Enhanced delayed-type hypersensitivity and diminished immediate-type hypersensitivity in mice lacking the inducible VPAC2 receptor for vasoactive intestinal peptide

Vasoactive intestinal peptide (VIP) and its G protein-coupled receptors, VPAC(1)R and VPAC(2)R, are prominent in the immune system and regulate many aspects of T cell-dependent immunity. In mouse T cells, VPAC(1)R is expressed constitutively, whereas VPAC(2)R is induced by immune stimuli. VPAC(2)R-null (VPAC(2)R(-/-)) mice on a C57BL/6 background are shown here to have normal basic immune characteristics, including serum Ig concentrations, blood levels of all leukocytes, and spleen number of total T cells (CD3(+)) and T cells bearing CD4, CD8, and CD28. Hapten-evoked cutaneous delayed-type hypersensitivity (DTH) was significantly enhanced in VPAC(2)R-null mice compared with age- and sex-matched wild-type mice. In contrast, generation of IgE anti-hapten antibodies and active cutaneous anaphylaxis were > or =70% lower in VPAC(2)R-null mice than in wild-type controls. Cytokine production by splenic CD4(+) T cells, stimulated with adherent anti-CD3 plus anti-CD28 antibodies, revealed higher levels of IL-2 (mean = 3-fold) and IFN-gamma (mean = 3-fold), and lower levels of IL-4 (mean = one-fifth) in VPAC(2)R-null mice than wild-type controls. Loss of VIP-VPAC(2)R maintenance of the normal ratio of Th2/Th1 cytokines thus leads to a state of enhanced DTH and depressed immediate-type hypersensitivity, which may alter both host defense and susceptibility to immune-mediated diseases.     

Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant

Seven fulvestrant resistant cell lines derived from the estrogen receptor α positive MCF-7 human breast cancer cell line were used to investigate the importance of epidermal growth factor receptor (ErbB1-4) signaling. We found an increase in mRNA expression of EGFR and the ErbB3/ErbB4 ligand heregulin2 (hrg2) and a decrease of ErbB4 in all resistant cell lines. Western analyses confirmed the upregulation of EGFR and hrg2 and the downregulation of ErbB4. Elevated activation of EGFR and ErbB3 was seen in all resistant cell lines and the ErbB3 activation occurred by an autocrine mechanism. ErbB4 activation was observed only in the parental MCF-7 cells. The downstream kinases pAkt and pErk were increased in five of seven and in all seven resistant cell lines, respectively. Treatment with the EGFR inhibitor gefitinib preferentially inhibited growth and reduced the S phase fraction in the resistant cell lines concomitant with inhibition of Erk and unaltered Akt activation. In concert, inhibition of Erk with U0126 preferentially reduced growth of resistant cell lines. Treatment with ErbB3 neutralizing antibodies inhibited ErbB3 activation and resulted in a modest but statistically significant growth inhibition of two resistant cell lines. These data indicate that ligand activated ErbB3 and EGFR, and Erk signaling play important roles in fulvestrant resistant cell growth. Furthermore, the decreased level of ErbB4 in resistant cells may facilitate heterodimerization of ErbB3 with EGFR and ErbB2. Our data support that a concerted action against EGFR, ErbB2 and ErbB3 may be required to obtain complete growth suppression of fulvestrant resistant cells.     

Secondary Antibodies as Tools to Improve Tumor to Non Tumor Ratio at Radioimmunolocalisation and Radioimmunotherapy

One way of selectively improving the efficiency of radioimmunolocalization and radioimmunotherapy is to eliminate redundant, circulating, non-targeting radiolabeled antibodies after saturation of the target sites. Secondary antibodies of different types have been proposed as clearing agents for such purposes. The conceptually different approaches of the 'secondary antibody' strategy including its advantages and limitations are discussed. This mini-review also presents a model describing the kinetics of the components (the antigen, the primary and secondary antibodies) and approaches required to improve the efficacy of both radioimmunolocalization and radioimmunotherapy     

Twenty Years with Monoclonal Antibodies: State of the art-Where do we go?

In this review, we have selected some parameters with the potential to improve the efficacy of RIL and RIT. Focus has partially been on the behaviour of radiolabeled antibodies in vivo in relation to properties and amounts of both target antigen and the antibodies used. If, out of the 28 factors listed in Table 1, some should be given preference in future work, it is our opinion that after the initial saturation of the tumour site a rapid decrease in redundant antibody is of significant importance. Furthermore, quantitative aspects of both antigens and antibodies should be more carefully evaluated when possible. By combining several of the listed approaches toward increasing efficiency, a more extensive use of RIL and RIT could be expected in the future     

Effects of human calcitonin gene-related peptide and substance P on human intracervical arteries

The contractile effects of substance P and human calcitonin gene-related peptide (human CGRP) on isolated human intracervical arteries were studied. Human cervical tissue specimens were excised after hysterectomy at various phases of the menstrual cycle (n = 14) and small intracervical arteries were dissected free by microtechnique. Ring preparations of the vessels were prepared and mounted in organ baths, and isometric circular tension was recorded. Neither compound affected resting tension. Both peptides showed potent relaxing effects on vessels precontracted by noradrenaline 10(-5) M. Substance P exhibited the higher potency, while human CGRP showed the higher efficacy. The relaxing effects of the two compounds were unaffected by pretreatment with indomethacin 10(-6) M, propranolol 10(-6) M and atropine 10(-6) M. The results support a role for the two peptides in the regulation of cervical blood flow.     

Inhibitory effects of nitrendipine on myometrial and vascular smooth muscle in human pregnant uterus and placenta

Human myometrial visceral and vascular preparations and placental chorionic and stem villous vessels were dissected from myometrial and placental specimens obtained at term Caesarean section and after vaginal delivery. Vascular ring preparations and myometrial strips were mounted in organ bath and isometric tension recorded. Only myometrial preparations developed spontaneous contractile activity, which was effectively blocked by the calcium channel blocker nitrendipine (NTD) 10(-7) M. Pretreatment with calcium-depleted medium for 30 min. almost abolished myometrial responses to high K+ (124 mmol), oxytocin (OX) and prostaglandin F2 alpha (PGF2 alpha). Vascular responses to high K+ (124 mmol) were also nearly abolished by such treatment. However, noradrenaline (NA), vasopressin (VP) and PGF2 alpha in myometrial arteries and PGF2 alpha in chorionic vessels and stem villous arteries induced significant, but reduced contractions after calcium depletion. In all vascular preparations, exposed to calcium-depleted medium, NTD (10(-8) M) almost abolished contractions induced by calcium (0.1-4.0 mM) in the presence of K+ (124 mmol) and depressed responses to calcium in the presence of the other agonists tested. NTD (10(-10)-10(-7) M) depressed myometrial contractions induced by K+, OX and PGF2 alpha more effective than vascular responses to K+, NA, VP and PGF2 alpha in the myometrial arteries and K+ and PGF2 alpha in the placental arteries. It is concluded that activation of contraction in vessels from the human utero-placental unit implies multiple cellular sources of calcium, while in myometrial smooth muscle, influx of superficially bound calcium may be an important initial step in contractile activation. Treatment with calcium channel blockers during late human pregnancy might involve relaxation of the myometrium together with vasodilatation of the myometrial and foetal placental vascular beds.     

Economics of mental well-being: a prospective study estimating associated health care costs and sickness benefit transfers in Denmark

The European Journal of Health Economics - Previous literature has examined the societal costs of mental illness, but few studies have estimated the costs associated with mental well-being. In this...     

Oesophageal Obstruction from a Pharmacobezoar Resulting in Death

Formation of an intestinal pharmacobezoar is a rare condition. It may form after intake of various oral pharmaceutical preparations of drugs, both as a result of an acute overdose and through chronic use of therapeutic doses of a drug. We report a case with a patient presenting with an oesophageal pharmacobezoar and complete obstruction of the oesophagus and severe toxic symptoms and death related to oral ingestion of multiple drugs.