Statin withdrawal and health-related quality of life in a primary cardiovascular prevention cohort.

PURPOSE: While some work has been done on Health-Related Quality of Life (HRQoL) in statin users, none has focused specifically on statin-associated muscle symptoms (SAMS) sufferers. The objective was to assess self-reported HRQoL, before and after statin withdrawal, in patients reporting SAMS. We hypothesized that the presence of SAMS associated with decreased self-reported physical and mental well-being. METHODS: Patients (50 men/28 women [M/W], aged 49 ± 9 years [Mean ± SD]) in primary cardiovascular prevention were recruited into three cohorts: statin users with (SAMS, 29 M/18W) or without symptoms (No SAMS, 10 M/5W) and controls (11 M/5W). The Short Form 36 Health Survey (SF-36) was used to assess HRQoL. All variables were measured before and after 2 months of statin withdrawal, and repeated measures analyses were used to verify withdrawal and group effects as well as their interaction. RESULTS: SF-36 physical and mental component scores (respectively, PCS and MCS) were lower in the SAMS group compared with other groups (both p < 0.01). Statin withdrawal led to an increase in LDL cholesterol for statin users (+69.0%, p < 0.01) and an improvement in well-being in the SAMS group, other groups showing no change. A time x category interaction (p = 0.02) was seen for PCS and post hoc analyses showed that statin withdrawal improved PCS and MCS (respectively, +12.5% [ES 0.77] and +5.1% [ES 0.27], both p < 0.05) in the SAMS group. CONCLUSION: Patients self-reporting SAMS showed improved HRQoL following drug withdrawal, but this was mirrored by a rise in LDL cholesterol. These findings should be considered by clinicians in the evaluation and follow-up of treatment with statins.

Influence of concomitant injuries on post-concussion symptoms after a mild traumatic brain injury - a prospective multicentre cohort study.

Objectives: To compare post-concussion symptoms (PCS) and return to normal activities between mild Traumatic Brain Injury (mTBI) patients with or without concomitant injuries at 7-and 90 days post-mTBI.Methods: Design: Sub-analysis of a multicentre prospective cohort study. PARTICIPANTS AND SETTING: patients with mTBI from 7 Canadian Emergency Departments. PROCEDURE: Research assistants conducted telephone follow-ups using the Rivermead Postconcussion Symptoms Questionnaire (RPQ) at 7-, 30- and 90 days post-mTBI. MAIN OUTCOME: Presence of PCS (RPQ: ≥3 symptoms) at 90 days. SECONDARY OUTCOMES: RPQ score ≥21, prevalence of individual RPQ symptoms and patients' return to normal activities, at 7- and 90-days. Adjusted risk ratios (RR) were calculated.Results: 1725 mTBI patients were included and 1055 (61.1%) had concomitant injuries. Patients with concomitant injuries were at higher risk of having ≥3 symptoms on the RPQ (RR:1.26 [95% CI 1.01-1.58]) at 90 days. They were also at higher risk of experiencing specific symptoms (dizziness, fatigue, headaches and taking longer to think) and of non-return to their normal activities (RR:2.11 [95% CI 1.30-3.45]).Conclusion: Patients with concomitant injuries have slightly more PCS and seemed to be at higher risk of non-return to their normal activities 90 days, compared to patients without concomitant injuries.

Measurement of skeletal muscle radiation attenuation and basis of its biological variation.

Skeletal muscle contains intramyocellular lipid droplets within the cytoplasm of myocytes as well as intermuscular adipocytes. These depots exhibit physiological and pathological variation which has been revealed with the advent of diagnostic imaging approaches: magnetic resonance (MR) imaging, MR spectroscopy and computed tomography (CT). CT uses computer-processed X-rays and is now being applied in muscle physiology research. The purpose of this review is to present CT methodologies and summarize factors that influence muscle radiation attenuation, a parameter which is inversely related to muscle fat content. Pre-defined radiation attenuation ranges are used to demarcate intermuscular adipose tissue [from -190 to -30 Hounsfield units (HU)] and muscle (-29 HU to +150 HU). Within the latter range, the mean muscle radiation attenuation [muscle (radio) density] is reported. Inconsistent criteria for the upper and lower HU cut-offs used to characterize muscle attenuation limit comparisons between investigations. This area of research would benefit from standardized criteria for reporting muscle attenuation. Available evidence suggests that muscle attenuation is plastic with physiological variation induced by the process of ageing, as well as by aerobic training, which probably reflects accumulation of lipids to fuel aerobic work. Pathological variation in muscle attenuation reflects excess fat deposition in the tissue and is observed in people with obesity, diabetes type II, myositis, osteoarthritis, spinal stenosis and cancer. A poor prognosis and different types of morbidity are predicted by the presence of reduced mean muscle attenuation values in patients with these conditions; however, the biological features of muscle with these characteristics require further investigation.

Neutrophils and macrophages accumulate sequentially following Achilles tendon injury.

Structural damage and inflammation occur following tendon injury. The purpose of this study was to determine the time course of inflammatory cell accumulation in two animal models of acute tendinopathy. In the first model, rat Achilles tendons were exposed by blunt dissection, injected with collagenase and sacrificed at 1, 3, 7, 14 and 28 days. In the second model, collagenase was injected percutaneously and rats were sacrificed after 1 and 3 days. Sham animals were sacrificed at 1 and 3 days in both models. Neutrophil and ED1 macrophage populations increased by 46- and 18-fold, respectively, after 1 day in surgically exposed Achilles tendons (EAT) injected with collagenase. Neutrophils dropped by 70% while the concentration of ED1 macrophages remained constant at day 3 post-injury. Neutrophils and ED1+ macrophages returned to control values after 7 and 14 days, respectively. ED2+ macrophages showed a tendency to increase at day 28 although no significant difference was observed relative to ambulatory controls. Collagenase injected percutaneously reduced the extent of inflammation compared with operated animals. Thus, injured tendons exhibited a specific sequence of inflammatory cell accumulation which varied in intensity according to the modality used for collagenase injection.

Evidence for horizontal gene transfer in evolution of elongation factor Tu in enterococci.

The elongation factor Tu, encoded by tuf genes, is a GTP binding protein that plays a central role in protein synthesis. One to three tuf genes per genome are present, depending on the bacterial species. Most low-G+C-content gram-positive bacteria carry only one tuf gene. We have designed degenerate PCR primers derived from consensus sequences of the tuf gene to amplify partial tuf sequences from 17 enterococcal species and other phylogenetically related species. The amplified DNA fragments were sequenced either by direct sequencing or by sequencing cloned inserts containing putative amplicons. Two different tuf genes (tufA and tufB) were found in 11 enterococcal species, including Enterococcus avium, Enterococcus casseliflavus, Enterococcus dispar, Enterococcus durans, Enterococcus faecium, Enterococcus gallinarum, Enterococcus hirae, Enterococcus malodoratus, Enterococcus mundtii, Enterococcus pseudoavium, and Enterococcus raffinosus. For the other six enterococcal species (Enterococcus cecorum, Enterococcus columbae, Enterococcus faecalis, Enterococcus sulfureus, Enterococcus saccharolyticus, and Enterococcus solitarius), only the tufA gene was present. Based on 16S rRNA gene sequence analysis, the 11 species having two tuf genes all have a common ancestor, while the six species having only one copy diverged from the enterococcal lineage before that common ancestor. The presence of one or two copies of the tuf gene in enterococci was confirmed by Southern hybridization. Phylogenetic analysis of tuf sequences demonstrated that the enterococcal tufA gene branches with the Bacillus, Listeria, and Staphylococcus genera, while the enterococcal tufB gene clusters with the genera Streptococcus and Lactococcus. Primary structure analysis showed that four amino acid residues encoded within the sequenced regions are conserved and unique to the enterococcal tufB genes and the tuf genes of streptococci and Lactococcus lactis. The data suggest that an ancestral streptococcus or a streptococcus-related species may have horizontally transferred a tuf gene to the common ancestor of the 11 enterococcal species which now carry two tuf genes.

Modulation of structural protein content of the myotendinous junction following eccentric contractions.

The objective of this study was to test the hypothesis that vinculin and talin, two cytoskeletal proteins of the myotendinous junction (MTJ), would be up-regulated following damaging eccentric contractions. Mouse plantar flexor muscles were submitted in situ to three 5 min periods of eccentric contractions. Talin and vinculin content, in vitro contractile properties and MTJ histology were examined at 0, 3, 7, 14, and 28 days post-exercise. The eccentric protocol led to significant decreases in maximum tetanic tension at 0, 3, and 7 days post-protocol. Histological examination did confirm that tissue damage was present at the MTJ where talin and vinculin are highly concentrated. In the type I soleus muscle talin content increased slightly at 7 days post-eccentric protocol compared to SHAM. In the type II plantaris muscle eccentric contraction led to an increase for vinculin and talin contents that was 2-3 fold higher than in the soleus; these significant changes were still present 28 days postexercise. These results show that eccentric contractions can trigger intense protein synthesis activity at the MTJ most likely related to myofibrillogenesis associated with MTJ remodeling.

Complement activation promotes muscle inflammation during modified muscle use.

Modified muscle use can result in muscle inflammation that is triggered by unidentified events. In the present investigation, we tested whether the activation of the complement system is a component of muscle inflammation that results from changes in muscle loading. Modified rat hindlimb muscle loading was achieved by removing weight-bearing from the hindlimbs for 10 days followed by reloading through normal ambulation. Experimental animals were injected with the recombinant, soluble complement receptor sCR1 to inhibit complement activation. Assays for complement C4 or factor B in sera showed that sCR1 produced large reductions in the capacity for activation of the complement system through both the classical and alternative pathways. Analysis of complement C4 concentration in serum in untreated animals showed that the classical pathway was activated during the first 2 hours of reloading. Analysis of factor B concentration in untreated animals showed activation of the alternative pathway at 6 hours of reloading. Administration of sCR1 significantly attenuated the invasion of neutrophils (-49%) and ED1(+) macrophages (-52%) that occurred in nontreated animals after 6 hours of reloading. The presence of sCR1 also reduced significantly the degree of edema by 22% as compared to untreated animals. Together, these data show that increased muscle loading activated the complement system which then briefly contributes to the early recruitment of inflammatory cells during modified muscle loading.

Accumulation of PDGF+ cells and internalisation of the PDGF receptor at myotendinous junction following modified hindlimb muscle use in the rat.

Morphological observations have shown previously that myotendinous junctions (MTJs) are sites where the associations between the cytoskeleton and the cell membrane are extensively remodelled during muscle growth and modified mechanical loading. The platelet derived growth factor (PDGF) molecule has been shown to induce cytoskeletal remodelling at focal contact sites of myoblasts in culture, the analogous structures of MTJs. The goals of the study were to determine whether PDGF is synthesised by mononuclear cells and whether PDGF receptors are internalised at the MTJs of the soleus muscle experiencing reloading. We also examined whether ED2+ macrophages that are nonphagocytic and activated inflammatory cells at MTJs during reloading secrete PDGF. Results obtained by immunohistochemistry showed that there was an increase in the number of cells expressing PDGF at remodelling MTJs and that the ED2+ macrophage population does not express PDGF at MTJs. According to morphological criteria, fibroblasts would be the logical candidates to secrete PDGF molecules near MTJs. Furthermore, the modification in muscle loading resulted in internalisation of PDGF receptors concentrated at the MTJ which accumulated predominantly around muscle nuclei. The enrichment of PDGF receptors and PDGF+ cells at MTJs and the internalisation of PDGF receptors during remodelling of MTJs suggest that PDGF may influence remodelling of MTJs following modified muscle use.

Macrophage invasion does not contribute to muscle membrane injury during inflammation.

Previous observations have shown that neutrophil invasion precedes macrophage invasion during muscle inflammation and that peak muscle injury is observed at the peak of ED1+ macrophage invasion. We tested the hypothesis that neutrophil invasion causes subsequent invasion by ED1+ macrophages and that ED1+ macrophages then contribute significantly to muscle membrane injury during modified muscle use. Rat hindlimbs were unloaded for 10 days followed by reloading by normal ambulation to induce inflammation. Membrane injury was measured by assaying Evans blue-bound serum protein influx through membrane lesions. Muscle neutrophil populations increased significantly during the first 2 h of reloading but ED1+ macrophages did not increase until 24 h. Neutrophil invasion was uncoupled from subsequent macrophage invasion by reloading rat hindlimbs for 2 h to cause neutrophil invasion, followed by resuspension for hours 2-24. This produced similar increases in neutrophil concentration as measured in muscles continuously reloaded for 24 h without causing an increase in macrophages. However, resuspension did not reduce the extent of muscle damage compared with that occurring in muscles that were reloaded continuously for 24 h. Thus, muscle invasion by neutrophils is not sufficient to cause invasion by ED1+ macrophages. In addition, muscle membrane injury that occurs during reloading is independent of invasion by ED1+ macrophages.

Increased endothelial cell expression of platelet-endothelial cell adhesion molecule-1 during hyperoxic lung injury.

Lung injury is a frequent consequence of oxygen (O2) therapy administered to newborns and adults with respiratory distress. Acute exposure to hyperoxia results in a well-described pathophysiologic response in the lungs. Because inflammation is an important component of pulmonary O2 toxicity, we have an interest in identifying the inflammatory mediators that increase during hyperoxia. Platelet-endothelial cell adhesion molecule-1 (PECAM-1), a member of the immunoglobulin superfamily that is expressed at the junctions between endothelial cells, is essential to the transendothelial migration of leukocytes. We hypothesized that increased expression of PECAM-1 occurs in pulmonary endothelial cells during hyperoxic lung injury. Adult mice were exposed to 100% O2 for up to 96 h. We analyzed PECAM-1 expression by RNA blot hybridization, in situ hybridization, and immunohistochemistry. A increase in PECAM-1 mRNA was seen as soon as 2 d of hyperoxia relative to unexposed control mice. PECAM-1 mRNA and protein were found in endothelial cells of both large and small arteries. The expression of PECAM-1 in capillary vessels was further confirmed using in situ hybridization at the electron microscope level. This increase in PECAM-1 expression coincided with the appearance of leukocytes in lung tissue. These observations suggest that PECAM-1 expression is a relatively early step in the inflammation cascade, and intervention at this phase may be critical to the prevention of further damage.

Mechanical loading regulates expression of talin and its mRNA, which are concentrated at myotendinous junctions.

The hypothesis that mechanical loading regulates talin expression in developing and adult muscle was tested using in vitro and in vivo models. Talin was selected for study because it is a key structural link between the cytoskeleton and cell membrane. In the in vitro model, C2C12 myotubes were subjected to cyclic strains for 48 h. In the in vivo model, rat hindlimb muscles were unloaded for 10 days, then reloaded for 2 days. Cyclic loading of myotubes resulted in significant increases in the quantity of talin (68%) and its 190-kDa proteolytic fragment (70%), as well as talin mRNA (180%), relative to unloaded myotube cultures. Similarly, talin concentration and its mRNA increased by 68 and 136%, respectively, in soleus muscles reloaded for 2 days relative to ambulatory controls. Immunohistochemistry and in situ RT-PCR showed that talin and its mRNA are concentrated and colocalized at myotendinous junctions. Thus these findings indicate that increased mechanical loading promotes talin synthesis, which occurs principally at myotendinous junctions, according to talin mRNA distribution.

Expression of dopamine D1-receptor mRNA in the carotid body of adult rabbits, cats and rats.

Dopamine is a major neurotransmitter in the carotid body of several animal species and its functional role at the level of peripheral arterial chemoreflex pathway is attributed to the presence of the dopamine D2-receptors. We present evidence that the dopamine D1-receptor mRNA is also expressed in the carotid body of adult rabbits, cats and rats. A DNA fragment of 611 bp of this receptor was first isolated from rabbit. The nucleic acid sequence of this fragment was found to be 84.5% identical to that of rat. This specific 611 bp fragment was used as a probe to detect, either by Northern analysis or by the reverse transcription-polymerase chain reaction, the dopamine D1-receptor mRNA. The results revealed the presence of dopamine D1-receptor transcript in the carotid body as well as in the petrosal ganglion and the superior cervical ganglion from the three animal models studied here. The physiological significance of dopamine D1-receptor expression in the carotid body is discussed.

Carbohydrate utilization in rat soleus muscle is influenced by carbonic anhydrase III activity.

Inhibition of carbonic anhydrase III (CA III; EC 4.2.1.1) activity in type I muscle can influence resistance to fatigue and glycogen utilization. Our aim was to determine if CA III inhibition could influence muscle pH and glycolytic rate. Muscle pH, hexosemonophosphates (HMP), glycolytic intermediates, ATP, and creatine phosphate (CP) were measured at rest and during a fatigue protocol in rat soleus muscles in vitro with or without CA inhibitors (CAI). In resting muscles, CAI resulted in a significant drop in pH (7.11 vs. 7.06, P < 0.05) and in a two- to threefold increase in HMP content compared with control muscles. Measurements of HMP and glycolytic intermediates during the fatigue protocol suggested, however, that the glycolytic flux was not influenced. Globally, muscles incubated with CAI showed larger perturbations of their CP and ATP content than control muscles. The accumulation of HMP induced by the CAI was found to be totally dependent on the combined presence of external glucose and contractile activity, suggesting that inhibiting CA III may augment the responsitivity of the contraction-induced glucose uptake process.

In vivo expression of intercellular adhesion molecule 1 in type II pneumocytes during hyperoxia.

Cell-to-cell communication is often disrupted when tissue damage occurs, triggering new signals to cope with the injury. The expression of intercellular adhesion molecule (ICAM-1), a protein involved in the migration, binding, and activation of leukocytes, is markedly increased in mouse lungs damaged by acute hyperoxic exposure. Type I alveolar epithelial cells are sensitive to hyperoxic lung injury, and must be removed from the air spaces following their destruction. In contrast, type II pneumocytes are relatively resistant to hyperoxia and may have a role in the removal process. Two reports demonstrate increased ICAM-1 in alveoli after hyperoxia (Welty et al., 1993, AJRCMB 9:393-400; and Kang et al., 1993, AJRCMB 9:350-355), but the cellular site(s) of ICAM-1 synthesis were not determined. We hypothesized that during in vivo exposure to 100% oxygen (O2), type II pneumocytes synthesize and secrete ICAM-1, an important step in attracting inflammatory cells to the site of injury. Adult mice were exposed to 100% O2 for up to 72 h. To determine whether type II cells express ICAM-1, tissue sections were studied by electron microscopy single-label in situ hybridization or light microscopy dual-label in situ hybridization, using radiolabeled and nonradiolabeled probes. In the lungs of unexposed animals, ICAM-1 mRNA was detected in many cells-including type I pneumocytes-but not in type II cells. After hyperoxia, ICAM-1 transcripts were detected in bona fide, surfactant protein C mRNA-containing, type II alveolar epithelial cells. This observation suggests that type II cells play an important and previously unrecognized role in pulmonary inflammation from O2 toxicity and emphasizes the importance of type II pneumocytes in alveolar repair after injury.

Effect of carbonic anhydrase III inhibition on substrate utilization and fatigue in rat soleus.

Carbonic anhydrase III (CA III; EC 4.2.1.1) is the most abundant cytosolic enzyme in type I skeletal muscle fibers. We have previously shown that inhibiting the CA III activity of type I muscle can influence fatigability. Our goal was to test the hypothesis that the influence on fatigability of CA III inhibition is linked to an increased utilization of carbohydrates. Rat soleus muscles were incubated in vitro in a physiological solution with or without CA inhibitor (methazolamide, 1 mM) and submitted to a fatigue protocol. When the bathing solution contained glucose, the muscles incubated with methazolamide maintained a higher level of tension production than control muscles for the first 55-60 min of the test compared with 35-40 min when glucose was not added. Measurement of muscle glycogen content revealed that muscles incubated with CA inhibitor were utilizing their glycogen at a higher rate than control muscles over the first 45 min of the fatigue protocol. When glycolysis was inhibited with sodium iodoacetate, fatigability was not influenced by the addition of a CA inhibitor. These results further support the existence of a link between CA III activity and energy metabolism in type I skeletal muscle fibers.

Fatigue and recovery of rat soleus muscle are influenced by inhibition of an intracellular carbonic anhydrase isoform.

Carbonic anhydrase III (CA III; EC 4.2.1.1) is the most abundant cytosolic enzyme in type I skeletal muscle fibers. Methazolamide, a specific CA inhibitor, was used to characterize the effects of inhibiting CA III on the resistance to fatigue and recovery of the rat soleus muscle using a 60-min fatigue protocol performed in vitro at 25 degrees C. Incubation with 10(-3) M methazolamide resulted in a smaller decrease in tension production during the fatigue protocol, thereby increasing the total tension-time integral for the fatigue test. However, the rate and extent of recovery after the test were lower in the experimental group compared with the control group. A similar effect was observed at physiological temperature (35 degrees C). The results indicate that inhibition of CA III significantly influences tension production as early as 30 s into the stimulation protocol. Inhibition of CA III only during the recovery period did not influence the recovery profile, thereby indicating that the impaired recovery was related to the presence of methazolamide during the stimulation period.

What do family practice graduates do? A comparative study.

Two groups of medical graduates from Université Laval were compared for their subsequent place and type of practice, age of patients, type and level of remuneration, and average costs generated per patient and per visit. The study group had completed a two year residency program in family medicine; the controls had completed a one-year internship. The family medicine graduates were more likely to have a varied practice in a community of less than 50,000 population, to make house calls and do nursing home or chronic hospital care, to earn in the middle range of income and to generate comparable costs per patient, but lower costs per visit. The internship graduates were more likely to limit their practices to one activity, and to be in the higher range of income. These findings could not be tested for statistical significance, but have implications for training programs and paying agencies.

Lacerations of the flexor hallucis longus in the young athlete.

Of ten patients with lacerations of the flexor hallucis longus tendon, nine were athletically inclined. In four, the laceration was not repaired and no disability was evident. A functioning flexor hallucis longus, therefore, does not seem to be essential for good push-off and balance in running sports. If both the flexor hallucis brevis and the flexor hallucis longus are lacerated and reconstitution of the longus is not possible, the brevis should be repaired, suturing the distal segment of the longus to brevis to prevent hyperextension deformity of the metatarsophalangeal joint. Hypersensitivity of the scar due to associated nerve injury is a frequent complication associated with laceration of the flexor hallucis longus.