Effects of vesnarinone, a novel orally active inotropic agent with an immunosuppressive action, on experimental cardiac transplantation in rats

BACKGROUND: Vesnarinone (VES) has been used for treatment of patients with congestive heart failure. In addition to inotropic effects, it seems to have immunosuppressive action. We tested the hypothesis that VES suppresses graft rejection, inotropic dysfunction caused by early rejection, and chronic coronary obstruction in a heterotopic rat cardiac transplantation model. METHODS: (1) To study acute rejection, hearts from Lewis-Brown Norway (LBN) rats were transplanted into Lewis rats, which were treated with or without VES (50 or 100 mg/kg/day orally). (2) In a functional study, LBN hearts with or without VES (100 mg/kg/ day) were isolated and perfused on day 3 after transplantation to assess inotropic response to isoproterenol (3 x 10(-8) M). (3) To study chronic rejection, Lewis hearts were transplanted into Fisher 344 rats, which were treated with or without VES (50 mg/kg/day) for 90 days. Coronary obstructive disease was assessed by morphometric analysis. There were five to six animals in each group. RESULTS: (1) VES (100 mg/kg/day) prolonged LBN heart survival (11.7 +/- 0.7 vs. 9.6 +/- 0.7 days in control; P < 0.05). (2) Left ventricular developed pressure was depressed in transplanted hearts regardless of VES treatment (84 +/- 12, 90 +/- 8 vs. 144 +/- 16 mmHg in untransplanted hearts; P < 0.01). The developed pressure after administration of isoproterenol in VES-treated hearts (184 +/- 20 mmHg) was higher than transplanted hearts without VES (118 +/- 16 mmHg; P < 0.05), and similar to untransplanted hearts (203 +/- 27 mmHg; P = NS). (3) Transplanted hearts treated with or without VES showed similar grades of rejection (2.0 +/- 0.3 vs. 2.6 +/- 0.2; P = NS), intimal area (6,996 +/- 3,186 vs. 13,441 +/- 5,165 microns2; NS), and coronary luminal obstruction (45 +/- 16% vs. 67 +/- 14%; NS). CONCLUSIONS: VES produces mild prolongation in survival of rat heart grafts, but has no significant effect on chronic graft atherosclerosis. VES preserves the positive inotropic effects of isoproterenol that are otherwise deteriorated by early acute rejection.     

Inaccuracies in estimates of life expectancies of patients with bronchial cancer in clinical decision making

Cell cultures were derived from adult human brain biopsies [from cortical gray (cultures 9-HB-G and 33-HB-G) and white (culture 14-HB-W) and stroke-injured white matter (culture 33-HB-IW)]. The morphology and growth rate of cultured cells were examined and correlated with the presence of vimentin and glial fibrillary acidic protein (GFAP). The cultures from various brain matters differed in cell morphology and rate of growth but not in GFAP and vimentin staining. Cells of primary and rapidly proliferating cultures were GFAP-negative and vimentin-positive. Spontaneous growth deceleration occurred in culture 14-HB-W within passages 5 to 10 and in cultures 9-HB-G, 33-HB-G, and 33-HB-W within passages 17 to 20. This deceleration, as well as the successive complete growth arrest, were accompanied by an appearance of GFAP-positive cells and an elevated intensity for vimentin staining. We propose that GFAP-positive astrocytes originate from glial precursor cells that migrate from the explants and differentiate under prolonged subcultivation.     

A Monte Carlo model for bone mineral measurement using dual energy X-ray absorptiometry

We discuss the surgical approach used for and outcome in 11 infants (< or =3 years) who were treated at our institution for ependymomas arising in the cerebellar-pontine (C-P) angle. The median age of the group was 19 months (range: 6-26 months). Of these 11 patients, the initial surgery for 8 was performed at our center and achieved a gross total resection (GTR) in 4 patients and a subtotal resection (STR) in the remaining 4. The 3 patients who had tumor debulking performed elsewhere were subsequently referred to our institution and had definitive surgery after receiving 3-4 courses of chemotherapy; one of these children had a GTR, whereas the remaining 2 had an STR. During the immediate postoperative period, 9 patients had cranial nerve deficits that necessitated placement of a tracheostomy and a gastrostomy feeding tube; these were discontinued in 6 of the 9 patients as the deficits resolved. The majority of the permanent cranial nerve deficits involved the sixth and seventh cranial nerves. Of the 11 patients, 4 have died (progressive disease, n = 1; accidental death, n = 2; withdrawal of life support, n = 1); the remaining 7 patients are alive, with a median follow-up of 37 months (range: 20-73 months). Aggressive surgical resection for tumors arising in the C-P region is associated with postoperative deficits, which resolve over time with appropriate supportive care. This approach may increase the number of children in whom GTR is achieved, thereby potentially increasing the cure rate for these patients.     

Immunity to Cryptosporidium muris infection in mice is expressed through gut CD4+ intraepithelial lymphocytes

The role of gut intraepithelial lymphocytes (IEL) in immunity to cryptosporidial infection was investigated with a murine infection model involving Cryptosporidium muris. Oocyst shedding was monitored in severe combined immunodeficiency (SCID) mice infected with C. muris following intravenous injection of mesenteric lymph node (MLN) cells or intestinal IEL from BALB/c donor mice which were naive or previously infected with C. muris. SCID mice receiving no lymphoid cells developed chronic infections and excreted large numbers of oocysts until the end of the experiment. SCID mice injected with IEL from immune animals, however, were able to overcome the infection, and furthermore, these animals produced fewer oocysts and recovered sooner than ones which received IEL or MLN cells from naive BALB/c donors. Similar levels of protection were obtained in SCID mice injected with either 2 X 10(6) IEL or MLN cells from immune donor mice. Depletion of CD4+ cells from immune IEL, however, abrogated the ability to transfer immunity to SCID mice, while depletion of CD8+ cells only marginally reduced the protective capacity of immune IEL. Finally, control SCID mice which received no lymphocytes had < or = 1% CD4+ cells in the IEL from the small intestine, whereas the IEL from SCID mice recovered from infection, as a result of injection with immune IEL, contained 15% CD4+ cells. Thus, the ability to control C. muris infection correlated with the presence of the protective CD4+ cells in the gut epithelium.     

Synthesis, estrogen receptor binding, and tissue distribution of a new iodovinylestradiol derivative (17alpha,20E)-21-[123I]Iodo-11beta-nitrato-19-norp regna-1,3,5 (10),20-tetraene-3,17-diol (E-[123I]NIVE)

We have synthesized and evaluated E-11beta-nitrato-17alpha-iodovinylestradiol (E-NIVE; E-3c) and its 123I-labelled form, as a new potential radioligand for imaging of estrogen receptor (ER)-positive human breast tumors. E-[123I]NIVE was prepared by stereospecific iododestannylation of the E-tri-n-butylstannylvinyl precursor (E-2c), obtained from reaction of 11beta-nitrato-estrone (8) with E-tributylstannylvinyllithium. In competitive binding studies, E-NIVE proved to have high binding affinity for both the rat and the human ER (Ki 280-730 pM), without significant binding to human sex hormone binding globulin. Distribution studies in normal and mammary tumor-bearing rats showed specific ER-mediated uptake of E-[123I]NIVE in the estrogen target tissues, i.e., uterus, ovaries, pituitary, and hypothalamus, but not in the mammary tumors. Selective retention in these target tissues, including tumor tissue, resulted in significant increases over time for the target tissue-to-muscle uptake ratios, but not for the target tissue-to-fat uptake ratios. The tumor-to-fat uptake ratio even appeared constantly below 1. In the primary estrogen target tissues, E-[123I]NIVE displayed high specific ER-mediated uptake and retention, which resulted in moderate target-to-nontarget tissue uptake ratios. In contrast, in tumor tissue, E-[123I]NIVE uptake appeared to be rather low and not ER-specific. As a consequence, E-[123I]NIVE appears to be a less favorable radioligand for ER imaging in breast cancer than the previously studied stereoisomers of 11beta-methoxy-17alpha-[123I]iodovinylestradiol (E- and Z-[123I]MIVE; [123I]E- and [123I]Z-3b).     

Acid-base and electrolyte effects of shortening steeplechase in a three-day-event

This study was designed to characterise the acid-base and electrolyte effects of shortening the distance required during steeplechase (Phase B) in the face of hot and humid weather conditions during a treadmill-simulated Speed and Endurance test. Eight conditioned Thoroughbred horses underwent 3 randomised permutations of a standardised exercise test on a high speed treadmill. Each test consisted of trotting at 3.7 m/s for 10 min (Phase A); galloping at 11 m/s (Phase B) for 4 (cool laboratory conditions), 3 (hot and humid), or 2 (hot and humid) min; trotting at 3.7 m/s for 30 min (Phase C); and walking at 1.8 m/s for 10 min (Phase X). The treadmill slope was 4% for trotting and galloping and 0% for walking. Cool versus hot and humid conditions were 20 degrees C and 50-60% relative humidity vs. 26-28 degrees C and 80-85% relative humidity, respectively. Pulmonary artery blood samples were obtained at rest prior to exercise (Rest); at the end of Phases A (A10) and B (B2-4); at 10 (C10), 20 (C20) and 30 (C30) min through Phase C; and at 5 min into Phase X (X5). Additional samples for lactate (LA) and glucose (GLC) analysis were obtained 5 min into Phase C (C5) and at the end of Phase X (X10). Samples were analysed for packed cell volume (PCV), haemoglobin (HB), total plasma protein (TP), sodium (Na), potassium (K), chloride (Cl), anion gap (AG), plasma glucose (GLC) and lactate (LA), pH, PCO2, bicarbonate (HCO3) and base excess (BE). Shortening steeplechase distance by 50% under hot and humid conditions (2 min B) resulted in a consistent return to control measurements (4 min B) only for plasma LA. Changes in PCV, HB, TP, K and Cl were related more to the longer galloping distance in the 4 min B trials than to hot vs. cold laboratory conditions. Alternatively, changes in LA, GLC, pH, PCO2 and AG were more related to hot and humid laboratory conditions than they were to galloping distance. These latter variables, when combined with physical measures such as core temperature, bodyweight loss, point of fatigue on Phase C and recovery heart rates may serve as the best monitors of positive responses in future studies of proposed modifications to Phase C, rather than those variables which were more distance than weather-related.     

Single photon emission computed tomographic blood flow and magnetic resonance volume imaging of basal ganglia in Huntington''s disease

During oogenesis in Drosophila, germ cells appear in sequential clusters of 16 interconnected cells. The events surrounding the differentiation of these cells are not fully understood. Here we present genetic and morphological analysis of mutations in the gene stand still (stil). Through complementation analyses we have refined the location of this gene to cyological region 49B-C. Our analyses of ovaries from ethylmethane sulfonate (EMS)-induced mutant alleles of this gene suggest that mutations in the stil gene produce a wide range of phenotypic abnormalities, from the absence of germ cells in the most severe alleles, to egg chambers with cytoskeletal defects in the less severe alleles. Our results suggest a role for this gene in specifying or maintaining a cytoskeletal component, with consequences during oogenesis and possibly during germ line sex determination.