Postnatal treatment of rats with the beta 2-adrenergic agonist salbutamol influences the volume of the sexually dimorphic nucleus in the preoptic area.

Sexual differentiation of the brain seems to be influenced by postnatal interaction of gonadal steroids with neurotransmitter systems, in particular the adrenergic system. Stimulation or inhibition of adrenergic receptors during early postnatal development had previously been shown to influence steroid-induced sexual differentiation of rat brain function. In the present study newborn male and female rats were treated daily for 5 days with salbutamol, a specific beta 2-receptor agonist, or with alprenolol, a beta-receptor antagonist and the volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) was examined in adulthood. This nucleus, one of the most striking sex differences in brain anatomy, is several-fold larger in male than in female rats. Postnatal treatment with salbutamol increased SDN-POA volume in female and in male rats. The effect was particularly striking in males, because any previous pre- and/or postnatal treatment of male rats with large amounts of gonadal steroids had been unable to increase the volume of the SDN-POA above normal. The beta-receptor antagonist alprenolol had no effect on SDN-POA differentiation. The results indicate that beta 2-adrenergic stimulation influences development and differentiation of the SDN-POA.

Studies on stimulation and properties of antiglobulin antibodies. II. Antiglobulin antibodies against homologous globulins and antigens of thermally denatured autologous sera in the sera of rabbits immunized with various antigens.

Sera of 48 rabbits after long-term immunization with suspensions of Diplococcus pneumoniae, Klebsiella friedländeri, Proteus OX19 and solution of bovine albumin were examined for antibodies reacting with homologous gamma-globulins and antigens of thermally denatured autologous sera. Appearance of antibodies of this type was related to duration of immunization, but not related to the type of antigen used. The experimental results were explained as a result of altered antigenic properties of antibodies following reaction with homologous antigen.

Studies on stimulation and properties of antiglobulin antibodies. I. Influence of heatig at 56 degrees C and 60 degrees C on antigenicity.

The autoimmunogenic properties of whole rabbit serum heated at 56 degrees C and 60 degrees C were studied in rabbits. Autologous rabbit serum heated 20 min at 60 degrees C was immunogenic. The state of induced immunity manifested itself by the appearance of antibodies to antigens of heterologous sera: human, goat and guinea pig. No antibodies for autologous sera were found, including autologous sera heated 20 min at 60 degrees C. The antibodies for heterologous sera directed against gamma-globulins were detected by the passive hemagglutination test and by precipitation in agar gel.

Studies on stimulation and properties of antiglobulin antibodies. III. Antiglobulin antibodies with different specificity in patients with bronchial asthma complicated by suppurative catarrh of the respiratory tract.

Sera from 14 of 50 patients suffering from bronchial asthma complicated by suppurative catarrh of the respiratory tract contained antibodies to homologous and heterologous gamma-globulins. The findings were attributed to hyperimmunization causing changed in antigenic properties of antibodies. Antigenically altered antibodies can act as autoimmunogenic stimuli inducing an immune response manifested by the appearance of antibodies to autologous gamma-globulins and cross reacting with homologous and heterologous gamma-globulins.

[Combined naevus flammeus and naevus fuscocoeruleus: phacomatosis pigmentovascularis type IIa]. / Kombinierter Naevus flammeus und Naevus fuscocoeruleus: Phacomatosis pigmentovascularis Typ IIa.

The association of nevus flammeus with mongolian spot, nevus fuscoceruleus, nevus spilus and, with variable frequency, with nevus anemicus has been termed phacomatosis pigmentovascularis, a genodermatosis first described by Ota and co-workers. Four different combinations have been specified. Most cases are reported from the Japanese literature. Phacomatosis pigmentovascularis may constitute an exclusively cutaneous disorder, but overlapping with other syndromes like Klippel-Trenaunay syndrome or Sturge-Weber syndrome is also possible. We report a 30-year-old woman with nevus flammeus on the back and right arm associated with nevus fuscoceruleus on the back.

[Immunohistochemical studies of breast and extra-mammary Paget's disease indicate an apocrine differentiation]. / Immunhistochemische Untersuchungen beim mammären und extramammären Morbus Paget weisen auf eine apokrine Differenzierung hin.

Using the PAP technique, paraffin-embedded and formalin-fixed tissue sections taken from 11 patients suffering from Paget's disease (5 mammary, 6 extramammary cases) were stained with antibodies against keratin, actin, S 100 protein, CEA, HMFG 1, cytokeratin 6 and 18 (Dako-CK-1), as well as the lectin SBA. We did not find any differences between mammary and extramammary Paget's disease. In both forms of the disease, all tumor cells showed reaction to antibodies against HMFG 1 and CEA and, in 50 to 100%, to the lectin SBA. The other antibodies investigated did not react with Paget's cells. Since HMFG 1 and Dako-CK-1 are selective markers of apocrine and eccrine sweat gland structures, respectively, our results suggest apocrine differentiation of both mammary and extramammary Paget's disease. At the same time, our findings rule out a possible histogenesis of Paget's cells from melanocytes (positive for S 100 protein) or keratinocytes (positive for Dako-CK-1 and antikeratin).

Postnatal treatment of rats with beta-adrenergic agonists or antagonists influences differentiation of sexual brain functions.

Sexual differentiation of the brain seems to be influenced by postnatal interaction of gonadal steroids with neurotransmitter systems, in particular the adrenergic system. Stimulation or inhibition of alpha-adrenergic receptors during early postnatal development had previously been shown to influence steroid-induced sexual differentiation of brain functions. In the present study newborn male and female rats were treated either with salbutamol, a selective beta 2-adrenergic receptor agonist, isoprenaline, a general beta-adrenergic receptor agonist, or with alprenolol, a general beta-adrenergic receptor antagonist. In adulthood the female animals were ovariectomized and were tested for the capacity to show an LH-surge response and female sexual behaviour after priming with estradiol benzoate (EB) and progesterone (P). Male animals were tested for expression of male sexual behavior and, after gonadectomy and priming with EB + P, for the capacity to show female lordosis behavior. In summary, our results suggest that activation or inhibition of beta-adrenergic receptors during postnatal development permanently impairs the responsiveness of the center for cyclic gonadotropin release to gonadal steroids in female rats and impairs the expression of ejaculatory behavior in male rats. A slight stimulatory effect on the expression of female lordosis behavior was observed in male and female rats after postnatal activation of beta-adrenergic receptors.

Influence of neurotransmitters on sexual differentiation of brain structure and function.

Newborn rats received daily subcutaneous treatment with compounds which influence serotoninergic, cholinergic, alpha-adrenergic and beta-adrenergic activity. In adulthood luteinizing hormone (LH) secretion pattern, female sexual behavior, and the volume of the sexually dimorphic nucleus of the preoptic are (SDN-POA) were determined. Postnatal administration of l-tryptophan increased the volume of the SDN-POA significantly when given alone or when given simultaneously with testosterone propionate (TP). Para-chlorophenyl-alanine (pCPA) also increased SDN-POA volume, but did not potentiate the stimulating influence of TP. Clonidine had no effect per se on SDN-POA development, but it significantly potentiated the effect of TP in females. Salbutamol increased SDN-POA volume in females and in males. Postnatal treatment of female rats with the alpha-adrenergic receptor antagonists prazosine and yohimbine or with the nicotin receptor antagonist mecamylamine had permanent potentiating effects on the pattern of LH secretion, whereas postnatal treatment with beta-adrenergic compounds reduced the LH-release response to gonadal steroids in adulthood. Postnatal treatment with clonidin or l-tryptophane inhibited differentiation of the capacity for lordosis behavior. Beta-receptor agonists postnatally had a potentiating effect on the capacity for lordosis behavior in female and male rats. Cholinergic stimulation postnatally inhibited differentiation of the capacity for lordosis behavior in female rats, but prevented the inhibitory effect of postnatal androgenization. There was no correlation between SDN-POA volume and any of the two functional parameters.

Dacarbazine and interferon alpha with or without interleukin 2 in metastatic melanoma: a randomized phase III multicentre trial of the Dermatologic Cooperative Oncology Group (DeCOG).

In several phase II-trials encouraging tumour responses rates in advanced metastatic melanoma (stage IV; AJCC-classification) have been reported for the application of biochemotherapy containing interleukin 2. This study was designed to compare the efficacy of therapy with dacarbazine (DTIC) and interferon alpha (IFN-alpha) only to that of therapy with DTIC and IFN-alpha with the addition of interleukin 2 (IL-2) in terms of the overall survival time and rate of objective remissions and to provide an elaborated toxicity profile for both types of therapy. 290 patients were randomized to receive either DTIC (850 mg/m(2)every 28 days) plus IFN-alpha2a/b (3 MIU/m(2), twice on day 1, once daily from days 2 to 5; 5 MIU/m(2)3 times a week from week 2 to 4) with or without IL-2 (4.5 MIU/m(2)for 3 hours i.v. on day 3; 9.0 MIU/m(2) i.v. day 3/4; 4.5 MIU/m(2) s.c. days 4 to 7). The treatment plan required at least 2 treatment cycles (8 weeks of therapy) for every patient. Of 290 randomized patients 281 were eligible for an intention-to-treat analysis. There was no difference in terms of survival time from treatment onset between the two arms (median 11.0 months each). In 273 patients treated according to protocol tumour response was assessable. The response rates did not differ between both arms (P = 0.87) with 18.0% objective responses (9.7% PR; 8.3% CR) for DTIC plus IFN-alpha as compared to 16.1% (8.8% PR; 7.3% CR) for DTIC, IFN-alpha and IL-2. Treatment cessation due to adverse reactions was significantly more common in patients receiving IL-2 (13.9%) than in patients receiving DTIC/IFN-alpha only (5.6%). In conclusion, there was neither a difference in survival time nor in tumour response rates when IL-2, applied according to the combined intravenous and subcutaneous schedule used for this study, was added to DTIC and IFN-alpha. However, toxicity was increased in melanoma patients treated with IL-2. Further phase III trials with continuous infusion and higher dosages must be performed before any final conclusions can be drawn on the potential usefulness of IL-2 in biochemotherapy of advanced melanoma.