Effect of cationic surfactant on the physicochemical and antibacterial properties of colloidal systems (emulsions and microemulsions).

Colloidal systems have been used to encapsulate, protect and release essential oils in mouthwashes. In this study, we investigated the effect of cetylpyridinium chloride (CPC) on the physicochemical properties and antimicrobial activity of oil-in-water colloidal systems containing tea tree oil (TTO) and the nonionic surfactant polysorbate 80. Our main aim was to evaluate whether CPC could improve the antimicrobial activity of TTO, since this activity is impaired when this essential oil is encapsulated with polysorbate 80. These systems were prepared with different amounts of TTO (0-0.5% w/w) and CPC (0-0.5% w/w), at a final concentration of 2% (w/w) polysorbate 80. Dynamic light scattering (DLS) results revealed the formation of oil-swollen micelles and oil droplets as a function of TTO concentration. Increases in CPC concentrations led to a reduction of around 88% in the mean diameter of oil-swollen micelles. Although this variation was of only 20% for the oil droplets, the samples appearance changed from turbid to transparent. The surface charge of colloidal structures was also markedly affected by the CPC as demonstrated by the transition in zeta potential from slightly negative to highly positive values. Electron paramagnetic resonance (EPR) studies showed that this transition is followed by significant increases in the fluidity of surfactant monolayer of both colloidal structures. The antimicrobial activity of colloidal systems was tested against a Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureaus) bacteria. Our results revealed that the inhibition of bacterial growth is observed for the same CPC concentration (0.05% w/w for E. coli and 0.3% w/w for S. aureus) regardless of TTO content. These findings suggest that TTO may not act as an active ingredient in polysorbate 80 containing mouthwashes.

Ozonated oil effect for prevention of medication-related osteonecrosis of the jaw (MRONJ) in rats undergoing zoledronic acid therapy.

OBJECTIVES: The aim of this study was to evaluate the preventive effect of ozonated oil on the development of MRONJ-like lesions at tooth extraction sites in rats submitted to zoledronic acid treatment. MATERIALS AND METHODS: Twelve rats were divided into two groups. Each rat received an injection of zoledronic acid solution once a week for 5 weeks before having its upper first molar extracted. In group 1, the clotted socket was maintained, while in the group 2, the socket was treated with ozonated oil for 10 min/day during 3 days. After euthanasia, block resection was performed for histological analysis. Necrotic bone was defined as the area of the bone with empty osteocyte lacunae and vital bone as the area with osteocyte-occupied lacunae. RESULTS: There was no statistically significant difference between the groups in the average area of vital bone (p = 0.2248) and the average area of necrotic bone (p = 0.1208). However, the average area of vital bone in group 1 was smaller (24.1 ± 2.9 cells/cm2) than in group 2 (26.8 ± 4.2 cells/cm2), and the average area of necrotic bone in group 1 was higher (7.0 ± 2.5 cells/cm2) than in group 2 (4.0 ± 1.1 cells/cm2), indicating that ozonated oil may reduce the development of osteonecrosis. CONCLUSIONS: Our findings suggest that ozonated oil might prevent MRONJ-like lesions at tooth extraction sites in rats submitted to a disease induction protocol. Further research should be conducted to confirm this hypothesis. CLINICAL RELEVANCE: MRONJ has been reported as a complication of surgical dental procedures, and there are currently no predictable preventive therapies.

Probable Sleep Bruxism in Children and its Relationship with Harmful Oral Habits, Type of Crossbite and Oral Breathing.

Objective: To establish the prevalence of Probable Sleep Bruxism (PSB) and its association with gender, breast or bottle-feeding, posterior and anterior crossbite, oral habits and oral breathing. Study Design: Consists of a cross-sectional study in which 151 children were submitted to a clinical oral examination for the evaluation of tooth wear, muscle discomfort and the presence of anterior and/or posterior crossbite. Parents/caregivers were asked about the frequency of teeth grinding during the child's sleep and the occurrence of harmful oral habits, as well as the type of childbirth and breastfeeding. Data were statistically analyzed through Chi-square or Fisher's exact tests at a 5% level of significance to determine an association among variables. Results: The prevalence of PSB was of 27.8% among the examined children. Among the analyzed variables, only oral breathing was statistically associated to PSB (p < 0.001), and it was verified that children with oral breathing are 2.71 times more likely to present sleep bruxism. Conclusions: The prevalence of PSB in schoolchildren was high and the disorder was associated with oral breathing. Thus, pediatric dentists have an important role in the diagnosis of sleep bruxism and in monitoring breathing-related disorders.

Barnidipine real-life tolerability in arterial hypertension: results from the BASIC-HT study.

INTRODUCTION: Blood pressure (BP) is generally poorly controlled in hypertensive patients. One cause is poor adherence to drugs, which can be improved by treatments combining good efficacy and tolerability. Barnidipine is a strong lipophilic calcium channel blocker (CCB) with efficacy similar to other dihydropyridines. OBJECTIVE: BASIC HT is an observational study in a large population of patients with essential hypertension to evaluate the tolerability of barnidipine in a real-life setting. METHODS: 20479 patients were enrolled in the study. Tolerability and efficacy was assessed at 2 visits during a 3-month period. 20275 patients were included in the analysis. RESULTS: Adverse events were reported by 10.6% of the patients, leading to treatment discontinuation in 3%. Events were those expected with CCBs. The drop-out rate was 8%. Mean systolic and diastolic pressure decreased from 159.6 to 138.2 and from 92.5 to 81.7 mmHg. CONCLUSION: The decrease in BP, is probably due to stimulation of good adherence by barnidipine.

Subtyping Brazilian Yersinia pestis strains by pulsed-field gel electrophoresis.

We subtyped Brazilian Yersinia pestis strains by pulsed-field gel electrophoresis (PFGE). This was done with 22 Brazilian Y. pestis strains: 17 from an outbreak and 5 from endemic routine surveillance. The strains were divided into 2 groups (I and II), 8 subgroups (A-H) and 19 PFGE profiles or pulsotypes. PFGE did not separate outbreak from non-outbreak strains, as identical pulsotype patterns were found among outbreak strains and strains obtained from surveillance. However, it was able to detect intraspecific genetic diversity among Brazilian strains. This PFGE technique was able to differentiate a homogeneous group of Brazilian Y. pestis strains.

Avaliação clínica de bochechos com extratos de Aroeira (Schinus terebinthifolius) e Camomila (Matricaria recutita L. ) sobre a placa bacteriana e a gengivite / Clinical evaluation of mouthwash with extracts from aroeira (Schinus terebinthifolius) and chamomile (Matricaria recutita L. ) on plaque and gingivitis

A presente pesquisa objetivou avaliar clinicamente o efeito de bochechos à base de extratos das plantas medicinais, aroeira (Schinus terebinthifolius) e camomila (Matricaria recutita L.), sobre o controle da placa bacteriana e o tratamento da gengivite. Para tanto, foi realizado um ensaio clínico randomizado, duplo cego, intervencionista, envolvendo 59 indivíduos adultos atendidos na Clínica do Curso de Odontologia da Universidade Estadual da Paraíba (UEPB). A amostra foi constituída por pacientes portadores de gengivite crônica. A referida amostra foi selecionada aleatoriamente e dividida em três grupos: bochecho com Clorexidina (grupo controle positivo); bochecho com Camomila (grupo teste 1); bochecho com Aroeira (grupo teste 2). Durante a primeira visita do paciente, e, previamente à realização dos bochechos, todos foram orientados quanto à higiene bucal e submetidos ao procedimento de raspagem e alisamento radicular (RAR) da boca toda em uma única sessão. Os bochechos foram realizados a partir do primeiro atendimento clínico até o 15º dia após o início do tratamento, na frequência de duas vezes ao dia. Para avaliação da condição periodontal da amostra realizada no 1º, 7º e 15º dias foram aplicados os Índices de Sangramento Gengival (ISG) e de Placa (IP). Os pacientes foram reavaliados 7 e 15 dias após o início do uso do respectivo bochecho. Os resultados apontaram que o IP e o ISG apresentaram redução significativa nos três grupos. Quanto ao IP, o bochecho de camomila obteve a maior redução de acúmulo de placa e o bochecho de aroeira, a menor redução. Para os índices de sangramento, os resultados foram equivalentes, de forma que não foram consideradas diferenças estatisticamente significativas entre os bochechos. Foram considerados satisfatórios os bochechos a base de Camomila (Matricaria recutita L.) e Aroeira (Schinus terebinthifolius) na redução do quadro de inflamação gengival da amostra, sendo o bochecho de Camomila (Matricaria recutita L.) o que apresentou melhor desempenho na redução do índice de placa bacteriana.

This study aimed to clinically evaluate the effect of mouthwash with extracts from the medicinal plants aroeira (Schinus terebinthifolius) and chamomile (Matricaria recutita L.) on plaque control and gingivitis treatment. Thus, a randomized, double-blind interventional clinical trial was conducted, involving 59 adults treated at the Clinics of the Dentistry Program of Univ Estadual da Paraíba (UEPB). The sample consisted of patients with chronic gingivitis. This sample was randomly selected and divided into three groups: mouthwash with chlorhexidine (positive control group), mouthwash with chamomile (test group 1); mouthwash with aroeira (test group 2). During the first visit, and prior to rinses, all patients were instructed in oral hygiene and subjected to scaling and root planing procedure (SRP) of the whole mouth in one single session. Rinses occurred from the first clinical appointment to the 15th day after the beginning of treatment, twice a day. To evaluate the periodontal condition of the sample on the 1st, 7th and 15th days, Gingival Bleeding Index (GBI) and Plaque Index (PI) were used. The patients were reassessed at 7 and 15 days after the beginning of the respective rinses. Results indicated that PI and GBI significantly decreased in all three groups. As to PI, chamomile mouthwash led to the greatest reduction in plaque buildup, while aroeira mouthwash resulted in the smallest reduction. For bleeding rates, results were equivalent so that statistical differences among rinses were not considered significant. Mouthwashes with chamomile (Matricaria recutita L.) and aroeira (Schinus terebinthifolius) were considered satisfactory in reducing gingival inflammation in the sample; in addition, mouthwash with chamomile (Matricaria recutita L.) showed the best performance in reducing the plaque index.

Oral health profile of cirrhotic patients awaiting liver transplantation in the Brazilian Northeast.

BACKGROUND: Infections are a frequent cause of morbidity and mortality among postoperative liver transplant (OLT) patients and a leading cause of decompensated chronic liver disease (CLD) among patients awaiting the procedure. Oral lesions that are frequently observed in subjects with CLD may represent foci for systemic infections before and after OLT. AIMS: To evaluate the oral health profile of patients with CLD awaiting OLT. METHODS: One hundred thirty one patients including 100 males of overall mean age 49.5 ± 10.8 years with CLD were listed for OLT and examined for oral health status according to a established protocol. RESULTS: One hundred thirty (99%) patients were partially edentulous; 66 (51%) had chewing difficulties; and 63 (48%) experienced reduced salivary flow. With respect to periodontal disease and oral infections, 68 (25%) had periodontitis, 63 (48%) had periapical lesion, 64 (49%) had abscesses, and 59 (45%) had root fragments. Loss of follow-up was observed in 21 subjects. Among the 110 other patients, 63 (57%) underwent dental treatments with complications in only two cases. Interestingly, mortality was significantly lower among treated (31%) versus nontreated patient (79%; P<.001). CONCLUSIONS: Poor oral health status observed in most CLD patients may represent a source of systemic infections before and after OLT. Treatment of such lesions was feasible in the majority of the patients and seemed to be associated with a reduction in mortality.

Clinical pharmacology of exogenously administered alkaline phosphatase.

PURPOSE: To evaluate the clinical pharmacology of exogenous alkaline phosphatase (AP). METHODS: Randomized, double-blind, placebo-controlled sequential protocols of (1) ascending doses and infusion duration (volunteers) and (2) fixed dose and duration (patients) were conducted at clinical pharmacology and intensive care units. A total of 103 subjects (67 male volunteers and 36 patients with severe sepsis) were administered exogenous, 10-min IV infusions (three ascending doses) or 24-72 h continuous (132.5-200 U kg(-1) 24 h(-1)) IV infusion with/without preceding loading dose and experimental endotoxemia for evaluations of pharmacokinetics, pharmacodynamics, safety parameters, antigenicity, inflammatory markers, and outcomes. RESULTS: Linearity and dose-proportionality were shown during 10-min infusions. The relatively short elimination half-life necessitated a loading dose to achieve stable enzyme levels. Pharmacokinetic parameters in volunteers and patients were similar. Innate immunity response was not significantly influenced by AP, while renal function significantly improved in sepsis patients. CONCLUSIONS: The pharmacokinetics of exogenous AP is linear, dose-proportional, exhibit a short half-life, and are not influenced by renal impairment or dialysis.

Genetic divergence between two sympatric species of the Lutzomyia longipalpis complex in the paralytic gene, a locus associated with insecticide resistance and lovesong production.

The sandfly Lutzomyia longipalpis s.l. is the main vector of American Visceral Leishmaniasis. L. longipalpis s.l. is a species complex but until recently the existence of cryptic sibling species among Brazilian populations was a controversial issue. A fragment of paralytic (para), a voltage dependent sodium channel gene associated with insecticide resistance and courtship song production in Drosophila, was isolated and used as a molecular marker to study the divergence between two sympatric siblings of the L. longipalpis complex from Sobral, Brazil. The results revealed para as the first single locus DNA marker presenting fixed differences between the two species in this locality. In addition, two low frequency amino-acid changes in an otherwise very conserved region of the channel were observed, raising the possibility that it might be associated with incipient resistance in this vector. To the best of our knowledge, the present study represents the first population genetics analysis of insecticide resistance genes in this important leishmaniasis vector.

Comparative analysis of a chemotherapy effect on the cuticular surface of Wuchereria bancrofti adult worms in vivo.

Wuchereria bancrofti is the main species responsible for human lymphatic filariasis and remains a major public health problem in tropical countries around the world. Diethylcarbamazine (DEC) has been used for decades in control programs as an effective microfilaricide, although its efficacy in killing adult worms is only around 50% and its direct mode of action is unclear. Recently, in an attempt to control and eliminate lymphatic filariasis, WHO has recommended albendazole (ALB), a broad-spectrum anthelminthic combined with DEC or ivermectin for mass treatment. Some studies have shown that DEC alone blocks oogenesis, fertilization in adult worms, and loss of the microfilarial sheath of several filarial species, whereas ALB is thought to target nematode tubulin. So far, the direct effect of ALB in combination with DEC has not been described in W. bancrofti adult worms. Therefore, the purpose of this study is to investigate by scanning electron microscopy if DEC coadministered with ALB can induce in vivo morphological alterations of the W. bancrofti adult worm surface obtained from a patient in whom the adult worm remained alive, checked serially by ultrasonography for 2 months after antifilarial treatment. Our analysis demonstrates that worms presented morphologic alterations in some regions suggesting cuticular surface damage. On the other hand, adult worms that were recovered from a patient treated with DEC alone after a single dose did not show such any abnormalities.

Plasma renin and the antihypertensive effect of the orally active renin inhibitor aliskiren in clinical hypertension.

BACKGROUND: Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension. METHODS: In 569 patients with mild-to-moderate hypertension, blood pressure (BP), plasma renin activity (PRA) and plasma renin concentration (PRC) were measured before and after 8 weeks of double-blind treatment with once-daily oral doses of aliskiren (150, 300 or 600 mg), irbesartan 150 mg or placebo. RESULTS: Aliskiren 150, 300 and 600 mg and irbesartan 150 mg significantly reduced mean cuff sitting systolic BP (SBP) from baseline (p < 0.001 vs. placebo). Aliskiren 150, 300 and 600 mg significantly reduced geometric mean PRA by 69%, 71% and 75% from baseline respectively (p < 0.05 vs. placebo). Irbesartan 150 mg significantly increased PRA by 109% (p < 0.05 vs. placebo). Aliskiren dose-dependently increased PRC from baseline by 157%, 246% and 497%, at 150, 300 and 600 mg respectively, compared with a 9% decrease with placebo (p < 0.05). PRC increased significantly more with aliskiren 300 and 600 mg compared with irbesartan 150 mg (105%; p < 0.05). Regression analysis showed no significant correlations between baseline PRA and changes in SBP in any of the treatment groups, but interestingly, the slopes of the regression lines between changes in SBP and log-transformed baseline PRA were +2.0 for placebo and -1.5, -1.8 and -2.3 for aliskiren 150, 300 and 600 mg respectively. The slope for irbesartan 150 mg (-1.4) was similar to that for aliskiren 150 mg. CONCLUSIONS: Aliskiren reduces SBP and PRA and increases PRC dose-dependently. In contrast, irbesartan reduces SBP but increases both PRC and PRA. As PRA is a measurement of angiotensin I-generating capacity, PRA can be used for measuring the ability of an antihypertensive agent to prevent the generation or action of Ang II, either directly (renin inhibitors, beta-blockers, central alpha(2)-agonists) or indirectly (AT(1)-receptor blockers, ACE inhibitors).

Children and adolescents infected with Wuchereria bancrofti in Greater Recife, Brazil: a randomized, year-long clinical trial of single treatments with diethylcarbamazine or diethylcarbamazine-albendazole.

In filariasis-endemic areas beyond sub-Saharan Africa, the World Health Organization's recommended strategy for interrupting transmission of the causative parasites is annual, single-dose, mass treatment with a combination of diethylcarbamazine (DEC; given at 6 mg/kg) and albendazole (ALB; given at 400 mg) for 4-6 years (the minimum estimated life-span of the adult parasites). In an open, hospital-based, randomized and controlled trial, with a blinded evaluation of outcome, 82 children and adolescents from Recife, all with Wuchereria bancrofti microfilaraemias, were given either DEC alone (6 mg/kg) or the same dose of DEC combined with ALB (at 400 mg/patient). Every 90 days for 1 year after the single treatment, each patient was checked for microfilaraemia by the filtration of up to 5 ml of venous blood collected at night. One year post-treatment, 16 (39%) of the 41 patients given DEC alone and 20 (49%) of the 41 given DEC-ALB were found microfilaraemic (relative risk=0.8, with a 95% confidence interval of 0.49-1.31) and the corresponding geometric mean levels of microfilaraemia were 2.0% and 1.8% of the levels recorded immediately pre-treatment, respectively (P>0.05). In terms of the prevalences and intensities of microfilaraemia, therefore, the addition of ALB to the DEC appeared to offer no significant benefit.

Comparison of plasma and saliva concentrations of levetiracetam following administration orally as a tablet and as a solution in healthy adult volunteers.

OBJECTIVE: Concentrations in saliva, as an alternative to concentrations in blood, can be advantageous for the monitoring of antiepileptic agents. This study assesses the relationship between saliva and plasma concentrations of levetiracetam after administration orally as a solution and as a tablet. The possibility that saliva concentrations of the drug are altered by contamination in the buccal cavity was also examined. METHODS: 4 healthy male subjects received a single 750 mg oral dose of levetiracetam as a 10% solution and 4 subjects received three 250 mg tablets (750 mg). Levetiracetam concentrations in plasma and saliva were monitored for 24 hours post dose. RESULTS: In subjects receiving the levetiracetam solution, maximum saliva concentrations were observed at the first collection point (15 min) after administration and these were 19-74 times higher than corresponding plasma levels. The mean saliva/plasma ratio rapidly decreased thereafter, becoming stable after 4 hours. In subjects receiving tablets, levetiracetam concentration profiles for saliva paralleled the plasma concentration profiles with a fairly constant saliva/plasma concentration ratio throughout the 24-hour sampling period. A significant linear correlation between levetiracetam saliva and plasma concentrations was demonstrated (Pearson r = 0.88; p < 0.001 for tablet (n = 35) and r = 0.87; p < 0.001 for solution at times > or = 4 hours post-dose (n = 20)). The saliva to plasma concentration ratio was 1.11 (95% confidence interval: 0.99 - 1.22) following tablet intake, and 1.55 (95% CI: 1.34 1.77) following oral solution (> or = 4 hours post dose). CONCLUSIONS: Using saliva to monitor therapeutic exposure to levetiracetam is feasible beginning 15 minutes after tablet intake but beginning 4 hours after intake of an oral solution.

Lipid and apoprotein changes during atorvastatin up-titration in hemodialysis patients with hypercholesterolemia: a placebo-controlled study.

BACKGROUND: Patients with end-stage renal disease commonly present with an atherogenic lipid profile characterized by the accumulation of triglyceride-rich, apoprotein B-containing "remnant" lipoproteins, small dense low-density lipoprotein, and low levels of high-density lipoprotein. They are at increased cardiovascular risk and may benefit from drastic lipid-lowering treatment with atorvastatin, a potent, broadacting lipid regulator. This study aims to assess the effects of atorvastatin on the lipid profile in hemodialysis patients, to determine wether atorvastatin is also effective at lowering lipid levels in this particular high-risk subgroup. METHODS: In this randomized, placebo-controlled, double-blind study in hemodialysis patients with hypercholesterolemia (n = 42, mean total cholesterol 243 +/- 33 mg/dl (6.3 +/- 0.8 mmol/l)), the efficacy of 4-weekly increasing doses of atorvastatin (10 - 40 mg daily) was investigated. Lipids and apoproteins were measured in plasma and isolated lipoprotein fractions. RESULTS: Mean total cholesterol and low-density lipoprotein cholesterol progressively decreased with increasing doses of atorvastatin (total cholesterol -33%, low-density lipoprotein cholesterol -43% after 12 weeks), while high-density lipoprotein cholesterol remained unchanged. Plasma levels of apoprotein B and apoprotein E were also significantly reduced by atorvastatin 10 mg, while up-titration to 20 and 40 mg daily provided additional benefits by lowering triglycerides and apoprotein C-III. At week 12, the fraction of small dense low-density lipoprotein was significantly reduced from 23% - 18%, and apoprotein B-containing intermediate-density lipoproteins were no longer detectable. CONCLUSION: In conclusion, atorvastatin not only treated hypercholesterolemia but also favorably affected the uremic lipid profile in patients on hemodialysis. Atorvastatin 4-weekly dose escalation up to 40 mg daily was well-tolerated. Further prospective studies are needed to evaluate the impact of this improved lipid profile on morbidity and mortality.

Re-evaluation and modification of the Stuivenberg Hospital Acute Renal Failure (SHARF) scoring system for the prognosis of acute renal failure: an independent multicentre, prospective study.

BACKGROUND: A prognostic scoring system for hospital mortality in acute renal failure (Stuivenberg Hospital Acute Renal Failure, SHARF score) was developed in a single-centre study. The scoring system consists of two scores, for the time of diagnosis of acute renal failure (ARF) and for 48 h later, each originally based on four parameters (age, serum albumin, prothrombin time and heart failure). The scoring system was now tested and adapted in a prospective study. METHODS: The study involved eight intensive care units. We studied 293 consecutive patients with ARF in 6 months. Their mortality was 50.5%. The causes of ARF were medical in 184 (63%) patients and surgical in 108 (37%). In the latter group, 74 (69%) patients underwent cardiac and 19 (18%) vascular surgery. RESULTS: As the performance of the original SHARF scores was much lower in the multicentre study than in the original single-centre study, we re-analysed the multicentre data to customize the original model for the population studied. The independent variables were the score developed in the original study plus all additonal parameters that were significant on univariate analysis. The new multivariate analysis revealed an additional subset of three parameters for inclusion in the model (serum bilirubin, sepsis and hypotension). For the modified SHARF II score, r(2) was 0.27 at 0 and 0.33 at 48 h, respectively, the receiver operating characteristic (ROC) values were 0.82 and 0.83, and the Hosmer-Lemeshow goodness-of-fit P values were 0.19 and 0.05. CONCLUSION: After customizing and by using two scoring moments, this prediction model for hospital mortality in ARF is useful in different settings for comparing groups of patients and centres, quality assessment and clinical trials. We do not recommend its use for individual patient prognosis.

Internal dynamics and ionization states of the macrophage migration inhibitory factor: comparison between wild-type and mutant forms.

The macrophage migration inhibitory factor (MIF) is a cytokine that shares a common structural architecture and catalytic strategy with three isomerases: 4-oxalocrotonate tautomerase, 5-carboxymethyl-2-hydroxymuconate isomerase, and D-dopachrome tautomerase. A highly conserved N-terminal proline acts as a base-acid during the proton transfer reaction catalyzed by these enzymes. Such unusual catalytic strategy appears to be possible only due to the N-terminal proline pK(a) shifted to 5.0-6.0 units. Mutations of this residue result in a significant decrease of the catalytic activity of MIF. Two hypotheses have been proposed to explain the catalytic inefficiency of MIF: the lower basicity of primary amines with regard to secondary ones and the increased flexibility resulting from the replacement of a proline by residues like glycine. To investigate that, we have performed molecular dynamics simulations of MIF wild-type and its mutant P1G, as well as calculated the protonation properties of several mutant forms. It was found that the N-terminal glycine does not show larger fluctuations compared to proline, but the former residue is more exposed to the solvent throughout the simulations. The apparent pK(a) of these residues displays very little change (as expected from the structural rigidity of MIF) and is not significantly affected by the surrounding ionizable residues. Instead, the hydrophobic character of the active site seems to be the main factor in determining the pKa of the N-terminal residue and the catalytic efficiency of MIF.

Pharmacokinetics of ertapenem in healthy young volunteers.

Ertapenem (INVANZ) is a new once-a-day parenteral beta-lactam antimicrobial shown to be effective as a single agent for treatment of various community-acquired and mixed infections. The single- and multiple-dose pharmacokinetics of ertapenem at doses up to 3 g were examined in healthy young men and women volunteers. Plasma and urine samples collected were analyzed using reversed-phase high-performance liquid chromatography with UV detection. Ertapenem is highly bound to plasma protein. The protein binding changes from approximately 95% bound at concentrations of <50 micro g/ml to approximately 92% bound at concentrations of 150 micro g/ml (concentration at the end of a 30-min infusion following the 1-g dose). The nonlinear protein binding of ertapenem resulted in a slightly less than dose proportional increase in the area under the curve from 0 h to infinity (AUC(0- infinity )) of total ertapenem. The single-dose AUC(0- infinity ) of unbound ertapenem was nearly dose proportional over the dose range of 0.5 to 2 g. The mean concentration of ertapenem in plasma ranged from approximately 145 to 175 micro g/ml at the end of a 30-min infusion, from approximately 30 to 34 micro g/ml at 6 h, and from approximately 9 to 11 micro g/ml at 12 h. The mean plasma t(1/2) ranged from 3.8 to 4.4 h. About 45% of the plasma clearance (CL(P)) was via renal clearance. The remainder of the CL(P) was primarily via the formation of the beta-lactam ring-opened metabolite that was excreted in urine. There were no clinically significant differences between the pharmacokinetics of ertapenem in men and women. Ertapenem does not accumulate after multiple once-daily dosing.

Molecular evolution of the cacophony IVS6 region in sandflies.

A number of insects produce acoustic signals during courtship. Genes involved in the control of the courtship song are particularly interesting from an evolutionary viewpoint because interspecific variation in this signal is potentially important as a reproductive isolation mechanism and, as a consequence, in the speciation process. The cacophony gene was identified by a mutation affecting the "lovesong" in Drosophila melanogaster. Phlebotomine sandflies (Diptera: Psychodidae) also produce acoustic stimuli during courtship and therefore cacophony can be used as an interesting molecular marker in evolutionary studies in these important disease vectors. In this paper we have studied the molecular evolution of the IVS6 region of cacophony in sandflies. We compared the level of divergence in the exon sequences encoding this conserved domain in Drosophila and Phlebotomines. We also analysed the high level of variation in an intron that is present in sandflies but that was lost in Drosophila during evolution. The available cacophony sequences were also used for a phylogenetic analysis of some species of the Neotropical genus Lutzomyia.

Computer simulation of the rough lipopolysaccharide membrane of Pseudomonas aeruginosa.

Lipopolysaccharides (LPSs) form the major constituent of the outer membrane of Gram-negative bacteria, and are believed to play a key role in processes that govern microbial metal binding, microbial adsorption to mineral surfaces, and microbe-mediated oxidation/reduction reactions at the bacterial exterior surface. A computational modeling capability is being developed for the study of geochemical reactions at the outer bacterial envelope of Gram-negative bacteria. A molecular model for the rough LPS of Pseudomonas aeruginosa has been designed based on experimentally determined structural information. An electrostatic model was developed based on Hartree-Fock SCF calculations of the complete LPS molecule to obtain partial atomic charges. The exterior of the bacterial membrane was assembled by replication of a single LPS molecule and a single phospholipid molecule. Molecular dynamics simulations of the rough LPS membrane of P. aeruginosa were carried out and trajectories were analyzed for the energetic and structural factors that determine the role of LPS in processes at the cell surface.