Mammography is the most effective method of breast cancer screening.

Screening is defined as identification of individuals within an asymptomatic population who have specified disease at a time when intervention may result in improvement of prognosis of the disease. Identification of the disease at the earlier phases of progression improves prognosis. All kinds of cancer screening may not have same benefit. Screening for breast cancer has been found to be beneficial. Randomized controlled trials and meta-analysis have shown that screening by mammography reduces breast cancer by 25% and can significantly reduce mortality from breast cancer. This article reviews methodology and bias, modalities, benefits, problems, results and current guidelines of breast cancer screening.

Immobilization of low and intermediate level of organic radioactive wastes in cement matrices.

The adequacy of cement-clay composite, for solidification/stabilization of organic radioactive spent liquid scintillator wastes and its resistance to frost attack were determined by a freezing/thawing (F/T) test. Frost resistance is assessed for the candidate cement-clay composite after 75 cycles of freezing and thawing by evaluating their mass durability index, compressive strength, apparent porosity, volume of open pores, water absorption, and bulk density. Infrared (IR), X-ray diffraction (XRD), differential thermal analysis (DTA), thermal gravimetric analysis (TGA) and scanning electron microscopy (SEM) were performed for the final waste form (FWF) before and after the F/T treatment to follow the changes that may take place in its microstructure during the hydration regime. The results were obtained indicate that the candidate composite exhibits acceptable resistance to freeze/thaw treatment and has adequate suitability to solidify and stabilize organic radioactive spent liquid scintillator wastes even at very exaggerating conditions (-50°C and +60°C).

Prevalence and risk indicators of myopia among schoolchildren in Amman, Jordan.

We aimed to identify the prevalence and risk factors of myopia among secondary-school students in Amman. Thus 1777 (1081 males and 696 females) students aged 12-17 years old were recruited from 8 schools randomly selected from 8 different geographic locations in Amman. Data were collected by questionnaire, and self-reported myopia was checked against school medical records. The prevalence of myopia was 17.6%, with no significant difference between males and females after adjusting for other possible variables. Myopia was significantly associated with age, family history of myopia, computer use, and reading and writing outside school. Playing sports was inversely associated with myopia but there was no association with watching television.

Prevalence and risk indicators of myopia among schoolchildren in Amman, Jordan

We aimed to identify the prevalence and risk factors of myopia among secondary-school students in Amman. Thus 1777 [1081 males and 696 females] students aged 12-17 years old were recruited from 8 schools randomly selected from 8 different geographic locations in Amman. Data were collected by questionnaire, and self-reported myopia was checked against school medical records. The prevalence of myopia was 17.6%, with no significant difference between males and females after adjusting for other possible variables. Myopia was significantly associated with age, family history of myopia, computer use, and reading and writing outside school. Playing sports was inversely associated with myopia but there was no association with watching television

Growth parameters and endocrine function in relation to echocardiographic parameters in children with ventricular septal defect without heart failure.

To determine the effect of ventricular function, size of ventricular septal defect (VSD), and endocrine function on linear growth in children with VSD, we studied 88 children with VSD over a period of 1 year. Growth was assessed by determining the height standard deviation scores (HtSDS) and growth velocity (GV) every 4 months. Two hundred age-matched normal children served as controls for the growth data. Endocrine evaluation was performed in 30 randomly selected children with VSD, and 20 age-matched children with constitutional delay of growth (CSS). Growth hormone (GH) response to clonidine provocation was evaluated and circulating free thyroxine (FT4) and insulin-like growth factor-I (IGF-I) concentrations measured. Echocardiographic evaluation of the different cardiac parameters including shunt size and shunt fraction (Qp/Qs) was performed using a colour-coded echodoppler. The HtSDS, body mass index (BMI), and mid-arm circumference (MAC) of children with VSD were significantly decreased compared to those for the normal control group. The dietary intake evaluated by the recall method, appeared to be adequate in the majority of these children (83/88). IGF-I concentrations were reduced in children with VSD (87.5 +/- 29 ng/ml) versus normal age-matched children (169 +/- 42 ng/ml). Basal and clonidine-stimulated GH concentrations were significantly higher in children with VSD (4.6 +/- 2.1 microg/l and 28.8 +/- 7.9 microg/l respectively) versus controls (17.8 +/- 4.2 microg/l). In these patients (n = 88) the HtSDS was correlated negatively with the size of the shunt (r = -0.793, p < 0.001), shunt fraction (Qp/Qs) (r = -0.76, p < 0.001), pulmonary mean gradient (r = -0.4, p = 0.006), and pulmonary maximum velocity (r = -0.32, p = 0.02). Growth velocity (GV) was correlated negatively with pulmonary maximum gradient (r = -0.3, p = 0.02), pulmonary maximum velocity (r = -0.37, p = 0.007), and pulmonary stroke volume (Qp) (r = -0.345, p = 0.01). The BMI and IGF-I concentrations were correlated significantly with the size of the shunt (r = -0.453, p < 0.01), Qp/Qs (r = -0.432, p < 0.01), HtSDS (r = 0.565, p < 0.01), and BMI (r = 0.435, p < 0.01). It appears that in patients with VSD, the size of the left-to-right shunt and the abnormal hemodynamics in the pulmonary circulation are important factors in the etiology of impaired growth. It is suggested that the hypermetabolic status of these patients compromise nutrition and this decreases IGF-I synthesis with subsequent slowing of linear growth and weight gain.

A unique interaction between polyamine and multidrug resistance (P-glycoprotein) transporters in cultured Chinese hamster ovary cells transfected with mouse mdr-1 gene.

We have shown that a functional link exists between the polyamine transporter and the multi-drug resistance (MDR) efflux transporter (P-glycoprotein, P-gp) in MDR-positive cancer cells. To further explore the nature of this interaction, we have examined the effect of reduced polyamine transport activity on cellular expression and activity of P-gp acquired by either selection or transfection. Chinese hamster ovary (CHO) cells and their polyamine transport-deficient mutants (CHOMGBG) were transfected with mouse mdr-1b gene. The activity of P-gp in these cells was quantified by measuring cellular accumulation of radiolabeled taxol and etoposide in the presence and absence of the P-gp modulator SDZ PSC-833 (valspodar; a semisynthetic undecapeptide derived from cyclosporin D). The mdr-1b-transfected CHO cells accumulated 2- to 3-fold less taxol and etoposide than the controls, an accumulation defect reversed by the potent MDR modulator PSC-833. Despite expression of P-gp on the surface of mdr-1b-transfected CHOMGBG cells, this classic MDR phenotype was not observed. Similarly, CHO cells, but not CHOMGBG cells, showed MDR activity after selection with doxorubicin as determined by reduced accumulation of radiolabeled taxol. Treatment with 50 microM of reduced polymer of spermine and glutaraldehyde, a selective blocker of the polyamine transport system, reduced MDR activity in mdr-1-transfected CHO cells and restored cellular accumulation of etoposide and taxol to control levels, effects not observed in mdr-1-transfected CHOMGBG cells. Notably, mdr-1-transfected CHO cells were 4- to 16-fold more resistant to the cytotoxic effects of the P-gp substrates doxorubicin, taxol, and etoposide than were the mdr-1-transfected CHOMGBG cells. CHO cells transfected with the mdr-1 gene exhibited a 23% reduction in cellular uptake of [14C]spermidine compared with untransfected controls; spermidine accumulation in CHOMGBG cells was no different than that in untransfected controls. These data suggest that the existence of a functioning polyamine transport system may be a requirement for MDR transporter activity, while the expression of functioning P-gp appears to reduce polyamine transporter activity.

A novel technique for visualizing the intracellular localization and distribution of transported polyamines in cultured pulmonary artery smooth muscle cells.

The use of a combination of monofluorescein adducts of spermidine (FL-SPD) and spermine (FL-SPM) with confocal laser scanning microscopy (CLSM) provides a useful means for monitoring the fate and time-dependent changes in the distribution of transported polyamines within living cells. Polyamine-fluorescein adducts were synthesized from fluorescein isothiocyanate and the appropriate polyamine. Monofluorescein polyamine adducts (ratio 1:1) were isolated using thin layer chromatography, and the structure and molecular weight of the monofluorescein polyamine adducts were confirmed using NMR and mass spectroscopy, respectively. The covalent linkage of the fluorescent adduct moiety to SPD and SPM did not influence their rate of uptake by bovine pulmonary artery smooth muscle cells (PASMC). Similar to 14C-SPD and 14C-SPM, the rate of uptake of 14C-FL-SPD and 14C-FL-SPM in PASMC was temperature-dependent. Treatment for 24 h with difluoromethylornithine (DFMO), a selective blocker of the enzyme ornithine decarboxylase and an inducer of the polyamine transport system, significantly increased the cellular uptake of 14C-FL-SPD and 14C-FL-SPM compared to that of control cells. When compared to control cells, treatment of PASMC with the pyrrolizidine alkaloid monocrotaline for 24 h also significantly increased the cellular uptake of 14C-FL-SPD and 14C-FL-SPM. On the other hand, 24 h treatment of PASMC with a polymer of SPM, a selective blocker of the polyamine transport system, or with free spermine, markedly reduced the cellular accumulation of 14C-FL-SPD and 14C-FL-SPM. After a 20-min treatment of PASMC with FL-SPD or FL-SPM, CLSM revealed that adduct fluorescence was localized in the cytoplasm of living cells. Treatment with DFMO increased the cytoplasmic accumulation of both FL-SPD and FL-SPM. In addition, the fluorescence observed in the cytoplasm of chinese hamster ovary cells (CHO) was significantly higher than that detected in the cytoplasm of their polyamine transport deficient variants (CHOMGBG). The results of this study provide the first evidence of the utility of a novel method for visualizing the uptake, distribution, and cellular localization of transported polyamines in viable cultured mammalian cells.

Oxidative stress mediates monocrotaline-induced alterations in tenascin expression in pulmonary artery endothelial cells.

Oxidative stress may be involved in monocrotaline (MCT)-induced endothelial cell injury and upregulation of extracellular matrix proteins in the pulmonary vasculature. To test this hypothesis, cytotoxicity, expression and distribution of tenascin (TN) as well as cellular oxidation were determined in porcine pulmonary artery endothelial cells (PAECs) exposed to MCT and/or to an oxygen radical scavenger, dimethylthiourea (DMTU). Relative to controls, treatment with 2.5 mM MCT for 24 hr produced cytotoxicity as evidenced by changes in cellular morphology, cell detachment, hypertrophy, reduction in cellular proliferation and severe cytoplasmic vacuolization. Parallel studies showed that MCT markedly altered the expression and distribution of TN in PAEC as determined by immunocytochemistry. Western analysis showed that MCT increased cellular TN content and promoted the appearance of an additional, smaller TN isoform. Northern analysis demonstrated an increase in the steady-state level of TN-specific mRNA in response to MCT treatment. Exposure to MCT also increased the synthesis of cell-associated and media-associated TN as determined by immunoprecipitation. In addition, MCT increased the intensity of cellular oxidative stress as measured by 2,7-dichlorofluorescein fluorescence. Co-treatment with DMTU prevented MCT-induced cytotoxicity, alterations in TN distribution and content, and reduced the increase in DCF fluorescence. These results suggest that MCT-induced cytotoxicity and upregulation of TN are mediated, at least in part, by induction of cellular oxidative stress.

Multiple polyamine regulatory pathways control compensatory cardiovascular hypertrophy in coarctation hypertension.

While a number of factors may initiate structural alterations within the cardiovascular system in response to hypertension, there are obligate cellular signaling mechanisms, such as the polyamines, through which they must operate. This study examined the effects of polyamine synthesis inhibition using eflornithine, a suicide inhibitor of ornithine decarboxylase on blood pressure, compensatory remodeling of the cardiovascular system, and cardiac and aortic polyamine contents using an aortic coarctation model in rats. Eflornithine treatment failed to reduce carotid arterial blood pressure and actually significantly elevated vascular pressure above and below the coarctation site by 14 days of hypertension. Eflornithine only transiently reduced aortic polyamine content of hypertensive rats while this agent reduced coarctation-induced aortic medial wall thickening and the synthesis/deposition of fibronectin and laminin in the hypertensive aorta. Increases in left ventricular mass and polyamine content were concomitantly reduced in hypertensive rats administered eflornithine. These results suggest that multiple polyamine regulatory pathways may maintain vascular polyamine content in response to aortic coarctation; however de novo polyamine synthesis is essential for select aspects of vascular remodeling, including matrix synthesis. Cardiac tissue, in contrast, may rely principally on de novo polyamine synthesis.

Eflornithine alters changes in vascular responsiveness associated with coarctation hypertension.

This study examined the temporal effects of the polyamine synthesis inhibitor eflornithine (alpha-difluoromethylornithine) on vascular responses to KCI, norepinephrine, sodium nitroprusside and acetylcholine in aortic rings from coarctation hypertensive rats. Coarctation hypertension reduced the contractile response of aortic rings to KCI and norepinephrine, increased sensitivity (reduced the EC50 value) to norepinephrine and attenuated relaxation to acetylcholine by 14 days of hypertension. Treatment of coarctation hypertensive rats with eflornithine resulted in a normalization of the contractile intensity to KCI and norepinephrine and relaxations to acetylcholine by 14 days of hypertension. Responses to sodium nitroprusside were similar in all groups at all time points. Hyperresponsiveness to norepinephrine produced by coarctation of the aorta was not affected by eflornithine. These studies indicate that normalization of vascular function can occur in the presence of significantly elevated blood pressure upon chronic administration of eflornithine. This functional normalization correlates with eflornithine-mediated regression of structural abnormalities normally associated with pressure overload hypertension.

Polyamine regulatory processes and oxidative stress in monocrotaline-treated pulmonary artery endothelial cells.

Alterations in polyamine metabolism may be a critical mechanism of monocrotaline (MCT)-induced structural remodeling of the pulmonary vasculature. In the present study, the hypothesis that MCT, through the induction of oxidative stress, modulates cellular polyamine regulatory mechanisms which in turn might be involved in the upregulation of fibronectin production in pulmonary artery endothelial cells (PAEC) was examined. A 24-h treatment with MCT significantly increased PAEC polyamine concentrations as compared to vehicle-treated cells. In addition, exposure to MCT caused an increase in abundance of ornithine decarboxylase (ODC) mRNA, upregulation of ODC activity and enhancement of spermidine import into PAEC. Inhibition of de novo polyamine synthesis further increased spermidine uptake in MCT-treated cells. The depletion of cellular polyamine contents through the blockade of both de novo polyamine biosynthesis and polyamine transport prevented MCT-induced increases in the medium level of fibronectin. In addition, PAEC treatment with MCT stimulated cellular oxidative stress as determined by increased levels of thiobarbituric acid reactive substances, enhanced dichlorofluorescein fluorescence and activation of NF-kappa B. A co-treatment with dimethylthiourea, an oxygen radical scavenger, prevented MCT-induced increases in cellular oxidation and attenuated disturbances in polyamine metabolism. These data suggest that MCT can stimulate polyamine regulatory processes in PAEC possibly through an increase in cellular oxidative stress. The present study may have significant implication in understanding mechanisms of MCT-induced pulmonary hypertension and remodeling of pulmonary vasculature.

Tenascin synthesis, deposition, and isoforms in monocrotaline-induced pulmonary hypertensive rat lungs.

Monocrotaline (MCT)-induced pulmonary hypertension is characterized by alterations in vascular extracellular matrix and neomuscularization of small blood vessels. Tenascin (TN) is a matrix glycoprotein which modulates cellular attachment, proliferation, and migration. The present study used immunohistochemistry and Northern analyses to examine the hypothesis that treatment of rats with the potent pneumotoxin MCT induces temporal alterations in TN synthesis/deposition in the affected lungs. MCT produced progressive pathological alterations in the cardiopulmonary system, including increased dry lung weight, right ventricular hypertrophy, and pulmonary hypertension by days 7, 14, and 21, respectively. TN positive foci were first observed in the parenchyma surrounding small muscularized pulmonary arteries in MCT-treated rats at day 4; these foci became both more pronounced and frequent as the disease progressed. TN was also observed in the media of the intrapulmonary artery at day 21. Northern analysis demonstrated increases in TN transcripts in MCT-treated rats as early as day 1. Furthermore, a unique transcript, apparently lacking some fibronectin type III-like units, was observed in mRNA extracted from these rats. These data demonstrate alterations in TN synthetic capacity and focal increases in TN deposition in lungs from MCT-treated rats and suggest that TN may be associated with the pathogenesis of pulmonary hypertension.

Temporal alterations in basement membrane components in the pulmonary vasculature of the chronically hypoxic rat: impact of hypoxia and recovery.

The hypoxic model of pulmonary hypertension was used to examine temporal alterations in the deposition of the basement membrane (BM) and components of fibronectin, laminin, and Type IV collagen within vascular, airway, and gas exchange compartments of the lung. Because hypoxic pulmonary hypertension is a reversible model of hypertension, changes in fibronectin and laminin synthesis/deposition in the recovering lung were also examined. Long-term hypoxic exposure produced decreases in body weight, increased right ventricular and lung dry weights and elevations in pulmonary arterial pressure. Immunohistochemical analysis revealed consistent and progressive increases in the deposition of fibronectin and laminin, but not type IV collagen, in the subendothelial and medial BMs of large and small pulmonary arteries, but not in airways or lung parenchyma. These changes were observed by day 4 of hypoxia and were most prominent in the conducting vasculature. Northern analysis showed a biphasic pattern of alterations in steady-state levels of BM component mRNA in hypoxic rats with early reductions at days 4 and 7 followed by increases at day 12. Recovery from 12 days of hypoxia resulted in regression of pulmonary hypertension and right ventricular hypertrophy but not increased lung weight. Immunohistochemical analysis of fibronectin, laminin, and type IV collagen levels in the vasculature showed a temporal regression to levels that were not remarkably different from time-matched controls at day 30 of recovery. Northern analysis of lungs from hypoxic-recovery rats revealed increased steady-state levels of mRNA for fibronectin, laminin, and type IV collagen at all time points. These data indicate that long-term hypoxic exposure elicits marked alterations in the synthetic capacity and deposition of the important cell attachment BM glycoproteins fibronectin and laminin. In addition, recovery from hypoxia appears to be characterized by a lack of increased fibronectin and laminin levels in the conducting vasculature, suggesting a marked and rapid reorganization of the vascular BMs on both hypoxic exposure and recovery from hypoxia.

The potential of a novel polyamine transport inhibitor in cancer chemotherapy.

The polyamines, putrescine (PUT), spermidine (SPD) and spermine (SPM), are a family of low molecular weight organic cations that are essential for cell growth, differentiation and neoplastic transformation. The marked compensatory increase in extracellular polyamine influx may be a reason for the unsatisfactory clinical chemotherapeutic effect of polyamine synthesis blockers like difluoromethylornithine (DFMO). In this study, a polymeric conjugate of SPM (poly-SPM) that blocks the import of polyamines into mammalian cells was used to test the potential therapeutic exploitation of the polyamine transport system in anticancer therapy. Our results indicate that a temperature-dependent polyamine transport system is expressed in two human cancer cell lines, MES-SA uterine sarcoma cells, K562 leukemic cells and their respective multiple drug resistance (MDR) positive counterparts, Dx5 and K562/R7 cells. The V(max) values for 14C-PUT and 14C-SPD uptake were significantly higher in MES-SA than in Dx5 cells, whereas the respective Km values were significantly lower. Addition of 20 microM poly-SPM reduced both the uptake of 14C-polyamines and the cellular polyamine contents in both cancer cell lines. In addition, the poly-SPM conjugate evoked a concentration-dependent cytotoxicity in MES-SA and K562 cells and their MDR-positive variants. Presence of aminoguanidine, an amine oxidase blocker, failed to alter the IC50 values generated with poly-SPM, which indicates that this polymer is not a substrate for amine oxidase. Moreover, coadministration of 25 microM SPD reversed the cytotoxic effect exerted by poly-SPM on both the MES-SA and Dx5 cells as reflected by an increase in their IC50 values. Relative to parental cells, the MDR-positive variants exhibited a lower 14C-polyamine uptake rate and were more resistant to the cytotoxic effect of poly-SPM. Pretreatment with 1 mM DFMO for 24 hr significantly increased polyamine transport, but failed to reduce intracellular SPM contents or exert a cytotoxic effect in both cancer cell lines. On other hand, the combination of DFMO and poly-SPM produced a greater depletion of polyamine content accompanied by a higher cytotoxicity than either agent alone. These results provide the first direct evidence that pharmacologic interruption of polyamine uptake may be an effective approach to cancer therapy. In addition, it appears that expression of MDR influences polyamine transport and renders cells more resistant to the cytotoxic effects of SPM polymer.

RGD-containing peptides induce endothelium-dependent and independent vasorelaxations of rat aortic rings.

Peptides containing the extracellular matrix peptide cell attachment sequence RGD possess potent, endothelium-dependent vasorelaxant properties. In the present study, the ability of RGD-containing peptides to cause vasorelaxation in the presence and absence of a functional endothelium was examined in rat aortic rings along with the ability of RGD-containing peptides to increase cGMP production in these vessels. The active RGD-containing peptide GRGDNP induced rapid relaxation in endothelium-intact, norepinephrine contracted rat aortic rings. When the endothelium was removed, RGD-containing peptides produced a slow relaxation of contracted rings which took approx. 40 min to reach maximum relaxation. Control RGD peptides were without effect either in the presence or absence of a functional endothelium. While acetylcholine and sodium nitroprusside stimulated cGMP production in endothelium-intact and denuded aortic segments, neither the control RGD peptide nor the active GRGDNP increased cGMP in these vessels when compared to controls upon either short (30 s) or long (45 min) incubation times. These data indicate that relaxations of rat aortic rings in response to RGD-containing peptides occur both in the presence and absence of an intact endothelium and that cGMP is likely not the sole mediator of these responses.

Reversal of doxorubicin, etoposide, vinblastine, and taxol resistance in multidrug resistant human sarcoma cells by a polymer of spermine.

We have previously described the synthesis of a cytotoxic polymeric conjugate of spermine (Poly-SPM) which is able to inhibit the transport of polyamines (spermine, spermidine, and putrescine) into normal and malignant cells. Recent studies examining the toxicity of Poly-SPM in parental and multidrug resistant (MDR) cancer cells have revealed a cross-resistance in the MDR variant Dx5 to the toxic effects of the conjugate in the MDR-positive cells. There were also differences in spermine and putrescine uptake rates between parental and MDR-positive with the MDR-positive cells having a lower Vmax and a higher Km. The ability of this Poly-SPM to reverse MDR was examined in MDR variants (Dx5 cells) of the human sarcoma cell line MES-SA. The cells express high levels of the mdr1 gene product, P-glycoprotein, and are 25-to 60-fold resistant to doxorubicin (DOX), etoposide (VP-16), vinblastine (VBL), and taxol (TAX). Cytotoxicity was measured by the MTT [3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. Poly-SPM (50 microM) lowered the drug concentration IC50 values in the Dx5 cells by 37-fold with VBL, 42-fold with DOX, 29-fold with VP-16, and 25-fold with TAX when compared to the control IC50 values without Poly-SPM. This reversal of resistance was concentration dependent, decreasing 17-fold with DOX, 6.1-fold with VBL, 19-fold with VP-16, and 5-fold with TAX when 25 microM Poly-SPM was used. No modulation was observed in the parental cell line MES-SA, which does not express the mdr1 gene. Poly-SPM had no influence on the IC50 of non-MDR chemotherapeutic agents such as cisplatin. The modulation studies correlated with the ability of Poly-SPM to reverse the cellular accumulation defect of [3H]-VBL and [3H]-TAX in the Dx5 but not MES-SA cells. Pretreatment of the Dx5 cell with alpha-difluoromethylornithine (DFMO at 2 and 5 microM) for 24 h increased the function of the MDR transporter to further decrease the cellular accumulation of VBL and TAX when compared to untreated cells. DFMO pretreatment is known to upregulate the polyamine transporter(s). These findings show that, in addition to inhibiting polyamine transport, Poly-SPM reverses MDR in Dx5 cells, suggesting a potential relationship between the polyamine influx transporter and the MDR efflux pump. This potential functional link between the polyamine influx transporter(s) and the MDR efflux transporter (P-glycoprotein) offers a novel approach to inhibiting this form of drug resistance.

A novel polymeric spermine conjugate inhibits polyamine transport in pulmonary artery smooth muscle cells.

The polyamines putrescine, spermidine and spermine (SPM) are low molecular weight organic cations that play essential intracellular regulatory roles in cell growth and differentiation. Whereas both de novo polyamine synthesis and transmembrane transport regulate cell polyamine contents, exploitation of pathways as pharmacologic targets has been limited by the lack of agents which specifically block polyamine transport. We now report the synthesis and biologic activity of novel polymeric glutaraldehyde conjugates of putrescine, spermidine and SPM which act at the cell membrane to inhibit polyamine uptake in cultured bovine pulmonary artery smooth muscle cells. Each conjugate caused dose-related inhibition of [14C]polyamine transport in pulmonary artery smooth muscle cells with the polymeric SPM conjugate being most effective in inhibiting the uptake of all three polyamines. Polymeric SPM failed to impair uptake of neutral or charged amino acids or to associate with pulmonary artery smooth muscle cells in a temperature-dependent manner. The polymeric SPM conjugate caused substantial decreases in cell polyamine contents which were associated with concentration-dependent cytotoxicity. Spectroscopic analyses of the polymeric SPM conjugate indicated that its molecular weight was 25 +/- 0.5 kDa, which is equivalent to approximately 90 monomeric--HN(CH2)3NH(CH2)4NH(CH2)3NH(CH2)5--units. These findings indicate that reduced polymeric glutaraldehyde conjugates of the polyamines may function as specific inhibitors of polyamine transport and thus provide a basis for examination of polyamine transport as a pharmacologic target in disorders characterized by dysregulated cell growth and differentiation.

Enhanced efficacy of praziquantel treatment in mice vaccinated with radiation attenuated cercariae of Schistosoma mansoni.

Normal, and vaccinated mice four weeks previously with radiation attenuated cercariae of S. mansoni (500/mouse) were challenged with normal cercariae (150/mouse), then treated one week later with praziquantel (400 mg/kg body weight, orally). Worm burden was determined to calculate the % immunity in all groups under study. Histopathological examination of liver, small and large intestine, spleen and lung was done. Serum IgE level was estimated using the immunoradiometric assay. (IRMA). The % immunity was highest among vaccinated, infected and treated group with minimal pathological changes recorded and highest IgE level. From the data collected, it was found that, the efficacy of praziquantel treatment was enhanced in vaccinated mice and that there was synergistic effect between drug treatment and vaccination when praziquantel was given seven days post-infection (challenge).

Effect of praziquantel on sex hormone levels in murine schistosomiasis mansoni.

Changes in sex hormonal levels were studied in Schistosoma mansoni infected and praziquantel treated mice (400 x 2 mg/Kg), drug control and in normal control groups. It was observed that schistosomiasis lead to increase in the level of testosterone, progesterone and 17B-esteradiol, 60 and 70 days postinfection in male and female mice, respectively. In praziquantel treated group the level of testosterone was lowered 10, 20 & 30 days post treatment, progesterone and 17 beta-estradiol fell 30 days post treatment after primary rise. The mechanism of recorded changes will be discussed in details.

Monocrotaline alters type II pneumocyte morphology and polyamine regulation.

Lungs from monocrotaline (MCT)-treated rats exhibit altered polyamine metabolism and content. One of the prominent morphological abnormalities in MCT-treated lungs is a decrease in population density of type II pneumocytes. Against this background, the present study tested the hypothesis that failure to maintain normal population density of type II pneumocytes is associated with MCT-induced derangements in polyamine biosynthesis and/or transmembrane polyamine transport. After a 24-hr treatment, cultured type II pneumocytes exhibited numerous vacuoles at the highest dose of 3.2 mM MCT but not at the lower dose of 1.6 mM MCT. Intracellular spermidine content was significantly reduced at the highest dose of MCT. Relative to controls, the abundance of mRNA for both ornithine decarboxylase, and S-adenosylmethionine decarboxylase, key regulatory enzymes in polyamine synthesis, was not altered. However, the activities of both of these enzymes were dramatically reduced. Increased mRNA for the catabolic polyamine enzyme, spermine/spermidine-N1-acetyltransferase (SAT), paralleled significant increases in SAT activity. MCT also caused a concentration-related inhibition of spermidine uptake in type II cells, characterized by a fourfold decrease in Vmax with little change in Km. These results show that MCT alters type II pneumocyte polyamine regulatory mechanisms and may help explain the decreased population density of type II pneumocytes in MCT-treated rats.