cells negative for OKT6 were found to express sialosyl-Le(X). In addition, sialosyl-Le(X)-positive but not OKT6-positive dendritic cells were found in the submucosa. These findings indicate that the carbohydrate antigen sialosyl-Le(X) is expressed earlier than the CD1a antigen in the maturation of the Langerhans cell lineage. Future studies should aim at investigating the importance of adhesion between sialosyl Le(X) and ELAM-1 in epithelial recruitment of Langerhans cells.


Immunity, microbial pathogenesis, and immunophilins: finding the keys, now where are the locks?

The discovery and clinical use of the immunosuppressants cyclosporin A, FK506, and rapamycin have greatly advanced solid organ and bone marrow transplantation. Though active as antibiotics against a variety of pathogens, their utility has been severely limited by toxicity. Research on the immunophilins, the major binding proteins of these drugs, has given new insights into protein folding and transport as well as mediators of signal transduction in mammalian cells. Microbial immunophilins may also have direct relevance to the intracellular survival of important human pathogens. Defining the mechanisms of enhanced virulence generated by these proteins holds great promise for understanding both the fundamental pathogenesis of these organisms and the immune response generated against them. Such an understanding may provide novel targets for the design of anti-infective agents as well as assist in the development of future immunosuppressives.


[A new tachykinin receptor revealed by substance P analogues in the guinea pig ileum].

[Pro9]SP and septide have been described as selective agonists for the SP receptor (NK-1 type). These two peptides contract with a great efficacy the guinea-pig ileum, but unexpectedly septide was practically devoid of affinity for the NK-1 site labelled by 3H-[Pro9]SP. Like septide, SP analogues like SP-O-CH3, [Apa9-10]SP and [Pro9,10]SP share the same peculiar properties. In addition, the contracting activity of these peptides is not explained by an interaction with NK-2 or NK-3 sites. GR 71,251, a compound which has been described as NK-1 antagonist, was more potent in inhibiting the septide- and the [Apa9-10]SP- than the [Pro9]SP-evoked contracting responses. Altogether, these results suggest that septide, SP-O-CH3, [Apa9-10]SP and [Pro9,10]SP exert their high contracting activity in the guinea-pig ileum by acting on a new type of tachykinin receptor.


[Development, during ontogenetic development of gymnotids, of substance p expression in tuberous organs (electroreceptors)].

The evolution of the neuropeptidic expression of Substance P has been investigated with immunohistochemistry in the cutaneous electroreceptors, tuberous organs, during ontogenetic development of Apteronotus leptorhynchus. In the present data, antiSP antiserum has been applied to serial sections of Apteronotus leptorhynchus larvae obtained from several egg layings. Larvae were taken during development from hatching up to one hundred days old. SP immunoreactivity appeared just after hatching, in the epidermal zones which give rise to cutaneous sense organs. Four days after hatching, the tuberous organs are differentiated and immunoreactivity was observed in these organs, in both sensory cells and accessory cells. From day 30 after hatching, there was a regular decrease in the number of tuberous organs showing labelled accessory cells, and one hundred days later only 8% of tuberous organs had immunoreactive accessory cells. The adult accessory cells were no longer labelled with anti-SP antiserum. The results showed that in Apteronotus leptorhynchus, the epidermal structures which give rise to the cutaneous sensory organs were immunoreactive at a very early stage of development; this suggests that SP could have an effect upon their differentiation.


Effect of established and putative anxiolytics on extracellular 5-HT and 5-HIAA in the ventral hippocampus of rats during behaviour on the elevated X-maze.

One of the proposed mechanisms of action for the anxiolytic effects of the benzodiazepines is via a decrease in central serotonergic neurotransmission. The aim of this study was to combine in vivo microdialysis in the rat with behaviour on the elevated X-maze to determine changes in 5-HT release in the ventral hippocampus with concomitant measurement of behaviour. Twenty minutes exposure to the elevated X-maze resulted in an increase in extracellular 5-HT in the ventral hippocampus with no change in extracellular 5-HIAA. Restricting the rat to either the open or the closed arms produced an increase in extracellular 5-HT, however the increase in 5-HT when restricted to the open arms was not significantly greater than that on the closed arms. Forty minutes pretreatment with diazepam (2.5 mg kg-1 IP) significantly inhibited the increase in extracellular 5-HT in the ventral hippocampus and had an anxiolytic profile over 5 min and 20 min exposures of the rats to the X-maze. Diazepam had no effect on basal 5-HT levels before exposure to the X-maze but reduced extracellular 5-HT levels when the animal was returned to the holding cage. Forty minutes pretreatment with the .5-HT1A receptor partial agonist ipsapirone (1 mg kg-1 IP) significantly inhibited the increase in extracellular 5-HT in the ventral hippocampus but did not produce behaviour different from vehicle controls after 5 or 20 min periods on the X-maze.(ABSTRACT TRUNCATED AT 250 WORDS)


The origin of P elements in Drosophila melanogaster.

The P family of transposable genetic elements is thought to be a recent addition to the Drosophila melanogaster genome. New evidence suggests that the elements came from another Drosophila species, possibly carried by parasitic mites. The transposition mechanism of P elements involves DNA gap repair which may have facilitated their rapid spread through D. melanogaster worldwide. These results provide new insight into the process of a transposon's invasion into a new species and the potential risk of extinction such an invasion might entail.


Thy-1, the enigmatic extrovert on the neuronal surface.

Thy-1 is a small glycoprotein of 110 amino acids which, folded in the characteristic structure of an immunoglobulin variable domain, are enchored to the plasma membrane via a glycophosphatidylinositol (GPI) tail (Fig. 1). It is a major component of the surface of various cell types, including neurons, at certain stages of their development. These qualities doubtlessly appeal to certain cognoscenti, but it is not clear why they would raise Thy-1 to the status of a favourite molecule. Indeed, few scientists readily admit to having a favourite. We study individual molecules because science is rooted in specific observations; but we do so in order to discover mechanisms of general importance. A molecule's appeal is dependent on its ability to reveal novel aspects of how nature works. Thy-1 has been unusual in this respect. It was the first lymphocyte surface antigen shown to be restricted to a functional subset of lymphocytes (T cells in the mouse), a finding crucial to the development of cellular immunology; it was one of the first cell surface molecules to be sequenced and indicated the importance of immunoglobulin domains and GPI anchors as structural motifs; it has been pivotal in studies demonstrating that GPI-anchored molecules are able to signal across the membrane they do not span. Thy-1 has revealed this much, however, with the charm of an adroit stripper: it has always promised glimpses of things more exciting than that displayed. In particular, the function of this molecule has never emerged.(ABSTRACT TRUNCATED AT 250 WORDS)


Fetuin--an old friend revisited.

Bovine fetuin, the first fetal protein to be described, has recently been shown to be a species homologue of a well known human plasma protein--alpha 2HS glycoprotein (alpha 2HS). The fetuins are now known to be members of the cystatin superfamily. The structural properties of the six fetuins that have been fully sequenced are compared. Despite the structural homology of these proteins, their described properties in the literature make them appear to be quite different. The diverse in vitro properties claimed for fetuin/alpha 2HS are reviewed. In vivo, fetuins are involved in the acute phase response. In development, in all species studied so far, fetuins are present in a specific cell population that forms the developing neocortex. The possible functional significance of this distribution is discussed.


The selectin family of carbohydrate-binding proteins: structure and importance of carbohydrate ligands for cell adhesion.

Protein-carbohydrate interactions have been found to be important in many steps in lymphocyte recirculation and inflammatory responses. A family of carbohydrate-binding proteins or lectins, termed selectins, has been discovered and shown to be involved directly in these processes. The three known selectins, termed L-, E- and P-selectins, have domains homologous to other Ca(2+)-dependent (C-type) lectins. L-selectin is expressed constitutively on lymphocytes, E-selectin is expressed by activated endothelial cells, and P-selectin is expressed by activated platelets and endothelial cells. Here, we review the nature of the carbohydrate determinants in tissues recognized by these selectins. The expression of specific sialylated, fucosylated and sulfated carbohydrates in activated endothelium and high endothelial venules promotes interactions with L-selectin on leukocyte surfaces. In contrast, E- and P-selectins recognize specific carbohydrate determinants related to sialyl Le(x) antigen on neutrophil and monocyte surfaces. The discovery of the selectins has generated excitement among glycoconjugate researchers that other carbohydrate-binding proteins and their cognate ligands will be found to function in regulating many types of cellular interactions.


Myelin P0-protein, more than just a structural protein?

The protein P0 has long been proposed to be responsible for the compact nature of peripheral myelin through interactions of both its extracellular and cytoplasmic domains. Recent studies support such a role for P0's extracellular region while more precise mapping of its adhesive domains are ongoing. As P0 is a member of the immunoglobulin gene superfamily and perhaps bears the closest similarity to the ancestral molecule of this whole family, these studies may also have more general implications for adhesive interactions. In addition, although long believed to be purely an inert, structural molecule, P0 has been reported to promote neurite outgrowth, which suggests a more dynamic role for this interesting molecule.


The effect of galanin on growth hormone-releasing factor and somatostatin release from median eminence fragments in vitro.

Galanin has been reported to stimulate secretion of GH in humans and rats. Thus, to investigate whether the effect of galanin on GH release is the result of either a stimulation of GH-releasing factor (GRF) and/or an inhibition of somatostatin (SRIF) release, we have evaluated the action of galanin on the release of SRIF and GRF from median eminence (ME) fragments in vitro. The MEs from adult male rats were incubated in Krebs-Ringer bicarbonate-glucose buffer, pH 7.4, at 37 degrees C, in an atmosphere of 95% O2, 5% CO2 with constant shaking for 30 min. Medium was discarded and replaced by medium containing various concentrations of galanin (10(-10)-10(-7) M). Galanin stimulated SRIF and GRF release in a dose-related manner. This effect was significant at concentrations varying from 10(-8) to 10(-7) M. To determine the mechanism by which galanin stimulated SRIF and GRF release, MEs were incubated with pimozide (dopaminergic blocker), phentolamine (alpha-adrenergic blocker) or naloxone (opioid blocker), at concentrations of 10(-6) M, and the effect of galanin was then evaluated. Phentolamine and naloxone did not alter the stimulatory effect of galanin, but when galanin was tested with pimozide, the galanin-induced release of SRIF and GRF was blocked. To determine whether the effect of galanin is mediated through D-1 and/or D-2 dopamine receptors, selective antagonists of D-1 (SCH 23390) and D-2 receptors (domperidone) were used (10(-7) M) in the presence of galanin (10(-7) M).(ABSTRACT TRUNCATED AT 250 WORDS)


Comparison of intensities between doubly charged ions [M + 2H]2+ and singly charged ions [M + H]+ of gramicidin S by electrospray mass spectrometry.

The reason why the intensity of doubly charged ions [M + 2H]2+ of gramicidin S is higher than that of singly charged ions [M + H]+ in electrospray is investigated by ion evaporation theory. As a result of comparison between the total free energies of extracting [M + 2H]2+ and [M + H]+ from a charged droplet to infinity, it is found that the total free energy of [M + 2H]2+ is estimated to be lower than that of [M + H]+. This clearly supports the experimental result. In addition, the importance of the electrostatic contribution in electrospray is demonstrated by showing the result that the total free energy of [M + 2H]2+ without electrostatic contribution is higher than that of [M + H]+.


Differential inhibition of the activities of reverse transcriptase and various cellular DNA polymerases by a traditional Kampo drug, sho-saiko-to.

A traditional Kampo drug, Sho-saiko-to, composed of several herb extracts, differentially inhibited the activities of reverse transcriptase and human cellular DNA polymerase alpha and beta. Reverse transcriptases from murine leukemia virus and human immunodeficiency virus were inhibited by over 80% and 50%, respectively, in the presence of 100 micrograms/ml Sho-saiko-to, whereas DNA polymerase alpha was much less sensitive to inhibition by this drug than were the reverse transcriptases. DNA polymerase gamma was not inhibited by this drug at concentrations of up to 500 micrograms/ml. Only DNA polymerase beta was moderately inhibited by Sho-saiko-to. Thus, it has been shown that the inhibition by Sho-saiko-to is relatively specific for reverse transcriptase and that the drug contains as yet unidentified inhibitory substance(s) for reverse transcriptase.


The utility of CD20 and CD43 in subclassification of low-grade B-cell lymphoma on paraffin sections.

To identify phenotypic differences among the low-grade lympho-proliferative disorders in paraffin-embedded tissue, we studied 49 cases. All 22 follicular small cleaved cell lymphomas (FSC) were CD43 negative and CD20 positive. In contrast, of 20 small lymphocytic lymphomas (SL), 90% were CD20 positive, 85% were CD43 positive, and 75% were positive for both. Of three lymphomas of intermediate differentiation (IDL), two were CD20 positive and two were CD43 positive. All four monocytoid B-cell lymphomas were positive for CD20 and 50% (two cases) were positive for CD43. Some 86% of 14 chronic lymphocytic leukemias (CLL) (on cytospins) were positive for CD43; all nine of the CLL studied for CD20 were positive and 89% (8/9) expressed both antibodies CD5 expression (on frozen sections or cytospin preparations) was compared to CD43 in 21 cases of SL and CLL. Some 77% were positive for both CD5 and CD20. All seven of the CD5-positive SL also expressed CD43. The antibody MT2 was also examined with the following results: FSC, 16/20 (80%) positive; SL, 18/19 (94%) positive; MBC, 3/3 positive; and ILL, 2/3 positive. All 56 cases tested were CD45RO (UCHL1) negative. We conclude that CD43 is expressed on most cases of low-grade lymphoproliferative disorders with the exception of FSC. Its pattern of expression seems similar to CD5; however, unlike CD5, CD43 can be studied in formalin-fixed tissue. MT2 is not helpful in distinguishing among these lesions.


Modification of tumor ploidy level via the choice of tissue taken as diploid reference in the digital cell image analysis of Feulgen-stained nuclei.

We studied the influence of five cell nucleus populations taken as diploid standards with respect to the normalization of a human breast carcinoma. Four normal human tissues (lymphocytes, thyroid, liver, and bladder specimens) were taken as external standards, while the normal breast cells "contaminating" the tumor were taken as the internal diploid standard. Nuclear size and nuclear DNA assessments were performed by means of a cell image processor computing the parameters on Feulgen-stained nuclei from fresh imprint smears fixed in an ethanol-formalin-acetic acid mixture. Our results demonstrate that the choice of normal tissue as the diploid standard markedly influences the ploidy level of breast carcinoma. Normalization according to the lymphocytes led to our obtaining a major hyposextaploid G0-G1 DNA peak in the breast cancer. Using thyroid and liver cells as a standard, we obtained a major pentaploid and sextaploid G0-G1 peak, respectively. Using bladder cells or the normal contaminating breast cells within the tumor, we obtained a major tetraploid G0-G1 peak. Finally, the normalization of the normal bladder cells against the liver cells led to our obtaining a near triploid bladder specimen. The reverse feature was also observed, e.g., the obtaining of biologically nonsensical hypodiploid liver cells after normalization against the normal bladder cells. Such postnormalization variations in ploidy level depend upon the mean nuclear size and the mean nuclear DNA content of the normal tissue taken as diploid standard.(ABSTRACT TRUNCATED AT 250 WORDS)


[Rhythmic pneumatic compression of the limb as a contributing element of postoperative deep vein thromboembolism prophylaxis in patients after orthopedic surgery].

A combined prophylaxis against postoperative deep venous thrombosis comprising of sequential pneumatic limb compression using RMP I/K apparatus and lysine or dextran 70.000 administration was of applied in 34 patients after total hip arthroplasty. In 14 cases lysine was the drug, dextran was used in remaining ones. Prophylaxis was evaluated by impedance plethysmography. No case of postoperative deep venous thrombosis was reported.


Donizetti and the music of mental derangement: Anna Bolena, Lucia di Lammermoor, and the composer's neurobiological illness.

The composer Gaetano Donizetti, who died in a state of mental derangement due to neurosyphilis, created some of opera's greatest scenes of psychosis. His letters reveal the clinical progression of his neurobiological illness, which was confirmed by autopsy. One can hypothesize that the composer's brain disease, which led to his psychosis and death, may have had an influence on his ability to create the powerful and unforgettable scenes of psychosis in his operas. In Anna Bolena, he captured in musical and dramatic terms Anne Boleyn's historically corroborated mental disorder during her imprisonment in the Tower of London. Sixteen years after having composed Anna Bolena, Donizetti himself would be locked up, against his will, in a mental institution. In Lucia di Lammermoor, Donizetti portrayed a girl given to hallucinations who, in her unforgettable "mad" scene, comes on stage, a pathetic embodiment of a human being in the throes of psychosis. Thirteen years after Lucia's première, Donizetti would die, psychotic and paralyzed, of untreated neurosyphilis. Studying Donizetti's neurosyphilis and the portrayals of psychosis in his operas can help one to appreciate the pain of human beings trapped in the prison of a brain subjected to the devastation of mental derangement.


Obstetrical events that shaped Western European history.

Taking into account that marriage, the family as a social unit, and concepts of legitimacy developed to ensure the devolution of property and that, when these concepts apply in a society based on hierarchically organized monarchies, they also involve the devolution of power, this essay furnishes examples of dislocations in such devolutions, in terms of familiar incidents in western European history. That Jane Seymour died in childbirth but her son Edward VI survived long enough to ensure the stability of the Church of England is the first example. The infertility of Mary Tudor, when married to Philip II of Spain, prevented the formation of an Anglo-Spanish dynasty that would have been Roman Catholic is the second example of such a dislocation. Likewise, the infertility of Charles II's wife, Catherine of Braganza, led to the succession of James II, a practicing Roman Catholic, whose attempts to undermine the Church of England led to the Glorious Revolution of 1788 and the preservation of English Protestantism. Another example is the death in 1817 of Princess Charlotte, in childbirth, which led to the scramble of George III's aging sons to marry and beget an heir to the throne. The only success led to the birth of the future Queen Victoria, whose dynastic competence remains unquestionable, but who herself had some passing involvement with obstetrical developments. Finally, the delivery of Kaiser Wilhelm II, who sustained a brachial plexus injury that produced Erb's palsy of the left arm, is considered, and the question of intrapartum fetal hypoxia is raised as a hypothesis, in addition to the mechanical trauma and its effect on his personality.


Politics and pellagra: the epidemic of pellagra in the U.S. in the early twentieth century.

The epidemic of pellagra in the first half of this century at its peak produced at least 250,000 cases and caused 7,000 deaths a year for several decades in 15 southern states. It also filled hospital wards in other states, which had a similar incidence but refused to report their cases. Political influences interfered, not only with surveillance of the disease, but also in its study, recognition of its cause, and the institution of preventive measures when they became known. Politicians and the general public felt that it was more acceptable for pellagra to be infectious than for it to be a form of malnutrition, a result of poverty and thus an embarrassing social problem. Retrospectively, a change in the method of milling cornmeal, degermination, which began shortly after 1900, probably accounted for the appearance of the epidemic; such a process was suggested at the time, but the suggestion was ignored.


The discovery of the body: human dissection and its cultural contexts in ancient Greece.

In the first half of the third century B.C, two Greeks, Herophilus of Chalcedon and his younger contemporary Erasistratus of Ceos, became the first and last ancient scientists to perform systematic dissections of human cadavers. In all probability, they also conducted vivisections of condemned criminals. Their anatomical and physiological discoveries were extraordinary. The uniqueness of these events presents an intriguing historical puzzle. Animals had been dissected by Aristotle in the preceding century (and partly dissected by other Greeks in earlier centuries), and, later, Galen (second century A.D.) and others again systematically dissected numerous animals. But no ancient scientists ever seem to have resumed systematic human dissection. This paper explores, first, the cultural factors--including traditional Greek attitudes to the corpse and to the skin, also as manifested in Greek sacred laws--that may have prevented systematic human dissection during almost all of Greek antiquity, from the Pre-Socratic philosopher-scientists of the sixth and fifth centuries B.C. to distinguished Greek physicians of the later Roman Empire. Second, the exceptional constellation of cultural, political, and social circumstances in early Alexandria that might have emboldened Herophilus to overcome the pressures of cultural traditions and to initiate systematic human dissection, is analyzed. Finally, the paper explores possible reasons for the mysteriously abrupt disappearance of systematic human dissection from Greek science after the death of Erasistratus and Herophilus.


On medicine and politics.

This paper explores the relationship between medicine and politics, between medical management of the human body and governmental management of the body politic. It argues that the increasing complexity both of society and of governmental administration of society in the modern age has made it impossible completely to separate medicine from politics. It demonstrates that, along with great potential for social benefit, "medico-politics" brought with it great danger; much harm has been done purportedly to heal the body politic. The paper concludes by suggesting a way for physicians to minimize this danger.


Medicine in Mississippi.

Adequate health care represents an issue that has always troubled rural America. From the earliest days of this country, affordable and quality health care has often been harder to find for those who those to live on the farm or in a small town or any place off the beaten path than it has for residents in urban areas. The State of Mississippi has undertaken an intensive program to widen access to health care--and, especially, to preventive health measures--by utilizing fully all available financial resources, including private foundations, by encouraging increased cooperation from our physicians and hospitals in caring for patients insured by Medicaid, and by involving the community in emphasizing the use of health care practitioners in delivering inexpensive but effective support to our rural population.


[Possibilities and limits of medical graphology. Determination of current status and perspectives (I)].

As is generally known, the writing movement reacts in a sensitive manner to numerous diseases, medications, stimulants and environmental poisons, as well as to psychic and physical influences. This reaction can occur quite early in the process. Therefore, laboratory data and the physical examination can be supplemented by the handwriting. The graphological analysis is particularly helpful in the following ways: early diagnosis, documenting the course of the disease, evaluating treatment, psychological relationships as well as the problems of old age. This review, presented in three parts, intends to demonstrate to the physician simple and time-saving possibilities, as well as analytical methods, that are most likely to promise success. This needs to be done by a competent graphologist.-Prejudices against graphological methods and exaggerated expectations will be reduced if proper information is presented.


[What does general practice hypertension mean?].

White coat hypertension means an isolated blood pressure elevation during conventional measurement in the doctor's office, while blood pressure is in the normal range outside the office over 24 hrs. The incidence is about 20-25% of all "hypertensives" identified in the office. Patients with white coat hypertension show no increased blood pressure variability outside the office, and they do not seem to be more anxious regarding psychological testing as compared with hypertensives. The white coat effect is very specific for the situation in the doctors office. The effect is more pronounced in younger and female patients. However, also in isolated systolic hypertension in the elderly the white coat effect is present to a substantial amount. Under dynamic exercise there is no different hemodynamic response in patients with white coat hypertension as compared with normotensives. Differences are however observed with regard to posture and under isometric exercise. So far, white coat hypertension seems to be a benign and harmless condition not related to an increased cardiovascular risk, which must not be treated.


[Conventional roentgen functional diagnosis--videodensitometry. 4. Conventional roentgen videodensitometry exemplified with peri-cardiac vessels].

It is possible to record movement-parameters by means of roentgen videodensitometry of the great central vessels as well the pulmonary artery as the thoracic aorta visible in fluoroscopic image (provided by videorecorder). We could noninvasively measure pre-ejection periods (PEP) for the right heart (PEP f) as well for the left heart (PEP g) by synchronous electrocardiography for each cardiac action and for each examination process. It is important to form a quotient between PEP f and PEP g in the individual case. First findings in patients with cardiac septal defects (with and without right heart block and pulmonary hypertension) show characteristic quotients and figures of the curves. In cases with electrocardiographic left heart block the elongated PEP g can be stated in graduated form. Further investigations on the mechanic interaction between the right and left heart, especially in cases of disorders in the heart conduction system, might be of interest.


[Postmenopausal osteoporosis from the viewpoint of the gynecologist].

Prophylaxis of postmenopausal osteoporosis is of major importance if estrogen replacement therapy is considered. Assessment of clinical symptoms, (standardized) x-ray analysis, and bone densitometry contribute to the final diagnosis. Incidence of osteoporotic fractures is rising due to alterations in life style and dietary habits. One out of three to four women eventually suffer from osteoporosis in the European countries, United States and Japan. Prevention of postmenopausal osteoporosis is achieved by adequate estrogen replacement therapy carried out for years, maintaining peripheral estradiol concentrations of 220 pmol/l. Doses of 2 mg estradiol or 0.625 mg of conjugated estrogen or 50-100 micrograms percutaneous estradiol/day are equally effective for prevention. The additional administration of a progestogen may be of specific value to increase the antiresorptive effect of estrogens. We distinguish between estrogen replacement in a cyclic or continuous way combined with a sequential or continuous progestogen in women with intact uterus.


[Mining medicine in the 18th century. On the 250th anniversary of the birthday of Ignaz von Born (1742-1791)].

Ignaz von Born (1742-1791) improved several technical and methodical approaches to mining and was thus instrumental in creating the prerequisites for reducing certain professional miner's diseases. Among these diseases, lead or saturnine poisoning (colica saturnina) caused by lead monoxide PbO, also known as litharge, was much dreaded (a 17th-century physician from Goslar wrote a treatise on "Lithargyrii fumo noxio morbifico, vulgo dicto 'pit cat'"); a miner's disease associated with phthisis and pareses of a then unknown etiology; and in some cases even with hookworm disease that was much later recognised as yet another professional disease of miners. During this era a new professional image of a mining engineering physician developed, with several of these doctors trying to go beyond merely curative measures: they aimed at achieving meaningful prevention that involved standard measures and behavioural patterns on the one hand and improvements in the professional mining procedure on the other.


[Diagnosis of brain death].

From the medical, the juridical as well as the theological point of view brain death represents the death of an individual. According to the German Chamber of Physicians, acute brain damage with coma, absence of all brainstem reflexes and apnoe allows the diagnosis of cerebral death, if repetition of the physical examination after distinct time intervals documents the irreversibility of this state. Additional investigations such as EEG, evoked potentials (BAEP), transcranial doppler sonography, brain scintigraphy or cerebral angiography allow to shorten this period if electrocortical silence, absence of waves 3-5 of BAEP or the cessation of cerebral perfusion has been proven. Strict observation of these criteria is mandatory for the diagnosis of brain death.


[Management of the organ donor].

Brain death is associated with loss of hypothalamic, pituitary and brain stem function resulting in apnea, bradycardia and hypotension, poikilothermia, and diabetes insipidus. In order to preserve body functions mechanical ventilation is continued with the aim to maintain an arterial partial pressure of oxygen of more than 100 mmHg. Previous fluid restrictions and the application of diuretics during the treatment of high intracranial pressure frequently result in dehydration. Progressive vasodilation may induce severe hypotension and fluid replacement with cristalloids and if necessary colloids may be called for until the central venous pressure reaches 10 cm H2O. Continuous substitution of potassium and the use of hypotonic solutions such as glucose 5% may avoid hypokalaemia and hypernatraemia, respectively. Inotropic support with dopamine (5-10 micrograms/kg.min) or adrenaline (0.01-0.1 micrograms/kg.min) may be needed to maintain normal mean arterial blood pressure (65 mmHg). Polyuria (5000 ml/24 h) can be treated by continuous intravenous infusion of antidiuretic hormone (0.5-2-10 U/h). Hypothermia must be prevented by warming all fluids (37 degrees C) and covering the patient with heat saving blankets.


[Organ preservation].

For organ preservation in Europe the Euro-Collins-, UW- and HTK-solution are preferred. While the HTK-solution is mainly used for heart preservation, the UW-solution has shown its advantages for longterm preservation of kidney, liver and pancreas. With regard to renal preservation the HTK-solution provides a higher buffer capacity. According to experimental and theroretical considerations the content of glucose in the Euro-Collins-solution does not seem to correspond to the current state of knowledge. In order to obtain a sufficient primary function renoprotective measurements have proven their efficacy, in addition to an optimal method of organ preservation. Especially in case of suboptimal donors the preservation time should be kept as short as possible.


[Immunosuppression after organ transplantation].

Immunosuppression after organ transplantation is based on pharmacologic interventions using steroids, azathioprin, sandimmun and anti-T-cell-globulins. During the induction-period the use of a high-dose combination-therapy guaranties a low incidence of rejection episodes. However infective complications may predominate. In the long-term phase the results of different immunosuppressive protocols are similar in respect to patient- and graft survival. This circumstance promotes the possibility to perform an individualised immunosuppression, which compiles to the personal demands of the graft recipient.


[Organ transplantation in childhood].

Organ transplantation in children has to consider the development of the children. One limitation is the organ size of orthotopic transplanted organs as liver, heart and lung. The activation of unspecific immune response in the pediatric recipients is a risk of rejection episodes especially in infants. The experiences of the Medical School Hannover with 203 pediatric renal recipients and with 117 pediatric liver recipients are reported. Congenital disorders with chronic organ insufficiency frequently lead to growth retardation and cardiovascular complications already before transplantation and determine the long term outcome especially in renal transplantation.


[Conservative therapy of liver failure].

Hepatic failure is characterized by decreasing liver function involving synthesis, regulation and detoxification. In most cases, acute liver failure results from acute viral hepatitis. Furthermore, intoxications or metabolic decompensation can cause fulminant hepatic failure. Chronic liver failure is defined as progressive decline in liver function in previously existing liver disease, mostly liver cirrhosis. Clinical manifestation of both acute and chronic hepatic failure is determined by hepatic encephalopathy and severe disturbance of the hemostatic system. Causal therapy does not exist; the inducing agent or reason should be eliminated. The major supportive strategy comprises removal of toxic metabolites from the intestine and stabilization of the hemostatic system. As prognosis of both acute and chronic liver failure is very poor, orthotopic liver transplantation represents the ultima ratio therapy.


[Indications and results of liver transplantation].

More than 20,000 human liver transplantations have been performed world-wide. The procedure has become universally accepted by hepatologists and applied most broadly for numerous indications in end-stage liver disease. Most common indications for transplantation are benign liver diseases, leading to cirrhosis and/or liver failure. In non-resectable tumor stages liver transplantations have been less frequently performed. The main problem remains to define the "best timing" for the operation. The disease stage will influence the incidence of perioperative complications, postoperative mortality and survival after transplantation. Liver transplantation should be considered, before chronic liver disease reaches its final stage and extra-hepatic liver-related organ complications determine the course. "Ultima ratio" decisions in very late disease stages will leave the patient with only a small chance of surviving. High tumor recurrence rates and inferior survival figures after liver transplantation in malignant liver diseases necessitate a restrictive indication policy in such patients. Probably neoadjuvant chemotherapy in conjunction with liver transplantation will expand the therapeutic modalities in unresectable situations.


[Experimental and clinical islets transplantation. Current status].

25 years have passed since the first enzymatic isolation of islets of Langerhans from the rat pancreas. During this period of time, it could be demonstrated that transplantation of syngeneic islets intraportally into streptozoticin-treated diabetic recipients (rat, mouse) does not only guarantee long term normoglycemia but inhibits also typical late complications of the disease. Allogeneic islets, however, exhibit strong immunogenicity (rejection within a few days) which can be overcome by various immunomodulating in vitro measures of the islets before transplantation. Isolated islets have been successfully transplanted also in larger animals as dogs and pigs, when transplanted in an autologous or allogeneic system. In human diabetes the success rate of islet transplantation up to now is low and cannot be compared with the results in experimental diabetes. The reasons are manyfold: islet damage due to long ischemia time, low number of islets, low purity, lack of diagnostic markers which indicate rejection, autoimmune destruction. The fact that in the meantime a few patients remain insulin independent after a single islet transplant with the maximum of 2 years indicates however that this method in principle may serve as a tool for the treatment of diabetes. This is underlined by several advantages compared to pancreatic organ transplantation as low risk of the procedure for the recipient and the possibility of repeated transplantation. In addition, in the future xenotransplantation of (porcine) islets might be feasible.


[Pancreas transplantation].

The results of pancreatic transplantation improved markedly during the last years. Transplantation of the pancreas together with the kidney is the most common treatment of Type I-diabetic patients. At present different surgical techniques are used for the handling of the exocrine secretion of the gland. However, each technique has its own advantages and disadvantages. A successful pancreatic transplantation provides a normal glucose metabolism in the majority of the patients. This leads to an improvement of the peripheral and autonomic neuropathy. Clinical observations suggest a beneficial effect on diabetic retinopathy and peripheral microcirculation. More long-term-results are mandatory to assess the preventive effect of pancreatic transplantation on the development of late diabetic complications. Timing of pancreatic transplantation has a major influence on the course of secondary complications. There is no need for further dietary restrictions or exogenous insulin replacement, so that a better quality of life can be achieved.


[Heart transplantation--indications and results].

Heart transplantation has become a standard procedure in the treatment for irreversible heart failure. Criteria for both recipients and donors have been extended. One year survival now reaches 81%. In the immediate postoperative course patients are endangered by infection. In the long-term course coronary artery disease of the transplanted heart becomes the most serious problem. Alteration of liver and kidney function due to chronic medication as well as malignancies and hypertension also occur. In case of chronic transplant failure retransplantation may be indicated. Acute cardiac failure before transplantation nowerdays can be treated by mechanical circulatory assist devices.


[Lung transplantation].

In the past 10 years, three different types of lung transplantation were introduced into clinical practice, the combined transplantation of the heart and both lungs (HLTx), unilateral single lung transplantation (SLTx), and bilateral sequential lung transplantation (DLTx). At present, the indications for the various procedures have not been ultimately defined. Through 1991, a total of about 1,100 HLTx, 460 SLTx, and 160 DLTx was performed worldwide. One- und 3-year survival rates amount to 75-60% resp. in HLTx, to 80-70% resp. in SLTx, and to 70-60% resp. in DLTx. In our own experience with 24 HLTx, 32 SLTx, and 18 DLTx patients, global survival rates at one and 3 years are 85 and 80%, resp. The vast majority of surviving patients is able to lead a near normal life both physically and socially.


[Corneal transplantation].

In contrast to organ transplantations corneal grafts are tissue transplantations with the advantage of a minority of immune stimulating cells. The incidence of allograft rejections is greater in penetrating grafts than in lamellar grafts because of endothelial immune reactions. The decompensation of the graft is caused by the damage of the endothelial layer. The influence of HLA-A, -B and -DR matching is proven in case of vascularised cornea or of repeated perforating keratoplasty. The introduction of the immunosuppressive therapy with Ciclosporin A was successful in maintaining a clear graft.


[Bone marrow transplantation. Overview and personal results].

Main indications for allogeneic bone marrow transplantation are severe aplastic anemia, severe combined immunodeficiency, acute leukemia and chronic myeloid leukemia. In standard risk situations survival rates are 50 to 80%. The probability of disease-free survival after bone marrow transplantation is depending on the stage of disease. If possible bone marrow transplantation should be performed early, not in advanced disease when conventional measures failed. Main problems are therapy-related organ toxicity, rejection, graft-versus-host disease and a long lasting risk of infection. Usually histocompatible relatives of the patients are selected as marrow donors. Bone marrow transplantation using unrelated donors is under investigation. Autologous transplantations with cryopreserved marrow are performed in acute leukemia, malignant lymphomas and some solid tumors, but prospective studies comparing transplantation and conventional therapeutic procedures are still missing.


[The gynecologist and hysterectomy].

Often it is postulated by mass media that too much hysterectomies would be performed by gynaecologists. Hysterectomy is today a relatively safe routine intervention. This may tempt to a generous indication. Elective hysterectomy has been looked at critically. Two factors play an important role, firstly the position of the women to her uterus, i. e. how does the women settle down her fertility in her life and secondly the position of the gynaecologist, which will be transmitted from him to the patient cousciously or instinctively. Then our position to alternative methods like endometrial ablation by hysteroscopic laser coagulation or laser assisted or pelviscopic hysterectomies has been demonstrated.


[Subjective complaints and hormonal reactions in the first 6 weeks after hysterectomy].

Hormone profiles (estradiol, testosterone, FSH, LH) and typical estradiol deficiency phenomena were investigated prospectively in the first 6 weeks after hysterectomy (n = 50) and after additional bilateral adnexectomy (n = 17). In the second group estradiol was replaced transdermally from the 2nd postoperative day (estradiol patch, 0.05 mg daily). In the 1st group 34% of patients showed a significant decrease in estradiol, 28% of patients a significant decrease in testosterone on the 3rd postoperative day which was no longer demonstrable after 6 weeks. In the second group no decrease in hormone levels was found. So the estradiol patch can replace estradiol to a sufficient degree and in particular physiologically even after bilateral oophorectomy Subjective complaints improved in both groups. Psychosomatic influence also seems to be of importance.


[Secretion of hCG by mononuclear cells--a specific and essential reaction in pregnancy?].

Mononuclear cells in peripheral blood secrete immunoreactive hCG (ir-hCG) when they are stimulated in in-vitro culture with the proteinkinase C - activator phorbol-myristat-acetate (TPA). We examined the ir-hCG secretion in 61 fertile and 191 pregnant women and 38 men. Mononuclear cells of pregnant women secrete after TPA stimulation significantly more ir-hCG than mononuclear cells on non-pregnant but fertile women. This effect can be detected as early as 23rd days of a menstrual cycle which is accompanied by conception and persisted over the entire duration of a pregnancy. Maximal effects were observed in the 7th to 19th and 30th to 34th weeks of pregnancy. An artefact caused by adhesive serum-hCG could be excluded. The elevated potential of the mononuclear cells to be stimulated remained intact for about 14 days after termination of a normal pregnancy in the first trimester. An ir-hCG secretion similar to that seen in nonpregnant women was found in patients with early abortion. The possible physiological importance of the in-vivo secretion of beta-HCG during pregnancy is discussed.


[The limits of hormone substitution in pollutant exposure and fertility disorders].

Heavy metals and chloro-organic compounds can influence female fertility at every phase of reproduction. They may induce hormonal disorders, preventing ovulations and pregnancies. They can also result in abortions and fetal malformations. For this reason, the urinary excretion of heavy metals was measured after oral load with the chelating agent dimercaptopropanesulfonate (Dimaval) in women with hormonal irregularities. In addition, blood was examined for various polychlorinated compounds (polychlorinated biphenyls - PCB -, hexachlorocyclohexane - HCH -, pentachlorophenole - PCP -, hexachlorobenzol - HCB -, dichlordiphenyltrichloroethane - DDT -, dichlorodiphenylethane - DDE -, tetrachlorodiphenylethane - DDD -). Mercury contaminations were seen most commonly and correlated significantly with the number of amalgam fillings and with the release of mercury while chewing. The latter was demonstrated with the so-called chewing-gum test. Women with hormonal disorders or alopecia had, on the average, the highest mercury excretion during the wash-out test. Cadmium excretion was pronounced for the following groups of women: those with technical professions, those suffering from thyroid dysfunctions, and those with habitual abortions and uterine fibroids. With increasing age, pesticide concentrations of the blood rose significantly. Women with endometriosis and with antihyroidal antibodies had significantly higher PCB values. Despite therapeutic intervention, fewer women with elevated DDT/DDE/DDD values conceived when compared to those with lower values. alpha-HCH concentrations were often elevated in women with uterine fibroids. With increasing PCP levels pregnancies often ended in abortion. Results of this investigation indicate that women with hormonal irregularities or specific fertility disorders should be examined for heavy metal and pesticide contamination prior to hormone treatment.


[Results of postoperative radiotherapy with iridium-192 in patients with ovarian cancer].

While the surgical and chemotherapeutic therapy is an established procedure for the treatment of ovarian cancer, the role of radiotherapy is not quite clear. We investigated whether the recurrence rate concerning the vaginal cuff and pelvis in ovarian cancer patients can be reduced by postoperative irradiation with afterloading technique. In retrospective analysis 20 patients with ovarian cancer, stage I-IV, received radiological contact therapy with 192-Iridium 2 x 7.5 Gy in 0.5 cm tissue depth after surgical and chemotherapeutic treatment. A control group of 20 patients with similar oncological parameters was formed. In both groups a local recurrence occurred in 6 women, which was confirmed clinically, histologically and by diagnostic devices. After 2 years, 6 of the irradiated patients survived and 11 of the control group. The results show, that the irradiation of the vaginal cuff, as applied in endometrial carcinoma, will not reduce local recurrence rate of ovarian cancer.


[Use of xylocaine in placing afterloading applicators in the gynecologic area--a simplified and analgesic method].

The afterloading contact therapy is an established method in the therapy strategies of extended gynecological malignancies. Unfortunately, the manipulations of application are painful in many cases. The results of the present paper suggests, that the pretherapeutic application of Lidocain (Xylocain) may decrease in pain symptomatic significantly. This findings have relevance for ambulant afterloading contact therapy.


[Rare site of malignant melanoma].

Primary melanoma of the vagina is a rare tumor associated with a poor prognosis. We report on a 82 years old woman with a malignant melanoma of the vagina. The treatment performed was the removal of the vaginal tumor and a hemivulvectomy followed by a chemotherapy over 6 month. A recurrence of the tumor and the development of metastases in the brain and in the lungs was observed 3 weeks after the end of the chemotherapy. The patient expired 10 month after the primary treatment.


[Systemic lupus erythematosus in puerperium].

Systemic LE is a rare complication in puerperium. A case of an acute exacerbation post partum is reported. The described case brings to attention the fact, that behind febrile conditions in puerperium could stand SLE.


Granulovacuolar degeneration in the hippocampal cortex of aging and demented patients--a quantitative study.

The occurrence and topographic analysis of granulovacuolar degeneration (GVD) in the hippocampal cortex of mentally normal controls (75 cases) and patients with Alzheimer's dementia (AD; 17 cases which included Alzheimer's disease and senile dementia of Alzheimer type), multi-infarct dementia (MID; 16 cases), Pick's disease (PD; 5 cases) and atypical dementia [5 cases; non-Alzheimer, non-Pick dementia with Fahr's syndrome (NANPDF)] were investigated. GVD was rarely found in control cases below the age of 60 years. In elderly normal brains, the statistically most representative ranking order of predilection for GVD (in decreasing severity) was: in the 60 s, CA1 > prosubiculum > CA2 (no GVD was found in the CA3 and CA4); in the 70 s, CA1 > prosubiculum > CA2 > CA3 > CA4; in the 80 s, CA1 > prosubiculum > CA2 > CA3 > CA4; in the 90 s, CA1 > prosubiculum > CA2 > CA3 > CA4. In the brains of demented patients, the rank order for GVD was: for AD, CA1 > CA2 > CA3 > prosubiculum > CA4; for MID, CA1 > prosubiculum > CA2 > CA3 > CA4; for PD, CA1 > CA2 > CA3 > prosubiculum > CA4; and for atypical dementia (NANPDF), CA1 > CA2 > prosubiculum > CA3 > CA4. The similarity of the predilection to ranking order was noted both in normal aged subjects and in MID as well as both in AD and in PD.(ABSTRACT TRUNCATED AT 250 WORDS)


Re-evaluation of ischemia-induced neuronal damage in hippocampal regions in the normothermic gerbil.

It has not been discussed whether transient forebrain ischemia of 5-min duration, which is a model frequently used to evaluate pharmacological protection against ischemic injury, is an optimal model in the CA1 field of this animal whose brain temperature is maintained at normothermic levels. The temperature of the brain during an ischemic insult strongly affects the extent of the resulting neuronal injury. If the brain temperature is not regulated, it usually falls in the gerbil by 2 degrees-4 degrees C during 5-min ischemia. However, the brain temperature during ischemic insult was not regulated in many previous studies. In the present study, the effects of transient (1 to 5 min) forebrain ischemia on the development of neuronal degeneration in hippocampal regions of the gerbil whose brain temperature was maintained at 37 degrees C were examined. In the CA1 field of the hippocampus, transient ischemia of 3- and 4-min duration caused almost the same maximal damage (88%-91% neuronal loss) as observed in the gerbils subjected to 5-min ischemia. Transient ischemia of 2- and 2.5-min duration provoked substantial neuronal damage in 25% and 55% of experimental gerbils, respectively. These results indicate that 5-min bilateral forebrain ischemia is more than is necessary to examine ischemia-induced neuronal degeneration in hippocampal CA1 field of the gerbil whose brain temperature is maintained at normothermic levels. In the normothermic gerbil brain, an ischemic period of 3-min already induces extensive neuronal death in the CA1 and, thus, constitutes a sensitive model to evaluate faint protective effects of drugs against ischemic injury in the normothermic gerbil.


Evidence that neurofibrillary tangles undergo glial modification.

Ghost tangles, neurofibrillary tangles (NFTs) emerging into extracellular space, appear to be subjected to some microglial association in addition to an invasion of astrocytic processes. Our findings lead us to speculate that the NFTs undergo structural and immunocytochemical modification. Electron microscopic observation of the NFTs in the vascular region indicated either the discharge of NFTs into the vessel or formation of NFTs in the astrocytic end-foot.


Differential distribution of neurofibrillary tangles in the cerebral cortex of dementia pugilistica and Alzheimer's disease cases.

Head trauma has been associated with the occurrence of Alzheimer's disease and plays a clear role in the etiopathogenesis of the boxers encephalopathy referred to as dementia pugilistica. Neurofibrillary tangles (NFT), one of the pathological hallmarks of Alzheimer's disease are observed in very high densities in the brains of former professional boxers suffering from dementia pugilistica. In Alzheimer's disease, NFT display striking regional and laminar distribution patterns that have been correlated with the localization of neurons forming specific corticocortical connections. In dementia pugilistica cases, NFT were concentrated in the superficial layers in the neocortex, whereas in Alzheimer's disease they predominated in the deep layers. Thus, the association cortex of brains from dementia pugilistica patients demonstrated an inverse NFT distribution as compared to Alzheimer's disease. This finding suggests that a more circumscribed population of cortical pyramidal neurons might be affected in dementia pugilistica than in Alzheimer's disease.


Developmental alteration of serotonin neurons in the raphe nucleus of rats with methylazoxymethanol-induced microcephaly.

Prenatal exposure of pregnant rats to methylazoxymethanol acetate (MAM), an anti-mitotic agent, on day 15 of gestation induces severe microcephaly in the offspring. The present study first investigated a developmental alteration of serotonin (5HT) neurons immunohistochemically in the dorsal and median raphe nuclei in serial sections in both control and microcephalic rats (MAM-rats) at 35 days of age. 5HT-immunoreactive neurons in the MAM-rats were reduced in number and irregularly distributed in the dorsal and median raphe nuclei compared with those in the control. The dendrites of neurons in these nuclei in the MAM-rats were very short and twisted. A follow-up observation on the development of the cerebral cortex at 5, 9 and 28 days of age was performed using Nissl-stained preparations, which revealed a disorganized cell arrangement in the cerebral cortex of the MAM-rats at the very early postnatal period. Furthermore, the distribution of 5HT-immunoreactive fibers into the cerebral cortex was also examined using brains of 28 days of age. In MAM-rats of this age, abnormally tortuous 5HT-immunoreactive fibers were observed in the cerebral cortex. 5HT neurons in the raphe nuclei are known to project their ascending axons widely into the entire cortical area during the 1st postnatal week. Thus, the association of disorganized cortical cell arrangement and the hyperdense and tortuous distribution of 5HT-immunoreactive fibers in the cerebral cortex support the idea of target-dependent secondary degeneration of 5HT neurons in the dorsal and median raphe nuclei of the MAM-rats.


Nuclear and mitochondrial changes of muscle fibers in AIDS after treatment with high doses of zidovudine.

Zidovudine (formerly azidothymidine) is a potent inhibitor of the human immunodeficiency virus (HIV) reverse transcriptase and represents the first approved drug showing clinical efficacy in HIV-associated diseases. However, considerable toxicity causing macrocytic anemia, neutropenia, and myopathy has been reported, with severe mitochondrial alterations as a special feature of this myopathy. The mitochondrial changes are consistent with the fact that zidovudine acts as an inhibitor of the mitochondrial gamma-polymerase. Electron microscopically, we could confirm the presence of severely altered mitochondria in a 32-year-old male, who developed a necrotizing myopathy after daily administration of 1,000 mg zidovudine over a period of 15 months. In addition, there were even more severe nuclear changes that, for the most part, have not been documented electron microscopically in HIV-related myopathy either with or without zidovudine treatment, especially in non-necrotic and non-regenerating fibers. Since various in vitro studies have shown interference of zidovudine with nuclear DNA metabolism even in human cell lines, we assume that the nuclear changes that we observed are at least in part related to zidovudine treatment.


Mapping of neurofibrillary degeneration in Alzheimer's disease: evaluation of heterogeneity using the quantification of abnormal tau proteins.

A biochemical mapping of neurofibrillary degeneration was performed in Brodmann areas of the brains of five patients with senile dementia of the Alzheimer type (AD). To quantify the degenerating process, we used an immunoblot method with antibodies directed against the abnormally phosphorylated tau proteins named Tau 55, 64 and 69, known to be early and reliable markers of the degenerating process in AD. The detection intensities were assessed using a numerical rating scale for each area and scores were grouped by lobe. In all cases, the detection of Tau 55, 64 and 69 was positive in all areas except in primary visual cortex (area 17) for two patients. The detections were especially strong in temporal neocortical and limbic areas and were higher in associative cortex than in primary sensory cortex. Scores from the occipital and frontal lobes differed strongly between patients as compared to the uniform degree of detection in the limbic, temporal and parietal lobes. Despite a relatively identical duration of the disease and an apparently global involvement of the cerebral cortex, the distribution of neurofibrillary degeneration in AD varies significantly across cortical areas and displays striking heterogeneity patterns along the rostrocaudal axis. The immunodetection of abnormal tau proteins using the Western blot method may provide complete and rapid quantitative data of the degenerating process in AD.


Ibotenic acid-induced calcium deposits in rat substantia nigra. Ultrastructure of their time-dependent formation.

The excitotoxin ibotenic acid (IBO) induces local calcium deposits upon injection into rat substantia nigra. Their formation has been investigated at the ultrastructural level in a time course study from 2 days to 8 weeks survival. Potassium bichromate stain was used to visualize pathological calcium accumulation. Two days after IBO application, reaction product for calcium was observed in mitochondria of degenerating perikarya and dendrites, but not in axons, boutons or glia. Four days after the lesion, calcium stain was found, in addition, in a seemingly free form in a few dendrites, especially those still contacted by intact boutons and not sequestrated by invading glia. Two days later, most of these calcium-accumulating dendrites were separated by astroglia from their synaptic partners. At the border between glia and dendrite a fibrillar matrix was formed which further accumulated calcium. During the following weeks this matrix enlarged stepwise and was infiltrated with calcium, thus giving a picture resembling the annual growth rings of trees. The evolving bodies incorporated smaller deposits in their vicinity, finally representing the large concretions seen at the light microscopic level from the 4th postoperative week onward. Similarities and dissimilarities of these observations with the results from other ultrastructural studies on excitotoxin lesions are detailed. It is suggested that the different outfit of neuronal subpopulations and of glia with ligand-gated and metabotropic glutamate receptors in the single brain region, as well as the local response repertoire of glial cells towards the excitotoxic injury with the subsequent formation of a calcium-accumulating matrix provide the molecular basis for the formation of calcium deposits.