SAID SHEHATA

The aim of this study was to employ two different mathematical approaches: first, a convolution approach using computer software; second, a mathematical calculation exploiting Wagner-Nelson calculation to predict in vivo plasma concentration-time profile from the in vitro release study for the once daily formulations of a model drug diltiazem hydrochloride. The once daily extended release tablets (120 mg) were prepared by the wet granulation technique. Ethanol or ethanolic solutions of ethylcellulose (N22), were used as granulating agents along with hydrophilic matrix polymers like hydroxypropyl methylcellulose (HPMC) (K 15M). The granules showed satisfactory flow properties, compressibility, moisture content and drug content. All the tablet formulations showed acceptable properties and complied with pharmacopeial limits. The in vitro drug release study revealed that formula F7-T which contains drug: HPMC ratio 1:1 and 20 mg of ethylcellulose was able to sustain the drug release for 24 h and satisfied the USP dissolution limits. Fitting the in vitro drug release data to Korsmeyer-Peppas equation indicated that the mechanism of drug release could be zero-order. The capsule formulation F14-C which consists of drug: HPMC ratio 1:2, 12 mg of ethylcellulose and 20 mg of polyox 100 showed in vitro drug release similar to the tablet F7-T using the similarity factor (f 2). The mechanism of drug release could be coupled diffusion, and polymer matrix relaxation. The percent dissolved data from the two formulations were used as input function to predict the in vivo plasma data by the two approaches (Convolution by Kinetica software and Wagner-Nelson calculation). The two methods were validated by prediction of plasma data from in vitro release data of FDA approved 300 mg extended release capsule. Prediction errors were estimated for Cmax and area under the curve (AUC) to determine the validity of the methods. The percent prediction error for each parameter is not exceeding 15%.

Our understanding of leaf acclimation in relation to temperature of fully grown or juvenile tree crowns is mainly based on research involving spatially uncontrolled growth temperature. In this study, we test the hypothesis that leaf morphology and chemical elements are modulated by within-crown growth temperature differences. We ask whether within-species variation can influence acclimation to elevated temperatures. Within-crown temperature dependence of leaf morphology, carbon and nitrogen was examined in two genotypes of Acer rubrum L. (red maple) from different latitudes, where the mean annual temperature varies between 7.2 and 19.4 °C. Crown sections were grown in temperature-controlled chambers at three daytime growth temperatures (25, 33 and 38 °C). Leaf growth and resource acquisition were measured at regular intervals over long-term (50 days) controlled daytime growth temperatures. We found significant intraspecific variation in temperature dependence of leaf carbon and nitrogen accumulation between genotypes. Additionally, there was evidence that leaf morphology depended on inherited adaptation. Leaf dry matter and nitrogen content decreased as growth temperature was elevated above 25 °C in the genotype native to the cooler climate, whereas they remained fairly constant in response to temperature in the genotype native to the warmer climate. Specific leaf area (SLA) was correlated positively to leaf nitrogen content in both genotypes. The SLA and the relative leaf dry matter content (LM), on the other hand, were correlated negatively to leaf thickness. However, intraspecific variation in SLA and LM versus leaf thickness was highly significant. Intraspecific differences in leaf temperature response between climatically divergent genotypes yielded important implications for convergent evolution of leaf adaptation. Comparison of our results with those of previous studies showed that leaf carbon allocation along a vertical temperature gradient was modulated by growth temperature in the genotype native to the cooler climate. This indicates that within-crown temperature-induced variations in leaf morphology and chemical content should be accounted for in forest ecosystem models.

The purpose of the present study was to prepare intranasal delivery system of sildenafil citrate and estimate its relative bioavailability after nasal administration in rabbits to attain rapid onset of action with good efficacy at lower doses. Sildenafil citrate saturated solubility was determined in different solvents, cosolvents, and microemulsion systems. For nasal application, sildenafil citrate was formulated in two different systems: the first was a cosolvent system (S3) of benzyl alcohol/ethanol/water/Transcutol/taurodeoxy cholate/Tween 20 (0.5:16.8:47.7:15.9:1:18.1% w/w). The second was a microemulsion system (ME6) containing Oleic acid: Labrasol/Transcutol/water (8.33:33.3:16.66:41.66% w/w). The prepared systems were characterized in relation to their clarity, particle size, viscosity, pH, and nasal ciliotoxicity. In vivo pharmacokinetic performance of the selected system ME6 (with no nasal ciliotoxicity) was evaluated in a group of six rabbits in a randomized crossover study and compared to the marketed oral tablets. The targeted solubility (>20 mg/ml) of sildenafil citrate was achieved with cosolvent systems S1, S3, and S5 and with microemulsion systems ME3-ME6. The saturated solubility of sildenafil citrate in cosolvent system S3 and microemulsion system ME6 were 22.98 +/- 1.26 and 23.79 +/- 1.16 mg/ml, respectively. Microemulsion formulation ME6 showed shorter t (max) (0.75 h) and higher AUC((0-infinity)) (1,412.42 ng h/ml) compared to the oral tablets which showed t (max) equals 1.25 h and AUC((0-infinity)) of 1,251.14 ng h/ml after administration to rabbits at dose level of 5 mg/kg. The relative bioavailability was 112.89%. In conclusion, the nasal absorption of sildenafil citrate microemulsion was found to be fast, indicating the potential of nasal delivery instead of the conventional oral administration of such drug.

The purpose of this study was to combine the advantages of self-nanoemulsifying drug delivery systems and tablets as a conventional dosage form emphasizing the excipients' effect on the development of a new dosage form. Systems composed of HCO-40, Transcutol HP, and medium-chain triglyceride were prepared. Essential properties of the prepared systems regarding carvedilol solubility, a model drug, and self-emulsification time were determined. In order to optimize self-nanoemulsifying drug delivery systems (SNEDDS), formulation dispersion-drug precipitation test was performed in the absence and presence of cellulosic polymers. Furthermore, SNEDDS was loaded onto liquisolid powders. P-glycoprotein (P-gp) activity of the selected SNEDDS was tested using HCT-116 cells. Carvedilol showed acceptable solubility in the selected excipients. It also demonstrated improvement in the stability upon dilution with aqueous media in the presence of cellulosic polymers. Use of granulated silicon dioxide improved the physical properties of liquisolid powders containing SNEDDS. It improved the compressibility of the selected powders and the tested SNEDDS showed marked P-gp inhibition activity. Prepared self-nanoemulsifying tablet produced acceptable properties of immediate-release dosage forms and expected to increase the bioavailability of carvedilol.

3-Cyanomethylidene oxindole derivatives were prepared in excellent yields utilizing DBU-promoted Knoevenagel condensation of isatin derivatives with active methylene reagents. The isolated products were then reacted with azaenamines via a DBU-promoted Michael addition to yield spirocyclic 2-oxindole derivatives with incorporated 6-amino-4H-pyridazines and their fused derivatives. © 2009 Elsevier Ltd. All rights reserved.

Background Previous trials showed that diabetic patients had worse hospital and long term outcome after coronary artery bypass grafting (CABG), than non diabetic patients. However, recent trials showed that diabetes mellitus (DM) was not found to be an independent risk for in-hospital mortality and post operative complications, after CABG. Objective To evaluate the impact of DM on short and mid-term outcome following first time isolated CABG. Methods This is a retrospective unicenter study which included one hundred and twenty patients, who had first time isolated CABG surgery during the period of June, 2006 to December, 2007. Sixty patients were non diabetic, thirty had non insulin dependent diabetes mellitus (NIDDM) and thirty had insulin dependent diabetes mellitus (IDDM). These patients were evaluated during the in-hospital period and for twelve months afterwards. Results The non diabetic, NIDDM and IDDM groups had comparable in-hospital mortality and complications, postoperative infection was not found to be related to DM. The twelve months follow up revealed that the non diabetic group had 10.2% major adverse cardiac and cerebrovascular events (MACCE) and the NIDDM group had 16% MACCE versus 34.8% MACCE in the IDDM group (P=0.04). After adjusting other variables through regression modeling, the use of insulin was independently associated with MACCE in the form of unstable angina, myocardial infarction, revascularization, cerebrovascular stroke and death, during the twelve months after CABG (OR=4.90, 95% CI 1.39-17.30, P=0.013). The diabetics who had NIDDM had no statistical significant correlation with composite clinical events (OR=1.75, 95% CI 0.42-7.19, P=0.43). However, the cardiac mortality during the follow up period was nearly equal between both the IDDM and the NIDDM groups, with 8.7% in the former group and 8% in the latter group, with no mortality in the non diabetic group (p=0.05). Conclusions DM was not found to be an independent risk for in-hospital mortality and complication. The insulin treated patients had a higher incidence of adverse cardiac events than the NIDDM patients and non diabetic patients, during the first twelve months after CABG. However, cardiac mortality was equal between both the IDDM and the NIDDM groups during the twelve months follow up.

A series of arylhydrazones 1a-c were prepared and reacted with α,β-unsaturated nitriles 2a-e to yield 1,4-dihydropyridazines and fused pyridazinoquinazoline. The prepared pyridazines and fused pyridazines are then used as precursors for synthesis of polycondensed pyridazine ring systems.

A series of azaterphenyl diamidines has been synthesized and evaluated for in vitro antiprotozoal activity against both Trypanosoma brucei rhodesiense (T. b. r.) and Plasmodium falciparum (P. f.) and in vivo efficacy in the STIB900 acute mouse model for T. b. r. Six of the 13 compounds showed IC(50) values less than 7 nM against T. b. r. Twelve of those exhibited IC(50) values less than 6 nM against P. f. and six of those showed IC(50) values 0.6 nM, which are more than 25-fold as potent as furamidine. Moreover, two of them showed more than 40-fold selectivity for P. f. versus T. b. r. Three compounds 15b, 19d and 19e exhibited in vivo efficacy against T. b. r. much superior to furamidine, and equivalent to or better than azafuramidine. The antiparasitic activity of these diamidines depends on the ring nitrogen atom(s) location relative to the amidine groups and generally correlates with DNA binding affinity.

The preparation of metal (II) complexes [CoCl(2).6H(2)O, Ni(CH(3)COO)(2).4H(2)O, Cu(CH(3)COO)(2).2H(2)O, and Zn (CH3COO)(2) .2H(2)O] with 2[N-(cinnamlidene) amino]-5-nitro phenol as a novel ligands and their biological evaluation against candida species was studied. The inhibitory effects of the tested metal complexes were tested against six pathogenic yeasts (Candida albicans, C. fructus, C. glabrata, C. oleophila, C. parapsilosis, and C. tropicalis). The effect of the most efficient metal complex (Zn(II) complex) was more pronounced at 1.25 microg/ml, while Ni(II) complex was exhibited the least suppressive effect. Co(II) and Zn(II) complexes act as potential antitumor agents, while Zn(II) complex has shown promising cytotoxic activity with slow candidal respiration rate. Addition of Zn(II) complex leading to suppression of cell wall components in all candidal cells accompanied with leaking out of amino acids. Purification of the cell wall mannoprotein of C. glabrata treated with Zn(II) complex was established, resulting one pure fissured protein peak. Cell wall protein modulation was showed by appearance of two new protein bands with molecular weights of 72 and 39 KDa in C. glabrata cells treated with Zn(II) complex compared with one pure protein band 55.6 KDa in the non treated yeast cell.

The preparation of metal (II) complexes [CoCl(2).6H(2)O, Ni(CH(3)COO)(2).4H(2)O, Cu(CH(3)COO)(2).2H(2)O, and Zn (CH3COO)(2) .2H(2)O] with 2[N-(cinnamlidene) amino]-5-nitro phenol as a novel ligands and their biological evaluation against candida species was studied. The inhibitory effects of the tested metal complexes were tested against six pathogenic yeasts (Candida albicans, C. fructus, C. glabrata, C. oleophila, C. parapsilosis, and C. tropicalis). The effect of the most efficient metal complex (Zn(II) complex) was more pronounced at 1.25 microg/ml, while Ni(II) complex was exhibited the least suppressive effect. Co(II) and Zn(II) complexes act as potential antitumor agents, while Zn(II) complex has shown promising cytotoxic activity with slow candidal respiration rate. Addition of Zn(II) complex leading to suppression of cell wall components in all candidal cells accompanied with leaking out of amino acids. Purification of the cell wall mannoprotein of C. glabrata treated with Zn(II) complex was established, resulting one pure fissured protein peak. Cell wall protein modulation was showed by appearance of two new protein bands with molecular weights of 72 and 39 KDa in C. glabrata cells treated with Zn(II) complex compared with one pure protein band 55.6 KDa in the non treated yeast cell.

OBJECTIVES: To investigate the possible modification of the cardioprotective effect of amlodipine when co-administered with quercetin in myocardial ischaemia/reperfusion-induced functional, metabolic and cellular alterations in rats.

METHODS: Oral doses of amlodipine (15 mg/kg) and quercetin (5 mg/kg), alone or in combination, were administered once daily for 1 week. Rats were then subjected to myocardial ischaemia/reperfusion (35(min)/10(min)). Heart rates and ventricular arrhythmias were recorded during ischaemia/reperfusion progress. At the end of reperfusion, activities of plasma creatine kinase (CK) and cardiac myeloperoxidase were determined. In addition, cardiac contents of lactate, ATP, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and total nitrate/nitrite (NO(x)) were estimated. Finally, histological examination was performed to visualize the protective cellular effects of different pretreatments.

KEY FINDINGS: Combined therapy provided significant improvement in the amlodipine effect toward preserving cardiac electrophysiologic functions, ATP and GSH contents as well as reducing the elevated plasma CK, cardiac TBARS and NO(x) contents.

CONCLUSION: Quercetin could add benefits to the cardioprotective effect of amlodipine against injury induced in the heart by ischaemia/reperfusion.

OBJECTIVES: To investigate the possible modification of the cardioprotective effect of amlodipine when co-administered with quercetin in myocardial ischaemia/reperfusion-induced functional, metabolic and cellular alterations in rats.

METHODS: Oral doses of amlodipine (15 mg/kg) and quercetin (5 mg/kg), alone or in combination, were administered once daily for 1 week. Rats were then subjected to myocardial ischaemia/reperfusion (35(min)/10(min)). Heart rates and ventricular arrhythmias were recorded during ischaemia/reperfusion progress. At the end of reperfusion, activities of plasma creatine kinase (CK) and cardiac myeloperoxidase were determined. In addition, cardiac contents of lactate, ATP, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and total nitrate/nitrite (NO(x)) were estimated. Finally, histological examination was performed to visualize the protective cellular effects of different pretreatments.

KEY FINDINGS: Combined therapy provided significant improvement in the amlodipine effect toward preserving cardiac electrophysiologic functions, ATP and GSH contents as well as reducing the elevated plasma CK, cardiac TBARS and NO(x) contents.

CONCLUSION: Quercetin could add benefits to the cardioprotective effect of amlodipine against injury induced in the heart by ischaemia/reperfusion.

PURPOSE: To assess the kinetics of molecular response to Imatinib Mesylate (IM) therapy in predicting progression free survival (PFS), sustained hematological, and cytogenetic responses in CPCML.

METHODS: Ninety five newly diagnosed CPCML Egyptian patients were treated with IM 400 mg daily dose. Cytogenetic analysis was performed at diagnosis and every 6 months. Molecular monitoring by RT-QPCR was performed at diagnosis and every 3 months during a median follow-up period (FUp) of 26 months. Mutation detection of ABL domain was performed by ASO-PCR.

RESULTS: Hematological response was 98% after three months of IM therapy. Out of 95 patients 59 showed 2 log reduction of BCR-ABL/ABL ratio after 6 months of whom 49 (83%) had complete cytogenetic response (CCyR) and 42 (71%) had major molecular response (MMR) at 12 months. BCR-ABL transcripts remained undetectable in 22 patients (39%) at 26 months. Among the remaining 34 patients not achieving 2 log reduction at 6 months only 5 (15%) had CCyR and MMR by 12 months. ABL domain mutations were detected in 11/15 (73%) resistant and suboptimal responding patients. Achieving 2 log reduction after 6 months of IM therapy significantly correlated with sustained cytogenetic and molecular responses (p<0.0001), with PFS at 2 years (p<0.03) and inversely with ABL gene mutations (p<0.001).

DISCUSSION: These data demonstrated the predictive value of early molecular response to IM in CPCML regarding disease course and PFS. A 2 log reduction at 6 months of IM treatment could be a cut off level predicting resistance, CCyR, or suggesting IM dose modification.

PURPOSE: To assess the kinetics of molecular response to Imatinib Mesylate (IM) therapy in predicting progression free survival (PFS), sustained hematological, and cytogenetic responses in CPCML.

METHODS: Ninety five newly diagnosed CPCML Egyptian patients were treated with IM 400 mg daily dose. Cytogenetic analysis was performed at diagnosis and every 6 months. Molecular monitoring by RT-QPCR was performed at diagnosis and every 3 months during a median follow-up period (FUp) of 26 months. Mutation detection of ABL domain was performed by ASO-PCR.

RESULTS: Hematological response was 98% after three months of IM therapy. Out of 95 patients 59 showed 2 log reduction of BCR-ABL/ABL ratio after 6 months of whom 49 (83%) had complete cytogenetic response (CCyR) and 42 (71%) had major molecular response (MMR) at 12 months. BCR-ABL transcripts remained undetectable in 22 patients (39%) at 26 months. Among the remaining 34 patients not achieving 2 log reduction at 6 months only 5 (15%) had CCyR and MMR by 12 months. ABL domain mutations were detected in 11/15 (73%) resistant and suboptimal responding patients. Achieving 2 log reduction after 6 months of IM therapy significantly correlated with sustained cytogenetic and molecular responses (p<0.0001), with PFS at 2 years (p<0.03) and inversely with ABL gene mutations (p<0.001).

DISCUSSION: These data demonstrated the predictive value of early molecular response to IM in CPCML regarding disease course and PFS. A 2 log reduction at 6 months of IM treatment could be a cut off level predicting resistance, CCyR, or suggesting IM dose modification.

OBJECTIVES: The aim of this work was to explore the value of serum vascular endothelial growth factor-A (VEGF-A) in patients with metastatic triple negative breast cancer (TNBC) treated with chemotherapy. The primary end point was overall survival (OS). Secondary end points were response rate (RR), progression-free survival (PFS) and VEGF-A level at baseline, mid-therapy and at the end of therapy.

DESIGN AND METHODS: Female patients aged 18 years or above with histologically proven metastatic TNBC were included. Serum VEFG-A levels were measured at baseline, after the 3rd and 6th cycles of FAC chemotherapy regimen (Fluorourcil, Adriamycin, and Cyclophamide).

RESULTS: The overall RR was 57%. The median PFS and OS were 7 and 11.2 months, respectively (95% CI: 4.3-9.7 and 3.8-18.5 months, respectively). Patients whose disease progressed despite therapy had a significantly higher baseline VEGF-A level than those who did not progress. VEGF-A level did not drop with continuation of therapy. Patients with high VEGF-A level had a significantly lower PFS but not OS than patients with low levels.

CONCLUSION: The outcome of metastatic TNBC is poor with FAC chemotherapy regimen. Alternative chemotherapeutic regimens and novel therapeutic approaches including targeting of VEGF and/or its receptors are warranted.

OBJECTIVES: The aim of this work was to explore the value of serum vascular endothelial growth factor-A (VEGF-A) in patients with metastatic triple negative breast cancer (TNBC) treated with chemotherapy. The primary end point was overall survival (OS). Secondary end points were response rate (RR), progression-free survival (PFS) and VEGF-A level at baseline, mid-therapy and at the end of therapy.

DESIGN AND METHODS: Female patients aged 18 years or above with histologically proven metastatic TNBC were included. Serum VEFG-A levels were measured at baseline, after the 3rd and 6th cycles of FAC chemotherapy regimen (Fluorourcil, Adriamycin, and Cyclophamide).

RESULTS: The overall RR was 57%. The median PFS and OS were 7 and 11.2 months, respectively (95% CI: 4.3-9.7 and 3.8-18.5 months, respectively). Patients whose disease progressed despite therapy had a significantly higher baseline VEGF-A level than those who did not progress. VEGF-A level did not drop with continuation of therapy. Patients with high VEGF-A level had a significantly lower PFS but not OS than patients with low levels.

CONCLUSION: The outcome of metastatic TNBC is poor with FAC chemotherapy regimen. Alternative chemotherapeutic regimens and novel therapeutic approaches including targeting of VEGF and/or its receptors are warranted.

OBJECTIVES: The recurrence of hepatitis C virus infection after liver transplant is common and may endanger both graft and patient survival. We investigated the frequency and outcome of and risk factors for the recurrence of that virus after living-donor liver transplant in hepatitis C virus positive recipients.

MATERIALS AND METHODS: Seventy-four adult hepatitis C virus positive subjects were monitored for 36 months after living-donor liver transplant and demographic and laboratory data for the recipients and donors were evaluated. Recurrent hepatitis C virus infection was diagnosed on the basis of viral replication revealed by polymerase chain reaction after transplant, elevated levels of transaminases, and the results of liver biopsy.

RESULTS: Hepatitis C virus recurrence was identified in 31.1% of the patients studied. Histopathologic recurrence was mild, and 91% of the subjects had a fibrosis score of < or = F2. No recipient exhibited cirrhosis or clinical decompensation during followup. Recurrent hepatitis C virus infection was associated with pretransplant and posttransplant viral load and antibody positive to hepatitis B core antigen. No other risk factors (sex, donor or recipient age, pretransplant Child-Pugh or Model for End-Stage Liver Disease scores, immunosuppressive drug therapy, and treatment with pulse steroids) were significantly correlated with the frequency of hepatitis C virus recurrence, the grade of the histologic activity index, or the stage of fibrosis.

CONCLUSIONS: In living-donor liver transplant recipients, patient and graft survival rates associated with hepatitis C virus (genotype 4) related cirrhosis were comparable to those in deceased-donor liver transplant recipients reported in the literature. Recurrent infection with hepatitic C virus after living-donor liver transplant was mild. After transplant, a higher viral load and the presence of antibody to hepatitis B core antigen could be risk factors for hepatitis C virus recurrence. Long-term follow-up in a large number of patients is required.

OBJECTIVE: To report our experience of total phallic reconstruction (TPR) with the use of the radial-artery free flap (RAFF) in patients who have had a subtotal penectomy for penile or urethral cancer, as the goal of TPR is the creation of a sensate and cosmetically acceptable phallus with an incorporated neourethra that allows the patient to void while standing, and with the insertion of a penile implant to resume sexual activities, improving quality of life.

PATIENTS AND METHODS: The notes of the 15 patients who had undergone RAFF TPR between January 1998 and May 2008 were reviewed retrospectively. The surgical outcome, cosmesis of the phallus, complications, eventual need for revision surgery and patient satisfaction were recorded during the follow-up.

RESULTS: This technique allowed the reconstruction of a cosmetically acceptable phallus in all patients. After a median (range) follow-up of 20 (1-68) months all patients were satisfied with the cosmesis and size of the phallus, and 14 were able to void while standing. Among the seven patients who have subsequently had insertion of a penile prosthesis, five can now engage in sexual intercourse. Urethral strictures and fistulae were the commonest complications in, respectively, three and four cases, and one patient had his penile prosthesis explanted because of infection.

CONCLUSIONS: RAFF phalloplasty is an excellent technique for TPR, giving excellent cosmetic and functional results.

INTRODUCTION: The flaccid penis undergoes retraction upon contraction of the dartos muscle. These contractions are most pronounced in the situations of cold, stress, and upon exercising, and can be the source of embarrassment to those who have a hyperactive retraction reflex, especially when exposed to their partners or to others in showers and dressing rooms, despite a normal and satisfactory length in the erect state.

AIM: In this work, we propose an alternative to surgery and penile extenders for alleviating penile retraction, by injection of botulinum toxin into the dartos to induce muscle relaxation. This is the first report of the technique.

METHODS: Ten male patients complaining of a short penis exclusively in the flaccid state, despite normal and satisfactory erect and outstretched lengths, were selected for the study. One hundred units of BOTOX were injected into the dartos muscle.

MAIN OUTCOME MEASURES: Frequency and amplitude of penile retraction, flaccid unstretched length, and patient satisfaction.

RESULTS: Seven out of 10 cases (70%) subjectively reported a decrease in the frequency and amplitude of penile retraction, as well as improvement in flaccid length. Clinical measurements were less pronounced but still showed an improvement that was mainly in terms of less retraction rather than more length. No side effects were reported. Improvement faded completely by the 6th month.

CONCLUSION: This preliminary report of botulinum toxin A (Botox) injection into the dartos muscle shows that Botox may have a potential effect in temporarily decreasing penile retractions in terms of frequency and amplitude.

OBJECTIVES: Obesity is a risk factor for type 2 diabetes mellitus. It results from an energy imbalance in which energy intake exceeds energy expenditure. The cellular fuel gauge 5'-AMP-activated protein kinase (AMPK) is a heterotrimeric protein consisting of one catalytic subunit (alpha) and two non-catalytic subunits (beta and gamma), and approximately equal levels of alpha1 and alpha2 complexes are present in the liver. AMPK regulates metabolic pathways in response to metabolic stress and in particular ATP depletion to switch on energy-producing catabolic pathways such as beta-oxidation of fatty acids and switch off energy-depleting processes such as synthesis of fatty acid and cholesterol. A high-fat diet alters AMPK-alpha1 gene expression in the liver and skeletal muscle of rats and results in body weight gain and hyperglycaemia. The aim of this study was to investigate and compare the potential effects of peroxisome proliferator-activated receptor (PPAR)-alpha agonists fenofibrate and n-3 polyunsaturated fatty acids (PUFAs) in modulation of AMPK-alpha1 activity in liver and skeletal muscle of high-fat diet fed rats.

METHODS: Reverse transcription-polymerase chain reaction was used for determination of AMPK-alpha1 in liver and soleus muscle and both PPAR-alpha and CPT-1 in hepatic tissues. Serum, total cholesterol, triacylglycerol, fatty acid and fasting blood glucose were determined colorimetrically.

KEY FINDINGS: Both PPAR-alpha agonists, fenofibrate and n-3 PUFA, increased the mRNA expression of AMPK-alpha1 activity in liver and skeletal muscle of obese diabetic rats. Fenofibrate was superior in its activation of hepatic mRNA expression of AMPK-alpha 1 to exert more lipolytic effect and body weight reduction, as estimated through the decrease of triacylglycerol output and serum levels of fatty acid on the one hand and the increase in CPT-1 mRNA expression, the key enzyme in beta-oxidation of fatty acid, on the other hand. n-3 PUFA activated AMPK-alpha1 mRNA expression in skeletal muscle much more than fenofibrate to reveal more hypoglycaemic effect.

CONCLUSIONS: The PPAR-alpha agonists fenofibrate and n-3 PUFA could efficiently activate AMPK-alpha1 mRNA expression in liver and skeletal muscle to exert body weight reduction and hypoglycaemic effect, respectively.

INTRODUCTION: One method used to accelerate orthodontic tooth movement is the corticotomy-facilitated (CF) technique. The purposes of this study were to (1) identify the effect of the CF technique on orthodontic tooth movement compared with the standard technique, and (2) explore the histologic basis of the difference between the 2 techniques.

METHODS: Six dogs, aged 6 to 9 months, were used in this study. Extraction of the maxillary second premolar and miniscrew placement were done bilaterally in the maxilla. On the right side, the corticotomy was performed. The first premolars were distalized against the miniscrews with nickel-titanium coil springs on both sides. One dog was killed each week after orthodontic force application.

RESULTS: The first premolar on the CF side moved significantly more rapidly (P <0.05). Histologic findings showed more active and extensive bone remodeling on both the compressive and tension sides in the CF group.

CONCLUSIONS: The CF technique doubled the rate of orthodontic tooth movement. Histologically, the more active and extensive bone remodeling in the CF group suggested that the acceleration of tooth movement associated with corticotomy is due to increased bone turnover and based on a regional acceleratory phenomenon.