Srsf2P95H initiates myeloid bias and myelodysplastic/myeloproliferative syndrome from hemopoietic stem cells.

Mutations in SRSF2 occur in myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasms (MPN). SRSF2 mutations cluster at proline 95, with the most frequent mutation being a histidine (P95H) substitution. They undergo positive selection, arise early in the course of disease, and have been identified in age-related clonal hemopoiesis. It is not clear how mutation of SRSF2 modifies hemopoiesis or contributes to the development of myeloid bias or MDS/MPN. Two prior mouse models of Srsf2P95H mutation have been reported; however, these models do not recapitulate many of the clinical features of SRSF2-mutant disease and relied on bone marrow (BM) transplantation stress to elicit the reported phenotypes. We describe a new conditional murine Srsf2P95H mutation model, where the P95H mutation is expressed physiologically and heterozygously from its endogenous locus after Cre activation. Using multiple Cre lines, we demonstrate that during native hemopoiesis (ie, no BM transplantation), the Srsf2P95H mutation needs to occur within the hemopoietic stem-cell-containing populations to promote myelomonocytic bias and expansion with corresponding transcriptional and RNA splicing changes. With age, nontransplanted Srsf2P95H animals developed a progressive, transplantable disease characterized by myeloid bias, morphological dysplasia, and monocytosis, hallmarks of MDS/MPN in humans. Analysis of cooccurring mutations within the BM demonstrated the acquisition of additional mutations that are recurrent in humans with SRSF2 mutations. The tractable Srsf2P95H/+ knock-in model we have generated is highly relevant to human disease and will serve to elucidate the effect of SRSF2 mutations on initiation and maintenance of MDS/MPN.

Review of insomnia pharmacotherapy options for the elderly: implications for managed care.

The prevalence of insomnia in the elderly is significant. If left untreated or inappropriately treated, insomnia may contribute to increased health care resource use. Therefore, better identification and management of insomnia is required for this patient population. The etiology and magnitude of insomnia due to changes in circadian rhythms, comorbid conditions, and pharmaceutical agents are not well documented, and the utilization of over-the-counter and non-Food and Drug Administration (FDA)-approved agents to induce sleep (including antihistamines and ethyl alcohol) have not been studied in a natural setting. Evaluating the actual type of insomnia remains much more art than science for the majority of patients and providers. Another issue to consider in this population involves the relationship between patient and physician and the traditional passive patient role. Nonpharmacologic approaches (ie, cognitive behavioral therapy) for insomnia management are effective and usually are first-line therapy. However, the challenges to implementing these approaches may limit their use, thus necessitating pharmacologic therapy. There are currently 3 FDA-approved drug classes for the treatment of insomnia: benzodiazepines, benzodiazepine receptor agonists, and melatonin receptor agonists. Although all agents in these classes are efficacious, benzodiazepines and benzodiazepine receptor agonists are associated with adverse events that must be considered when treating insomnia in the elderly. Melatonin agonists have a mechanism of action that regulates normal sleep-wake cycles and readjusts circadian rhythms, which may confer a better safety profile than traditional sedative-hypnotics that target gamma-aminobutyric acid receptors. Because the 3 currently approved drug classes for insomnia have similar efficacy, safety considerations should be of paramount importance for the elderly patient; however, additional data are needed to appropriately assess the risk-benefit ratios of each.

A longitudinal cross-level model of leader and salesperson influences on sales force technology use and performance.

The authors examined the influence of the introduction of a new suite of technology tools on the performance of 592 salespersons. They hypothesized that the salespersons' work experience would have a negative effect on their technology self-efficacy, which in turn would relate positively to their use of technology. Sales performance was hypothesized to be positively related to both past performance and the use of new technology tools. Further, the authors hypothesized that leaders' commitment to sales technology would enhance salespersons' technology self-efficacy and usage, and leaders' empowering behaviors would influence salespersons' technology self-efficacy and moderate the individual-level relationships. Hierarchical linear modeling analyses confirmed all of the hypothesized individual-level relationships and most of the cross-level relationships stemming from average leader behaviors. In particular, empowering leadership exhibited multiple cross-level interactions, as anticipated. Results are discussed in terms of the importance of social-psychological factors related to the success of sales force technology interventions.