Kevin J. Gilmore

Superantigens Subvert the Neutrophil Response To Promote Abscess Formation and Enhance Staphylococcus aureus Survival In Vivo

ABSTRACT Staphylococcus aureus is a versatile bacterial pathogen that produces T cell-activating toxins known as superantigens (SAgs). Although excessive immune activation by SAgs can induce a dysregulated cytokine storm as a component of what is known as toxic shock syndrome (TSS), the contribution of SAgs to the staphylococcal infection process is not well defined. Here, we evaluated the role of the bacterial superantigen staphylococcal enterotoxin A (SEA) in a bacteremia model using humanized transgenic mice expressing SAg-responsive HLA-DR4 molecules. Infection with S. aureus Newman induced SEA-dependent Vβ skewing of T cells and enhanced bacterial survival in the liver compared with infection by sea knockout strain. SEA-induced gamma interferon, interleukin-12, and chemokine responses resulted in increased infiltration of CD11b+ Ly6G+ neutrophils into the liver, promoting the formation of abscesses that contained large numbers of viable staphylococci. Hepatic abscesses occurred significantly more frequently in S. aureus Newman-infected livers than in livers infected with the Newman sea knockout strain, promoting the survival of S. aureus in vivo. This represents a novel mechanism during infection whereby S. aureus utilizes SAgs to form a specialized niche and manipulate the immune system.

Motor unit number and transmission stability in octogenarian world class athletes: Can age-related deficits be outrun?

Our group has shown a greater number of functioning motor units (MU) in a cohort of highly active older (∼65 yr) masters runners relative to age-matched controls. Because of the precipitous loss in the number of functioning MUs in the eighth and ninth decades of life it is unknown whether older world class octogenarian masters athletes (MA) would also have greater numbers of functioning MUs compared with age-matched controls. We measured MU numbers and neuromuscular transmission stability in the tibialis anterior of world champion MAs (∼80 yr) and compared the values with healthy age-matched controls (∼80 yr). Decomposition-enhanced spike-triggered averaging was used to collect surface and intramuscular electromyography signals during dorsiflexion at ∼25% of maximum voluntary isometric contraction. Near fiber (NF) MU potential analysis was used to assess neuromuscular transmission stability. For the MAs compared with age-matched controls, the amount of excitable muscle mass (compound muscle action potential) was 14% greater (P < 0.05), there was a trend (P = 0.07) toward a 27% smaller surface-detected MU potential representative of less collateral reinnervation, and 28% more functioning MUs (P < 0.05). Additionally, the MAs had greater MU neuromuscular stability than the controls, as indicated by lower NF jitter and jiggle values (P < 0.05). These results demonstrate that high-performing octogenarians better maintain neuromuscular stability of the MU and mitigate the loss of MUs associated with aging well into the later decades of life during which time the loss of muscle mass and strength becomes functionally relevant. Future studies may identify the concomitant roles genetics and exercise play in neuroprotection.

Neuromuscular function in different stages of sarcopenia.

This study applied the screening tool developed by the European Working Group on Sarcopenia in Older People (EWGSOP) on seniors aged over 65years and concurrently tested various laboratory-based indices of neuromuscular function. Twenty-four healthy and independent living older adults (9 men, 15 women) with a mean age of 79.1±5.8years participated. Based on gait speed, handgrip strength and muscle mass all subjects were categorized into one of the three conceptual sarcopenia stages (pre-sarcopenia, sarcopenia, severe sarcopenia). Maximal strength of dorsiflexors in the left leg was measured and voluntary activation was assessed by the interpolated twitch technique. In addition, isometric evoked contractile properties were recorded. Skeletal muscle mass was assessed by ultrasound from nine sites. There were roughly equal number of subjects in each sarcopenic category, and age was not different among the 3 groups. There were no differences in handgrip strength and skeletal muscle mass index among the 3 groups. Gait speed was significantly slower (p<0.01) in the severe sarcopenic subjects compared to the pre-sarcopenic group. With no differences in voluntary activation among the groups, the maximal voluntary contractions (MVCs) for severe sarcopenic subjects were 29% lower (p=0.02) and with 19% slower (p=0.02) voluntary rates of torque development (RTD) compared to sarcopenic subjects. Furthermore, the severe group was 34% lower (p=0.04) with 36% slower (p=0.02) RTD compared to pre-sarcopenic subjects. Peak twitch tension was 54% lower (p<0.01) in the severe group compared with the pre-sarcopenic group. Maximal twitch RTD were 40% (p=0.03) slower for the severe group compared to the sarcopenia group, and 51% slower (p=0.03) compared with the pre-sarcopenia group, but when normalized to peak torques there were no statistical differences. The laboratory tests found neuromuscular differences among the 3 groups which generally supported the classification scheme and helped to illustrate some key factors that could explain differences in functional capacities. These initial findings support the assumption that this categorization is relevant for identifying older adults with different neuromuscular properties. However, further studies are needed to provide more insight into the specific neuromuscular changes in the three sarcopenia stages, and how these changes relate to functional capacity. Such studies could ultimately contribute to identifying optimal interventions to improve neuromuscular functioning.

Motor unit number estimation and neuromuscular fidelity in 3 stages of sarcopenia

Introduction: Loss of motor units (MUs) and alterations in MU properties are major factors in development of sarcopenia. The purpose of this study was to compare MU properties among 3 groups categorized as either pre‐sarcopenic (n = 7), sarcopenic (n = 7), or severely sarcopenic (n = 5), all with similarly aged subjects (75–82 years). Methods: Using decomposition‐enhanced quantitative electromyography, MU number estimates and neuromuscular stability measures of near‐fiber (NF) jitter and jiggle were derived in addition to contractile properties of ankle dorsiflexors. Results: MU number estimates were similar across groups; however, maximal voluntary strength in the severe sarcopenia group was 27% and 37% less than the sarcopenic and pre‐sarcopenic groups, respectively. Moreover, NF jiggle was 31% greater in the severe group compared with pre‐sarcopenia, NF jitter was 43% greater in the severe group compared with the pre‐sarcopenic group. Conclusion: Unlike MU number estimates, strength and MU stability differed across groups and related to degree of sarcopenia. Muscle Nerve 55: 676–684, 2017

Motor Unit Number Estimations and Neuromuscular Fidelity in Three Stages of Sarcopenia.

Introduction: Loss of motor units (MUs) and alterations in MU properties are major factors in development of sarcopenia. The purpose of this study was to compare MU properties among 3 groups categorized as either pre‐sarcopenic (n = 7), sarcopenic (n = 7), or severely sarcopenic (n = 5), all with similarly aged subjects (75–82 years). Methods: Using decomposition‐enhanced quantitative electromyography, MU number estimates and neuromuscular stability measures of near‐fiber (NF) jitter and jiggle were derived in addition to contractile properties of ankle dorsiflexors. Results: MU number estimates were similar across groups; however, maximal voluntary strength in the severe sarcopenia group was 27% and 37% less than the sarcopenic and pre‐sarcopenic groups, respectively. Moreover, NF jiggle was 31% greater in the severe group compared with pre‐sarcopenia, NF jitter was 43% greater in the severe group compared with the pre‐sarcopenic group. Conclusion: Unlike MU number estimates, strength and MU stability differed across groups and related to degree of sarcopenia. Muscle Nerve 55: 676–684, 2017

The effect of very old age on anconeus motor unit loss and compensatory remodelling.

Introduction: It is not known how the process of compensatory remodeling through collateral reinnervation continues into very old age (>80 years) or whether there is a limit to effective motor unit (MU) reinnervation. Therefore, we explore electrophysiological properties related to motor unit number estimates (MUNEs) in very old participants (79–90 years of age) compared with young controls (25–29 years of age). Methods: Decomposition‐enhanced spike‐triggered averaging was used to collect surface and intramuscular electromyography information from the anconeus to derive a MUNE. Results: Young participants had a MUNE of ∼38 and ∼25 at 30% and 50% root mean squared maximum voluntary contraction (RMSMVC) with surface motor unit potentials (S‐MUPs) of ∼145 μV and 236 μV, respectively. Older participants had a MUNE of ∼23 and ∼16 at 30% and 50% RMSMVC with S‐MUPs of 168 μV and 232 μV, respectively. Discussion: In this muscle, an age limit to successful remodeling through collateral reinnervation, to compensate for the presumed ongoing losses of MUs, may have been surpassed. Muscle Nerve 57: 659–663, 2018

Neuromuscular changes of the aged human hamstrings

Despite the life-long importance for posture and locomotion, neuromuscular properties of the hamstrings muscle have not been explored with adult aging. The purpose of this study was to assess and compare age-related effects on contractile function, spinal motor neuron output expressed as motor unit (MU) discharge rates in the hamstrings of 11 young (26 ± 4 yr) and 10 old (80 ± 5 yr) men. Maximal voluntary isometric contractions (MVC), stimulated contractile properties, and surface and intramuscular electromyography (EMG) from submaximal to MVC were recorded in the biceps femoris (BF) and semimembranosus-semitendinosus (SS) muscles. MVC torque was ~50% less in the old with both age groups attaining ≥93% mean voluntary activation. Evoked twitches in the old were ~50% lower in amplitude and >150% longer in duration compared with those in the young. At successive voluntary contractions of 25, 50, and 100% MVC, MU discharge rates were up to 45% lower in old, with no differences in relative submaximal surface EMG between age groups. Furthermore, the old had significantly lower MU discharge rates in the SS at all contraction intensities compared with the BF muscle. Men in their 8th to 10th decades of life demonstrate substantially lower strength and MU discharge rates in this functionally important large lower limb muscle group, with greater age-related effect on discharge rates in the medial hamstrings. These findings, compared with those in other muscles studied, highlight that the neuromuscular properties of limb muscles, and indeed within functionally similar portions of a muscle group, are not all affected equally by the aging process. NEW & NOTEWORTHY In the hamstrings, we found that both contractile function and motor unit discharge rates across the range of voluntary intensities were lower in the old. The differences in discharge rates due to age were greater in the medial hamstrings muscle group compared with the lateral hamstrings. Compared with previous studies, these results highlight that not all muscles are affected equally by aging and there may be compartmental differences within functionally similar muscles.

Electrophysiological and neuromuscular stability of persons with chronic inflammatory demyelinating polyneuropathy (CIDP).

We assessed motor unit (MU) properties and neuromuscular stability in the tibialis anterior (TA) of chronic inflammatory demyelinating polyneuropathy (CIDP) patients using decomposition‐based quantitative electromyography.

Reductions in muscle quality and quantity in chronic inflammatory demyelinating polyneuropathy patients assessed by magnetic resonance imaging: CIDP Musculature Assessed by MRI

Introduction: Weakness in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) may be caused by decreases in muscle quantity and quality, but this has not been explored. Methods: Twelve patients with CIDP (mean age 61 years) and 10 age‐matched (mean age 59 years) control subjects were assessed for ankle dorsiflexion strength, and two different MRI scans (T1 and T2) of leg musculature. Results: Isometric strength was 36% lower in CIDP patients compared with controls. Tibialis anterior muscle volumes of CIDP patients were smaller by ∼17% compared with controls, and non‐contractile tissue volume was ∼58% greater in CIDP patients. When normalized to total muscle or corrected contractile volume, strength was ∼29% and ∼18% lower, respectively, in CIDP patients. Discussion: These results provide insight into the structural integrity of muscle contractile proteins and pathologic changes to whole‐muscle tissue composition that contribute to impaired muscle function in CIDP. Muscle Nerve 58: 396–401, 2018