Functional Expression of P-glycoprotein and Organic Anion Transporting Polypeptides at the Blood-Brain Barrier: Understanding Transport Mechanisms for Improved CNS Drug Delivery?

Drug delivery to the central nervous system (CNS) is greatly limited by the blood-brain barrier (BBB). Physical and biochemical properties of the BBB have rendered treatment of CNS diseases, including those with a hypoxia/reoxygenation (H/R) component, extremely difficult. Targeting endogenous BBB transporters from the ATP-binding cassette (ABC) superfamily (i.e., P-glycoprotein (P-gp)) or from the solute carrier (SLC) family (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents)) has been suggested as a strategy that can improve delivery of drugs to the brain. With respect to P-gp, direct pharmacological inhibition using small molecules or selective regulation by targeting intracellular signaling pathways has been explored. These approaches have been largely unsuccessful due to toxicity issues and unpredictable pharmacokinetics. Therefore, our laboratory has proposed that optimization of CNS drug delivery, particularly for treatment of diseases with an H/R component, can be achieved by targeting Oatp isoforms at the BBB. As the major drug transporting Oatp isoform, Oatp1a4 has demonstrated blood-to-brain transport of substrate drugs with neuroprotective properties. Furthermore, our laboratory has shown that targeting Oatp1a4 regulation (i.e., TGF-β signaling mediated via the ALK-1 and ALK-5 transmembrane receptors) represents an opportunity to control Oatp1a4 functional expression for the purpose of delivering therapeutics to the CNS. In this review, we will discuss limitations of targeting P-gp-mediated transport activity and the advantages of targeting Oatp-mediated transport. Through this discussion, we will also provide critical information on novel approaches to improve CNS drug delivery by targeting endogenous uptake transporters expressed at the BBB.     

A Review on Cement Asphalt Emulsion Mortar Composites,Structural Development,and Performances

The use of cement emulsified asphalt mortar (CA mortar) in the track structure of high-speed speed railways has been gaining considerations by many researchers due to its coupled merits of the strength of cement as well as the flexibility of asphalt material. The asphalt to cement ratio (A/C) and the compatibility among constituent materials are crucial to the properties of CA mortar. To improve the performance properties and application of CA mortar, it is imperative to have a broad understanding of the composition mechanisms and compatibility between constituent materials. This paper summarizes interesting research outcomes related to the composition and properties of CA mortar. The consumption of water by cement promotes the breakdown of emulsified asphalt, likewise, the adsorption of asphalt droplets on the surface of cement grains retards the hydration process of cement. An appropriate A/C is required for the cement hydration rate to match the speed of demulsification of asphalt emulsion. Depending on the type and properties for which the CA mortar is designed to possess, the A/C ranges from 0.2 to 0.6 for type 1 (CAM I), and 0.6 to 1.2 for type 2 (CAM II). This paper also discusses measures taken to improve performance properties, compatibility, the interaction between constituent materials of CA mortar, and the use of additives as a partial replacement of cement in CA mortar production. The current review also suggests areas of interest for future research studies. This paper is useful to those who aim to understand or study the composition mechanisms and performance properties of CA mortar.     

Host-based Prophylaxis Successfully Targets Liver Stage Malaria Parasites

Eliminating malaria parasites during the asymptomatic but obligate liver stages (LSs) of infection would stop disease and subsequent transmission. Unfortunately, only a single licensed drug that targets all LSs, Primaquine, is available. Targeting host proteins might significantly expand the repertoire of prophylactic drugs against malaria. Here, we demonstrate that both Bcl-2 inhibitors and P53 agonists dramatically reduce LS burden in a mouse malaria model in vitro and in vivo by altering the activity of key hepatocyte factors on which the parasite relies. Bcl-2 inhibitors act primarily by inducing apoptosis in infected hepatocytes, whereas P53 agonists eliminate parasites in an apoptosis-independent fashion. In combination, Bcl-2 inhibitors and P53 agonists act synergistically to delay, and in some cases completely prevent, the onset of blood stage disease. Both families of drugs are highly effective at doses that do not cause substantial hepatocyte cell death in vitro or liver damage in vivo. P53 agonists and Bcl-2 inhibitors were also effective when administered to humanized mice infected with Plasmodium falciparum. Our data demonstrate that host-based prophylaxis could be developed into an effective intervention strategy that eliminates LS parasites before the onset of clinical disease and thus opens a new avenue to prevent malaria.     

Wilms’ tumour: Determinants of prognosis in an African setting

Background:

The few studies available in the literature on Wilms’ tumour (WT) from sub-Saharan Africa have reported a dismal outcome for children with the tumour. This study evaluated the risk factors that have been correlated with outcome in the literature and compare these with outcome among our patients.

Materials and Methods:

Cases of histologically confirmed WT between 2009 and 2013 in a tertiary hospital in Northwestern Nigeria were evaluated for gender, age, laterality, symptoms, duration before presentation, stage at presentation, histologic subtype and p53 mutation. These were then correlated with outcome.

Results:

Totally, 30 cases of WT were diagnosed with mean age of 4.8 ± 1.9 years; and male:female ratio of 2:1. No statistically significant relationship with outcome was found for gender (P = 0.138) or histologic subtype (P = 0.671). The most significant variables which positively influenced the outcome were presentation at earlier stages (P = 0.007) and completion of therapy (P = 0.0007). p53 mutation was seen in 3 (16.7%) of 18 cases and was not associated with a poor outcome (P = 0.089). However, 2 of the 3 cases presented in Stage IV and none of them survived the 1^st year.

Conclusion:

This study shows that even though p53 mutation was associated with a more aggressive phenotype, the most significant determinants of a good outcome among patients in a developing country like ours is non-blastemal dominant histologic subtype, early stage at presentation and completion of therapy.Key words: Blastema, outcome, p53, Wilms’ tumour     

The Eradication of Helicobacter pylori is Affected by Body Mass Index (BMI)

Background

Bariatric surgeons often advocate preoperative Helicobacter pylori (H. pylori) testing and eradication because of the increased risk of postoperative ulcers and foregut symptoms in H. pylori-positive patients. The aim of this pilot study was to evaluate whether body mass index (BMI) might influence the success rate of eradication.

Methods

Eighty one nondiabetic naïve H. pylori-positive patients were divided into two groups according to their BMI, with 41 in the control group (normal BMI) and 40 in the overweight/obese group (BMI ≥25). Gastroscopy was performed and multiple biopsies were obtained from the antrum and corpus. Both groups were given a triple therapy consisting of pantoprazole 40 mg for 2 weeks plus amoxicillin 1 g tris in die (t.i.d), and clarithromycin 250 mg t.i.d, for the first week of treatment. Eradication was confirmed by the ¹³C-urea breath test at 3 months.

Results

Successful eradication was observed in 55.0% of the overweight/obese group compared with 85.4% [p?p?p?Conclusion Overweight/obese nondiabetic patients showed a significantly lower rate of eradication rate of H. pylori infection than controls. BMI and corpus-predominant gastritis appear to be independent risk factors for eradication failure.     

Oxidative Stress and Carcinogenesis: Potential of Phytochemicals in Breast Cancer Therapy

Breast cancer remains a burden in both developed and developing countries, with higher mortality in developing countries. Attempts to eradicate cancer have not been successful despite the progress made in the development of more novel chemotherapeutic drugs. Reactive-oxygen-species-mediated oxidative stress is known to play a role in breast cancer pathogenesis via genetic and epigenetic modifications, resulting in uncontrolled cell proliferation. Phytochemicals could provide leads for the development of alternative therapeutic agents due to their antioxidant activity, as well as their ability to induce apoptosis in cancer cells. However, most of the studies carried out using in vitro models do not continue with further studies in estrogen-receptor-positive in vivo breast cancer models, or fail to examine the possible biochemical mechanisms of phytochemical-based amelioration. This review examines oxidative-stress-mediated carcinogenesis and the potential of phytochemicals as anticancer agents.     

Psychiatric morbidity among housemaids in Kuwait. III: Vulnerability factors

BACKGROUND: Housemaids are a relatively homogenous immigrant subgroup in terms of their gender; ethnic origin; and socio-cultural, educational and occupational background. Psychiatric morbidity among housemaids is two to five times higher than the native female population. AIMS: To determine the possible pre-immigration risk factors for prospective psychiatric breakdown among the housemaids. METHODS: The sample consisted of all the housemaids (N = 197) hospitalised during the two-year study period. The controls comprised all the newly arrived housemaids (N = 502). The measures obtained included demographic characteristics and previous history of physical illness, psychiatric illness, hospitalisation and family history of psychiatric disorder. RESULTS: More than a quarter of the hospitalised group broke down within one month of their arrival. The hospitalised group had a significant excess of Sri Lankan housemaids; non-Muslims; those with less than four years of education and those with a previous history of physical illness, psychiatric illness or hospitalisation. CONCLUSIONS: A number of potential risk factors results in premature repatriation of housemaids on mental health grounds. Preventive measures involving recruitment procedures and pre-departure orientation courses are needed to minimise the expatriate failure among the housemaids.     

Antidiarrhoeal activity of the aqueous extract of Terminalia avicennoides roots

The antidiarrhoeal effects of the aqueous root extract of Terminalia avicennoides were evaluated in rodents. Studies were carried out on the isolated rabbit jejunum, gastrointestinal motility in vivo and on castor oil-induced diarrhoea in mice. The results revealed that the extract exhibited a concentration-dependent inhibition of the spontaneous pendular movement of the isolated rabbit jejunum and attenuated acetylcholine induced contractions. The extract (100, 200 and 400 mg/kg) also caused a dose-dependent decrease of gastrointestinal transit and markedly protected mice against castor oil-induced diarrhoea. The intraperitoneal LD(50) of the extract was found to be 871.4-917.4 mg/kg in mice (95% confidence). A preliminary phytochemical screening of the aqueous extract of T. avicennoides roots revealed the presence of tannins, saponins and flavonoids. The results obtained showed that the water extract of T. avicennoides roots may contain some biologically active principles that may be active against diarrhoea and this may be the basis for its use traditionally for gastrointestinal disorders.