A systematic review of aerobic and resistance exercise and inflammatory markers in people with multiple sclerosis.

Inflammation is a driver in the demyelination process in patients with multiple sclerosis (MS) and can influence disability levels. Both single and repeated bouts of exercise can decrease inflammatory markers in people with MS (PwMS). This systematic review evaluates whether exercise can influence inflammation and disability in individuals with MS. Experimental studies were reviewed that had to meet the following eligibility requirements: a sample of PwMS, an intervention of exercise (either aerobic, resistance, or a combination of each), and an outcome that included at least one inflammatory (cytokine) reaction. The main outcome measure was an evaluation of inflammation, as indicated by a change in any cytokine level. Other measures included muscle strength, balance, flexibility, walking ability, disability statues, and quality of life (QOL). A total of nine studies were included in the final review. Exercise interventions included predominantly cycling, although a few resistance training trials were mentioned. Small decreases were found in IL-17 and IFN-γ after exercise. Functional outcome measures and perceived disability status were improved posttraining. We conclude that while interventions such as exercise may impact QOL, they do not have a significant influence on inflammation associated with MS. Exercise is an accessible alternative that not only helps to decrease impairments but also limit the restrictions associated with participation in society. While functional outcomes after exercise improved, these improvements may not be attributable to changes in levels of cytokines or inflammatory markers.

Differential Contributions of DNA-Binding Proteins to Polycomb Response Element Activity at the Drosophila giant Gene.

Polycomb-group (PcG) proteins are evolutionarily conserved epigenetic regulators whose primary function is to maintain the transcriptional repression of target genes. Recruitment of Drosophila melanogaster PcG proteins to target genes requires the presence of one or more Polycomb Response Elements (PREs). The functions or necessity for more than one PRE at a gene are not clear and individual PREs at some loci may have distinct regulatory roles. Various combinations of sequence-specific DNA-binding proteins are present at a given PRE, but only Pleiohomeotic (Pho) is present at all strong PREs. The giant (gt) locus has two PREs, a proximal PRE1 and a distal PRE2. During early embryonic development, Pho binds to PRE1 ∼30-min prior to stable binding to PRE2. This observation indicated a possible dependence of PRE2 on PRE1 for PcG recruitment; however, we find here that PRE2 recruits PcG proteins and maintains transcriptional repression independently of Pho binding to PRE1. Pho-like (Phol) is partially redundant with Pho during larval development and binds to the same DNA sequences in vitro Although binding of Pho to PRE1 is dependent on the presence of consensus Pho-Phol-binding sites, Phol binding is less so and appears to play a minimal role in recruiting other PcG proteins to gt Another PRE-binding protein, Sp1/Kruppel-like factor, is dependent on the presence of Pho for PRE1 binding. Further, we show that, in addition to silencing gene expression, PcG proteins dampen transcription of an active gene.

Genetic susceptibility to benzene-induced toxicity: role of NADPH: quinone oxidoreductase-1.

Enzymes that activate and detoxify benzene are likely genetic determinants of benzene-induced toxicity.NAD(P)H: quinone oxidoreductase-1 (NQO1) detoxifies benzoquinones, proposed toxic metabolites of benzene. NQO1 deficiency in humans is associated with an increased risk of leukemia, specifically acute myelogenous leukemia, and benzene poisoning. We examined the importance of NQO1 in benzene-induced toxicity by hypothesizing that NQO1-deficient (NQO1-/-) mice are more sensitive to benzene than mice with wild-type NQO1 (NQO1+/+; 129/Sv background strain). Male and female NQO1-/- and NQO1+/+ mice were exposed to inhaled benzene (0, 10, 50, or 100 ppm) for 2 weeks, 6 h/day, 5 days/week. Micronucleated peripheral blood cells were counted to assess genotoxicity. Peripheral blood counts and bone marrow histology were used to assess hematotoxicity and myelotoxicity. p21 mRNA levels in bone marrow cells were used as determinants of DNA damage response. Female NQO1-/- mice were more sensitive (6-fold) to benzene-induced genotoxicity than the female NQO1+/+ mice. Female NQO1-/- mice had a 9-fold increase (100 versus 0 ppm) in micronucleated reticulocytes compared with a 3-fold increase in the female NQO1+/+ mice. However, the induced genotoxic response in male mice was similar between the two genotypes (> or = 10-fold increase at 100 ppm versus 0 ppm). Male and female NQO1-/- mice exhibited greater hematotoxicity than NQO1+/+ mice. p21 mRNA levels were induced significantly in male mice (>10-fold) from both strains and female NQO1-/- mice (> 8-fold), which indicates an activated DNA damage response. These results indicate that NQO1 deficiency results in substantially greater benzene-induced toxicity. However, the specific patterns of toxicity differed between the male and female mice.

A novel case of superior rectus injury and its subsequent surgery.

We report a presumed damage to the left superior rectus (SR) muscle following a dog bite injury that resulted in a marked weakness of elevation and vertical diplopia. A 30-year-old male presented in October 2010 following a dog bite around his left superotemporal orbit. An ophthalmic examination was unremarkable. The patient immediately complained of vertical diplopia, which did not settle during a period of observation lasting approximately 9 months following the attack. An orthoptist examination confirmed a marked restriction of upgaze. A diagnosis of isolated SR injury, secondary to the dog bite, was suspected. A left Knapp procedure was performed. The surgery was uneventful with scar tissue found around the SR. Three months following his surgery, the patient was orthophoric in both primary positions and in the downgaze with a residual 20-prism dioptre hypotropia in the upgaze. Our patient was unusual in that the bite weakened the SR in isolation. We also show the successful management of this novel case using a simple Knapp procedure.

A paper-based multiplexed transaminase test for low-cost, point-of-care liver function testing.

In developed nations, monitoring for drug-induced liver injury through serial measurements of serum transaminases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] in at-risk individuals is the standard of care. Despite the need, monitoring for drug-related hepatotoxicity in resource-limited settings is often limited by expense and logistics, even for patients at highest risk. This article describes the development and clinical testing of a paper-based, multiplexed microfluidic assay designed for rapid, semiquantitative measurement of AST and ALT in a fingerstick specimen. Using 223 clinical specimens obtained by venipuncture and 10 fingerstick specimens from healthy volunteers, we have shown that our assay can, in 15 min, provide visual measurements of AST and ALT in whole blood or serum, which allow the user to place those values into one of three readout "bins" [<3× upper limit of normal (ULN), 3 to 5× ULN, and >5× ULN, corresponding to tuberculosis/HIV treatment guidelines] with >90% accuracy. These data suggest that the ultimate point-of-care fingerstick device will have high impact on patient care in low-resource settings.

The effect of scleral exoplant removal on strabismus following retinal detachment repair.

PURPOSE: Scleral buckling for retinal detachment is a well-reported cause of secondary strabismus. We analyzed the effects on motility of removal of the exoplant alone to determine whether this is warranted as a separate step in the surgical management of these patients. METHODS: A retrospective case series of patients who underwent scleral exoplant removal due to symptomatic strabismus development following retinal detachment repair from 2007 to 2009 was conducted. Manifest horizontal and vertical deviations were treated as vectors of a single combined deviation (|dev|). Pre- and postoperative manifest |dev| in the primary position (|dev|(pp)) and in the gaze position of maximal deviation (|dev|(max)) were analyzed. RESULTS: Five patients were identified, all with symptomatic, binocular diplopia in the primary position prior to exoplant removal. Median |dev|(pp) prior to exoplant removal was 21(Δ) and following removal was 21(Δ) (P = 0.81). The median |dev|(max) prior to exoplant removal was 33(Δ) and following removal, 22(Δ) (P = 0.82). Median follow-up was 8 months. There were no cases of retinal redetachment following the exoplant removal. No patient reported any subjective improvement of their diplopia. All 5 patients went on to have strabismus surgery as a separate procedure. CONCLUSIONS: Median primary position deviation was unchanged by scleral buckle removal, and Exoplant removal has minimal long-term benefit on the strabismus following scleral buckling procedures.

A soluble activin type IIB receptor improves function in a mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurologic disease characterized by progressive weakness that results in death within a few years of onset by respiratory failure. Myostatin is a member of the TGF-beta superfamily that is predominantly expressed in muscle and acts as a negative regulator of muscle growth. Attenuating myostatin has previously been shown to produce increased muscle mass and strength in normal and disease animal models. In this study, a mouse model of ALS (SOD1(G93A) transgenic mice) was treated with a soluble activin receptor, type IIB (ActRIIB.mFc) which is a putative endogenous signaling receptor for myostatin in addition to other ligands of the TGF-beta superfamily. ActRIIB.mFc treatment produces a delay in the onset of weakness, an increase in body weight and grip strength, and an enlargement of muscle size whether initiated pre-symptomatically or after symptom onset. Treatment with ActRIIB.mFc did not increase survival or neuromuscular junction innervation in SOD1(G93A) transgenic mice. Pharmacologic treatment with ActRIIB.mFc was superior in all measurements to genetic deletion of myostatin in SOD1(G93A) transgenic mice. The improved function of SOD1(G93A) transgenic mice following treatment with ActRIIB.mFc is encouraging for the development of TGF-beta pathway inhibitors to increase muscle strength in patients with ALS.

Voluntary wheel running ameliorates vascular smooth muscle hyper-contractility in type 2 diabetic db/db mice.

Physical activity reduces cardiovascular disease related mortality in diabetic patients. However, it is unknown if the diabetic state reduces voluntary physical activity and, if so, if the voluntary physical activity at the reduced level is sufficient to improve cardiovascular risk factors. To address these two specific questions, we investigated voluntary wheel running performance in an obese and type 2 diabetic mouse model, the db/db mice. In addition, we determined the effects of running on body mass, blood glucose, insulin, plasma free fatty acids, cholesterol, and vascular smooth muscle hyper-contractility. Our results showed that daily running distance, time, and speed were significantly reduced in the db/db mice to about 23%, 32%, and 71%, respectively, of that in non-diabetic control mice. However, this low level of running was sufficient to induce a reduction in the vascular smooth muscle hyper-contractility, cholesterol, and some plasma free fatty acids, as well as to delay the decrease in blood insulin. These changes occurred in the absence of weight loss and a detectable decrease in blood glucose. Thus, the results of this study demonstrated that voluntary wheel running activity was dramatically reduced in db/db mice. However, the low levels of running were beneficial, in the absence of effects on obesity or blood glucose, with significant reductions in cardiovascular risk factors and potential delays in beta-cell dysfunction.

Expression of beta-catenin is necessary for physiological growth of adult skeletal muscle.

Expression of beta-catenin is known to be important for developmental processes such as embryonic pattern formation and determination of cell fate. Inappropriate expression, however, has been linked to pathological states such as cancer. Here we report that expression of beta-catenin is necessary for physiological growth of skeletal muscle in response to mechanical overload. Conditional inactivation of beta-catenin was induced in control and overloaded muscle through intramuscular injection of adenovirus expressing Cre recombinase in beta-catenin floxed mice. Individual muscle fiber analysis was performed to identify positively transfected/inactivated cells and determine fiber cross-sectional area. The results demonstrate that fiber growth is completely inhibited when the beta-catenin expression is lost. This effect was cell autonomous, as fibers that did not exhibit recombination in the floxed mice grew to the same magnitude as infected/noninfected fibers from wild-type mice. These findings suggest that beta-catenin may be a primary molecular site through which multiple signaling pathways converge in regulating physiological growth.