Nanocarrier-assisted sub-cellular targeting to the site of mitochondria improves the pro-apoptotic activity of paclitaxel

Many drug molecules exert their biological action on intracellular molecular targets present on or inside various cellular organelles. Consequently, it has become more evident that the efficiency and efficacy of drug action is dependent largely on how well an unaided drug molecule is able to reach its intracellular target. We hypothesized that the biological action of such drug molecules might be improved by specific delivery to the appropriate sub-cellular site by a pharmaceutical carrier designed for the purpose. To test our hypothesis, we used paclitaxel, a molecule that has recently been shown to have pro-apoptotic biological targets on the mitochondria but has a quantitative structure–activity relationship-predicted cytosolic accumulation and no affinity for mitochondria. Using a mitochondria-specific nanocarrier system (DQAsomes) prepared from the amphiphilic quinolinium derivative dequalinium chloride to deliver paclitaxel to mitochondria in cells, we report that it is possible to improve the pro-apoptotic action of paclitaxel.     

Toxicokinetics as a key to the integrated toxicity risk assessment based primarily on non-animal approaches

Toxicokinetics (TK) is the endpoint that informs about the penetration into and fate within the body of a toxic substance, including the possible emergence of metabolites. Traditionally, the data needed to understand those phenomena have been obtained in vivo. Currently, with a drive towards non-animal testing approaches, TK has been identified as a key element to integrate the results from in silico, in vitro and already available in vivo studies. TK is needed to estimate the range of target organ doses that can be expected from realistic human external exposure scenarios. This information is crucial for determining the dose/concentration range that should be used for in vitro testing. Vice versa, TK is necessary to convert the in vitro results, generated at tissue/cell or sub-cellular level, into dose response or potency information relating to the entire target organism, i.e. the human body (in vitro–in vivo extrapolation, IVIVE). Physiologically based toxicokinetic modelling (PBTK) is currently regarded as the most adequate approach to simulate human TK and extrapolate between in vitro and in vivo contexts. The fact that PBTK models are mechanism-based which allows them to be ‘generic’ to a certain extent (various extrapolations possible) has been critical for their success so far. The need for high-quality in vitro and in silico data on absorption, distribution, metabolism as well as excretion (ADME) as input for PBTK models to predict human dose–response curves is currently a bottleneck for integrative risk assessment.     

How the cerebral serotonin homeostasis predicts environmental changes: a model to explain seasonal changes of brain 5-HTT as intermediate phenotype of the 5-HTTLPR

Molecular imaging studies with positron emission tomography have revealed that the availability of serotonin transporter (5-HTT) in the human brain fluctuates over the course of the year. This effect is most pronounced in carriers of the short allele of the 5-HTT promoter region (5-HTTLPR), which has in several previous studies been linked to an increased risk to develop mood disorders. We argue that long-lasting fluctuations in the cerebral serotonin transmission, which is regulated via the 5-HTT, are responsible for mediating responses to environmental changes based on an assessment of the expected “safety” of the environment; this response is obtained in part through serotonergic modulation of the hypothalamic–pituitary–adrenal (HPA) axis. We posit that the intermediate phenotype of the s-allele may properly be understood as mediating a trade-off, wherein increased responsiveness of cerebral serotonin transmission to seasonal and other forms of environmental change imparts greater behavioral flexibility, at the expense of increased vulnerability to stress. This model may explain the somewhat higher prevalence of the s-allele in some human populations dwelling at geographic latitudes with pronounced seasonal climatic changes, while this hypothesis does not rule out that genetic drift plays an additional or even exclusive role. We argue that s-allele manifests as an intermediate phenotype in terms of an increased responsiveness of the 5-HTT expression to number of daylight hours, which may serve as a stable surrogate marker of other environmental factors, such as availability of food and safety of the environment in populations that live closer to the geographic poles.     

Epistaxis in Kaduna,Nigeria: a review of 101 cases

Background

Epistaxis is defined as a hemorrhage from the nostril, nasal cavity, or nasopharynx. Sufferers and clinicians may develop significant anxiety despite the fact that majority of patients are treated successfully by the first attending physician.

Objective

To review aetiology and management outcomes of epistaxis in a resource constrained setting.

Methodology

A retrospective review of 101 patients seen with epistaxis at the National Ear Care Centre, Kaduna over 7years (January 2002– December 2008).

Results

The age of patients ranged between 2 and 75years. The incidence of epistaxis of 0.5% was recorded out of total patient visit and slight male preponderance with a male:female ratio of 1.4:1. Dry-hot and cold harmattan weather had the highest prevalence. Trauma and infections were the main aetiological factors identified but over 40% of cases are idiopathic in origin. About 25% presented with active bleeding and 11% required admission. All were managed conservatively. Less than 2% received blood transfusion.

Conclusion

Epistaxis is a common emergency that requires prompt intervention to reduce further morbidity and prevent mortality. Non operative intervention was a satisfactory approach in this study.     

Interviews with patients with advanced cancer—another step towards an international cancer pain classification system

Purpose

Patients’ involvement in the development of assessment tools is recommended, and the European Palliative Care Research Collaborative has adhered to this when developing a shared language for cancer pain, an international assessment and classification system. Study objectives were to investigate how patients ranked the relevance of several previously identified pain domains, to investigate patients’ perception of the pain experience and to disclose additional, relevant pain domains for cancer pain classification to those identified in the literature.

Methods

Semistructured interviews with advanced cancer patients treated with opioids were performed and analysed verbatim. Patients scored the relevance of predefined pain domains on an 11-point Numerical Rating Scale.

Results

Thirty-three Norwegian and Austrian patients were included (16 females and 17 males); the mean age was 63?years, and the mean Karnofsky performance score was 65. The ranking of domains was as follows etiology (mean Numerical Rating Scale score, 8.5), duration (8.0), intensity (7.4), coping (7.1), physical (5.9) and psychological functioning (5.8). Sleep was identified as a new candidate domain to include in the system. The patients emphasised consequences of having pain, for example, poor physical functioning and psychological distress.

Conclusions

Previously identified pain domains were confirmed to be relevant to the patients; however, the ranking differed from the experts’ ranking. Sleep disturbances may be added as a domain in a future classification system.     

X-inactivation patterns in carriers of X-linked myotubular myopathy

X-linked myotubular myopathy is a rare severe muscle disorder in affected male neonates. Most female carriers are free from symptoms. Skewed X inactivation has been proposed to be responsible for the affected phenotype seen in some carriers. We have compared the X inactivation patterns in blood DNA with the clinical phenotype in carriers of X-linked myotubular myopathy. The X-inactivation analysis was performed using HpaII predigestion of DNA followed by polymerase chain reaction of the highly polymorphic CAG repeat of the androgen receptor (AR) gene. The frequency of skewed X inactivation was similar in the X-linked myotubular myopathy carriers (22%) and in 235 controls (18%). Three overtly affected carriers had skewed X inactivation with the mutated X as the predominantly active X in at least two of them. Four females with mild symptoms had random X inactivation. The unaffected X-linked myotubular myopathy carriers had either skewed X inactivation in favour of expression from the normal X or random X-inactivation. Thus, there was a tendency for females with a more severe phenotype to have a skewed pattern of X inactivation, while females with an intermediate phenotype had a random pattern of X-inactivation.     

From papers to practices: district level priority setting processes and criteria for family planning, maternal, newborn and child health interventions in Tanzania

Background

Successful priority setting is increasingly known to be an important aspect in achieving better family planning, maternal, newborn and child health (FMNCH) outcomes in developing countries. However, far too little attention has been paid to capturing and analysing the priority setting processes and criteria for FMNCH at district level. This paper seeks to capture and analyse the priority setting processes and criteria for FMNCH at district level in Tanzania. Specifically, we assess the FMNCH actor's engagement and understanding, the criteria used in decision making and the way criteria are identified, the information or evidence and tools used to prioritize FMNCH interventions at district level in Tanzania.

Methods

We conducted an exploratory study mixing both qualitative and quantitative methods to capture and analyse the priority setting for FMNCH at district level, and identify the criteria for priority setting. We purposively sampled the participants to be included in the study. We collected the data using the nominal group technique (NGT), in-depth interviews (IDIs) with key informants and documentary review. We analysed the collected data using both content analysis for qualitative data and correlation analysis for quantitative data.

Results

We found a number of shortfalls in the district's priority setting processes and criteria which may lead to inefficient and unfair priority setting decisions in FMNCH. In addition, participants identified the priority setting criteria and established the perceived relative importance of the identified criteria. However, we noted differences exist in judging the relative importance attached to the criteria by different stakeholders in the districts.

Conclusions

In Tanzania, FMNCH contents in both general development policies and sector policies are well articulated. However, the current priority setting process for FMNCH at district levels are wanting in several aspects rendering the priority setting process for FMNCH inefficient and unfair (or unsuccessful). To improve district level priority setting process for the FMNCH interventions, we recommend a fundamental revision of the current FMNCH interventions priority setting process. The improvement strategy should utilize rigorous research methods combining both normative and empirical methods to further analyze and correct past problems at the same time use the good practices to improve the current priority setting process for FMNCH interventions. The suggested improvements might give room for efficient and fair (or successful) priority setting process for FMNCH interventions.     

Postprostatectomy radiation therapy: an evidence-based review

While the majority of men with localized prostate cancer who undergo a radical prostatectomy will remain disease free, men with certain clinical and pathological features are known to be at an increased risk for developing a biochemical recurrence and, ultimately, distant metastatic disease. The optimal management of these patients continues to be a source of controversy. To date, three randomized Phase III trials have demonstrated that adjuvant radiation therapy (ART) for patients with certain adverse pathological features results in an improvement in several clinically-relevant end points, including biochemical recurrence-free survival and overall survival. Despite the evidence from these trials showing a benefit for ART, many believe that ART results in overtreatment and unwarranted treatment morbidity for a significant number of patients. Many physicians, therefore, instead advocate for close observation followed by early salvage radiation therapy (SRT) at the time of a biochemical recurrence. The purpose of this review is to evaluate the evidence for and to distinguish between ART and early SRT. We will also highlight current and future areas of research for this patient population, including radiation treatment dose escalation, hypofractionation and androgen deprivation therapy. We will also discuss the cost-effectiveness of ART and early SRT.     

Doubling in the use of thyroid hormone replacement therapy in Denmark: association to iodization of salt?

Iodization of salt is an effective strategy to prevent iodine deficiency disorders. Recent studies, however, indicate that increasing the iodine intake in a population may give rise to an increased incidence of hypothyroidism, but the association has not been fully clarified. In Denmark, iodization of salt was initiated in 1998 because of mild-to-moderate iodine deficiency. The aim of this study was to evaluate the effect of the raised iodine intake on the nationwide incident use of thyroid hormone replacement therapy (levothyroxine) to treat hypothyroidism. Data on all use of levothyroxine was extracted from the Register of Medicinal Product Statistics during the period 1995–2009 and linked to other nationwide registers by use of the Danish identification number. Persons with previous thyroid surgery were excluded. In the studied period 71,565 incident users were identified. The incidence rate increased 75% in the moderately iodine deficient region (72.2 incident users/100,000 person-years in 1997 to 126.6 in 2008) and 87% in the mildly deficient region (86.9–162.9). When stratified by sex and age-group (00–39, 40–64, 65+) the largest relative increase was seen among women in the youngest age-group, where more than a doubling was seen. The mechanisms behind the increase may be a result of iodine-induced hypothyroidism, although a higher diagnostic activity with regard to thyroid dysfunction and intensified treatment of subclinical hypothyroidism may also play a role. Our findings stress the need for caution when initiating iodine fortification programs to keep the intake within the optimal range, and the need for continuous monitoring.