The effect of atherogenic infusions of the triglyceride-rich, lipid emulsion, Lipofundin-S, on the in vitro growth characteristics of rat aortic smooth muscle cells.

This study shows that arterial smooth muscle cells (SMC) isolated from rats receiving atherogenic doses of the lipid emulsion, Lipofundin-S, alter their in vitro growth properties. Compared to cells from control animals, SMC isolated from Lipofundin-S-infused rats show a reduction in both saturation density and response to increasing serum concentrations, without a change in the baseline proliferation. Also, SMC isolated from lipid-treated animals and grown for five days in the presence of 30, 150, or 300 pg/ml estradiol show a 30% increase in growth vs. cells from controls. Epinephrine at 1 microM stimulates growth in SMC from control rats, while causing no growth enhancement over five days in cells from lipid-infused animals. Thus, atherogenic infusions of Lipofundin-S into rats cause phenotypic changes in arterial SMC which can be passed to successive cell generations in vitro.     

Inhibition of growth of PC-82 human prostate cancer line xenografts in nude mice by bombesin antagonist RC-3095 or combination of agonist [D-Trp6]-luteinizing hormone-releasing hormone and somatostatin analog RC-160.

The effects of treatment with a bombesin receptor antagonist [D-Tpi6, Leu13 psi (CH2NH) Leu14]BN(6-14)(RC-3095) and the combination of an agonist of luteinizing hormone-releasing hormone [D-Trp6]-LH-RH and somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Val- Cys-Trp-NH2 (RC-160) were studied in nude mice bearing xenografts of the hormone-dependent human prostate tumor PC-82. During the 5 weeks of treatment, tumor growth was decreased in all treated groups compared with controls. Bombesin antagonist RC-3095 and the combination of [D-Trp6]-LH-RH and RC-160 caused a greater inhibition of tumor growth than [D-Trp6]-LH-RH or RC-160 alone as based on measurement of tumor volume and percentage change in tumor volume. The largest decrease in tumor weight was also seen in the groups treated with the bombesin antagonist and with the combination of RC-160 and [D-Trp6]-LH-RH. Serum prostatic-specific antigen levels were greatly decreased, and insulin-like growth factor I (IGF-I) as well as growth hormone levels were reduced in all treated groups. Specific binding sites for [D-Trp6]-LH-RH, epidermal growth factor (EGF), IGF-I, and somatostatin (SS-14) were found in the tumor membranes. Receptors for EGF were significantly down-regulated by treatment with the bombesin antagonist or RC-160. Combination of LH-RH agonists with somatostatin analog RC-160 might be considered for improvement of hormonal therapy for prostate cancer. The finding that bombesin antagonist RC-3095 inhibits the growth of PC-82 prostate cancer suggests the merit of further studies to evaluate the possible usefulness of antagonists of bombesin in the management of prostatic carcinoma.     

Transitional mucosa at anastomosis. A cause of local tumor recurrence in patients with rectal cancer after anterior resection.

Transitional mucosa adjacent to colorectal cancers is essentially characterized by an excess of sialomucins at the expense of the normally predominant sulphomucins in epithelial cells lining the intestinal crypts which presents the early stage of oncogenic transformation of colorectal epithelium. The presence or absence of sialomucins at the resection margins was studied histochemically using the high iron diamine-alcian blue(HID-AB) stain in 64 rectal cancer patients in Dukes' B stage who underwent curative anterior resection. The correlation was revealed between the presence of sialomucins at the resection margins and subsequent development of local tumour recurrence. Fourteen of 27 patients (51.9%) with sialomucins predominant pattern at either resection margin developed local recurrence compared with 4 of 37 patients (10.8%) with sulphomucins predominant pattern (P less than 0.001). It is suggested that determination of the transitional mucosa around anastomosis in patients treated for the rectal carcinoma by anterior resection appears to identify those with a higher risk of local recurrence.     

Antibodies to glutamic acid decarboxylase discriminate major types of diabetes mellitus.

Insulin-dependent diabetes mellitus (IDDM) is marked by circulating antibodies to a 64,000-M(r) islet cell antigen identified as glutamic acid decarboxylase (GAD). We describe a radioimmunoprecipitation assay with GAD isolated from pig brain. The sera tested were from 80 patients with IDDM including 26 with disease of recent onset and 54 with disease of longer duration (3-42 yr), 20 with non-insulin-dependent diabetes mellitus (NIDDM), and 55 nondiabetic subjects. Conventional assays for islet cell cytoplasmic antibodies were performed concurrently. The level of antibody in serum was expressed in units based on percentage reactivity of a standard reference serum. The frequency of antibody to GAD in IDDM was 69% in short-duration cases and 59% in long-duration cases. The latter was substantially higher than the frequency of islet cell cytoplasmic antibody. Antibodies to GAD were elevated (means +/- 3 SD) in 5% NIDDM cases and in none of the nondiabetic subjects. A simple laboratory test with a defined autoantigen has substantial implications for population screening and early diagnosis of IDDM and for better understanding of its pathogenesis.     

Neuropeptide Y action in the rat hippocampal slice: site and mechanism of presynaptic inhibition

Neuropeptide Y (NPY), the most abundant peptide in mammalian CNS, has been shown to inhibit excitatory neurotransmission presynaptically at the stratum radiatum-CA1 synapse in the in vitro rat hippocampal slice. We examined the site and mechanism of this inhibition in a series of in vitro intra- and extracellular recordings in areas CA1 and CA3, the source of much of the excitatory synaptic input to the CA1 neurons. NPY's inhibitory action at the stratum radiatum-CA1 synapse was unaffected by high concentrations of the antagonists bicuculline, theophylline, or atropine, suggesting that it does not act by stimulating the release of the known presynaptic inhibitory transmitters GABA, adenosine, or ACh, respectively. Bath application of 10(-6) NPY, a concentration that strongly inhibited the stratum radiatum-CA1 synapse had no effect on CA3 neuron resting potential, input resistance or action potential amplitude, threshold, or duration. NPY also does not alter the amplitude or duration of the prolonged CA3 action potentials evoked in the presence of TTX, tetraethyl-ammonium, and elevated external Ca2+ or those evoked in the presence of TTX and Ba2+ ions. NPY therefore does not alter the passive or active properties of the somata of the presynaptic CA3 neurons. Neither the afferent fiber volley of the Schaffer collaterals in stratum radiatum of area CA1 nor the excitability of the CA3 terminals in CA1 was affected by NPY application. However, application of the transient K+ current blocker, 4-aminopyridine (4-AP) at concentrations of 10 and 50 microM, completely abolished the action of 10(-6) M NPY on the stratum radiatum-CA1 excitatory synaptic potentials. This action of 4-AP could be reversed by reducing extracellular Ca2+ concentrations from a control level of 1.5 to 0.7 mM (in 10 microM 4-AP) and to 0.5 mM (in 50 microM 4-AP). The evidence suggests that NPY inhibits excitatory synaptic transmission at the Schaffer collateral-CA1 synapse by acting directly at the terminal to reduce a Ca2+ influx.     

Percutaneous transluminal coronary angioplasty. A growing surgical problem

The incidence of prior percutaneous transluminal coronary angioplasty in surgical cases is nearly doubling yearly. In 1985, 11.4% of our bypass patients had one or more prior angioplasties. One hundred thirty-five patients with prior angioplasty are compared to 2,205 patients without angioplasty undergoing surgical revascularization. The mortality is 3.2 times higher in the angioplasty patients than in the control patients and the perioperative infarction rate is 2.5 times higher. Forty-four patients were taken directly to the operating room from the catheterization laboratory, 50 were operated on within 10 days, and 41 underwent operation more than 10 days after angioplasty. All of these late failures were of the lesion previously dilated. The infarction rate was less in patients taken immediately to the operating room on an emergency basis than in those whose operation was delayed up to 10 days (30% versus 70%). All patients who died had angioplasty of the anterior descending coronary artery. Angioplasty of this artery increases operative mortality should surgical treatment become necessary acutely. Patients should be informed before angioplasty of the increased surgical risks after a failed angioplasty procedure.     

Investigation of an artificial intelligence technology--Model trees. Novel applications for an immediate release tablet formulation database.

This study has investigated an artificial intelligence technology - model trees - as a modelling tool applied to an immediate release tablet formulation database. The modelling performance was compared with artificial neural networks that have been well established and widely applied in the pharmaceutical product formulation fields. The predictability of generated models was validated on unseen data and judged by correlation coefficient R(2). Output from the model tree analyses produced multivariate linear equations which predicted tablet tensile strength, disintegration time, and drug dissolution profiles of similar quality to neural network models. However, additional and valuable knowledge hidden in the formulation database was extracted from these equations. It is concluded that, as a transparent technology, model trees are useful tools to formulators.     

The role of macrophages in demyelination

Experimental allergic encephalomyelitis (EAE) is an autoimmune inflammatory disease of the central nervous system (CNS). In particular in the CsA-induced chronic relapsing form (CREAE), pronounced demyelination occurs, in temporal association with relapses. It is still a matter of discussion which cell type ultimately is responsible for the actual process of demyelination. Macrophages, cytotoxic T lymphocytes and also astrocytes are possible candidates. In this short overview, the role of macrophages in the pathogenesis of EAE is discussed. It is shown that in particular, newly recruited macrophages play a crucial role in the generation of clinical signs. Possible mechanisms by which macrophages are involved in the pathogenesis of demyelinating diseases are presented.