Quantitative differences in salivary pathogen load during tick transmission underlie strain-specific variation in transmission efficiency of Anaplasma marginale

The relative fitness of arthropod-borne pathogens within the vector can be a major determinant of pathogen prevalence within the mammalian host population. Strains of the tick-borne rickettsia Anaplasma marginale differ markedly in transmission efficiency, with a consequent impact on pathogen strain structure. We have identified two A. marginale strains with significant differences in the transmission phenotype that is effected following infection of the salivary gland. We have proposed competing hypotheses to explain the phenotypes: (i) both strains are secreted equally, but there is an intrinsic difference in infectivity for the mammalian host, or (ii) one strain is secreted at a significantly higher level and thus represents delivery of a greater pathogen dose. Quantitative analysis of pathogen replication and secretion revealed that the high-efficiency St. Maries strain replicated to a 10-fold-higher titer and that a significantly greater percentage of infected ticks secreted A. marginale into the saliva and did so at a significantly higher level than for the low-efficiency Israel vaccine strain. Furthermore, the transmission phenotype of the vaccine strain could be restored to that of the St. Maries strain simply by increasing the delivered pathogen dose, either by direct inoculation of salivary gland organisms or by increasing the number of ticks during transmission feeding. We identified morphological differences in the colonization of each strain within the salivary glands and propose that these reflect strain-specific differences in replication and secretion pathways linked to the vector-pathogen interaction.     

The serotonin transporter 5‐HTTPR polymorphism is associated with current and lifetime depression in persons with chronic psychotic disorders

Objective: Variation in the serotonin transporter gene (SLC6A4) promoter region has been shown to influence depression in persons who have been exposed to a number of stressful life events. Method: We evaluated whether genetic variation in 5‐HTTLPR, influences current depression, lifetime history of depression and quantitative measures of depression in persons with chronic psychotic disorders. This is an association study of a genetic variant with quantitative and categorical definitions of depression conducted in the southwest US, Mexico and Costa Rica. We analyzed 260 subjects with a history of psychosis, from a sample of 129 families. Results: We found that persons carrying at least one short allele had a statistically significant increased lifetime risk for depressive syndromes (P < 0.02, odds ratio 2.18, 95% CI 1.10–4.20). Conclusion: The ‘ss’ or ‘sl’ genotype at the 5‐HTTLPR promoter polymorphic locus increases the risk of psychotic individuals to develop major depression during the course of their illness.     

Efficacy and safety of milnacipran 100 mg/day in patients with fibromyalgia: Results of a randomized,double‐blind,placebo‐controlled trial

Objective

To assess the efficacy and safety of milnacipran at a dosage of 100 mg/day (50 mg twice daily) for monotherapy treatment of fibromyalgia.

Methods

A double‐blind, placebo‐controlled trial was performed to assess 1,025 patients with fibromyalgia who were randomized to receive milnacipran 100 mg/day (n = 516) or placebo (n = 509). Patients underwent 4–6 weeks of flexible dose escalation followed by 12 weeks of stable‐dose treatment. Two composite responder definitions were used as primary end points to classify the response to treatment. The 2‐measure composite response required achievement of ≥30% improvement from baseline in the pain score and a rating of “very much improved” or “much improved” on the Patient's Global Impression of Change (PGIC) scale. The 3‐measure composite response required satisfaction of these same 2 improvement criteria for pain and global status as well as improvement in physical function on the Short Form 36 (SF‐36) physical component summary (PCS) score.

Results

After 12 weeks of stable‐dose treatment, a significantly greater proportion of milnacipran‐treated patients compared with placebo‐treated patients showed clinically meaningful improvements, as evidenced by the proportion of patients meeting the 2‐measure composite responder criteria (P < 0.001 in the baseline observation carried forward [BOCF] analysis) and 3‐measure composite responder criteria (P < 0.001 in the BOCF). Milnacipran‐treated patients also demonstrated significantly greater improvements from baseline on multiple secondary outcomes, including 24‐hour and weekly recall pain score, PGIC score, SF‐36 PCS and mental component summary scores, average pain severity score on the Brief Pain Inventory, Fibromyalgia Impact Questionnaire total score (all P < 0.001 versus placebo), and Multidimensional Fatigue Inventory total score (P = 0.036 versus placebo). Milnacipran was well tolerated by most patients, with nausea being the most commonly reported adverse event (placebo‐adjusted rate of 15.8%).

Conclusion

Milnacipran administered at a dosage of 100 mg/day improved pain, global status, fatigue, and physical and mental function in patients with fibromyalgia.

     

Institutional Profile: University of California San Diego Pharmacogenomics Education Program (PharmGenEd™): bridging the gap between science and practice

Clinical application of evidence-based pharmacogenomics information has the potential to help healthcare professionals provide safe and effective medication management to patients. However, there is a gap between the advances of pharmacogenomics discovery and the health professionals' knowledge regarding pharmacogenomics testing and therapeutic uses. Furthermore, pharmacogenomics education materials for healthcare professionals have not been readily available or accessible. Pharmacogenomics Education Program (PharmGenEd?) is an evidence-based pharmacogenomics education program developed at the University of California San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences and the School of Medicine (CA, USA), with funding support from the Centers for Disease Control and Prevention. Program components include continuing education modules, train-the-trainer materials and shared curriculum modules based on therapeutic topics, and virtual communities with online resources.