PEER systematic review of randomized controlled trials: Management of chronic low back pain in primary care.

OBJECTIVE: To determine the proportion of chronic low back pain patients who achieve a clinically meaningful response from different pharmacologic and nonpharmacologic treatments. DATA SOURCES: MEDLINE, EMBASE, Cochrane Library, and gray literature search. STUDY SELECTION: Published randomized controlled trials (RCTs) that reported a responder analysis of adults with chronic low back pain treated with any of the following 15 interventions: oral or topical nonsteroidal anti-inflammatory drugs (NSAIDs), exercise, acupuncture, spinal manipulation therapy, corticosteroid injections, acetaminophen, oral opioids, anticonvulsants, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors, cannabinoids, oral muscle relaxants, or topical rubefacients. SYNTHESIS: A total of 63 RCTs were included. There was moderate certainty that exercise (risk ratio [RR] of 1.71; 95% CI 1.37 to 2.15; number needed to treat [NNT] of 7), oral NSAIDs (RR = 1.44; 95% CI 1.17 to 1.78; NNT = 6), and SNRIs (duloxetine; RR = 1.25; 95% CI 1.13 to 1.38; NNT = 10) provide clinically meaningful benefits to patients with chronic low back pain. Exercise was the only intervention with sustained benefit (up to 48 weeks). There was low certainty that spinal manipulation therapy and topical rubefacients benefit patients. The benefit of acupuncture disappeared in higher-quality, longer (> 4 weeks) trials. Very low-quality evidence demonstrated that corticosteroid injections are ineffective. Patients treated with opioids had a greater likelihood of discontinuing treatment owing to an adverse event (number needed to harm of 5) than continuing treatment to derive any clinically meaningful benefit (NNT = 16), while those treated with SNRIs (duloxetine) had a similar likelihood of continuing treatment to attain benefit (NNT = 10) as those discontinuing the medication owing to an adverse event (number need to harm of 11). One trial each of anticonvulsants and topical NSAIDs found similar benefit to that of placebo. No RCTs of acetaminophen, cannabinoids, muscle relaxants, selective serotonin reuptake inhibitors, or tricyclic antidepressants met the inclusion criteria. CONCLUSION: Exercise, oral NSAIDs, and SNRIs (duloxetine) provide a clinically meaningful reduction in pain, with exercise being the only intervention that demonstrated sustained benefit after the intervention ended. Future high-quality trials that report responder analyses are required to provide a better understanding of the benefits and harms of interventions for patients with chronic low back pain.

Integrating clinical medicine and population health: where to from here?

Efforts to contain healthcare costs have led a renewed clinician interest in addressing population-level outcomes, with some proposing that the integration of population health into clinical practice represents a novel concept entitled "clinical population medicine" (CPM). This commentary offers an examination of the function and utility of CPM. In reviewing relevant literature, we note several inconsistencies in CPM's purported mandate, which ranges from simply incorporating the social determinants of health into clinical practice to broad involvement in community health planning. The latter of these seems to overlap, and potentially conflict, with the work of public health practitioners, and cited examples of activities used to define "CPM" seem to apply a label to established clinician activities around the determinants of health that would be captured more simply as research, evaluation, or advocacy undertaken by clinicians in other areas of practice. Our analysis suggests that CPM may have value in encouraging clinicians to incorporate community determinants and contextual considerations into their practices, but must take care to remain complementary and distinct from public health practice.

Roles for lysine acetyltransferases during mammalian hibernation.

The thirteen-lined ground squirrel (Ictidomys tridecemlineatus) is a well-known model for studying hibernation. While in a torpid state, these animals globally suppress energy expensive processes, while supporting specialized pathways necessary for survival. Lysine acetyltransferases (KATs) play a crucial role in modulating the expression and activity of a wide-variety of cellular pathways and processes, and therefore, may play a role during hibernation when the cell is shifting to an energy conservative, cytoprotective state. Here we measured protein levels of four KATs (CBP, PCAF, GCN5L2, HAT1), total histone acetyltransferase (HAT) activity, and the levels of acetylation of histone H3 lysine 9 (H3K9ac), in multiple tissues across the torpor-arousal cycle. Our results show a tissue-specific response of KATs, particularly in the adipose tissues where specific KATs (PCAF and GCN5L2), HAT activity, and H3K9ac increased in the metabolically active BAT while HAT1, HAT activity and H3K9ac decreased in WAT. Liver showed significant increases in the KAT PCAF whereas skeletal muscle had decreased CBP and GCN5L2. Both liver and skeletal muscle showed no change in HAT activity and H3K9me3 increased in muscle during torpor. Together, these results suggest KATs may play specialized roles in the different tissues of the ground squirrel to contribute to the hibernator phenotype.

Characterization of the SIRT family of NAD+-dependent protein deacetylases in the context of a mammalian model of hibernation, the thirteen-lined ground squirrel.

Hibernating mammals employ strong metabolic rate depression to survive the winter, thereby avoiding the high energy costs of maintaining a euthermic lifestyle in the face of low seasonal temperatures and limited food resources. Characteristics of this natural torpor include a significant reduction in body temperature, a shift to a lipid-based metabolism, global suppression of ATP-expensive activities, and the upregulation of selected genes that mediate biochemical reorganization and cytoprotection. Sirtuin (SIRT) proteins, an evolutionarily conserved family of NAD(+)-dependent protein deacetylases, have been shown to play important roles in the post-translational regulation of many metabolic and cytoprotective processes, suggesting a potential function for these enzymes in the control of hibernation. To assess this possibility, protein levels of the seven mammalian SIRTs (SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 and SIRT7), total SIRT activity, and the acetylation status of two downstream SIRT targets (SOD2K68 and NF-κB p65K310) were measured in skeletal muscle, liver, brown adipose and white adipose tissues of the hibernating thirteen-lined ground squirrel (Ictidomys tridecemlineatus) over the course of the torpor-arousal cycle. The analysis revealed tissue-specific responses of different SIRTs at various points throughout hibernation, including a potentially interesting correlation between increased levels of SIRT3 protein, heightened total SIRT activity, and decreased acetylation of SIRT3 downstream target SOD2K68 in skeletal muscle during late torpor. These results provide evidence to suggest a possible role for the SIRT family of protein deacetylases in the regulation of the metabolic and cellular protective pathways that mediate the process of mammalian hibernation.

Characterization of adipocyte stress response pathways during hibernation in thirteen-lined ground squirrels.

To avoid the harsh conditions of winter climates, hibernating mammals undergo a systematic depression of physiological function by reducing their metabolic rate. During this process, hibernators are exposed to significant stresses (e.g., low body temperature, ischemia-reperfusion) that must be dealt with appropriately to avoid irreversible tissue damage. Consequently, we investigated the contribution of stress-responsive antioxidant enzymes, heat shock proteins, signal transduction pathways (e.g., mitogen-activated protein kinases, MAPK), and transcription factors for their role in conferring tolerance to stress in the hibernating thirteen-lined ground squirrel (Ictidomys tridecemlineatus). Using a combination of multiplex protein panels and traditional immunoblotting procedures, we have focused on these stress factors in brown adipose tissue (BAT) and white adipose tissue (WAT) over cycles of torpor-arousal since they provide the means for heat production as a result of non-shivering thermogenesis and the mobilization of critical energy reserves, respectively. We show the differential and tissue-specific regulation of stress factors including a unified upregulation of the antioxidant enzyme Thioredoxin 1 in both tissues, an upregulation of superoxide dismutase (SOD1 and SOD2) in WAT, and an increase in heat shock proteins during the transitory periods of the torpor-arousal cycle (HSP90α in BAT and HSP60 in WAT). Additionally, an upregulation of the active form of ERK1/2 and p38 in BAT and select transcription factors (e.g., CREB-1 and ELK-1) in both tissues were identified. These data provide us with greater insight into the molecular mechanisms responsible for this animal's natural stress tolerance and outline molecular signatures which define stress resistance.

A high-throughput protocol for message RNA quantification using RNA dot-blots.

This study develops a method to rapidly measure the relative abundance of mRNA in total RNA samples using a dot-blotting technique and biotin-labeled detection probes that recognize the polyadenylate tail on mRNA. We demonstrate the effectiveness of this technique by determining the relative total amounts of mRNA in three tissues of turtles (Trachemys scripta elegans) exposed to normoxic versus anoxic conditions. The data emphasize the usefulness of the method for the simple and rapid analysis of relative total mRNA levels for a variety of comparison purposes.

Anti-apoptotic signaling as a cytoprotective mechanism in mammalian hibernation.

In the context of normal cell turnover, apoptosis is a natural phenomenon involved in making essential life and death decisions. Apoptotic pathways balance signals which promote cell death (pro-apoptotic pathways) or counteract these signals (anti-apoptotic pathways). We proposed that changes in anti-apoptotic proteins would occur during mammalian hibernation to aid cell preservation during prolonged torpor under cellular conditions that are highly injurious to most mammals (e.g. low body temperatures, ischemia). Immunoblotting was used to analyze the expression of proteins associated with pro-survival in six tissues of thirteen-lined ground squirrels, Ictidomys tridecemlineatus. The brain showed a concerted response to torpor with significant increases in the levels of all anti-apoptotic targets analyzed (Bcl-2, Bcl-xL, BI-1, Mcl-1, cIAP1/2, xIAP) as well as enhanced phosphorylation of Bcl-2 at S70 and T56. Heart responded similarly with most anti-apoptotic proteins elevated significantly during torpor except for Bcl-xL and xIAP that decreased and Mcl-1 that was unaltered. In liver, BI-1 increased whereas cIAP1/2 decreased. In kidney, there was an increase in BI-1, cIAP and xIAP but decreases in Bcl-xL and p-Bcl-2(T56) content. In brown adipose tissue, protein levels of BI-1, cIAP1/2, and xIAP decreased significantly during torpor (compared with euthermia) whereas Bcl-2, Bcl-xL, Mcl-1 were unaltered; however, Bcl-2 showed enhanced phosphorylation at Thr56 but not at Ser70. In skeletal muscle, only xIAP levels changed significantly during torpor (an increase). The data show that anti-apoptotic pathways have organ-specific responses in hibernators with a prominent potential role in heart and brain where coordinated enhancement of anti-apoptotic proteins occurred in response to torpor.