In vitro susceptibility of Plasmodium falciparum to monodesethylamodiaquine, quinine, mefloquine and halofantrine in Abidjan (Côte d'Ivoire)

Background

Malaria is the primary cause of hospitalization in Côte d''Ivoire. Early treatment is one of the strategies to control this illness. However, the spread of resistance of Plasmodium falciparum to antimalarial drugs can seriously compromise this strategy.

Objectives

The aim of this study was to assess the in vitro susceptibility of P. falciparum to monodesethylamodiaquine and aminoalcohols in Abidjan (Côte d''Ivoire).

Methods

We assessed the in vitro susceptibility of isolates collected from patients with uncomplicated malaria by using the WHO optical microtest technique.

Results

The proportions of resistance to monodesethylamodiaquine, méfloquine and halofantrine were 12.5%, 15.6% and 25.9%, respectively. For quinine, none of isolates showed evidence of in vitro resistance. However, two isolates (6.1%) had IC₅₀ values above 300 nM. The IC₅₀ of each drug was positively and significantly correlated to that of the other three drugs, and the correlation was higher between halofantrine and mefloquine.

Conclusions

Our results showed that the in vitro chloroquine resistance reported in previous studies has been extended to other antimalarial drugs investigated in this study except for quinine. Therefore, it is necessary to implement a long-term monitoring system of antimalarial drug resistance.     

Genetic polymorphisms in MDR1, CYP3A4 and CYP3A5 genes in a Ghanaian population: a plausible explanation for altered metabolism of ivermectin in humans?

Background  

Ivermectin, a substrate of multidrug resistance (MDR1) gene and cytochrome P450 (CYP) 3A4, has been used successfully in the treatment of onchocerciasis in Ghana. However, there have been reports of suboptimal response in some patients after repeated treatment. Polymorphisms in host MDR1 and CYP3A genes may explain the observed suboptimal response to ivermectin. We genotyped relevant functional polymorphisms of MDR1 and CYP3A in a random sample of healthy Ghanaians and compared the data with that of ivermectin-treated patients with a view to exploring the relationship between suboptimal response to ivermectin and MDR1 and CYP3A allelic frequencies.     

In vitro analysis of PNIPAAm–PEG,a novel,injectable scaffold for spinal cord repair

Nervous tissue engineering in combination with other therapeutic strategies is an emerging trend for the treatment of different CNS disorders and injuries. We propose to use poly(N-isopropylacrylamide)-co-poly(ethylene glycol) (PNIPAAm–PEG) as a minimally invasive, injectable scaffold platform for the repair of spinal cord injury (SCI). The scaffold allows cell attachment, and provides mechanical support and a sustained release of neurotrophins. In order to use PNIPAAm–PEG as an injectable scaffold for treatment of SCI, it must maintain its mass and volume over time in physiological conditions. To provide mechanical support at the injury site, it is also critical that the engineered scaffold matches the compressive modulus of the native neuronal tissue. This study focused on studying the ability of the scaffold to release bioactive neurotrophins and matching the material properties to those of the native neuronal tissue. We found that the release of both BDNF and NT-3 was sustained for up to 4 weeks, with a minimal burst exhibited for both neurotrophins. The bioactivity of the released NT-3 and BDNF was confirmed after 4 weeks. In addition, our results show that the PNIPAAm–PEG scaffold can be designed to match the desired mechanical properties of the native neuronal tissue, with a compressive modulus in the 3–5 kPa range. The scaffold was also compatible with bone marrow stromal cells, allowing their survival and attachment for up to 31 days. These results indicate that PNIPAAm–PEG is a promising multifunctional scaffold for the treatment of SCI.     

In vitro and in vivo evaluation of a novel antiherpetic flavonoid, 4′-phenylflavone, and its synergistic actions with acyclovir

The development of therapeutic agents for preventing herpes simplex virus (HSV) infections has become urgently necessary because of the increasing incidence of this virus and its role as a cofactor in the transmission of human immunodeficiency virus infection. We have evaluated the antiviral activities of a series of natural and synthetic flavonoids and found that a synthetic flavonoid, 4'-phenylflavone, showed the highest activity against acyclovir (ACV)-sensitive and ACV-resistant strains of HSV-1, as well as HSV-2, with a selectivity index of 213, 35 and 55, respectively. Although the attachment and penetration of HSV-1 to host cells and the synthesis of viral proteins were not inhibited, the infectivity of the virus and the amount of progeny virus released were reduced by 4'-phenylflavone treatment in a dose-dependent manner. 4'-Phenylflavone plus ACV synergistically inhibited the replication of HSV-1. This flavonoid also showed efficacy in vivo and potentiated the antiherpetic effect of ACV in a mouse model of genital herpes. Our results suggest that 4'-phenylflavone might be useful as a candidate for the development of novel antiherpetic therapeutics.     

Synthesis,characterizations, in vitro and in vivo evaluation of Etoricoxib-loaded Poly (Caprolactone) microparticles – a potential Intra-articular drug delivery system for the treatment of Osteoarthritis

Intra-articular Drug delivery systems (IA-DDS) deliver the drug directly to the diseased joint space with significantly lowered systemic toxicities. In this work, we explored Etoricoxib (COX-2 inhibitor)-loaded Poly caprolactone (PCL) microparticles (MPs) as a potential IA-DDS. MPs were prepared by Oil/Water (O/W) emulsion-solvent evaporation method. Formulation parameters like polymer to drug ratio, stabilizer concentration were optimized to get the maximum encapsulation efficiency. The prepared particles were characterized using Scanning Electron Microscopy (SEM), Fourier Transform Infrared Spectroscopy (FTIR), X-ray Diffraction studies (XRD), and Differential Scanning Calorimetry (DSC). The particles were found to be spherical and smooth-surfaced using SEM. FTIR studies proved that there was no chemical interaction between the drug and the polymer. XRD and DSC studies confirmed that Etoricoxib existed in its amorphous form while PCL had retained its semi-crystalline phase during the micro-encapsulation process. In vitro drug release studies proved that there was controlled release of the drug from the MPs for nearly 28 days. In vivo synovial drug clearance studies on SD rats proved that drug leach out rate from the joint region to the systemic circulation was slow which indicated that MPs had a good drug retention capacity. In vivo fluorescence imaging results confirmed that MPs could stay longer in the joint region for almost a month. Thus, PCL microparticles could be a potential IA-DDS for the treatment of the diseased joint regions especially for Osteoarthritis.     

Polyclonal Outbreak of KPC-3-Producing Enterobacter cloacae at a Single Hospital in Montréal,Québec,Canada

From September 2010 to December 2011, 26 KPC-3-producing Enterobacter cloacae isolates were identified from 16 patients at a single hospital. Analyses revealed the bla_KPC gene to be localized on multiple plasmids in a diverse nonclonal E. cloacae genetic background. These findings highlight the potential complexity of a KPC outbreak at a single hospital.     

Preparation,characterization, and in vitro drug release behavior of glutathione-sensitive long-circulation micelles based on polyethylene glycol prodrug

In this paper, a kind of glutathione-sensitive polymeric micelles was prepared through assembling in aqueous solution of an amphiphilic polymeric prodrug which was synthesized by linkage of 6-mercaptopurine (6-MP) and polyethylene glycol monomethyl ether using propiolic acid as a connecting arm. The glutathione (GSH)-sensitive strategy is based on a Michael addition–elimination reaction, that is the amphiphilic polymeric prodrug which contains α, β-unsaturated carbonyl group acts as a Michael acceptor to receive the attack of nucleophile – glutathione, and undergoes elimination reaction to release the original drug. Transmission electron microscope observation showed that the polymeric micelles (PMs) had a spherical-like morphology with a mean diameter of 28 ± 3.2 nm. The dynamic light scattering investigation data exhibited that the size and distribution changes of PMs are negligible after being placed for 15 days. In vitro drug release study indicated that only less than 13% of 6-MP was released from the micelles under GSH stimulation at micromolar level, while 34.5, 53.7, and 77.8% accumulative release rates were achieved under GSH stimulation at millimolar level (1, 2 and 10 mM), respectively. The cell inhibition rate of PM solution against HL-60 cells carried out by MTT method reached 85%. The cellular uptake and the intracellular drug release of PMs in HL-60 cells were observed through determining the intracellular 6-MP content by UV–vis spectrophotometer. In vitro macrophage uptake study showed a low phagocytosis rate, indicating the long-circulation ability of the PMs.     

The implementation of a culturally grounded,school-based,drug prevention curriculum in rural Hawai‘i

This article describes the process of infusing implementation strategies in the development of a school-based drug prevention curriculum for rural Native Hawaiian youth. The curriculum (Ho‘ouna Pono) is a video-enhanced, teacher-implemented curriculum developed using a culturally grounded and community-based participatory research approach. Throughout the development of the curriculum, strategies reflective of the domains of the Consolidated Framework for Implementation Research (CFIR) were integrated into the teacher training manual, to promote the implementation, adoption, and sustainability of the curriculum in rural Hawai‘i. These strategies were validated through qualitative data across two interrelated studies with community stakeholders in rural Hawai‘i. Implications for prevention, community, and educational practices are described in this article.     

Urban schistosomiasis in Cameroon: a longitudinal study of its transmission in a new site of an extension of the intestinal schistosomiasis focus in Mélen, Yaoundé

In order to to set up the present situation on schistosomiasis in the neighbourhoods around the University of Yaounde I campus, a malacological survey (collection of freshwater snails, their identification and tests on cercarial emergence) was carried out monthly over 12 months in 2 water sources, followed by a parasitological diagnosis of intestinal schistosomiasis in subjects who acknowledge having come into contact with the infested water course. The malacological survey revealed 4 freshwater gastropod species, two (Bulinus globosus and Biomphalaria pfeifferi) of which are intermediate hosts of schistosomes. Biomphalaria pfeifferi specimens from the former quarry pond of Ngoa-Ekellé neighbourhood showed an average infestation rate of 9.7%, and emitted schistosome cercariae throughout the whole period of study The parasitological diagnosis included 112 (81.2%) out of the 138 individuals identified, including 55 males and 57 females; 27 out of the 112 subjects had S. mansoni eggs in stools, making a prevalence rate of 24.1%. These patients were composed of 21 males and 6 females. The prevalence of S. mansoni is therefore significantly higher in males. The average parasitic load for our sample was 248 eggs/g of stools. It was much higher (384 eggs/g stools) for males (280 eggs/g stools) than for females (136 eggs/g stools). The differences of prevalences and parasitic loads between sex can be explained in part by the varying activities of interest according to the different groups in the infested watering places.     

In vitro activity of nemonoxacin, tigecycline, and other antimicrobial agents against Helicobacter pylori isolates in Taiwan, 1998–2007

The minimum inhibitory concentrations (MICs) of 330 nonduplicate Helicobacter pylori isolates to nemonoxacin, tigecycline, and eight other antimicrobial agents were determined by using the agar dilution method. Sequencing the quinolone resistance-determining regions (QRDRs) in the gyrA gene of these isolates was also performed. Resistance to clarithromycin showed an increasing trend during the ten-year study period and was highest (38%) in 2005. Tigecycline had potent in vitro activities against all isolates, with an MIC₉₀ of 0.06 μg/ml. Among the quinolones tested, nemonoxacin (MIC₅₀ of 0.12 μg/ml and MIC₉₀ of 0.25 μg/ml) and gemifloxacin had one to two-fold better in vitro activities than ciprofloxacin, levofloxacin, and moxifloxacin. Among the nine isolates (2.7%) with levofloxacin resistance, four (44.4%) were also resistant to metronidazole, three (33.3%) to clarithromycin, and two (22.2%) to amoxicillin. Isolates with levofloxacin resistance exhibited one or two of three amino acid alterations (Ser-70, Asn-87, and Asp-91) involved in QRDRs in the gyrA gene. A double mutation at Ser70Cys and Asn87Ile had a higher level of resistance. The results of this study suggest a potentially useful role of nemonoxacin and tigecycline in the treatment of infections caused by H. pylori. The gyrA mutation at Ser-70 is a novel finding and has an impact on levofloxacin resistance.     

In vitro activities of moxifloxacin and tigecycline against bacterial isolates associated with intraabdominal infections at a medical center in Taiwan, 2001–2006

A total of 569 nonduplicate isolates recovered from patients with community-onset or hospital-onset intraabdominal infections (IAIs) from 2001 to 2006 were studied. These included 28 Staphylococcus aureus and 541 Gram-negative isolates (33.6% Escherichia coli, 29.0% Klebsiella pneumoniae, 8.1% Acinetobacter baumannii, and 6.3% Pseudomonas aeruginosa). Minimum inhibitory concentrations (MICs) of the isolates to moxifloxacin, imipenem, and ciprofloxacin were determined using the agar dilution method and to tigecycline using the broth microdilution method. Extended-spectrum β-lactamase (ESBL) producers were found in 15.5% (29 out of 182) of E. coli, 15.3% (24 out of 157) of K. pneumoniae, and 15.4% (2 out of 13) of K. oxytoca isolates. More than 85% of Enterobacteriaceae were susceptible to moxifloxacin, but this percentage was lower among E. coli (78%). The percentage of E. coli (K. pneumoniae) isolates that were not susceptible to moxifloxacin was 6% (0%) in 2001, 39% (17%) in 2003, and 21% (14%) in 2006. Tigecycline exhibited good in vitro activities against all S. aureus and >95% of all Enterobacteriaceae tested. Among the 24 isolates of ESBL-producing K. pneumoniae, 4 had tigecycline MICs ≥2 μg/ml. Eighty percent of A. baumannii isolates exhibited tigecycline MICs of ≤2 μg/ml. This study found that moxifloxacin and tigecycline exhibited good in vitro activity against bacterial isolates causing IAIs.     

In vitro activities of omadacycline,eravacycline, cefiderocol,apramycin, and comparator antibiotics against Acinetobacter baumannii causing bloodstream infections in Greece, 2020–2021: a multicenter study

Resistance of Acinetobacter baumannii to multiple clinically important antimicrobials has increased to very high rates in Greece, rendering most of them obsolete. The aim of this study was to determine the molecular epidemiology and susceptibilities of A. baumannii isolates collected from different hospitals across Greece. Single-patient A. baumannii strains isolated from blood cultures (n = 271), from 19 hospitals, in a 6-month period (November 2020–April 2021) were subjected to minimum inhibitory concentration determination and molecular testing for carbapenemase, 16S rRNA methyltransferase and mcr gene detection and epidemiological evaluation. 98.9% of all isolates produced carbapenemase OXA-23. The vast majority (91.8%) of OXA-23 producers harbored the armA and were assigned mainly (94.3%) to sequence group G1, corresponding to IC II. Apramycin (EBL-1003) was the most active agent inhibiting 100% of the isolates at ≤16 mg/L, followed by cefiderocol which was active against at least 86% of them. Minocycline, colistin and ampicillin-sulbactam exhibited only sparse activity (S <19%), while eravacycline was 8- and 2-fold more active than minocycline and tigecycline respectively, by comparison of their MIC₅₀/₉₀ values. OXA-23-ArmA producing A. baumannii of international clone II appears to be the prevailing epidemiological type of this organism in Greece. Cefiderocol could provide a useful alternative for difficult to treat Gram-negative infections, while apramycin (EBL-1003), the structurally unique aminoglycoside currently in clinical development, may represent a highly promising agent against multi-drug resistant A. baumanni infections, due to its high susceptibility rates and low toxicity.

     

In vitro testing of Al2O3–Nb composite for femoral head applications in total hip arthroplasty

Alumina (Al₂O₃) bearings in total hip arthroplasty lead to low wear rates, but catastrophic failure of Al₂O₃ femoral heads, while rare, remains a concern. In the present work, a composite of Al₂O₃ and niobium (Nb) was tested in vitro for potential use as an alternative femoral head material in vivo. Dense composite laminates of Al₂O₃ and Nb were fabricated by hot pressing, and their microstructure and mechanical properties were evaluated. The flexural strength of Al₂O₃–Nb laminates in four-point loading was 720 ± 40 MPa, compared with a value of 460 ± 110 MPa for Al₂O₃. Scanning electron microscopy and X-ray diffraction showed a well-bonded interface between the Al₂O₃ and Nb without measurable formation of an interfacial reaction phase. The interfacial shear strength between Al₂O₃ and Nb, measured by a double-notched specimen test, was 290 ± 15 MPa. The feasibility of fabricating prototype femoral heads (32 mm in diameter), consisting of an Al₂O₃ surface layer (2–3 mm thick) and a Nb core, by hot pressing was shown. The composite femoral head combined the low wear of an Al₂O₃ articulating surface with the safety of a ductile metal femoral head.     

In vitro,in vivo and numerical assessment of the working principle of the truCCOMS™ continuous cardiac output catheter system

The truCCOMS? cardiac output monitor system provides a continuous and instantaneous measurement of cardiac output, derived from the amount of energy required for heating a filament to maintain a fixed 2 °C blood temperature difference between two thermistors located distally on a pulmonary artery catheter. Clinical studies, however, reported relatively poor accuracy of the cardiac output estimation, possibly due to linearly assumed power–cardiac output relationship used for calibration of the catheters. We experimentally studied the shape of the truCCOMS? calibration relationship (i) in a hydraulic bench model of the right heart and (ii) in vivo intact animal model. The results showed a nonlinear relationship between the power input into the heating element and the cardiac output; which could satisfactorily be described with an exponential relationship. Comparison of the performance of the same catheters in vitro and in vivo showed that the in vitro determined calibration relationship should not be used for in vivo measurements. Finally, we also simulated the working principle of the catheter using a simplified numerical model of the blood flow and heat transfer around the catheter. The computed results also suggested a pronounced nonlinear relationship between power and cardiac output in pulsatile conditions. We conclude that the observed over- and underestimation of high- and low flows, respectively, by the current truCCOMS? system is likely to arise from its linear calibration relationship. An appropriate calibration scheme accounting for the intrinsic nonlinear power–cardiac output relationship and the difference between in vitro and in vivo conditions should improve the clinical performance of the system.     

Is there a gender difference in associates of adolescents’ lifetime illicit drug use in Tehran,Iran?

Introduction

Information regarding gender differences in drug use of adolescents is essential for designing gender-specific drug prevention policies. This study was conducted in high school students in Tehran, Iran, in 2007. Here, we report the gender differences in lifetime prevalence as well as psychosocial associates of drug use.

Material and methods

This was a gender analysis of the data collected in a drug use survey conducted in a random sample of high school adolescents (573 boys and 551 girls) in Tehran, Iran, 2007. Demographic characteristics, parental and peers’ substance use, school performance, religious beliefs, attachment, self-esteem and emotional intelligence (EI) were entered in logistic regression analyses to predict the lifetime illicit drug use in boy and girls, separately.

Results

Boys were more likely to report lifetime illicit drug use than girls (10.1% vs. 6.4%, p = 0.023). Differences in the risk profile associated with lifetime illicit drug use by gender included history of substance use in the family, higher score of attachment, and having an employed mother as predictors of substance use in boys, but not girls.

Conclusions

Understanding this gender difference in predictors of lifetime use of illicit drugs in high school adolescents facilitates the design of gender-sensitive drug use preventive programmes. It seems that family variables may have more value in prevention of illicit drug use in male adolescents.     

Dynamics of malaria transmission in Kafiné, a rice growing village in a humid savannah area of Côte d'Ivoire

A study on malaria transmission based on samples of mosquitoes caught on human subjects was conducted from February to August 1995 in the rice growing area of Kafine, a village located in the Niakaramandougou district of northern C?te d'Ivoire. The village is surrounded by 117,500 acres of rice fields. Irrigation is sub-permanent in the rice field and harvests number two a year. During the 6 months of the study, 12.353 mosquitoes were caught. The average biting rate was 118.8 bites per man per night (b/m/n). Mansonia, Culex and Aedes represented only 17.5% of the total number of mosquitoes caught. Anopheles accounted for 82.5% of the number of anthropophilic mosquitoes. Anopheles gambiae s.s. represented 83.7% of the total Anopheles species. As a whole, the average biting rate recorded for the Anopheles was 98 b/m/n. The average biting rate of An. gambiae was 90.4 b/m/n. The highest rate (121.5 b/m/n) was recorded in April. During the dry and rainy season, the indoor biting cycle per hour of An. gambiae s.s. was studied from 6 p.m. to 6 a.m. In both seasons, a marked biting activity was noticed between 10 p.m. and 5 a.m. The average annual parity rate reached 40.2% but it ranged from 59.8% (n = 82) in February to 19% (n = 63) in May. The mean sporozoitic index of An. gambiae throughout the study period was 1.1% (14 positive salivary glands/1.251 dissected). The index ranged from 0 in April, May and June to 6.2 (n = 192) in July. The rate did not vary with rainfall but with the different stages of rice growing. The non-synchronisation of agricultural practises for each growing cycle seemed to be a conclusive factor in the transmission of malaria in this locality. Malaria transmission at Kafine can be characterised by 3 main elements: transmission is intensive with an estimated inoculation rate of 1 ib/m/n; transmission is more related to double phase rice cultivation (regardless of synchronisation on plots) than to rainfall; transmission shows particular variations linked to rice cultivation cycles with an increase during periods of ripeness and harvest. The nuisance caused by higher mosquito density has brought people to comply with use of pyrethroid impregnated bed nets advocated for wide use by the National Malaria Control Program.     

In vitro–in vivo sequence studies as a method of selecting the most efficacious alcohol-based solution for hygienic hand disinfection

The use of alcohol-based hand rubs serves to reduce hospital-acquired infections. Many products of this type are now on offer and it is essential to know how to rank their efficacy. A sequence of tests is proposed here to compare any given new alcohol-based solution against the reference solution (60% 2-iso-propyl-alcohol) with 30 s of contact time: (i) in vitro (with pig skin as carrier) testing of >30 species of microorganism; (ii) in vitro assessment of residual efficacy (after 30 min of drying); (iii) in vivo study of transient microbiota (modification of the EN 1500 standard procedure) using four ATCC strains; (iv) in vivo study of resident hand microbiota. After performing the in vitro evaluation of seven alcohol-based hand rubs, the two most efficacious (chlorhexidine-quac-alcohol and mecetronium-alcohol) were chosen and studied, comparatively with the reference solution (60% iso-propyl alcohol), in vitro (for chemical sustainability on the skin) and in vivo (against transient and resident microbiota). Chlorhexidine-quac-alcohol proved to be significantly superior to mecetronium-alcohol or the reference solution in all tests, except against resident microbiota for which the improvement was not statistically significant.