Thermosensitive and Mucoadhesive Pluronic-Hydroxypropylmethylcellulose Hydrogel Containing the Mini-CD4 M48U1 Is a Promising Efficient Barrier against HIV Diffusion through Macaque Cervicovaginal Mucus

To be efficient, vaginal microbicide hydrogels should form a barrier against viral infections and prevent virus spreading through mucus. Multiple particle tracking was used to quantify the mobility of 170-nm fluorescently labeled COOH-modified polystyrene particles (COOH-PS) into thermosensitive hydrogels composed of amphiphilic triblock copolymers with block compositions EO_n-PO_m-EO_n (where EO refers to ethylene oxide and PO to propylene oxide) containing mucoadhesive hydroxypropylmethylcellulose (HPMC). COOH-PS were used to mimic the size and the surface charge of HIV-1. Analysis of COOH-PS trajectories showed that particle mobility was decreased by Pluronic hydrogels in comparison with cynomolgus macaque cervicovaginal mucus and hydroxyethylcellulose hydrogel (HEC; 1.5% by weight [wt%]) used as negative controls. Formulation of the peptide mini-CD4 M48U1 used as an anti-HIV-1 molecule into a mixture of Pluronic F127 (20 wt%) and HPMC (1 wt%) did not affect its anti-HIV-1 activity in comparison with HEC hydrogel. The 50% inhibitory concentration (IC₅₀) was 0.53 μg/ml (0.17 μM) for M48U1-HEC and 0.58 μg/ml (0.19 μM) for M48U1-F127-HPMC. The present work suggests that hydrogels composed of F127-HPMC (20/1 wt%, respectively) can be used to create an efficient barrier against particle diffusion in comparison to conventional HEC hydrogels.     

Idiopathic chylopericardium: A case report from Saudi Arabia

Chylopericardium is a rare clinical condition in which chyle leaks into the pericardial space owing to lymphatic system derangement. It can be idiopathic or occur secondarily to another clinical condition. Optimal management is accomplished through surgical intervention to impede leaks and drain fluid. In this report, we discuss an initially asymptomatic patient with a pre-employment chest radiograph that revealed cardiomegaly. An echocardiogram revealed pericardial effusion. Medical workup was unable to determine secondary causes for effusion. Pericardiocentesis revealed milky-colored fluid with a high lymphocyte count, and a lymphoscintigraphy lymphangiogram revealed a leak into the pericardium and decreased flow through left iliac and left periaortic lymph nodes. Since the patient was asymptomatic, she was treated conservatively with diet changes, pericardial drainage, and a pericardial window procedure. This type of case risks being misdiagnosed as tuberculosis, especially in countries where tuberculosis is endemic. In such cases, assessing pericardial fluid for chyle is crucial.     

Migraine in Assiut Governorate,Egypt: epidemiology,risk factors,comorbid conditions and predictors of change from episodic to chronic migraine

Abstract

Objectives: Headache is one of the most common complaints in medicine. Epidemiological and population-based studies reported that migraine has a variable prevalence worldwide. This study was done to estimate the prevalence of migraine across various age groups in Assiut district, Egypt.

Methods: This is a door-to-door study. It included 4700 randomly selected individuals.

Results: Headache was reported in 1668 subjects (35.49%), of them, 87.65% (n = 1462) had primary headaches. Migraine prevalence was 10.51% with female-to-male ratio of 2.4:1 particularly in ages of 20–40 years. The mean age of patients was 31.46 ± 13.39 years and age at onset was 24.16 ± 12.10 years. Nearly, 63.5% had frequent attacks, 65.2% of the attacks were severe enough to stop daily activities and lasted for >1 day in 32.5% of females compared to 40.7% and 14.5% for males. Chronic or daily migraine was more in females (35.3% versus 20.7% for males). Approximately, 5.6% had chronic migraine and 1.2% had daily migraine from the start, while 24.2% had transformation from episodic to chronic migraine within 6.1 ± 4.4 years. Migraine was prevalent among those with middle educational levels and labor workers. The duration of migraine attacks was found to reduce with age but the chronic/daily migraine increased with age. Hypertension, anxiety, irritable bowel syndrome, and depression were common comorbidities with migraine.

Conclusions: We believe that the work done in this study is informative as it determined the actual prevalence of migraine across various age groups and the important predictors of change in the severity, duration, and frequency of migraine in our locality.     

Methods for the Preparation and Manufacture of Polymeric Nanoparticles

This review summarizes the different methods of preparation of polymer nanoparticles including nanospheres and nanocapsules. The first part summarizes the basic principle of each method of nanoparticle preparation. It presents the most recent innovations and progresses obtained over the last decade and which were not included in previous reviews on the subject. Strategies for the obtaining of nanoparticles with controlled in vivo fate are described in the second part of the review. A paragraph summarizing scaling up of nanoparticle production and presenting corresponding pilot set-up is considered in the third part of the review. Treatments of nanoparticles, applied after the synthesis, are described in the next part including purification, sterilization, lyophilization and concentration. Finally, methods to obtain labelled nanoparticles for in vitro and in vivo investigations are described in the last part of this review.     

Bivalent sequential binding of docetaxel to methyl-β-cyclodextrin

New docetaxel (Dtx) and cyclodextrin (CD) inclusion complexes having improved apparent water solubility (up to 9.98 mg mL⁻¹) were obtained from phase solubility diagrams. γ-CD and SBE-β-CD offered only poor solubility enhancements while considerable increases in apparent solubility were obtained with Me-β-CD (20%, w/w) and HP-β-CD (40%, w/w) (9.98 mg mL⁻¹ and 7.43 mg mL⁻¹, respectively). The complexation mechanism between Dtx and Me-β-CD was investigated by circular dichroism spectrometry, two-dimensional ¹H NMR (NOESY) in D₂O, isothermal titration calorimetry (ITC) and molecular docking calculations. Circular dichroism and NOESY confirmed the existence of non-covalent interactions between Dtx and Me-β-CD and suggested that the tert-butyl group (C₆-C₉) and two aromatic groups (C₂₄-C₂₉ and C₃₀-C₃₅) of Dtx interacted with the Me-β-CD molecules. The combination of ITC results to molecular docking calculations led to the identification of an unconventional sequential binding mechanism between Me-β-CD and Dtx. In this sequential binding, a Me-β-CD molecule first interacted with both tert-butyl and C₃₀-C₃₅ aromatic groups (K₁: 744 M⁻¹). Then a second Me-β-CD molecule interacted with the C₂₄-C₂₉ aromatic group (K₂: 202 M⁻¹). The entropy of the first interaction was positive, whereas a negative value of entropy was found for the second interaction. The opposite behavior observed for these two sites was explained by differences in the hydrophobic contact surface and functional group flexibility.     

Virological response after short-term CCR5 antagonist exposure in HIV-infected patients: frequency of subjects with virological response and associated factors

The virological response after an 8-day maraviroc monotherapy has been proposed to be an alternative method to determine whether an CCR5 antagonist should be prescribed to HIV-infected patients. The frequency of patients eligible for a combined antiretroviral therapy which includes maraviroc on the basis of the result of this clinical test is not well-known at the moment. In the same way, clinical and immunovirological factors associated with the virological response after antagonist exposure need to be determined. Ninety consecutive HIV-infected patients were exposed to an 8-day maraviroc monotherapy. The virological response was considered positive if either a reduction of ≥1-log₁₀ HIV RNA copies/ml or an undetectable viral load (<40 HIV RNA copies/ml) was achieved. CXCR4- and CCR5-tropic virus levels were determined by using patients'' viral isolates and multiple rounds of infection of indicator cell lines (U87-CXCR4 and U87-CCR5). The frequency of patients with a positive virological response was 72.2% (94.7% and 66.2% for treatment-naïve and pretreated patients, respectively). The positive response rates dramatically decreased in patients with lower CD4⁺ T-cell counts. The CXCR4-tropic virus level was the only variable independently associated with the virological response after short-term maraviroc exposure. Lower CD4⁺ T-cell strata were associated with higher CXCR4-tropic virus levels. These results support the suggestion that CCR5 antagonists should be an early treatment option before the expansion of CXCR4-tropic strains.     

Note on the formulation of thermosensitive and mucoadhesive vaginal hydrogels containing the miniCD4 M48U1 as anti-HIV-1 microbicide

The miniCD4 M48U1 was formulated into thermosensitive and mucoadhesive pluronic^® hydrogels as anti-HIV-1 microbicide. The release kinetics of M48U1 from F127/HPMC (20/1 wt%) and F127/F68/HPMC (22.5/2.5/1 wt%) studied during 24 h by using Franz diffusion cells showed that HEC hydrogel (1.5 wt%) used as control released 93% of the peptide, while about 25% of M48U1 remained in pluronic^® hydrogels. The formulation of M48U1 in pluronic^® hydrogels ensures a local delivery because no diffusion of the peptide was detected through vaginal Cynomolgus macaque mucosa using Ussing chamber. Finally, toxicological studies showed no significant difference in the HeLa cell viability of the pluronic^® hydrogels in comparison with HEC and phosphate buffer saline.     

Scale-up of polyamide and polyester Parsol MCX nanocapsules by interfacial polycondensation and solvent diffusion method

The scale-up of oil-containing polyamide nanocapsules produced by simultaneous interfacial polycondensation and solvent diffusion was successfully achieved. Up to 1500 mL were produced by using a Y-shaped mixer device. The sizes of nanocapsules containing olive oil were modulated from 646 to 211 nm by changing process parameters without modification of the formulation composition. All the results of nanocapsule diameters (d_sc) expressed as a function of the Reynolds number (Re) showed the existence of a typical power–law relationship. It was demonstrated that the high turbulences created upon nanocapsule formation are the most important parameter allowing to nanocapsule size to be controlled without modifying the formulation composition. Finally, the power–law relationship was used to predict the size of nanocapsules composed of polyamide or polyester and loaded with Parsol^® MCX. The physico-chemical properties of both polyamide and polyester nanocapsules at the laboratory scale were compared to the ones obtained at the pilot scale. The encapsulation efficiency was higher than 98% in both types of nanocapsules at the laboratory and the pilot scales. The in vitro releases of Parsol^® MCX from polyester nanocapsules were reproducible at both scales. This is the first time such a power–law was described for the preparation of nanocapsules by interfacial polycondensation and solvent diffusion.     

Review of non-clinical risk models to aid prevention of breast cancer

A disease risk model is a statistical method which assesses the probability that an individual will develop one or more diseases within a stated period of time. Such models take into account the presence or absence of specific epidemiological risk factors associated with the disease and thereby potentially identify individuals at higher risk. Such models are currently used clinically to identify people at higher risk, including identifying women who are at increased risk of developing breast cancer. Many genetic and non-genetic breast cancer risk models have been developed previously. We have evaluated existing non-genetic/non-clinical models for breast cancer that incorporate modifiable risk factors. This review focuses on risk models that can be used by women themselves in the community in the absence of clinical risk factors characterization. The inclusion of modifiable factors in these models means that they can be used to improve primary prevention and health education pertinent for breast cancer. Literature searches were conducted using PubMed, ScienceDirect and the Cochrane Database of Systematic Reviews. Fourteen studies were eligible for review with sample sizes ranging from 654 to 248,407 participants. All models reviewed had acceptable calibration measures, with expected/observed (E/O) ratios ranging from 0.79 to 1.17. However, discrimination measures were variable across studies with concordance statistics (C-statistics) ranging from 0.56 to 0.89. We conclude that breast cancer risk models that include modifiable risk factors have been well calibrated but have less ability to discriminate. The latter may be a consequence of the omission of some significant risk factors in the models or from applying models to studies with limited sample sizes. More importantly, external validation is missing for most of the models. Generalization across models is also problematic as some variables may not be considered applicable to some populations and each model performance is conditioned by particular population characteristics. In conclusion, it is clear that there is still a need to develop a more reliable model for estimating breast cancer risk which has a good calibration, ability to accurately discriminate high risk and with better generalizability across populations.