The hypothesis that pharmacologic inhibitors of Ras can be effective anti-cancer agents has led to the development of Farnesyltransferase inhibitors (FTIs). These agents inhibit the requisite processing of a number of cellular proteins including Ras. FTIs have shown good anti-tumor efficacy and little toxicity in preclinical models and based on these results, numerous clinical trials are currently underway to evaluate the clinical potential of these agents in patients with cancer. However, contrary to the ideas that led to their design, mechanistic studies have not confirmed that they inhibit tumors through the inhibition of Ras. FTIs inhibit the growth of a broad variety of human tumor cells in vitro and studies to date have not identified cellular characteristics that predict the antitumor efficacy of this class of agents. We have studied a panel of breast cancer cell lines that differ widely in their sensitivity to FTI in order to determine which molecular characteristics may determine sensitivity to this class of agents. In these cells we find that FTI sensitivity does not correlate with the relative expression of Ras isoforms or the inhibition of Ras processing, growth factor signaling, expression of estrogen receptor or the overexpression of growth factor receptors. Looking for other molecular correlates of FTI sensitivity we have compared the activity of farnesylprotein transferase (FPTase) among these cells and although we find no overall correlation with FTI sensitivity, we find that two cell lines with unusually low FPTase activity are sensitive. Comparing p53 genotype with FTI-sensitivity we find that although most cell lines in our panel have mutant p53, all three cell lines with wild-type p53 are quite sensitive to FTI. In fact, MCF-7 cells which have both wild-type p53 and the lowest FPTase activity are the most FTI-sensitive cell type we have ever seen. Although these studies do not identify any single molecular marker that can accurately predict FTI sensitivity in breast tumors, they highlight the potential roles of FPTase activity and p53 function for further analysis.

Farnesyl transferase inhibitors (FTIs) are a novel class of anti-cancer agents that competitively inhibit farnesyl protein transferase (FTase). Initially developed to inhibit the prenylation necessary for Ras activation, their mechanism of action seems to be more complex, involving other proteins unrelated to Ras. FTIs have been developed and tested across a wide range of human cancers. At least 3 agents within this family have been investigated in hematologic malignancies. These are tipifarnib (R115777, Zarnestra), lonafarnib (SCH66336, Sarasar), both of which are orally administered, and BMS-214662, which is given intravenously. Preliminary results from clinical trials demonstrate enzyme target inhibition, a favorable toxicity profile and promising efficacy. Ongoing studies will better determine their mechanism of action and the role of combination with other agents, defining their place in the therapeutic arsenal of hematologic disorders.

Protein farnesylation is required for the localization and function of several proteins pivotal to signal transduction pathways and cytoskeletal organization, among which are the ras proteins. Mutations in one family member K-ras occur in 50% of non-small cell lung cancer and have been associated with poor prognosis. Because the ability of ras to induce malignant transformation depends on its plasma membrane localization, farnesyltransferase inhibitors (FTIs) were designed to curtail ras-mediated aberrant signals, which stimulate cell proliferation, apoptosis, invasion, and angiogenesis. However, current evidence suggests that the antitumor activity of FTIs may be ras-independent. This article reviews preclinical and clinical data pertinent to the use of FTIs in lung cancer.

BACKGROUND

The response to erythropoiesis-stimulating agents (ESA) in patients with chronic kidney disease (CKD) is variable. The body mass index (BMI) variations can modify the response to ESA. The objective was to assess the effect of body composition on the response to ESA in dialysis patients.

METHODS

This is an observational cross-sectional study. Prevalent hemodialysis and peritoneal dialysis (PD) patients were selected. In the same day, a single blood test, a body composition analysis using bioimpedance spectroscopy and anthropometric measurements were performed. We collected ESA doses. We analyzed erythropoietin resistance index (ERI). The ERI was calculated dividing the weekly weight-adjusted (kg) dose of ESA (IU) by the hemoglobin level (g/dL).

RESULTS

The study was comprised of 218 patients (58% men; age 65 (16) years old; 80% hemodialysis, 20% PD). There was an inverse correlation between ERI and BMI (p=0.01), fat tissue index (FTI) (p=0.01) and prealbumin (p=0.04). We found an independent association between higher ERI levels and lower FTI and prealbumin values.

CONCLUSIONS

Response to ESA is influenced by body composition. Fat tissue favors the body's response to ESA.

Interleukin-12 (IL-12) gene was shown to produce both IL-12 and p40 subunit. The excess production of the p40 subunit as a natural antagonist of IL-12 is a major obstacle of IL-12 gene-based cancer therapy. We previously reported that IL-12N220L gene, which selectively reduces the secretion of the p40 subunit, induces long-lasting stronger type 1 helper T cells (T(H)1) and cytotoxic T lymphocyte (CTL) immunity in hepatitis C virus (HCV) E2 DNA vaccination model and higher protection from challenge with tumor cells expressing E2 than IL-12 in a prophylactic setting. Here, we demonstrated that intratumoral injection of IL-12N220L-expressing adenovirus showed better tumor growth inhibition and higher survival rate than that of IL-12 or granulocyte macrophage-colony stimulating factor (GM-CSF)-expressing adenovirus in a therapeutic setting. In particular, the mice cured by IL-12N220L treatment were protected against intravenous rechallenge of the same tumor cells better than those by IL-12 treatment. In addition, the enhanced antitumor activity of IL-12N220L was confirmed in B16F10 lung metastasis model, which correlated with the frequency of tumor-specific interferon (IFN)-gamma-secreting cells. When tested in CT26/NP tumor that expresses influenza nucleoprotein (NP) as a tumor antigen, IL-12N220L induced stronger NP-specific T(H)1 and CTL responses than IL-12, particularly at a later time point, indicating the generating long-term tumor-specific memory T-cell responses. Moreover, the potent antitumor effects of IL-12N220L were further augmented by combination with chemotherapy using farnesyltransferase inhibitor (FTI), LB42908. Taken together, our results suggest that IL-12N220L is superior to IL-12 in cancer immunotherapy, which can be further enhanced by combination with chemotherapy.

OBJECTIVE

There is a growing body of evidence that the long-term hemodialysis (HD) treatment leads to disturbances of carnitine homeostasis but the results of L-carnitine supplementation in HD patients have been conflicting. In the present prospective study, we investigated the effectiveness of intravenous L-carnitine in mitigating dialysis-related protein-energy wasting (PEW) based on pre-treatment albumin levels.

METHODS

Fifty patients (46% male, mean age 63±18.28 years, HD vintage 37.5 (7-288) months) received 1 g L-carnitine intravenously at the end of every HD session for 12 months. Clinical data were obtained from the medical records and charts. Intradialytic hypotension periods (defined as a decrease of systolic blood pressure by ≥ 20 mmHg) were recorded. Dietary habits were evaluated using a self-administered questionnaire prior to L-carnitine supplementation. Laboratory parameters were measured prior to the supplementation and controlled in 6-months intervals. Anthropometric measurements were performed prior to HD session, including "dry" body weight and height, body mass index (BMI), and body composition analysis using bioimpedance spectroscopy. Malnutrition-inflammation score (MIS) was used as a scoring system representing the severity of PEW and an indicator of general functional capacity.

RESULTS

A significant increase in total cholesterol, predominantly on the account of LDL was found (p=0.005). Simultaneously, HDL decreased (p=0.001) while triglyceride levels remained unchanged. Although the rise in serum prealbumin could be observed, lean tissue index (LTI) decreased and fat tissue index (FTI) increased which resulted in reduction of the LTI/FTI ratio (p=0.002). When divided into two groups according to the pre-treatment albumin values (< 35 g/L or ≥35 g/L), patients from the higher albumin group showed significant increase in prealbumin (p=0.005), and improved MIS (p=0.03). Multivariate regression analysis showed that higher FTI after introduction of L-carnitine led to greater hemodynamic stability (OR 1.709, 95% CI 1.006-2.905, p=0.048). As there was no differences in HD treatment characteristics, primery kidney disease or residual diuresis we could conclude that positive energy balance (with an increase in prealbumin and FTI) eventually led to better hemodynamic stability.

CONCLUSIONS

Our results show significant effects of L-carnitine supplementation on lipid metabolism. Further clinical trials, as well as experimental research are needed to define the role of lipid metabolism in CKD population. Significant benefits of L-carnitine supplementation in patients with better initial serum albumin levels suggest that this therapy should not be restricted to patients with the worst nutritional and overall status.

Farnesyltransferase inhibitors (FTIs) are novel anticancer drugs that inhibit the secretion of pro-angiogenic factors by Ras-transformed cancer cells. FTIs also inhibit angiogenesis in a rat corneal model, suggesting that FTIs have anti-angiogenic properties that extend beyond targeting cancer cells. Our hypothesis was that FTIs may directly target endothelial cell functions in angiogenesis. We examined the effects of FTI treatment on a range of assays designed to pick apart the individual functions of endothelial cells during angiogenesis. We found that FTIs inhibit endothelial cell proliferation, causing a failure of mitosis and accumulation of binucleate cells. FTIs also block the directional migration of endothelial cells toward VEGF, the major pro-angiogenic factor in adult tissues. In a co-culture assay of angiogenesis, FTI treatment significantly inhibits tube formation, but has no effect on pre-existing structures. Defects in tube formation could be replicated by specific targeting of endothelial cell farnesyltransferase using RNA interference. Our data show that FTIs directly target endothelial cells in angiogenesis, explaining previous in vivo findings. Importantly, these results suggest that the therapeutic use of FTIs may extend beyond cancer to include the treatment of other diseases involving pathological angiogenesis.

Conventional (CONV) neuromuscular electrical stimulation (NMES) (i.e., short pulse duration, low frequencies) induces a higher energetic response as compared to voluntary contractions (VOL). In contrast, wide-pulse, high-frequency (WPHF) NMES might elicit--at least in some subjects (i.e., responders)--a different motor unit recruitment compared to CONV that resembles the physiological muscle activation pattern of VOL. We therefore hypothesized that for these responder subjects, the metabolic demand of WPHF would be lower than CONV and comparable to VOL. 18 healthy subjects performed isometric plantar flexions at 10% of their maximal voluntary contraction force for CONV (25 Hz, 0.05 ms), WPHF (100 Hz, 1 ms) and VOL protocols. For each protocol, force time integral (FTI) was quantified and subjects were classified as responders and non-responders to WPHF based on k-means clustering analysis. Furthermore, a fatigue index based on FTI loss at the end of each protocol compared with the beginning of the protocol was calculated. Phosphocreatine depletion (ΔPCr) was assessed using 31P magnetic resonance spectroscopy. Responders developed four times higher FTI's during WPHF (99 ± 37 × 10(3) N.s) than non-responders (26 ± 12 × 10(3) N.s). For both responders and non-responders, CONV was metabolically more demanding than VOL when ΔPCr was expressed relative to the FTI. Only for the responder group, the ∆PCr/FTI ratio of WPHF (0.74 ± 0.19 M/N.s) was significantly lower compared to CONV (1.48 ± 0.46 M/N.s) but similar to VOL (0.65 ± 0.21 M/N.s). Moreover, the fatigue index was not different between WPHF (-16%) and CONV (-25%) for the responders. WPHF could therefore be considered as the less demanding NMES modality--at least in this subgroup of subjects--by possibly exhibiting a muscle activation pattern similar to VOL contractions.

Rice (Oryza sativa L.) is the only cereal crop that possesses the ability to germinate under flooded or other oxygen-deficient conditions. Rapid elongation of the coleoptile is a perfect response to flooding during germination, with coleoptile length differing among various rice varieties. Despite multiple studies have uncovered valuable information concerning this trait by focusing on the physiological metabolism of oxygen stress, the underlying genetic mechanism still remains unknown. In the present study, we screened coleoptile lengths of 432 indica varieties germinated in two environments (normal and flooded) and found more variation existing in flooded coleoptile length (FCL) rather than in normal coleoptile length (NCL). With the phenotypic data of NCL, FCL and FTI (flooding tolerance index), a genome-wide association study was performed by using 5291 single nucleotide polymorphism (SNP) markers. We detected 2, 11, and 9 significant SNPs under a mixed linear mode for NCL, FCL, and FTI, respectively. Of these SNPs, five were shared by FCL and FTI. Haplotype and phenotype effect analysis on the highest ranking locus indicated one of the two haplotypes contributed to coleoptile elongation remarkably. To better understand the controlling gene of this locus, reported expression profile data was applied. We focused on LOC_Os06g03520, a candidate gene which was highly induced by anoxia (∼507 fold). Sequence analysis in 51 varieties demonstrated Hap.2 associated perfectly with flooding tolerance. Further studies on this gene may help explore the molecular mechanism of rice flooding tolerance during germination. We believe our discoveries may conduce to isolating major genes and aid the improvement of flooding tolerance in modern breeding programs.

BACKGROUND

Statins are potent inhibitors of cholesterol biosynthesis and are clinically beneficial in preventing cardiovascular diseases, however, the therapeutic utility of these drugs is limited by myotoxicity. Here, we explored the mechanism of statin-mediated activation of ERK5 in the human endothelium with the goal of identifying compounds that confer endothelial protection but are nontoxic to muscle.

METHODS

An ERK5-one hybrid luciferase reporter transfected into COS-7 cells with pharmacological and molecular manipulations dissected the signaling pathway leading to statin activation of ERK5. qRT-PCR of HUVEC cells documented the transcriptional activation of endothelial-protective genes. Lastly, morphological and cellular ATP analysis, and induction of atrogin-1 in C2C12 myotubes were used to assess statin-induced myopathy.

RESULTS

Statin activation of ERK5 is dependent on the cellular reduction of GGPPs. Furthermore, we found that the combination of FTI-277 (inhibitor of farnesyl transferase) and GGTI-298 (inhibitor of geranylgeranyl transferase I) mimicked the statin-mediated activation of ERK5. FTI-277 and GGTI-298 together recapitulated the beneficial effects of statins by transcriptionally upregulating anti-inflammatory mediators such as eNOS, THBD, and KLF2. Finally, C2C12 skeletal myotubes treated with both FTI-277 and GGTI-298 evoked less morphological and cellular changes recognized as biomarkers of statin-associated myopathy.

CONCLUSIONS

Statin-induced endothelial protection and myopathy are mediated by distinct metabolic intermediates and co-inhibition of farnesyl transferase and geranylgeranyl transferase I confer endothelial protection without myopathy.

CONCLUSIONS

The combinatorial FTI-277 and GGTI-298 drug regimen provides a promising alternative avenue for endothelial protection without myopathy.

Additive manufacturing (AM) techniques and so-called 2D materials have undergone an explosive growth in the past decade. The former opens multiple possibilities in the manufacturing of multifunctional complex structures, and the latter on a wide range of applications from energy to water purification. Extrusion-based 3D printing, also known as Direct Ink Writing (DIW), robocasting, and often simply 3D printing, provides a unique approach to introduce advanced and high-added-value materials with limited availability into lab-scale manufacturing. On the other hand, 2D colloids of graphene oxide (GO) exhibit a fascinating rheology and can aid the processing of different materials to develop 'printable' formulations. This work provides an in-depth rheological study of GO suspensions with a wide range of behaviours from Newtonian-like to viscoelastic 'printable' soft solids. The combination of extensional and shear rheology reveals the network formation process as GO concentration increases from <0.1 vol% to 3 vol%. Our results also demonstrate that the quantification of 'printability' can be based on three rheology parameters: the stiffness of the network via the storage modulus (G'), the solid-to-liquid transition or flow stress (σf), and the flow transition index, which relates the flow and yield stresses (FTI = σf/σy).

BACKGROUND

Key determinants for lesion formation in catheter ablation are contact force, radiofrequency (RF) power and time. The aim of this study was to evaluate the clinical applicability of ablation index (AI), a novel non-linear formula based on these components, and to compare AI with the conventional linear force-time interval (FTI) in pulmonary vein isolation (PVI). Methods and Results: Target AI ranges were defined for anatomical segments of the ipsilateral pulmonary veins. The operator was blinded to AI during PVI for the initial 11 patients (group A), and was unblinded for the remaining 23 patients (group B). We assessed (1) the clinical value of AI to avoid excessively high and low values with an operator blinded vs. non-blinded to AI; and (2) the relation of AI and FTI in predefined ranges. In group A, 235/564 lesions (41.7%) were in the predefined target range as compared with 1,171/1,412 lesions (82.9%) in group B (P<0.001). A given AI may correspond to a wide range of FTI, as reflected by a quartile coefficient of dispersion for AI of 0.11 vs. a quartile coefficient of dispersion for FTI of 0.36.

CONCLUSIONS

Incorporating RF current power, the non-linear AI provides more comprehensive information during PVI compared with FTI. Given that the FTI for a given AI varies widely, the value of FTI in clinical practice is questionable.

OBJECTIVE

Abnormalities of the thyroid axis are documented in adult mood disorders. The most consistent findings have been observed in major depressive disorder with elevations of thyroxine (T4) or free-T4 (fT4) within the euthyroid range that decrease with treatment. The literature on adolescents is limited, and it is unknown whether similar findings might be present in this population.

METHODS

First admissions to a university hospital adolescent psychiatry unit were reviewed. Fourteen depressed and 13 manic patients satisfied inclusion and exclusion criteria. None had a history of thyroid illness or medical illness or were taking medications known to affect thyroid function. Basal serum thyrotropin, T4, fT4, triiodothyronine (T3), reverse-T3, free thyroxine index (FTI), and T3 resin uptake levels were compared with those of a group of adolescent normal controls.

RESULTS

T4 (but not fT4) was elevated in depressed and manic patients compared with controls (p < .05). In manic patients, T3 was decreased and reverse-T3 was increased (p < .05). There were no significant differences in relation to age, sex, or suicidality.

CONCLUSIONS

We observed significant differences in basal thyroid hormone levels in depressed and manic adolescents. Our results suggest the presence of abnormalities of thyroid function in adolescent mood disorders similar to those described in mood-disordered adults.

Rocker profile shoes (rocker shoes) are one of the treatment options of metatarsalgia and forefoot stress fractures. The efficacy of rocker shoes in unloading the forefoot pressure has been shown in walking. In running, however, the effect of rocker shoes on forefoot pressure is unknown. Eighteen healthy female runners participated in this study. In-shoe plantar pressures were recorded during running with the standard running shoes and rocker shoes. Shoe comfort was assessed after each shoe measurement. Peak pressure (PP), maximum mean pressure (MMP) and force-time integral (FTI) were determined for seven foot areas. The effects of shoes on the different outcome variables were statistically analyzed using a linear mixed model. Running with the rocker shoes caused a significant reduction (p<0.001) in all pressure parameters in the central and lateral forefoot. FTI and MMP were also reduced by 11% and 12% in the medial forefoot while running with rocker shoes. Running with rocker shoes resulted in a significant increase in all pressure parameters at the heel region (p<0.001). Running with rocker shoes received a significant (p<0.01) lower comfort rate than running with standard running shoes. Rocker shoes might be beneficial for runners who are recovering from metatarsalgia or stress fractures of the forefoot region, as it reduces plantar pressure in the forefoot region.

OBJECTIVE

This study sought to assess the impact of ablation power and catheter irrigation during clinical radiofrequency ablation using impedance drop.

BACKGROUND

In preclinical studies, ablation power and catheter irrigation are determinants of ablation efficacy.

METHODS

Static 30-s left atrial ablations were delivered in patients undergoing their first atrial fibrillation ablation. Impedance drop during ablation (as a measure of efficacy) was compared using the following: the force time integral (FTI); the FTI-P (a cumulative multiple FTI and ablation power), and ablation index (AI), a weighted algorithm including contact force, power, and duration. Comparison was also made between a conventionally irrigated (SmartTouch [ST]) versus surround flow (STSF) contact force-sensing catheter.

RESULTS

We analyzed 1,013 ablations. For both catheters, the Spearman correlation was higher between impedance drop and AI (rho = 0.89 ST, 0.84 STSF) than FTI-P (rho = 0.71 ST, 0.53 STSF) or FTI (rho = 0.77 ST, 0.52 STSF); p < 0.0005 for each. STSF ablations had lower minimum catheter tip temperatures (25°C [interquartile range (IQR): 25°C to 27°C] vs. 35°C [IQR: 34°C to 36°C]; p < 0.005), and lesser impedance drop per FTI or AI (p < 0.005 for both). For STSF, impedance drop plateaued sooner than for ST with respect to FTI (184g.s vs. 463g.s) and AI (370 AI vs. 430 AI).

CONCLUSIONS

AI is a more complete ablation descriptor than is FTI or FTI-P, reflected by a stronger correlation with impedance drop. STSF ablations have lower impedance drop per AI or FTI than ST ablations do, suggesting different targets should be used if ablating guided by impedance drop with STSF. With ST, ablation beyond 430 AI provides minimal additional biophysical efficacy, suggesting an upper limit to use for clinical ablation.

OBJECTIVE

Malnutrition and protein energy wasting (PEW) determined by Subjective Global Assessment (SGA) is associated with increased mortality. There is an inverse relationship between body mass and overhydration in dialysis patients. Is the predictive accuracy of SGA (for death) independent of hydration status? Can bioimpedance spectroscopy analysis of lean tissue index (LTI) and fat tissue index (FTI) accurately identify dialysis patients with protein energy wasting and increased mortality?

METHODS

We report an observational study of 455 peritoneal dialysis (PD) patients.

RESULTS

We found that 96 patients (21%) were malnourished (SGA score between 1 and 5), and 192 (42%) had LTI values below 10th centile (age, gender adjusted). FTI was significantly lower in the SGA-defined malnourished cohort. By contrast, there was an inverse relationship between LTI and FTI. Malnourished (by SGA) patients were significantly more overhydrated (P < .0001), but SGA remained highly predictive of survival in multivariate analysis that included hydration status (hazard ratio: 3.12, 95% confidence interval 1.86-5.23, P < .0001). Obesity (patients with the highest 20% FTI) predicted survival (hazard ratio of death was 0.47, 95% confidence interval 0.16-0.85, P < .02) on univariate but not multivariate analysis.

CONCLUSIONS

We have confirmed that SGA is an accurate predictor of mortality in PD patients, and its predictive value is independent of the hydration status. Predictive power of SGA was not affected when LTI and FTI were included in multivariate analysis. Patients with low LTI were different from patients with low SGA (associated with high FTI). Sensitivity and specificity of Body Composition Monitor to diagnose patients with low SGA readings were poor (area under the curve for receiver operator characteristics analysis 0.66). The phenomenon of reverse epidemiology (high FTI predicting a survival advantage) was found in our PD cohort.

Peritoneal dialysis (PD) patients are characterized by protein malnutrition and muscle wasting. Reliable, easy, and cheap methods for evaluating nutrition are desirable. Three methods are commonly available: dual-energy X-ray absorptiometry (DXA), bioimpedance (BI), and subjective global assessment (SGA).The objective of the study was to compare the previously mentioned methods for assessment of body composition and nutritional status in PD patients.

The study is cross-sectional and consisted of 72 PD patients from a single center PD ambulatorium.

Participants were measured twice by DXA, twice by BI, and once by SGA. Measurements included lean tissue mass (LTM), fat tissue mass (FT) and, for BI, overhydration (OH), intracellular water (ICW), and extracellular water (ECW). LTM and FT were indexed to body area (Lean Tissue Index [LTI] and Fat Tissue Index [FTI], respectively), and ICW for height (ICW/ht). We assessed conventional biochemical and clinical variables, using values for normal individuals as a reference.

There was good overall agreement between BI and DXA but considerable intra-individual variation (1 standard deviation: FT 5.7 kg; LTM 5.6 kg). Factors affecting the differences were FT, ICW, LTM, and ICW. Obesity (DXA 43%; BI 54%) and muscle wasting (BI 28%; SGA 53%) were common. Agreement between BI and SGA was poor. Thirty-eight percent of patients judged malnourished by SGA also had a low LTI; 23% with normal SGA had low LTI. SGA was closer related to LTI (BI) than LTI (DXA). Plasma albumin was correlated to LTI, FTI, and ICW/ht, and comorbidity to OH, clinical malnutrition, reduced FTI, but not LTI.

Agreement between DXA and BI was high on a population basis but not at an individual level. Obesity and muscle wasting were common in this population. OH might reduce DXA accuracy in PD patients. LTI and ICW may be useful measures to supplement SGA in assessing nutrition.

BACKGROUND

Preclinical work suggests factors including catheter orientation and contact consistency during individual radiofrequency ablations influence lesion size. Our aim was to investigate factors affecting catheter contact in the left atrium (LA) and their effects on ablation.

RESULTS

A total of 2,298 8-second static LA mapping points were studied in 30 patients undergoing ablation for AF (16 in AF, 14 sinus rhythm [SR], 18 remote robotic navigation [RRN] procedures) using a contact force (CF) sensing catheter. CF variability (CFV: difference between 20 Hz-sampled CF waveform mean peak and trough) increased with mean CF, Spearman's ρ = 0.6, P < 0.005. Catheter drift correlated weakly with CF (Pearson's correlation -0.06, P = 0.005). CFV was higher in SR than AF and with RRN (P < 0.001). In AF, there was less catheter drift for RRN than manual navigation points but the converse was true in SR. In 747 static 30 second LA ablations, the influence of contact parameters on ablation efficacy was compared by multivariate analysis of impedance drop during ablation: a lesser drop suggesting reduced efficacy. For a given force time integral (FTI), increased CFV (>5 g) and locational drift (>3.5 mm), perpendicular contact, SR and RRN usage were associated with a lesser impedance drop with ablation (P < 0.005 for each), suggesting reduced efficacy.

CONCLUSIONS

Beyond the FTI, the quality of catheter contact influences ablation efficacy, and clinical catheter contact is affected by multiple factors, including the atrial rhythm and catheter navigation mode. Maximal efficacy is provided by parallel contact with CFV ≤5 g, catheter drift ≤3.5 mm, and manual navigation.

Here, we developed and validated a headspace-solid-phase microextraction-gas chromatography/mass spectrometry (HS-SPME-GC/MS) method for the determination of 14 volatile perfluorinated alkylated substances (PFASs) in water and sediment samples according to SANTE 11945/2015 guidelines. Three fluorotelomer alcohols (FTOHs), two perfluoroalkyl iodides (PFIs), three fluorotelomer iodides (FTIs), four fluorotelomer acrylates and methacrylates (FTACs and FTMACs) and two perfluoroalkyl sulfonamides (FASAs) were analysed simultaneously to assess the occurrence of these compounds from their emission sources to the outlets in water treatment plants. Several SPME parameters were optimised for both water and sediment to maximise responses and keep analysis time to a minimum. In tap water, the limits of quantification (LOQs) were found to be between 20ng/L and 100ng/L depending on the analyte, with mean recoveries ranging from 76 to 126%. For sediments, LOQs ranged from 1 to 3ng/g dry weight depending on the target compound, with mean recoveries ranging from 74 to 125%. SPME considerably reduced sample preparation time and its use provided a sensitive, fast and simple technique. We then used this HS-SPME-GC/MS method to investigate the presence of volatile PFASs in the vicinity of an industrial facility. Only 8:2 FTOH and 10:2 FTOH were detected in a few water and sediment samples at sub-ppb concentration levels. Moreover, several non-target fluorotelomers (12:2 FTOH, 14:2 FTOH and 10:2 FTI) were identified in raw effluent samples. These long-chain fluorotelomers have high bioaccumulative potential in the aquatic environment compared with short-chain fluorotelomers such as 6:2 FTOH and 6:2 FTI.

The pituitary, thyroid, and ovarian hormone levels were measured by enzyme and fluorescence polarization immunoassays in 18 women with successful renal transplants (recipients): 10 menstruating, mean age 34.7 years, mean time after transplantation (Tx) 112.00 months, mean SCr 130.60 mumol/L; and 8 menopausal, mean age 52.7 years, mean time after Tx 61.00 months, and mean SCr 119.00 mumol/L. Five women of the menstruating group conceived 7 times and gave birth to 4 healthy infants. The findings were compared to 30 age-matched healthy subjects (controls) and to 13 women under chronic hemodialysis (hemodialyzed patients): 2 menstruating, 24 and 36 years old, and 11 menopausal, mean age 59.4 years. Serum prolactin (PRL) showed a highly significant increase in hemodialyzed patients (p less than .0001) compared to controls. In recipients, PRL levels were significantly lower than in hemodialyzed patients, but higher than in controls (p less than .0001). LH and FSH were elevated in menstruating hemodialyzed patients (p less than .0001, p less than .02, respectively) and significantly high in menopausal hemodialyzed patients (p less than .02, p less than .01, respectively). In menstruating recipients, LH was also highly elevated (p less than .001), while FSH showed no significant difference from controls. In menopausal recipients the increase of LH was less prominent (p less than .02) but FSH was highly increased (p less than .001). T3, T4, and FTI were absolutely normal in recipients, while they were significantly lower than normal (p less than .0001) in hemodialyzed patients. Estradiol showed no significant difference in both groups of recipients, as well as in menopausal hemodialyzed patients.(ABSTRACT TRUNCATED AT 250 WORDS)

During terrestrial locomotion, limb muscles must generate mechanical work and stabilize joints against the ground reaction force. These demands can require high force production that imposes substantial loads on limb bones. To better understand how muscle contractile function influences patterns of bone loading in terrestrial locomotion, and refine force platform equilibrium models used to estimate limb bone safety factors, we correlated in vivo recordings of femoral strain with muscle activation and strain in a major propulsive hindlimb muscle, flexor tibialis internus (FTI), of a species with a published model of hindlimb force production (river cooter turtles, Pseudemys concinna). Electromyography (EMG) recordings indicate FTI activity prior to footfall that continues through approximately 50% of the stance phase. Large EMG bursts occur just after footfall when the muscle has reached its maximum length and is beginning to actively shorten, concurrent with increasing compressive strain on the anterior femur. The FTI muscle shortens through 35% of stance, with mean fascicle shortening strains reaching 14.0 ± 5.4% resting length (L0 ). At the time of peak compressive strains on the femur, the muscle fascicles remain active, but fascicles typically lengthen until mid-stance as the knee extends. Influenced by the activity of the dorsal knee extensor femorotibialis, the FTI muscle continues to passively lengthen simultaneously with knee extension and a shift to tensile axial strain on the anterior femur at approximately 40% of stance. The near coincidence in timing of peak compressive bone strain and peak muscle shortening (5.4 ± 4.1% stance) indicates a close correlation between the action of the hip extensor/knee flexor, FTI, and femoral loading in the cooter hindlimb. In the context of equilibrium models of limb bone loading, these results may help explain differences in safety factor estimates observed between previous force platform and in vivo strain analyses in cooters.

In this paper, we describe the effect of the inhibitor of farnesyltransferase (FTI-277) on radioresistance induced by the 24-kDa isoform of FGF2 in human cells expressing wild-type RAS. Treatment with FTI-277 (20 microM) for 48 h prior to irradiation led to a significant decrease in survival of radioresistant cells expressing the 24-kDa isoform (HeLa 3A) but had no effect on the survival of control cells (HeLa PINA). The radiosensitizing effect of FTI-277 is accompanied by a stimulation of postmitotic cell death in HeLa 3A cells and by a reduction in G(2)/M-phase arrest in both cell types. These results clearly demonstrate that at least one farnesylated protein is involved in the regulation of the radioresistance induced by the 24-kDa isoform of FGF2. Furthermore, the radiation-induced G(2)/M-phase arrest is also under the control of farnesylated protein. This work also demonstrates that FTase inhibitors may be effective radiosensitizers of certain human tumors with wild-type RAS.

A controlled longitudinal prospective study is reported of physical and neuropsychological progress up to 12 years in 152 children with congenital hypothyroidism (CH), detected by newborn screening in the Australian state of Victoria and born between the onset of screening in mid-1977 and December 1988. Linear growth of the CH children was normal. Throughout they were slightly heavier and the median head circumference was slightly larger compared with reference data. Those with thyroid aplasia required a marginally larger dose of thyroxine to achieve euthyroidism. Assessment of cognitive outcome in the children with permanent primary CH revealed the mean scores at 2, 5 and 8 years to be from 8.5 (p<0.001) to 10.2 (p<0.001) points lower than in a group of 60 euthyroid controls. However, there was large overlap and, of the affected children, only 10.1% at 2 years, 3.9% at 5 years and 6.8% at 8 years fell more than 2 SD below the means of the euthyroid controls. On univariate analysis, variables shown to have significant correlation with cognitive outcome at 8 years in the CH children were newborn activity, baseline TT4 and FTI, initial T4 dosage, socio-economic classification, maternal age, maternal education and presence of a serious accompanying disorder. On multiple regression analysis, significant variables were baseline bone age, maternal age and education, and presence of a serious accompanying disorder. No single thyroidal or extra-thyroidal variable could be identified to account for the discrepancy between the children with CH and the controls.

Using MacroModel, peptide, peptidomimetic and non-peptidomimetic inhibitors of the zinc metalloenzyme, farnesyltransferase (FTase), were docked into the enzyme binding site. Inhibitor flexibility, farnesyl pyrophosphate substrate flexibility, and partial protein flexibility were taken into account in these docking studies. In addition to CVFM and CVIM, as well as our own inhibitors FTI-276 and FTI-2148, we have docked other farnesyltransferase inhibitors (FTIs) including Zarnestra, which presently is in advanced clinical trials. The AMBER* force field was employed, augmented with parameters that were derived for zinc. A single binding site model that was derived from the crystal structure of CVFM complexed with farnesyltransferase and farnesylpyrophosphate was used for these studies. The docking results using the lowest energy structure from the simulation, or one of the lowest energy structures, were generally in excellent agreement with the X-ray structures. One of the most important findings of this study is that numerous alternative conformations for the methionine side chain can be accommodated by the enzyme suggesting that the methionine pocket can tolerate groups larger than methionine at the C-terminus of the tetrapeptide and suggesting alternative locations for the placement of side chains that may improve potency.