The nephrotic syndrome in Nigerian children is known to be largely associated with the endemicity of quartan malaria. Routine thyroid function studies were carried out on 24 children with clinical and biochemical evidence of the nephrotic syndrome. The children, aged four to 14 years, were all in the active phase of their disease, presenting with facial and pedal oedema and ascites. There was severe hypoalbuninaemia [mean (S.E.); 19.2 (1.1) g/l], hypercholesterolaemia; 10.5 (1.0) mmol/l and severe albuminuria ranging from 1 to 10 g/l. There was no clinical evidence of thyroid disease. The results of thyroid function tests in these children were compared with those of 181 apparently healthy children of the same age range. The mean total serum thyroxine levels (S.E.) were 118.3 (2.6) and 50.0 (6.4) nmol/l in controls and patients, respectively; T3 resin uptake values were 29.8 (0.2)% and 33.1 (1.2)%; the free thyroxine index (FTI) was 34.7 (0.8) and 16.7 (1.9) while thyrotropin (TSH) levels were 4.8 (0.2) and 10.6 (1.0) mU/l (IRP. MRC 68/38), respectively. The findings of low levels of thyroxine and FTI in association with high levels of TSH suggest that a state of primary hypothyroidism exists in these nephrotic children.

Measurement of free thyroxin (FT4) by a recently introduced commercial assay (Amerlex Free T4 RIA) was compared with the calculated free thyroxin index (FT4I) for serum from 104 postpartum women. Of these, 63 had transient thyroid dysfunction due to autoimmune thyroiditis, six had transient Graves' thyrotoxicosis, and 35 were euthyroid with no signs of autoimmune thyroid disease. The correlation between results for FT4 and the calculated FTI for 95 serum samples from women with no signs of autoimmune thyroiditis (r = 0.941; p = 0.0001) was almost identical to that for 270 serum samples from women with thyroid microsomal autoantibodies characteristic of autoimmune thyroiditis (r = 0.937; p = 0.0001). Furthermore, we observed no difference when the autoimmune group was subdivided according to low or high titers of thyroid microsomal antibodies. In no case did autoantibodies to thyroxin interfere with the FT4 assay. However, one woman had a spuriously low value for FT4I owing to interference by autoantibodies to triiodothyronine with the triiodothyronine resin uptake test. We conclude that the FT4 RIA assay provided diagnostic information in this group of postpartum women equivalent to that of the more elaborate procedure of determining FT4I.

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder maintained by cancer stem cells. To target this population, we investigated the mechanism of action of BMS-214662, developed as a farnesyl transferase inhibitor (FTI) and unique in inducing apoptosis in these cells. By contrast, a related congener and equally effective FTI, BMS-225975 does not induce apoptosis, indicating a novel mechanism of action. BMS-214662 significantly and selectively induced apoptosis in primitive CD34(+)38(-) CML compared with normal cells. Apoptosis proceeded via the intrinsic pathway: Bax conformational changes, loss of mitochondrial membrane potential, generation of reactive oxygen species, release of cytochrome c, and caspase-9/3 activation were noted. Up-regulation of protein kinase Cbeta (PKCbeta), down-regulation of E2F1, and phosphorylation of cyclin A-associated cyclin-dependent kinase 2 preceded these changes. Cotreatment of CML CD34(+) and CD34(+)38(-) cells with PKC modulators, bryostatin-1, or hispidin markedly decreased these early events and the subsequent apoptosis. None of these events was elicited by BMS-214662 in normal CD34(+) cells or by BMS-225975 in CML CD34(+) cells. These data suggest that BMS-214662 selectively elicits a latent apoptotic pathway in CML stem cells that is initiated by up-regulation of PKCbeta and mediated by Bax activation, providing a molecular framework for development of novel therapeutics.

Histological changes in the contralateral testis in 8 prepubertal children whose ages ranged from 3 to 7.5 years with a history of testicular torsion and subsequent atrophy were studied. The following histological parameters were evaluated: fertility tubular index (FTI), Sertoli cell index (SCI) and minimum tubular diameter (MTD). According to our findings and following Nistal and Paniagua's classification (1984) for tubular alterations, we found 5 cases (62.5%) who present the following alterations. Type 1 (case 2): FTI was decreased above 50% corresponding to slight germinal hypoplasia with normal MTD and SCI. Type 2 (cases 3 and 5): testis with remarkable germinal hypoplasia; FTI was between 30 and 50% while MTD was below normal values. Type 3 (case 8): testis with diffuse tubular hypoplasia; FTI was below 30%, whereas MTD showed 33% decrease regarding normal values. Type 4 (case 6): testes with hyperplasia of Sertoli cells; SCI was increased one third with regard to that corresponding to his age; FTI showed severe hypoplasia of germ cells. No relationship between alterations in either the age of the patients or the time elapsed since the torsion was observed. Because of all these facts and the young age of our patients, we believe that the alterations found in the contralateral testis were due to congenital dysgenesia.

OBJECTIVE

We aimed to assess the impact of task demands and individual characteristics on threat detection in baggage screeners.

BACKGROUND

Airport security staff work under time constraints to ensure optimal threat detection. Understanding the impact of individual characteristics and task demands on performance is vital to ensure accurate threat detection.

METHODS

We examined threat detection in baggage screeners as a function of event rate (i.e., number of bags per minute) and time on task across 4 months. We measured performance in terms of the accuracy of detection of Fictitious Threat Items (FTIs) randomly superimposed on X-ray images of real passenger bags.

RESULTS

Analyses of the percentage of correct FTI identifications (hits) show that longer shifts with high baggage throughput result in worse threat detection. Importantly, these significant performance decrements emerge within the first 10 min of these busy screening shifts only.

CONCLUSIONS

Longer shift lengths, especially when combined with high baggage throughput, increase the likelihood that threats go undetected.

CONCLUSIONS

Shorter shift rotations, although perhaps difficult to implement during busy screening periods, would ensure more consistently high vigilance in baggage screeners and, therefore, optimal threat detection and passenger safety.

BACKGROUND

We showed in a previous study that prenylated proteins play a role in estradiol stimulation of proliferation. However, these proteins antagonize the ability of estrogen receptor (ER) alpha to stimulate estrogen response element (ERE)-dependent transcriptional activity, potentially through the formation of a co-regulator complex. The present study investigates, in further detail, how prenylated proteins modulate the transcriptional activities mediated by ERalpha and by ERbeta.

METHODS

The ERE-beta-globin-Luc-SV-Neo plasmid was either stably transfected into MCF-7 cells or HeLa cells (MELN cells and HELN cells, respectively) or transiently transfected into MCF-7 cells using polyethylenimine. Cells deprived of estradiol were analyzed for ERE-dependent luciferase activity 16 hours after estradiol stimulation and treatment with FTI-277 (a farnesyltransferase inhibitor) or with GGTI-298 (a geranylgeranyltransferase I inhibitor). In HELN cells, the effect of prenyltransferase inhibitors on luciferase activity was compared after transient transfection of plasmids coding either the full-length ERalpha, the full-length ERbeta, the AF-1-deleted ERalpha or the AF-2-deleted ERalpha. The presence of ERalpha was then detected by immunocytochemistry in either the nuclei or the cytoplasms of MCF-7 cells. Finally, Clostridium botulinum C3 exoenzyme treatment was used to determine the involvement of Rho proteins in ERE-dependent luciferase activity.

RESULTS

FTI-277 and GGTI-298 only stimulate ERE-dependent luciferase activity in stably transfected MCF-7 cells. They stimulate both ERalpha-mediated and ERbeta-mediated ERE-dependent luciferase activity in HELN cells, in the presence of and in the absence of estradiol. The roles of both AF-1 and AF-2 are significant in this effect. Nuclear ERalpha is decreased in the presence of prenyltransferase inhibitors in MCF-7 cells, again in the presence of and in the absence of estradiol. By contrast, cytoplasmic ERalpha is mainly decreased after treatment with FTI-277, in the presence of and in the absence of estradiol. The involvement of Rho proteins in ERE-dependent luciferase activity in MELN cells is clearly established.

CONCLUSIONS

Together, these results demonstrate that prenylated proteins (at least RhoA, RhoB and/or RhoC) antagonize the ability of ERalpha and ERbeta to stimulate ERE-dependent transcriptional activity, potentially acting through both AF-1 and AF-2 transcriptional activities.

BACKGROUND

Intradural transection of the filum terminale (FTI) is often used to treat tethered cord syndrome. Recently, some have proposed that the extradural part of the filum terminale (FTE) can be sectioned with equal results but with fewer complications. Therefore, the present cadaveric study aimed to evaluate the anatomical foundation of such procedures.

METHODS

A posterior lumbosacral approach was performed on five fresh-frozen cadaveric specimens to expose both the FTI and FTE. Tension was then applied to the FTE and observations and measurements made of any movement of the FTI. Other morphological measurements (e.g., length, diameter) of the FTI and FTE were also made.

RESULTS

Although very minimal movement of the FTI was seen in the majority of specimens following tension on the FTE, no specimen was found to have more cranial movement of the conus medullaris or cauda equina. The mean length and diameter of the FTI was 52.2 and 0.38 mm, respectively. The mean length and diameter of the FTE was 77 and 0.60 mm, respectively. The force necessary to move the FTI with tension applied to the FTE had a mean of 0.03 N. The average distance that the FTI moved with distal FTE tension was 1.33 mm. All specimens had a thecal sac that terminated at the S2 vertebral level. And no specimen had a low-lying conus medullaris, cutaneous stigmata of occult spinal dysraphism, or grossly visible adipose tissue in either the FTI or FTE.

CONCLUSIONS

Based on our studies, tension placed on the FTE has very little effect on the FTI and no obvious effect on the conus medullaris or cauda equina. Therefore, isolated transection of the FTE for a patient with tethered cord syndrome is unlikely to have significant effect. To our knowledge, this is the first study to quantitate the distal forces needed on the FTE to move the FTI.

Previous studies have demonstrated that mitogen-activated protein kinase (MAPK) is involved in the pathogenesis of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). Ras, an upstream regulator of MAPK, may be activated following SAH. The aim of this study was to investigate the role of Ras in cerebral vasospasm in a rabbit model of SAH. We first investigated the time course of Ras and ERK1/2 activation in the basilar artery after SAH. Next, for the time point at which Ras was maximally activated, we assessed the effect of FTI-277 (a Ras farnesyltransferase inhibitor) on cerebral vasospasm. SAH was induced by injecting autologous blood into the cisterna magna on both day 0 and day 2. FTI-277 was injected into the cisterna magna every 24 hours, beginning 30 minutes after blood injection to the last day of the experiment. Elevated expression of Ras-GTP and phosphorylated ERK1/2 was detected in the basilar artery after SAH and expression peaked on day 3. FTI-277 administration resulted in lower Ras-GTP and phosphorylated ERK1/2 levels and markedly attenuated vasospasm in the basilar arteries relative to animals that did not receive FTI-277. Our results suggest that Ras protein is activated in the arterial wall after SAH and contributes to vasospasm development.

OBJECTIVE

This study aimed to evaluate feasibility and safety as well as 1-year clinical outcome of pulmonary vein isolation (PVI) using a unique radiofrequency ablation catheter ("Thermocool SmartTouch SurroundFlow"; STSF) incorporating both, contact force (CF) sensing technology and enhanced tip irrigation with 56 holes, in one device.

METHODS

A total of 110 patients suffering from drug-refractory atrial fibrillation underwent wide area circumferential PVI using either the STSF ablation catheter (75 consecutive patients, study group) or a CF catheter with conventional tip irrigation ("Thermocool SmartTouch", 35 consecutive patients, control group). For each ablation lesion, a target CF of ≥ 10-39 g and a force time integral (FTI) of>> 400 g s was targeted.

RESULTS

Acute PVI was achieved in all patients with target CF obtained in>> 85% of ablation points when using either device. Mean procedure time (131.3 ± 33.7 min in the study group vs. 133.0 ± 42.0 min in the control group; p = 0.99), mean fluoroscopy time (14.0 ± 6 vs. 13.5 ± 6.6 min; p = 0.56) and total ablation time were not significantly different (1751.0 ± 394.0 vs. 1604.6 ± 287.8 s; p = 0.2). However, there was a marked reduction in total irrigation fluid delivery by 51.7% (265.52 ± 64.4 vs. 539.6 ± 118.2 ml; p < 0.01). The Kaplan-Meier estimate 12-month arrhythmia-free survival after the index procedure following a 3-month blanking period was 79.9% (95% CI 70.4%, 90.4%) for the study group and 66.7% for the control group (95% CI 50.2%, 88.5%). This finding did not reach statistical significance (p = 0.18). Major complications occurred in 2/75 patients (2.7%; one pericardial tamponade and one transient ischemic attack) in the study group and no patient in the control group (p = 18).

CONCLUSIONS

PVI using the STSF catheter is safe and effective and results in beneficial 1-year clinical outcome. The improved tip irrigation leads to a significant reduction in procedural fluid burden.

BACKGROUND

Adequate catheter/atrial tissue contact is critical for lesion formation during radiofrequency (RF) ablation of atrial fibrillation (AF). Late gadolinium enhancement magnetic resonance imaging (LGE-MRI) is a unique tool for the evaluation of lesion formation and detection of acute esophageal injury.

METHODS

LGE-MRIs were obtained prior, within 24 hours of, and at 115 ± 62 days after first AF ablation in 36 patients. The Visitag module of CARTO3 was used to collect contact force (CF) and duration from a CF sensing ablation catheter for each registered ablation point. The minimum CF resulting in permanent lesions was determined. Esophageal enhancement detected by acute LGE-MRI was classified as mild, moderate, and severe. The CF resulting in esophageal enhancement was determined.

RESULTS

A total of 4,642 registered ablation tags at 50 W power were analyzed. The mean RF duration (5.9 ± 3.7 vs. 5.6 ± 3.2 seconds, P < 0.05), CF (11.5 ± 5.6 vs. 10.9 ± 5.4 g, P < 0.001), and force time integral (FTI) (67.3 ± 54.5 vs. 62.2 ± 52.7 gs, P < 0.01) were significantly higher between ablation tags with and without associated LGE-MRI detected scar. The mean CF (15.7 ± 6.1 vs. 12.6 ± 5.9 g, P < 0.05, n = 17 patients) in areas of esophageal enhancement was greater than areas without.

CONCLUSIONS

Left atrial short duration ablation lesions with a CF greater than 12 g are more likely to be associated with permanent lesion formation. Ablating on top of the esophagus, CF less than 15 g would help minimize esophageal wall injury.

A series of amino acid-based linkers was used to investigate the effects of various substituents upon the potency, pharmacokinetic properties, and conformation of macrocyclic farnesyl-protein transferase inhibitors (FTIs). As a result of the studies described herein, highly potent FTIs with improved pharmacokinetic profiles have been identified.

Biological effectiveness is an important parameter in determining optimal dosages of molecular targeted drugs, such as farnesyl transferase inhibitors. To determine concentration-effect relationships, robust and quantitative biological assays are a prerequisite. Here, we present a novel assay for protein farnesylation that is based on generation of the biomarker farnesylmethylcysteine (FmC). Quantification was performed with liquid chromatography coupled to tandem mass spectrometry. The assay has been validated based on the most recent FDA guidelines for bioanalytical validation, and all results were within requirements. FmC is formed under the action of an endogenous protease that is activated upon cell lysis. The biomarker could be detected in A549 human lung cancer cells as well as in human peripheral blood mononuclear cells. Incubation of A549 cells with AZD3409, a novel prenyl transferase inhibitor, resulted in a significant decrease of the FmC concentration in the lysates. These findings provide a very good starting point for use of this assay in preclinical and clinical dose finding studies with FTIs.

In a preliminary study, 11 male patients with lepromatous leprosy were evaluated with regard to endocrinopathy and hormonal status. Basal circulating hormone levels were estimated with a view to correlating the biochemical findings and clinical features. Thyroid hormones T3 and T4, Free Thyroxine Index (FTI), TSH, and cortisol were within normal limits, indicating that further study of these hormones would not be worthwhile. The finding of elevated levels of prolactin as well as the gonadotrophins LH and FSH, however, promises to yield more valuable information if studied in greater detail in a larger group of patients.

BACKGROUND

Indians are the largest single ethnic minority group in the United Kingdom and form more than one million of the current population. No studies have investigated foot pressure differences between Caucasians and Indians.

OBJECTIVE

The aim of our study was to investigate the in-shoe pressure differences in Caucasians and Indians using the Pedar(®)-m (Novel GmbH, Germany).

METHODS

The study included 12 Caucasians and 21 Indians. Peak pressure (PP), contact area (CA), contact time (CT), pressure-time integral (PTI), force-time integral (FTI), instant of peak pressure (IPP), maximum force (MaxF) and mean force (MeanF) were recorded.

RESULTS

Caucasians had higher significant PP compared to Indians under the heel (293 kPa vs. 251 kPa; P<0.001), 1st metatarsal head (294 kPa vs. 233 kPa; P=0.01), 2nd metatarsal head (266 kPa vs. 236 kPa; P=0.03), 3rd metatarsal head (254 kPa vs. 223 kPa; P=0.04), and the 5th metatarsal head (168 kPa vs. 133 kPa; P=0.04). There was no significant difference in the contact area between the two race groups. The PTI was statistically significantly higher in Caucasians in the region of the 1st metatarsal head (79 kPas vs. 62 kPas; P=0.03) and 5th metatarsal head (58 kPas vs. 44 kPas; P=0.03). There were no significant differences among CT, FTI, IPP, MaxF and MeanF among them.

CONCLUSIONS

The PP under the heel, 1st, 2nd, 3rd and 5th metatarsal heads and the PTI under the 1st and 5th metatarsal heads in Caucasians is higher than in Indians. There is no difference in the CA.

New CA(1)A(2)X peptidomimetics are described as Ras farnesyl transferase inhibitors (FTIs). They include cysteine and methionine as mimetics of the C-terminus sequence of farnesylated proteins. Furthermore, cysteine was replaced by heterocycles, taking into account the role of zinc and the metabolic instability of amino acids. The molecular docking of 8 in the active site of the enzyme and the pharmacological evaluation of the compounds are illustrative of a new class of FTIs.

Four suites of behavioral traits have been associated with four broad neural systems: the 1) dopamine and related norepinephrine system; 2) serotonin; 3) testosterone; 4) and estrogen and oxytocin system. A 56-item questionnaire, the Fisher Temperament Inventory (FTI), was developed to define four temperament dimensions associated with these behavioral traits and neural systems. The questionnaire has been used to suggest romantic partner compatibility. The dimensions were named: Curious/Energetic; Cautious/Social Norm Compliant; Analytical/Tough-minded; and Prosocial/Empathetic. For the present study, the FTI was administered to participants in two functional magnetic resonance imaging studies that elicited feelings of love and attachment, near-universal human experiences. Scores for the Curious/Energetic dimension co-varied with activation in a region of the substantia nigra, consistent with the prediction that this dimension reflects activity in the dopamine system. Scores for the Cautious/Social Norm Compliant dimension correlated with activation in the ventrolateral prefrontal cortex in regions associated with social norm compliance, a trait linked with the serotonin system. Scores on the Analytical/Tough-minded scale co-varied with activity in regions of the occipital and parietal cortices associated with visual acuity and mathematical thinking, traits linked with testosterone. Also, testosterone contributes to brain architecture in these areas. Scores on the Prosocial/Empathetic scale correlated with activity in regions of the inferior frontal gyrus, anterior insula and fusiform gyrus. These are regions associated with mirror neurons or empathy, a trait linked with the estrogen/oxytocin system, and where estrogen contributes to brain architecture. These findings, replicated across two studies, suggest that the FTI measures influences of four broad neural systems, and that these temperament dimensions and neural systems could constitute foundational mechanisms in personality structure and play a role in romantic partnerships.

This research was carried out to define the effects on men of head-out water immersion in a bath at 38.41 +/- 0.04 degrees C (mean +/- S.E.) with a method similar to that used for therapeutical rehabilitation and time of immersion of 30 minutes. Beta-endorphin, renin activity, aldosterone, cortisol, HGH, FSH, LH, TSH, T3, T4 and prolactin haematic levels were analysed. Seventeen healthy subjects (fourteen males and three females), aged 21-65 years (mean age 29.8 +/- 2.6) were studied. Water immersion caused a decrease in FSH and LH haematic concentrations; no significant changes occurred in beta-endorphin, renin activity, aldosterone, prolactin, cortisol, HGH, TSH, T3, T4 and FTI values. Thirty minutes after the end of immersion, FSH and LH levels returned to pre-immersion values. The probable pathogenesis of these observations is suggested.

Progesterone receptor (PR) stimulation promotes survival in human and rat periovulatory granulosa cells. PR antagonists, Org 31710 and RU 486, both increase apoptosis and decrease cholesterol synthesis in these cells. The decrease in cholesterol synthesis also causes decreased synthesis of other products branching from the cholesterol synthesis pathway, including substrates for protein prenylation. In this study we focus on the link between apoptosis and prenylation in human periovulatory granulosa cells. A decreased cholesterol synthesis and increased apoptosis was verified in experiments with human periovulatory granulosa cells treated with the PR antagonists Org 31710 or RU 486 by measuring caspase-3/7 activity and incorporation of 14C-acetate into cholesterol and progesterone. Correspondingly, specific inhibition of cholesterol synthesis in periovulatory human granulosa cells using HMG-CoA reductase inhibitors (lovastatin or simvastatin) increased apoptosis, measured as caspase-3/7 activity. The increase in apoptosis caused by simvastatin or Org 31710 was partially reversed by addition of the protein prenylation precursors farnesol or geranylgeraniol. In addition, the prenylation inhibitors FTI R115777 and GGTI 2147 increased apoptosis in these cells. In conclusion our data suggest that PR antagonists increase apoptosis and reduce cholesterol synthesis in periovulatory granulosa cells and that the resulting depletion of substrates for protein prenylation may contribute to the increased apoptosis sensitivity.

6:2 Fluorotelomer iodide [6:2 FTI, F(CF2)6CH2CH2I] is the industrial raw material used to manufacture 6:2 fluorotelomer alcohol [6:2 FTOH, F(CF2)6CH2CH2OH] and 6:2 FTOH-based products. During its manufacture and industrial use, workers may be exposed to via oral, dermal or inhalation of 6:2 FTI. Therefore it is useful to understand how 6:2 FTI may be metabolized and into what transformation products. 6:2 FTI in vitro rat liver microsomal metabolism was explored for the first time to compare its biotransformation potential with that of [1,2-(14)C] 6:2 FTOH [F(CF2)6(14)CH2(14)CH2OH]. 6:2 FTI and 6:2 FTOH metabolite yields were determined in closed-bottle systems using Sprague Dawley and Wistar Han rat microsomes after incubation at 37 °C for up to 6h with NADPH (reduced form of nicotinamide adenine dinucleotide phosphate)-addition and NADPH-regenerating systems, respectively. 5:3 acid [F(CF2)5CH2CH2COOH] was the most abundant metabolite for 6:2 FTI (3.3-6.3 mol%) and 6:2 FTOH (9-12 mol%). Perfluorobutanoic acid (PFBA), perfluoropentanoic acid (PFPeA), and perfluorohexanoic acid (PFHxA) in sum accounted for 1.3-2.2 mol% from 6:2 FTI and 2.7-4.4 mol% from 6:2 FTOH biotransformation. Perfluoroheptanoic acid (PFHpA) accounted for 0.14-0.36 mol% from 6:2 FTI but only 0.01-0.06 mol% from 6:2 FTOH biotransformation. These results suggest that mammalian systems exposed to 6:2 FTI or 6:2 FTOH would form 5:3 acid, PFBA, PFPeA, PFHxA as the primary stable metabolites, whereas more PFHpA would be expected from 6:2 FTI biotransformation.

BACKGROUND

Polyfluorinated iodine alkanes (PFIs) are important intermediates in the synthesis of organic fluoride products. Recently, PFIs have been detected in fluoropolymers as residual raw materials, as well as in the ambient environment.

OBJECTIVE

High production volumes and potential environmental releases of PFIs might become a concern, but the exposure risk and toxicity of these chemicals are still unclear. In this study, we investigated the potential estrogenic effects of PFIs.

METHODS

We studied the estrogenic effects of fluorinated iodine alkanes (FIAs), fluorinated telomer iodides (FTIs), and fluorinated diiodine alkanes (FDIAs) using the E-screen and MVLN assays and the evaluation of estrogen-responsive genes in MCF-7 cells.

RESULTS

FIAs have an iodine atom at one end of the perfluorinated carbon chain. 1-Iodoperfluorohexane (PFHxI) and 1-iodoperfluorooctane (PFOI) promoted the proliferation of MCF-7 cells, induced luciferase activity in MVLN cells, and up-regulated the expression of TFF1 and EGR3. In these assays, other FIAs gave negative responses. FDIAs have an iodine atom at each end of the perfluorinated carbon chain, and all the FDIAs showed estrogenic effects. The estrogenic potencies of FIAs and FDIAs correlate well with the carbon chain length of the chemicals. The optimum chain length for estrogenic effects is six carbons, and then eight and four carbons. All FTIs have a single iodine atom at the end of a partially fluorinated carbon chain. None of the FTIs showed estrogenic effects in the tests.

CONCLUSIONS

The estrogenic effects of PFIs are dependent on the structural features of iodine substitution and chain length. This research will be helpful in further understanding the estrogenic effects of perfluorinated compounds.

The parasite Plasmodium falciparum causes severe malaria and is the most dangerous to humans. However, it exhibits resistance to their drugs. Farnesyltransferase has been identified in pathogenic protozoa of the genera Plasmodium and the target of farnesyltransferase includes Ras family. Therefore, the inhibition of farnesyltransferase has been suggested as a new strategy for the treatment of malaria. However, the exact functional mechanism of this agent is still unknown. In addition, the effect of farnesyltransferase inhibitor (FTIs) on mitochondrial level of malaria parasites is not fully understood. In this study, therefore, the effect of a FTI R115777 on the function of mitochondria of P. falciparum was investigated experimentally. As a result, FTI R115777 was found to suppress the infection rate of malaria parasites under in vitro condition. It also reduces the copy number of mtDNA-encoded cytochrome c oxidase III. In addition, the mitochondrial membrane potential (ΔΨm) and the green fluorescence intensity of MitoTracker were decreased by FTI R115777. Chloroquine and atovaquone were measured by the mtDNA copy number as mitochondrial non-specific or specific inhibitor, respectively. Chloroquine did not affect the copy number of mtDNA-encoded cytochrome c oxidase III, while atovaquone induced to change the mtDNA copy number. These results suggest that FTI R115777 has strong influence on the mitochondrial function of P. falciparum. It may have therapeutic potential for malaria by targeting the mitochondria of parasites.

The treatment of patients with chronic myeloid leukemia (CML) is evolving rapidly. With conventional chemotherapy the clinical course is characterized by a chronic phase (median duration, 4 to 5 years), followed by an accelerated phase with transition to a terminal blast crisis. Treatment with busulfan or hydroxyurea does not alter the natural history. Interferon alfa (IFN-alpha) prolongs life expectancy by approximately 20 months but is associated with significant toxicity. Evidence indicates that bone marrow transplantation from a related human leukocyte antigen (HLA)-identical donor can be curative in younger patients. However, transplantation is available to only a minority of patients and entails severe toxicity and transplant-related mortality. Dramatic advances in the understanding of the molecular pathophysiology of CML have led to a new era of targeted therapy. The specific tyrosine kinase inhibitor imatinib mesylate demonstrates a high level of efficacy in CML with acceptable toxicity. Farnesyltransferase inhibitors (FTIs) are another important class of targeted agents with the potential to act at multiple sites within dysregulated signal transduction networks. ZARNESTRA (formerly R115777, Ortho Biotech Oncology, Raritan, NJ), an oral FTI, has shown activity and is well tolerated in both chronic- and accelerated-phase patients. With their mechanistic specificity, the new modalities offer the promise of increased antileukemic activity and an improved therapeutic index.

Ras, a small GTPase protein, is thought to mediate Th2-dependent eosinophilic inflammation in asthma. Ras requires cell membrane association for its biological activity, and this requires the posttranslational modification of Ras with an isoprenyl group by farnesyltransferase (FTase) or geranylgeranyltransferase (GGTase). We hypothesized that inhibition of FTase using FTase inhibitor (FTI)-277 would attenuate allergic asthma by depleting membrane-associated Ras. We used the OVA mouse model of allergic inflammation and human airway epithelial (HBE1) cells to determine the role of FTase in inflammatory cell recruitment. BALB/c mice were first sensitized then exposed to 1% OVA aerosol or filtered air, and half were injected daily with FTI-277 (20 mg/kg per day). Treatment of mice with FTI-277 had no significant effect on lung membrane-anchored Ras, Ras protein levels, or Ras GTPase activity. In OVA-exposed mice, FTI-277 treatment increased eosinophilic inflammation, goblet cell hyperplasia, and airway hyperreactivity. Human bronchial epithelial (HBE1) cells were pretreated with 5, 10, or 20 μM FTI-277 prior to and during 12 h IL-13 (20 ng/ml) stimulation. In HBE1 cells, FTase inhibition with FTI-277 had no significant effect on IL-13-induced STAT6 phosphorylation, eotaxin-3 peptide secretion, or Ras translocation. However, addition of exogenous FPP unexpectedly augmented IL-13-induced STAT6 phosphorylation and eotaxin-3 secretion from HBE1 cells without affecting Ras translocation. Pharmacological inhibition of FTase exacerbates allergic asthma, suggesting a protective role for FTase or possibly Ras farnesylation. FPP synergistically augments epithelial eotaxin-3 secretion, indicating a novel Ras-independent farnesylation mechanism or direct FPP effect that promotes epithelial eotaxin-3 production in allergic asthma.

We investigated the effects of atorvastatin (Ator) on cardiomyocyte hypertrophy (CMH) induced by rat parathyroid hormone 1-34 (PTH1-34) and Ras-extracellular signal regulated protein kinases 1/2 (ERK1/2) signaling. Rat cardiomyocytes were randomly divided into seven groups: normal controls (NC), PTH1-34 (10(-7) mol/L), Ator (10(-5) mol/L), farnesyl transferase inhibitors-276 (FTI-276, 4 × 10(-5) mol/L), PTH1-34 + Ator, PTH1-34 + FTI-276 and PTH1-34 + Ator + mevalonic acid (MVA, 10(-4) mol/L). After treatment, the hypertrophic responses of cardiomyocytes were assessed by measuring cell diameter, detecting protein synthesis, and single-cell protein content. The concentrations of hypertrophic markers such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were measured by ELISA. Protein expressions of ERK1/2, p-ERK1/2 and Ras were detected by western blotting. The results showed that compared with the PTH1-34 group, cellular diameter, 3H-leucine incorporation, single-cell protein content, ANP and BNP concentration decreased by 12.07 µm, 1622 cpm/well, 84.34 pg, 7.13 ng/L and 20.04 µg/L, respectively, and the expressions of Ras and p-ERK1/2 were downregulated in PTH1-34 + Ator group (P < 0.05). Compared to the PTH1-34 + Ator group, the corresponding hypertrophic responses and hypertrophic markers increased by 4.95 µm, 750 cpm/well, 49.08 pg, 3.12 ng/L and 9.35 µg/L, respectively, and the expressions of Ras and p-ERK1/2 were upregulated in the PTH1-34 + Ator + MVA group (P < 0.05). In conclusion, Ator prevents neonatal rat CMH induced by PTH1-34 and Ras-ERK signaling may be involved in this process.