Contributions of the ubiquitin–proteasome pathway and apoptosis to human skeletal muscle wasting with age

The primary mechanism that contributes to decreasing skeletal muscle strength and size with healthy aging is not presently known. This study examined the contribution of the ubiquitin–proteasome pathway and apoptosis to skeletal muscle wasting in older adults (n = 21; mean age = 72.76 ± 8.31 years) and young controls (n = 21; mean age = 21.48 ± 2.93 years). Subjects underwent a percutaneous muscle biopsy of the vastus lateralis to determine: (1) ubiquitin ligase gene expression (MAFbx and MuRF1); (2) frequency of apoptosis; and (3) individual fiber type and cross-sectional area. In addition, a whole muscle strength test was also performed. A one-way ANOVA revealed significant increases in the number of positive TUNEL cells in older adults (87%; p < 0.05), although no significant increase in caspase-3/7 activity was detected. Additionally, ubiquitin ligase gene expression, individual muscle fiber type and CSA were not different between old and young subjects. Muscle strength was also significantly lower in old compared to young subjects (p < 0.05). In conclusion, this study indicates a preferential role for apoptosis contributing to decreases in muscle function with age.     

Temporal encoding of two-dimensional patterns by single units in primate inferior temporal cortex. I. Response characteristics

We seek a general approach to determine what stimulus features visual neurons are sensitive to and how those features are represented by the neuron's responses. Because lesions of inferior temporal (IT) cortex interfere with a monkey's ability to perform pattern discrimination tasks we studied IT neurons. Previous single-unit studies have shown that IT neurons sometimes respond more strongly to complex stimuli (brushes, hands, faces) than to simple stimuli (bars, slits, edges). However, it is not known how specific stimulus parameters are represented by responses. We studied the responses of IT neurons in alert behaving monkeys to a large set of two-dimensional black and white patterns. The stimulus set was based on 64 Walsh functions that can be used to represent any picture with a resolution of one part in eight along each of two dimensions. The responses to these stimuli spanned a continuum from inhibition to strong excitation. A statistical test showed that the spike count was determined by which Walsh stimulus was presented. Hence, these stimuli form an adequate set for testing IT neurons. The responses showed temporal modulation of the spike train that could not be represented by a change in the spike count alone. Examples of this modulation were changes in latency, changes in the duration of the response, and alternating periods of excitation and inhibition. This temporal modulation may be important in representing stimulus parameters. The next paper in this series develops a method for quantifying this temporal modulation and shows that it is dependent on the stimulus. The third paper in this series shows that this temporal modulation contains more information about stimulus parameters than is contained in the spike count alone.     

Wear-particle-induced osteoclast osteolysis: the role of particulates and mechanical strain

Periprosthetic osteolysis involves osteoclast activation by wear particulates and their exposure to mechanical perturbation through exposure to shear forces generated by periprosthetic fluid as well as interface micromotion. This study aimed to determine the interactions between wear particulates, mechanical stimulation, and osteoclasts. In static cultures, wear particulates increased osteoclast differentiation. Addition of neutralizing antibodies to RANKL (receptor activator of nuclear factor kappa ligand) inhibited the particle-induced increase in osteoclast numbers. Cyclic 5000 microstrains were applied with the use of a custom-built device to marrow-derived cultures to assess the effect on osteoclast differentiation. Mechanical strain application alone decreased osteoclast differentiation, which was further decreased by the addition of particles despite increases in the soluble RANKL to osteoprotegerin (OPG) ratio. Mechanical strain alone induced mature osteoclast apoptosis in a dose-dependent manner. In contrast, in the mature osteoclast model, the addition of nonmetal particulates protected the osteoclasts from becoming apoptopic. Titanium (Ti) and cobalt chromium (CoCr) particles, however, induced osteoclast apoptosis, whereas polyethylene (PE) and polymethylmethacrylate (PMMA) did not. Wear particulates and mechanical stimulation interact via an eicosanoid-dependent pathway to alter osteoclast function and survival. The addition of mechanical perturbation to a particle-laden system thus appears to enhance the potential for osteolytic activity by enhancing osteoclast survival.     

Exercise improves biomarkers of health and stress in animals fed ad libitum

Voluntary and forced exercise decrease morbidity and mortality in laboratory animals. Caloric restriction has similar effects on health and unique benefits on life span. Nonetheless, in most experiments, animals do not have access to physical activity and are fed ad libitum (AL). We hypothesized that with regular access to either unlimited running wheel exercise (EX) or limited physical activity (PA), key biomarkers of health would be enhanced enough to counter some consequences of a sedentary AL lifestyle. This 16-month study compared body weight, tumor number and size, tissue lesions, oxidative stress, and reactive stress in (1) sedentary animals with no access to physical activity (SED); (2) animals with access to hour-long, twice weekly activity in a large box (PA); and (3) animals with access every other day to a running wheel (EX). At the end of the study, EX body weight was 8-9% lower than PA and SED. In addition, EX had no kidney lesions versus 50% in PA and SED, and had smaller tumor size (10+/-2 vs. 14+/-4 and 30+/-4 mm). Exhaustive exercise lowered glutathione/oxidized glutathione ratio in EX and PA, but in SED, the ratio was depressed even in resting animals. In all treatments, prolactin (PRL) levels were lower in resting animals than in acutely exercised animals. In conclusion, EX had the most favorable health biomarkers while SED had the least. PA did not confer gross health benefits different than the SED group, but was biochemically more similar to EX animals.     

Immunohistochemical Localization of p53 in Human Thyroid Neoplasms: Correlation with Biological Behavior

Molecular analyses of thyroid tumors have documented mutations in the tumor suppressor p53 gene almost exclusively in anaplastic carcinomas. In contrast, immunohistochemistry has localized p53 in differentiated papillary and follicular thyroid cancers. To establish the significance of p53 immunolocalization in these lesions, 78 thyroid tumors of follicular derivation were examined. All tumors were classified by strict criteria and the extent of tumor was determined morphologically. Immunohistochemical staining for p53 was performed on paraffin sections of formalin-fixed tumor tissue. The results of staining were correlated with diagnosis, tumor extent and clinical outcome. Immunopositivity for p53 was diffuse and strong in all five anaplastic carcinomas examined. There was no staining in five of six follicular adenomas. Four of nine follicular carcinomas had some degree of nuclear staining, but this was focal; all nine tumors were confined to the thyroid at the time of examination. Of 49 papillary carcinomas, 26 were intrathyroidal, and 7 of these were occult; there was no p53 positivity in any occult lesion and only 5 of the 19 palpable lesions stained. In contrast, among 23 papillary carcinomas with extrathyroidal extension or metastases, only 9 were negative for p53 immunoreactivity. Five of seven tall cell papillary carcinomas and one of two insular carcinomas had p53 immunopositivity and this correlated with aggressive behavior. These results support the tumorigenic role of p53 mutations postulated for anaplastic thyroid carcinomas and indicate that localization of p53 by immunohistochemistry is a useful prognostic index of clinical behavior in differentiated thyroid carcinomas of follicular cell derivation.     

Temporal encoding of two-dimensional patterns by single units in primate primary visual cortex. II. Information transmission

1. Previously, we studied how picture information was processed by neurons in inferior temporal cortex. We found that responses varying in both response strength and temporal waveform carried information about briefly flashed stationary black-and-white patterns. Now, we have applied that same paradigm to the study of striate cortical neurons. 2. In this approach the responses to a set of basic black and white pictures were quantified through use of a set of basic waveforms, the principal components (extracted from all the responses of each neuron). We found that the first principal component, which corresponds to the response strength, and others, which correspond to different basic temporal activity patterns, were significantly related to the stimuli, i.e., the stimulus drove both the response strength and its temporal pattern. 3. Our previous study had shown that, when information theory was used to quantify the stimulus-response relation, inferior temporal neurons convey over twice as much information in a response code that includes temporal modulation as in a response code that includes only the response strength. This study shows that striate cortical neurons also carry twice as much information in a temporal code as in a response strength code. Thus single visual neurons at both ends of a cortical processing chain for visual pattern use a multidimensional temporal code to carry stimulus-related information. 4. These results support our multiplex-filter hypothesis, which states that single visual system neurons can be regarded as several simultaneously active parallel channels, each of which conveys independent information about the stimulus.     

Cross-correlation of EMG reveals widespread synchronization of motor units during some slow movements in intact cats

It is commonly assumed that the motor units comprising a single mammalian muscle will be recruited asynchronously at subtetanic firing rates to produce smoothly modulated force output. However, electromyograms from certain neck muscles, recorded by implanted bipolar "patch" electrodes having large contacts, often exhibited a rhythmic clustering of spike activity whose patterns suggested that motor-unit firing was synchronized both within and across muscles. We have developed a computerized processing system that digitizes EMG activity and calculates auto- and cross-correlation products of selected segments. The presence or absence of synchronization caused by neural mechanisms can be identified and differentiated from that due to the rhythmicity of the behavior itself (e.g. shaking) or due to cross-talk, according to the shapes of the resultant correlograms. These methods have so far been applied to the study of hindlimb and neck muscle EMG during various natural motor behaviors, but they provide a general, quantitative tool for the study of an important aspect of motor control that may be overlooked by conventional sampling and smoothing techniques.     

The significance of incomplete excision in patients with basal cell carcinoma

Sixty-seven patients with incompletely excised basal cell carcinomas are reviewed. No recurrences were seen in seven patients who had immediate supplementary treatment; 23 of 60 patients submitted to a "wait and see" regimen developed recurrent disease, Recurrence was commoner in those in whom both the lateral and deep margins were involved, and when the incomplete excision was for recurrent disease. The latter recurrences were more difficult to control in patients who had previously had radiotherapy, when the deep margin was involved and when a flap had been used to close the resulting defect. A case is made for immediate re-excision for all patients with incompletely excised basal cell carcinomas.