Long-term follow-up of spinal and bulbar muscular atrophy in Taiwan.

BACKGROUND/PURPOSE: Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy disease, is a rare neurodegenerative disorder presenting with insidious onset of weakness in bulbar and limb muscles. Information regarding long-term clinical and functional progression has been limited, especially for the Taiwanese population. The purpose of the study aimed to investigate early diagnosis and long-term prognosis of SBMA. METHODS: We retrospectively analyzed 21 genetically confirmed SBMA patients who visited our hospital between 1993 and 2010, focusing on clinical symptoms, nerve conduction studies, and functional disability. We also analyzed the relationship between length of cytosine-adenine-guanine (CAG) repeats and age of disease onset. RESULTS: Weakness developed at a mean age of 39 ± 7 years (mean ± standard deviation). The length of CAG repeats and age at onset of weakness showed inverse (but nonsignificant) correlation. The most common symptoms at initial presentation were hand tremor (86%), limb weakness (86%), and perioral fasciculation (76%). Creatine kinase (CK) was elevated in 17 out of 18 patients. Initial nerve conduction studies showed statistical difference from normal controls, especially decreased amplitudes of compound motor action potential (CMAP) and sensory nerve action potential (SNAP). Functional disability showed very slow progression, with only three patients becoming wheelchair-dependent during follow-up at a median age of 72 years. CONCLUSION: Patients with SBMA may present with a myriad of symptoms, including limbs weakness, tremor, muscle atrophy, and perioral fasciculations. Elevated serum CK and decreased CMAP and SNAP amplitudes were supportive laboratory findings of SBMA. Disease progression was gradual, and most patients remained functionally independent many years after the onset of weakness.

Estrogen status and skeletal muscle recovery from disuse atrophy.

Although estrogen loss can alter skeletal muscle recovery from disuse, the specific components of muscle regrowth that are estrogen sensitive have not been described. The primary purpose of this study was to determine the components of skeletal muscle mass recovery that are biological targets of estrogen. Intact, ovariectomized (OVX), and ovariectomized with 17beta-estradiol replacement (OVX+E2) female rats were subjected to hindlimb suspension for 10 days and then returned to normal cage ambulation for the duration of recovery. Soleus muscle mass returned to control levels by day 7 of recovery in the intact animals, whereas OVX soleus mass did not recover until day 14. Intact rats recovered soleus mean myofiber cross-sectional area (CSA) by day 14 of recovery, whereas the OVX soleus remained decreased (42%) at day 14. OVX mean fiber CSA did return to control levels by day 28 of recovery. The OVX+E2 treatment group recovered mean CSA at day 14, as in the intact animals. Myofibers demonstrating central nuclei were increased at day 14 in the OVX group, but not in intact or OVX+E2 animals. The percent noncontractile tissue was also increased 29% in OVX muscle at day 14, but not in either intact or OVX+E2 groups. In addition, collagen 1a mRNA was increased 45% in OVX muscle at day 14 of recovery. These results suggest that myofiber growth, myofiber regeneration, and extracellular matrix remodeling are estrogen-sensitive components of soleus muscle mass recovery from disuse atrophy.

Analytical and diagnostic performance of troponin assays in patients suspicious for acute coronary syndromes.

BACKGROUND: The controversy whether there is a clinically significant difference between troponin T (cTnT) and troponin I (cTnI) in regard to predictive value and cardiac specificity is still ongoing. METHODS: We evaluated enzyme-linked immunosorbent assay systems for cTnI and cTnT in patients with acute coronary syndromes and multiple control groups to define threshold values for risk stratification and compare their predictive value. RESULTS: In 312 patients with noncardiac chest pain, cTnI levels were below the detection limit of 0.2 microg/L and cTnT levels were 0.011 [0.010-0. 013] microg/L. In patients with end-stage renal failure (n = 26) and acute (n = 38) or chronic (n = 16) skeletal muscle damage, median concentrations were 0.20 [0.20-0.35], below the detection limit, and 0.20 [0.20-0.25] for cTnI, and 0.04 [0.01-0.10], 0.011 [0.005-0.025], and 0.032 [0.009-0.054] microg/L for cTnT. In patients with acute coronary syndromes (n = 1130), maximized prognostic value for 30-day outcome (death, infarction) was observed at a threshold level of 1.0 microg/L for cTnI (29.0% positive) and at 0.06 microg/L for cTnT (35. 0% positive). Significant differences in the area-under-the-curve values were observed between cTnI and cTnT (0.685 vs. 0.802; p = 0. 005). For both markers, the area-under-the-curve values did not increase with the second (within 24 h after enrollment) or third (48 h) blood draw. CTnI showed a less strong association with 30-day outcome than cTnT. When cTnI was put in a logistic multiple-regression model first, cTnT did add significant information. CONCLUSION: By using the defined threshold values and the employed test systems, single testing for cTnI and cTnT within 12 h after symptom onset was appropriate for risk stratification. Despite the lower cardiac specificity for cTnT, it appears to have a stronger association with the patients' outcome, whereas, as previously shown, the ability to identify patients who benefit from treatment with a GP IIb/IIIa receptor antagonist is similar.

Prevention of muscle disuse atrophy by low-frequency electrical stimulation in rats.

When muscles lose neural drive, they atrophy rapidly. Neuromuscular electrical stimulation (NMS) has been used in attempts to prevent or reverse the atrophy, but optimal stimulation programs and parameters are not well defined. In this study, we investigated the effects of four different stimulation patterns on disuse atrophy produced in the tibialis anterior, lateral gastrocnemius, and soleus muscles of rats paralyzed with tetrodotoxin for seven days. Stimulation paradigms differed from one another by their stimulation frequency (2 or 10 pulses/s) and by their stimulation period (2 or 10 h a day). Results showed that stimulation with 2 pulses/s, paradigms were more effective at preventing disuse muscle atrophy than higher-frequency stimulation. The most marked difference was in the slow soleus muscle, which had only 10% mean atrophy when stimulated at 2 pulses/s for 10 h, compared to 26% atrophy when stimulated at 10 pulses/s for either 2 or 10 h and 32% atrophy in unstimulated, paralyzed controls. The level of atrophic change was not correlated with the levels of serum creatine kinase, used as an index of muscle damage. Results suggest that remediation of disuse atrophy may be accomplished using unphysiologically low rates of motor-unit activation despite the relatively low force produced by such unfused contractions. This may have significant implications for the design of therapies for muscle paralysis consequent to upper-motoneuron lesions.

Moderate intensity resistive exercise improves metaphyseal cancellous bone recovery following an initial disuse period, but does not mitigate decrements during a subsequent disuse period in adult rats.

Spaceflight provides a unique environment for skeletal tissue causing decrements in structural and densitometric properties of bone. Previously, we used the adult hindlimb unloaded (HU) rat model to show that previous exposure to HU had minimal effects on bone structure after a second HU exposure followed by recovery. Furthermore, we found that the decrements during second HU exposure were milder than the initial HU cycle. In this study, we used a moderate intensity resistance exercise protocol as an anabolic stimulus during recovery to test the hypothesis that resistance exercise following an exposure to HU will significantly enhance recovery of densitometric, structural, and, more importantly, mechanical properties of trabecular and cortical bone. We also hypothesized that resistance exercise during recovery, and prior to the second unloading period, will mitigate the losses during the second exposure. The hypothesis that exercise during recovery following hindlimb unloading will improve bone quality was supported by our data, as total BMC, total vBMD, and cancellous bone formation at the proximal tibia metaphysis increased significantly during exercise period, and total BMC/vBMD exceeded age-matched control and non-exercised values significantly by the end of recovery. However, our results did not support the hypothesis that resistance exercise prior to a subsequent unloading period will mitigate the detrimental effects of the second exposure, as the losses during the second exposure in total BMC, total vBMD, and cortical area at the proximal tibia metaphysis for the exercised animals were similar to those of the non-exercised group. Therefore, exercise did not mitigate effects of the second HU exposure in terms of pre-to-post HU changes in these variables, but it did produce beneficial effects in a broader sense.

Contributions of severe burn and disuse to bone structure and strength in rats.

Burn and disuse results in metabolic and bone changes associated with substantial and sustained bone loss. Such loss can lead to an increased fracture incidence and osteopenia. We studied the independent effects of burn and disuse on bone morphology, composition and strength, and microstructure of the bone alterations 14days after injury. Sprague-Dawley rats were randomized into four groups: Sham/Ambulatory (SA), Burn/Ambulatory (BA), Sham/Hindlimb Unloaded (SH) and Burn/Hindlimb Unloaded (BH). Burn groups received a 40% total body surface area full-thickness scald burn. Disuse by hindlimb unloading was initiated immediately following injury. Bone turnover was determined in plasma and urine. Femur biomechanical parameters were measured by three-point bending tests and bone microarchitecture was determined by micro-computed tomography (uCT). On day 14, a significant reduction in body mass was observed as a result of burn, disuse and a combination of both. In terms of bone health, disuse alone and in combination affected femur weight, length and bone mineral content. Bending failure energy, an index of femur strength, was significantly reduced in all groups and maximum bending stress was lower when burn and disuse were combined. Osteocalcin was reduced in BA compared to the other groups, indicating influence of burn. The reductions observed in femur weight, BMC, biomechanical parameters and indices of bone formation are primarily responses to the combination of burn and disuse. These results offer insight into bone degradation following severe injury and disuse.

Cancellous bone formation response to simulated resistance training during disuse is blunted by concurrent alendronate treatment.

The purpose of this study was to assess the effectiveness of simulated resistance training (SRT) exercise combined with alendronate (ALEN) in mitigating or preventing disuse-associated losses in cancellous bone microarchitecture and formation. Sixty male Sprague-Dawley rats (6 months old) were randomly assigned to either cage control (CC), hind limb unloading (HU), HU plus either ALEN (HU + ALEN), SRT (HU + SRT), or a combination of ALEN and SRT (HU + SRT/ALEN) for 28 days. HU + SRT and HU + SRT/ALEN rats were anesthetized and subjected to muscle contractions once every 3 days during HU (four sets of five repetitions, 1000 ms isometric + 1000 ms eccentric). Additionally, HU + ALEN and HU + SRT/ALEN rats received 10 µg/kg of body weight of ALEN three times per week. HU reduced cancellous bone-formation rate (BFR) by 80%, with no effect of ALEN treatment (-85% versus CC). SRT during HU significantly increased cancellous BFR by 123% versus CC, whereas HU + SRT/ALEN inhibited the anabolic effect of SRT (-70% versus HU + SRT). SRT increased bone volume and trabecular thickness by 19% and 9%, respectively, compared with CC. Additionally, osteoid surface (OS/BS) was significantly greater in HU + SRT rats versus CC (+32%). Adding ALEN to SRT during HU reduced Oc.S/BS (-75%), Ob.S/BS (-72%), OS/BS (-61%), and serum TRACP5b (-36%) versus CC. SRT and ALEN each independently suppressed a nearly twofold increase in adipocyte number evidenced with HU and inhibited increases in osteocyte apoptosis. These results demonstrate the anabolic effect of a low volume of high-intensity muscle contractions during disuse and suggest that both bone resorption and bone formation are suppressed when SRT is combined with bisphosphonate treatment.

Serum creatine kinase levels in spinobulbar muscular atrophy and amyotrophic lateral sclerosis.

We compared serum creatine kinase (CK) levels between spinobulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS) and reviewed available histochemical studies of frozen sections of muscle biopsies. CK levels and the frequency of patients with elevated CK levels were significantly higher in the SBMA group when compared with the ALS group. CK levels occasionally approached values up to 8 times the upper limit of normal in the SBMA group. In addition to the chronic neurogenic changes in the muscle biopsy, all SBMA patients showed one or more myopathic changes. Increased numbers of markedly hypertrophic fibers were consistently seen in all patients. It is not clear whether the elevated CK level is directly related to the increased number of hypertrophic fibers or to other myopathic features. Based on these findings, we recommend genetic testing for SBMA in cases of male patients with motor neuron disease who present with a significantly elevated serum creatine kinase level, even when other characteristic clinical features of SBMA are absent.

Progressive myopathy with circulating autoantibody against giantin in the Golgi apparatus.

A woman aged 59 years with adult-onset progressive myopathy had anti-Golgi (giantin) autoantibody in the serum. Limb-muscle biopsy revealed chronic myopathy with paucity of cellular reactions and reduced immunostaining for alpha-dystroglycan. The similarity of the current patient with cases of hereditary alpha-dystroglycanopathies (Fukuyama-type congenital muscular dystrophy, Walker-Warburg syndrome, muscle-eye-brain disease, congenital muscular dystrophy type 1C, and limb-girdle muscular dystrophy type 2I) suggests that the Golgi apparatus is the target organelle in a subset of myopathies.