Inhibition of murine renal carcinoma pulmonary metastases by systemic administration of interferon gamma: mechanism of action and potential for combination with interleukin 4

We have previously demonstrated that IFN-gamma causes cell growth inhibition and up-regulation of MHC antigens in human renal cell carcinoma cell lines. In this study, we have investigated the therapeutic potential of IFN-gamma for the treatment of 5-day established pulmonary metastases induced by i.v. injection of Renca cells, a murine renal adenocarcinoma. We found that systemic injections of IFN-gamma significantly reduced the number of lung metastases in a dose-dependent manner and increased mouse survival. Histological evaluation of IFN-gamma-treated lungs showed residual small tumor nodules containing extensive necrosis and mononuclear infiltrates. Immunohistochemistry studies on lung sections showed macrophage infiltration into tumor nodules, and in vivo depletion of macrophages partially inhibited IFN-gamma antitumor effect, suggesting a role for the macrophages in tumor destruction. Lymphocyte depletion of either natural killer (NK) cells or CD4+ or CD8+ T-cell subsets or both T-cell subsets did not affect the IFN-gamma effect, whereas depletion of both NK and T cells decreased the antitumor activity of IFN-gamma. These data indicate that neither T cells nor NK cells are essential for this activity but that either lymphocyte population can contribute to the IFN-gamma effect. An optimal dose of IFN-gamma inhibited by 60% the growth of Renca cells treated for 3 days in vitro, but this effect was transient and less pronounced in a long-term colony assay, suggesting that IFN-gamma direct growth inhibition may play a role but may not be sufficient to mediate its antitumor effect in vivo. In vitro, IFN-gamma caused up-regulation of class I MHC antigens and induction of class II antigen expression in Renca cells, an effect that may enhance Renca immunogenicity but may be relevant only when a T-cell response is elicited. A sequential administration of IFN-gamma followed by interleukin 4 was therapeutically better than IFN-gamma alone for the treatment of advanced pulmonary metastases, probably due to different antitumor mechanisms induced by these two cytokines.     

Legal basis of vaccine prophylaxis in Russia]

As a complementary modality, therapeutic touch is gaining increasing recognition. Not only are nurses incorporating therapeutic touch into their daily patient care, but patients also are requesting this healing modality. Nurse leaders also use this nursing intervention to weave their vision of healing into their managerial role.     

A review of carisoprodol deaths in Jefferson County, Alabama

BACKGROUND: Carisoprodol is a skeletal muscle relaxant with the potential for abuse. A carisoprodol overdose is rarely considered fatal. Nevertheless, we encountered carisoprodol in several cases, prompting review of our experience. METHODS: We did a retrospective study of cases examined at the Jefferson County Coroner/Medical Examiner Office from January 1, 1986, to October 31, 1997, reviewing investigative reports and autopsy findings. RESULTS: Carisoprodol was present in 24 cases. Seventeen decedents died of acute drug intoxication. Carisoprodol was never the sole drug detected at autopsy, nor was it ever the sole cause of death. Propoxyphene was a co-intoxicant in 8 of the 24 cases. CONCLUSIONS: Carisoprodol causes respiratory depression. Since the mechanism of death was respiratory depression in 82% of the decedents who died of acute intoxication, we consider that carisoprodol was probably responsible, in part, for those deaths. The simultaneous use of propoxyphene and carisoprodol seems to be especially dangerous.     

A developmental study of the acquisition of Russian colour terms

We report a study of the acquisition of colour terms by Russian children which had two main aims: first, to test Berlin & Kay's (1969) theory of colour universals using acquisition order as a measure of basicness; and secondly, to see if the two BLUE terms of Russian are genuinely basic. Two hundred children aged from three to six-years-old were tested on three colour-tasks--colour term listing, colour term production and colour term comprehension. To a reasonable approximation, the order of colour term acquisition was in accord with Berlin & Kay's theory, but the data are also consistent with the weaker claim that primary terms tend to be learned before derived terms. On balance the data were consistent with Russian exceptionally, having an extra term for the BLUE region. But, the two BLUE terms--goluboj 'light blue' and sinij 'dark blue'--were confused more often than other pairs of terms even by the five- to six-year-old sample.     

Collateral blood supply through the ophthalmic artery: a steal phenomenon analyzed by color Doppler imaging

OBJECTIVE: This study aimed to evaluate the retrobulbar circulatory effects of reversed ophthalmic artery flow (ROAF) on the ophthalmic artery branches by means of color Doppler imaging. DESIGN: The design was a case-controlled study. PARTICIPANTS: Among 56 consecutive patients with severe (>70% stenosis) occlusive carotid artery disease, 15 patients (26.8%) with ROAF were identified. The control group consisted of 15 patients with similar degrees of carotid artery stenosis and forward ophthalmic artery flow. INTERVENTION: Arteriography and measurement of the retrobulbar hemodynamic parameters with color Doppler imaging were performed. MAIN OUTCOME MEASURES: Blood flow velocities and resistive index in the ophthalmic, central retinal, and temporal short posterior ciliary arteries were measured. RESULTS: Arteriography confirmed the diagnosis of ROAF in all 15 patients. There was no patient with ROAF diagnosed by arteriography and not diagnosed by color Doppler imaging. The frequency of bilateral severe occlusive carotid artery disease was significantly higher in the ROAF group (40%) compared to the control group (6.6%) (P = 0.04). Patients with ROAF showed significantly reduced vascular resistance in the ophthalmic artery (P = 0.03), higher vascular resistance, and lower blood flow velocities in the central retinal and temporal short posterior ciliary arteries (P < 0.05). CONCLUSION: This study suggests that patients with ROAF show a steal phenomenon, characterized by a shunt to the low-resistance intracranial circuit and reduction of retrobulbar blood flow.     

Segregation and integration of cytoplasmic and nuclear materials during cleavage and induced fusion of blastomeres of mouse early embryos

Phenylbutazone was administered intravenously (i.v.) to a group of four lactating cows at a dosage of 6 mg/kg body weight. Whole plasma, protein-free plasma and milk were analysed for phenylbutazone residues. Pharmacokinetic parameters of total and free phenylbutazone in plasma were calculated using a non compartmental method. In regards to whole plasma data, the mean volume of distribution at steady state (Vss), was 147 mL/kg body weight, with a mean (+/-SEM) terminal elimination half-life (t1/2) of 40+/-6 h. The mean clearance (Cl) was 3 mL/h/kg body weight. The Vss as determined from the protein-free plasma fraction was 50021 mL/kg body weight. This larger Vss of free phenylbutazone compared to total plasma phenylbutazone was attributed to a high degree of plasma protein binding, as well as the greater penetration of free phenylbutazone into tissues. The mean t1/2 of free phenylbutazone was 39+/-5 h. This similarity to the t1/2 estimated from total plasma phenylbutazone data is attributed to an equilibrium between free and plasma phenylbutazone during the terminal elimination phase. Mean t1/2 as determined from milk, applying a urinary excretion rate model, was 47+/-4 h. Milk clearance of phenylbutazone was 0.009 mL/h/kg body weight, or about 0.34% of total body clearance. Furthermore, evidence suggests that phenylbutazone either binds to milk proteins, or is actively transported into milk, as its concentration in milk was greater than that predicted due to a simple partitioning from plasma into milk.     

Life table study of Aedes aegypti (Diptera: Culicidae) in Puerto Rico fed only human blood versus blood plus sugar

Life table studies were performed in 1996 with Aedes aegypti (L.) during the low (cool/dry) and high (hot/rainy) dengue virus transmission seasons in Puerto Rico. Mated adult females from field-collected pupae were placed individually in cages and divided into 2 treatment groups: one was fed only human blood and the other human blood plus a 10% sucrose solution. Survival and number of eggs laid were recorded daily for each female. During both seasons, age specific survivorship was higher for the blood plus sugar group, groups fed only human blood had higher reproductive outputs (mx), and net replacement rates (Ro) for blood only groups were higher than for those fed blood plus sugar. Intrinsic rates of growth (r) were the same for both treatments during the low (cool/dry) transmission season, but higher for the blood-only treatment during the high (hot/rainy) transmission season. Our results indicate that feeding on only human blood provides an evolutionary advantage to Ae. aegypti females in Puerto Rico. These results are similar to those from an earlier study carried out with Ae. aegypti in Thailand; the advantage of feeding on human blood does not seem to be restricted to a particular geographic region. We also found that the benefits associated with human feeding persist through epidemiologically different times of the year. We conclude that feeding on human blood is reproductively beneficial for Ae. aegypti, which may increase their contact with human hosts, and therefore may influence their vectorial capacity for dengue viruses through frequent feeding on blood.     

Efficacy of anterior, posterior and total fundoplication in an experimental model

BACKGROUND: This study examined the effect of different types of laparoscopic fundoplication on an incompetent lower oesophageal sphincter to test their effectiveness at preventing gastro-oesophageal reflux in the early postoperative period. METHODS: An experimental porcine model was used. Initial oesophageal myotomy ensured an incompetent lower oesophageal sphincter with free reflux of 'intragastric fluid'. Anterior, posterior or total fundoplication was then performed laparoscopically in 15 laboratory pigs (five in each group). Fundoplication competence and efficacy were determined 2 weeks after laparoscopic antireflux surgery by inflating the stomach with liquid through a gastrostomy cannula. Some animals were also studied at 4 and 6 weeks. Lower oesophageal sphincter pressure was determined using a water-perfused oesophageal manometry catheter incorporating a Dent sleeve. RESULTS: All three types of fundoplication produced similar increases in postoperative resting lower oesophageal sphincter pressure and restored adequate competence to the gastro-oesophageal junction. CONCLUSION: All three variants of laparoscopic fundoplication restore gastro-oesophageal competence in the early postoperative period.     

Systemic interleukin 2 therapy for human prostate tumors in a nude mouse model

Once the regional lymph nodes become involved in prostate carcinoma, 85% of patients develop distant metastases within 5 years, and metastatic disease is difficult to treat. We have investigated the effect of systemic interleukin 2 (IL-2) treatment on metastatic prostate carcinoma using a xenograft tumor model. Cells from a PC-3/IF cell line, produced by intrafemoral injection of human PC-3 prostate carcinoma cells, were injected in the prostate of Balb/c nude mice. Prostate tumors and para-aortic lymph nodes were resected, and tumor cells were recultured and passaged in the prostate in vivo to produce new cell lines. On day 6 following prostatic injection of these cell lines, mice were treated with i.p. injections of IL-2 at 25,000-50,000 units/ day for 5 consecutive days. The effect of IL-2 on tumor progression was assessed, and histological studies were performed on prostate tumor and lymph node sections. The tumor cell lines generated by serial prostate injection were tumorigenic and metastasized to regional para-aortic lymph nodes. Tumors of 0.4 cm were obtained by day 16 and grew to 1-1.5 cm by day 40 with metastasis to para-aortic lymph nodes. Following two to three weekly courses of 5 days of 25,000-40,000 units/day of IL-2, the growth of prostate tumors was inhibited by 94%. Higher doses of 50,000 units/ day were toxic. Histologically, prostate sections showed vascular damage manifested by multifocal hemorrhages and an influx of lymphocytes and polymorphonuclear cells into disintegrating tumors and areas of necrosis containing numerous apoptotic cells. In contrast to control mice, para-aortic lymph nodes were not enlarged in responding mice. These findings suggest that systemic IL-2 therapy can induce an antitumor response in prostate tumors and control their growth and metastasis.     

Protein-protein and protein-DNA interactions in the type I restriction endonuclease R.EcoR124I

The type I restriction-modification system EcoR124I recognizes and binds to the split DNA recognition sequence 5'-GAAN(6)RTCG-3'. The methyltransferase, consisting of HsdM and HsdS subunits with the composition M2S, can interact with one or more subunits of the HsdR subunit to form the endonuclease. The interaction of the methyltransferase with HsdR has been investigated by surface plasmon resonance, showing that there are two non-equivalent binding sites for HsdR which differ in binding affinity by at least two orders of magnitude. DNA footprinting experiments using Exonuclease III suggest that the addition of HsdR to the methyltransferase (at a stoichiometry of either 1:1 or 2:1) increases the stability of the resulting DNA-protein complex but does not increase the size of the footprint. More extensive in situ footprinting experiments using copper-phenanthroline on the DNA-protein complexes formed by M2S, R1M2S and R2M2S also show no difference in the detailed cleavage pattern, with approximately 18 nucleotides protected on both strands in each complex. Thus the HsdR subunit(s) of the endonuclease stabilise the interaction of the M2S complex with DNA, but do not directly contribute to DNA binding. In addition, the thymidine nucleotide in the tetranucleotide recognition sequence GTCG is hyper-reactive to cleavage in each case, suggesting that the DNA structure in this region is altered in these complexes.