Cellular damage, including wounding, drives C. elegans stress-induced sleep.

Across animal phyla, sleep is associated with increased cellular repair, suggesting that cellular damage may be a core component of sleep pressure. In support of this notion, sleep in the nematode Caenorhabditis elegans can be triggered by damaging conditions, including noxious heat, high salt, and ultraviolet light exposure. It is not clear, however, whether this stress-induced sleep (SIS) is a direct consequence of cellular damage, or of a resulting energy deficit, or whether it is triggered simply by the sensation of noxious conditions. Here, we show that thermosensation is dispensable for heat-induced sleep, that osmosensation is dispensable for salt-induced sleep, and that wounding is also a sleep trigger, together indicating that SIS is not triggered by sensation of noxious environments. We present evidence that genetic variation in cellular repair pathways impacts sleep amount, and that SIS involves systemic monitoring of cellular damage. We show that the low-energy sensor AMP-activated protein kinase (AMPK) is not required for SIS, suggesting that energy deficit is not the primary sleep trigger. Instead, AMPK-deficient animals display enhanced SIS responses, and pharmacological activation of AMPK reduces SIS, suggesting that ATP-dependent repair of cellular damage mitigates sleep pressure.

Cellular stress induces a protective sleep-like state in C. elegans.

Sleep is recognized to be ancient in origin, with vertebrates and invertebrates experiencing behaviorally quiescent states that are regulated by conserved genetic mechanisms. Despite its conservation throughout phylogeny, the function of sleep remains debated. Hypotheses for the purpose of sleep include nervous-system-specific functions such as modulation of synaptic strength and clearance of metabolites from the brain, as well as more generalized cellular functions such as energy conservation and macromolecule biosynthesis. These models are supported by the identification of synaptic and metabolic processes that are perturbed during prolonged wakefulness. It remains to be seen whether perturbations of cellular homeostasis in turn drive sleep. Here we show that under conditions of cellular stress, including noxious heat, cold, hypertonicity, and tissue damage, the nematode Caenorhabditis elegans engages a behavioral quiescence program. The stress-induced quiescent state displays properties of sleep and is dependent on the ALA neuron, which mediates the conserved soporific effect of epidermal growth factor (EGF) ligand overexpression. We characterize heat-induced quiescence in detail and show that it is indeed dependent on components of EGF signaling, providing physiological relevance to the behavioral effects of EGF family ligands. We find that after noxious heat exposure, quiescence-defective animals show elevated expression of cellular stress reporter genes and are impaired for survival, demonstrating the benefit of stress-induced behavioral quiescence. These data provide evidence that cellular stress can induce a protective sleep-like state in C. elegans and suggest that a deeply conserved function of sleep is to mitigate disruptions of cellular homeostasis.

The impact of drug samples on prescribing to the uninsured.

OBJECTIVE: To determine whether drug samples are associated with physicians prescribing fewer generic, less costly medications. METHODS: We conducted a retrospective study at a large university-affiliated internal medicine practice containing over 70 physicians. Using a pharmacy database, we identified all prescriptions written to uninsured or Medicaid patients that belonged to one of four classes of chronic medications. For the 9 months before and after the clinic closed its drug sample closet, we calculated the percentage of medications prescribed as generics and the mean cost of a 30-day supply of a prescription. RESULTS: Of 8911 prescriptions, 1973 met inclusion criteria. For uninsured patients, the percentage of medications prescribed as generics rose from 12% to 30% after the clinic closed its drug sample closet (P = 0.004). By consecutive three month periods, the percentage of prescribed generic medications rose steadily to a maximum of 40% (P < 0.001). For Medicaid patients, there was no significant change in generic prescribing (63% generic with samples versus 65% generic without samples, P = 0.42). Two factors were associated with generic prescribing in logistic regression: the absence of drug samples (OR 4.54, 95% CI 1.37-15.0) and the prescriber being an attending physician (OR 5.26, 95% CI 2.24-12.4). There was no statistically significant change in cost for either group. CONCLUSIONS: Physicians were three times more likely to prescribe generic medications to uninsured patients after drug samples were removed from the office. Drug samples may paradoxically lead to higher costs if physicians with access to samples prescribe more brand-name only drugs.

Demographic Change, Social Security Systems, and Savings.

In theory, improvements in healthy life expectancy should generate increases in the average age of retirement, with little effect on savings rates. In many countries, however, retirement incentives in social security programs prevent retirement ages from keeping pace with changes in life expectancy, leading to an increased need for life-cycle savings. Analyzing a cross-country panel of macroeconomic data, we find that increased longevity raises aggregate savings rates in countries with universal pension coverage and retirement incentives, though the effect disappears in countries with pay-as-you-go systems and high replacement rates.

Patient characteristics and clinical management of patients with shoulder pain in U.S. primary care settings: secondary data analysis of the National Ambulatory Medical Care Survey.

BACKGROUND: Although shoulder pain is a commonly encountered problem in primary care, there are few studies examining its presenting characteristics and clinical management in this setting. METHODS: We performed secondary data analysis of 692 office visits for shoulder pain collected through the National Ambulatory Medical Care Survey (Survey years 1993-2000). Information on demographic characteristics, history and place of injury, and clinical management (physician order of imaging, physiotherapy, and steroid intraarticular injection) were examined. RESULTS: Shoulder pain was associated with an injury in one third (33.2% (230/692)) of office visits in this population of US primary care physicians. Males, and younger adults (age < or = 52) more often associated their shoulder pain with previous injury, but there were no racial differences in injury status. Injury-related shoulder pain was related to work in over one-fifth (21.3% (43/202)) of visits. An x-ray was performed in 29.0% (164/566) of office visits, a finding that did not differ by gender, race, or by age status. Other imaging (CT scan, MRI, or ultrasound) was infrequently performed (6.5%, 37/566). Physiotherapy was ordered in 23.9% (135/566) of visits for shoulder pain. Younger adults and patients with a history of injury more often had physiotherapy ordered, but there was no significant difference in the ordering of physiotherapy by gender or race. Examination of the use of intraarticular injection was not possible with this data set. CONCLUSION: These data from the largest sample of patients with shoulder pain presenting to primary care settings offer insights into the presenting characteristics and clinical management of shoulder pain at the primary care level. The National Ambulatory Medical Care Survey is a useful resource for examining the clinical management of specific symptoms in U.S. primary care offices.

The role of histology in the study of leprosy

The study of histologic changes in leprosy antedates by approximately a generation the discovery of Mycobacterium leprae by G. Armauer Hansen. The history of the histopathology of leprosy sugests two distinct periods. The first began in 1847 with Danielssen´s and Boeck´s illustration of a section of a nodule, and continued into the 1920´s. It was a period observation and record, and was followed by a later phase in which histologic studies entered into modern classification of types of leprosy. This has been an interpretive period, contribuing importantly to modern concepts of the mechanisms of the disease.