The role of muscles in joint degeneration and osteoarthritis

The purpose of this work was to establish a controlled and reversible muscle weakness model for studying the effects of weakness on joint degeneration leading to osteoarthritis (OA). The knee extensor muscles of rabbits were injected with single or repeat doses of Botulinum type-A toxin (BTX-A) to partially inhibit acetylcholine (ACh) release at the neuromuscular junction. BTX-A-injected muscles atrophied, they became weaker and push-off forces during hopping were reduced compared to control. BTX-A injections had the greatest effect at short-muscle length and low-stimulation frequencies. Superimposing BTX-A injections on anterior cruciate ligament transection did not cause greater muscle atrophy or weakness than BTX-A injections alone. Monthly repeat injections could be used to keep muscles weak for half a year without any obvious adverse effects to the animals. Gross morphology of the knees and histology of articular cartilage suggested that, in some animals, 4 weeks of muscle weakness resulted in initial signs of joint degeneration, indicating that weakness may be an independent risk factor for joint degeneration leading to OA.     

Longevity of Breeding Sows in Relation to Leg Weakness Symptoms at Six Months of Age

The objective of this study was to evaluate the influence of leg weakness symptoms measured early in life (at 6 months of age) on the longevity of the sows, i.e. the age at culling due to locomotory problems in a Danish pig herd. One hundred and eighty-seven gilts at 6 months of age were selected according to different leg weakness symptoms and were followed until culling and judged for leg weakness once in every gestation using a scale from 1 (normal) to 4 (severe changes). Age at culling, and the main and secondary reasons for culling were recorded. The influence of leg weakness symptoms on longevity was evaluated by survival analysis. Though only 12% of the gilts showed a stiff locomotion half of the sows had suffered from this and nearly one third had been distinctly lame at some time in their life. Buck-kneed forelegs, upright pasterns, legs turned out, standing under position and swaying hindquarters were associated with stiff locomotion or lameness, whereas weak pasterns on hind legs and splayed digits on forelegs were associated with brisk movement (freedom from locomotor problems). The following leg weakness symptoms at the gilt stage were found to have significant negative effects on longevity: buck-kneed forelegs, swaying hindquarters, and standing under position on hind legs.     

Multiple viral determinants mediate myopathogenicity in coxsackievirus B1-induced chronic inflammatory myopathy

Mice infected with myopathic coxsackievirus B1 Tucson (CVB1(T)) develop chronic inflammatory myopathy (CIM) consisting of hind limb weakness and inflammation. Amyopathic virus variants are infectious but attenuated for CIM. In this report, viral clones, chimeras, and sequencing were used to identify viral determinants of CIM. Chimeras identified several regions involved in CIM and localized a weakness determinant to nucleotides 2493 to 3200 of VP1. Sequencing of multiple clones and viruses identified five candidate determinants that were strictly conserved in myopathic viruses with one located in the 5' untranslated region (UTR), three in the VP1 capsid, and one in the 3C protease. Taken together, these studies implicate Tyr-87 and/or Val-136 as candidate determinants of weakness. They also indicate that there are at least two determinants of inflammation and one additional determinant of weakness encoded by myopathic CVB1(T).     

Fine mapping and allelic dosage effect of <Emphasis Type="Italic">Hwc1</Emphasis>, a complementary hybrid weakness gene in rice

Hybrid weakness is a reproductive barrier that is found in many plant species. In rice, the hybrid weakness caused by two complementary genes, Hwc1 and Hwc2, has been surveyed intensively. However, their gene products and the molecular mechanism that causes hybrid weakness have remained unknown. We performed linkage analyses of Hwc1, narrowed down the area of interest to 60 kb, and identified eight candidate genes. In the F(2) population, in which both Hwc1 and Hwc2 genes were segregated, plants were separable into four classes according to their respective phenotypes: severe type, semi-severe type, F(1) type, and normal type. Severe type plants show such severe symptoms that they could produce only tiny shoot-like structures; they were unable to generate roots. Genetic analyses using closely linked DNA markers of the two genes showed that the symptoms of the F(2) plants were explainable by the genotypes of Hwc1 and Hwc2. Weakness was observed in plants that have both Hwc1 and Hwc2. In Hwc1 homozygote, the symptoms worsened and severe type or semi-severe type plants appeared. Consequently, Hwc1 should have a gene dosage effect and be a semi-dominant gene. The dosage effect of Hwc2 was recognizable, but it was not so severe as that in Hwc1. These results are useful to elucidate the mechanism that causes the hybrid weakness phenomenon and the role of each causal gene in hybrid weakness.     

Gluteus maximus and soleus compensate for simulated quadriceps atrophy and activation failure during walking

Important activities of daily living, like walking and stair climbing, may be impaired by muscle weakness. In particular, quadriceps weakness is common in populations such as those with knee osteoarthritis (OA) and following ACL injury and may be a result of muscle atrophy or reduced voluntary muscle activation. While weak quadriceps have been strongly correlated with functional limitations in these populations, the important cause–effect relationships between abnormal lower extremity muscle function and patient function remain unknown. As a first step towards determining those relationships, the purpose of this study was to estimate changes in muscle forces and contributions to support and progression to maintain normal gait in response to two sources of quadriceps weakness: atrophy and activation failure. We used muscle-driven simulations to track normal gait kinematics in healthy subjects and applied simulated quadriceps weakness as atrophy and activation failure to evaluate compensation patterns associated with the individual sources of weakness. We found that the gluteus maximus and soleus muscles display the greatest ability to compensate for simulated quadriceps weakness. Also, by simulating two different causes of muscle weakness, this model suggested different compensation strategies by the lower extremity musculature in response to atrophy and activation deficits. Estimating the compensation strategies that are necessary to maintain normal gait will enable investigations of the role of muscle weakness in abnormal gait and inform potential rehabilitation strategies to improve such conditions.     

Hypophosphatemia is responsible for skeletal muscle weakness of vitamin D deficiency

A deficiency of vitamin D results in muscle weakness as well as rickets in children and osteomalacia in the adult. To study the basis for this weakness, severe vitamin D deficiency was produced in rats as revealed by a low level or absence of 25-hydroxyvitamin D₃ in the serum. Vitamin D deficiency was achieved by feeding purified diets to weanlings for 16 weeks. Muscle force, peak contraction (P), time-to-half contraction (T_1/2), time-to-peak contraction (T_P), and time-to-half recovery (T_1/2r) were measured. A significant reduction in muscle force was found when vitamin D deficiency was accompanied by hypophosphatemia. Within 2 days of correcting the hypophosphatemia, muscle strength was normalized. When serum calcium and serum phosphorus were maintained in the normal range in vitamin D-deficient rats, muscle weakness did not develop. Further, hypocalcemia together with vitamin D deficiency did not produce muscle weakness. These results strongly suggest that muscle weakness noted in rachitic patients is the result of the hypophosphatemia of vitamin D deficiency.     

Side Effects of Hypotensive Agents Evaluated by a Self-administered Questionnaire

A self-administered symptom questionnaire was completed by 477 patients in a hypertension clinic. The complaints of the patients were analysed according to the type of therapy being given and the dose of drug taken. Methyldopa therapy was associated with sleepiness, weakness of the limbs, sleeping longer at night, and rising more frequently at night to pass urine. Diarrhoea, impotence, failure of ejaculation, blurred vision, depression, and the symptoms of postural hypotension were not related to methyldopa therapy. Bethanidine administration was related to postural hypotension, impotence, and failure of ejaculation but not to weakness of the limbs, blurred vision, depression, or diarrhoea. Patients receiving guanethidine complained of postural hypotension, failure of ejaculation, and had their bowels open more frequently. Similarly, patients receiving propranolol had an increased frequency of defaecation but also tended to complain of weakness of the limbs.Considering each drug individually, 5% of patients failed to take the prescribed dose of diuretic whereas     

Influence of weak hip abductor muscles on joint contact forces during normal walking: probabilistic modeling analysis

The weakness of hip abductor muscles is related to lower-limb joint osteoarthritis, and joint overloading may increase the risk for disease progression. The relationship between muscle strength, structural joint deterioration and joint loading makes the latter an important parameter in the study of onset and follow-up of the disease. Since the relationship between hip abductor weakness and joint loading still remains an open question, the purpose of this study was to adopt a probabilistic modeling approach to give insights into how the weakness of hip abductor muscles, in the extent to which normal gait could be unaltered, affects ipsilateral joint contact forces. A generic musculoskeletal model was scaled to each healthy subject included in the study, and the maximum force-generating capacity of each hip abductor muscle in the model was perturbed to evaluate how all physiologically possible configurations of hip abductor weakness affected the joint contact forces during walking. In general, the muscular system was able to compensate for abductor weakness. The reduced force-generating capacity of the abductor muscles affected joint contact forces to a mild extent, with 50th percentile mean differences up to 0.5 BW (maximum 1.7 BW). There were greater increases in the peak knee joint loads than in loads at the hip or ankle. Gluteus medius, particularly the anterior compartment, was the abductor muscle with the most influence on hip and knee loads. Further studies should assess if these increases in joint loading may affect initiation and progression of osteoarthritis.     

衰弱对老年急性冠脉综合征患者短期预后的影响

目的:探讨衰弱对老年急性冠脉综合征(ACS)患者短期预后的影响。方法:选择2015年8月1日至2015年12月31日在我院老年医学中心住院的181例ACS患者为研究对象。全面评估患者临床特征和合并症情况,采用国际老年营养学会提出的简易虚弱问卷(FRAIL)评估患者的衰弱情况,并根据评估结果将患者分为衰弱组(n=108)和非衰弱组(n=73)。采用门诊随访和电话随访的方式进行3个月随访,分析衰弱对ACS患者预后的影响。结果:共有181例患者纳入研究,随访率100%,其中衰弱患者108例(59.67%)。随访期两组患者再住院、全因死亡和再发急性心肌梗死等随访终点事件发生率比较,差异均有统计学意义(P0.05)。多因素Logistic回归分析结果提示衰弱是老年ACS患者短期再住院、全因死亡和再发急性心肌梗死的独立风险因素(OR=3.286,4.976,4.346;P=0.032,0.022,0.012)。结论:衰弱是老年ACS患者再住院、全因死亡和再发急性心肌梗死等短期预后的独立风险因素。     

Osteochondrosis / Osteoarthrosis and Claw Disorders in Sows,Associated with Leg Weakness

The objective of this study was to investigate the associations between different leg weakness symptoms and osteochondrosis/osteoarthrosis and claw disorders in sows together with the influence of age on these findings. One hundred and seventeen sows in one herd were followed from 6 months of age until culling and judged for leg weakness once in every gestation using a scale from 1 (normal) to 4 (severe changes). At slaughter changes in joints, growth plates and claws were scored on a scale from 1 (normal) to 5 (very severe changes). Osteoarthrotic changes were strongly associated with osteochondral changes in humeral and femoral condyles. The clinical signs of osteochondrosis and osteoarthrosis were found to be: buck-kneed forelegs, turn out of fore and hind legs, upright pasterns on hind legs, stiff locomotion, lameness and tendency to slip. The clinical signs of claw lesions were found to be: buck-kneed forelegs, upright pasterns, steep hock joints, turn out of hind legs, standing under position on hind legs, stiff movements, swaying hindquarters, goose-stepping hind legs, tendency to slip and lameness. Overgrown claws were strongly associated with leg weakness indicating the need for claw trimming in sow populations.     

Diaphragm single-fiber weakness and loss of myosin in congestive heart failure rats

Diaphragm weakness commonly occurs in patients with congestive heart failure (CHF) and is an independent predictor of mortality. However, the pathophysiology of diaphragm weakness is poorly understood. We hypothesized that CHF induces diaphragm weakness at the single-fiber level by decreasing myosin content. In addition, we hypothesized that myofibrillar Ca(2+) sensitivity is decreased and cross-bridge kinetics are slower in CHF diaphragm fibers. Finally, we hypothesized that loss of myosin in CHF diaphragm weakness is associated with increased proteolytic activities of caspase-3 and the proteasome. In skinned diaphragm single fibers of rats with CHF, induced by left coronary artery ligation, maximum force generation was reduced by approximately 35% (P < 0.01) compared with sham-operated animals for slow, 2a, and 2x fibers. In these CHF diaphragm fibers, myosin heavy chain content per half-sarcomere was concomitantly decreased (P < 0.01). Ca(2+) sensitivity of force generation and the rate constant of tension redevelopment were significantly reduced in CHF diaphragm fibers compared with sham-operated animals for all fiber types. The cleavage activity of the proteolytic enzyme caspase-3 and the proteasome were approximately 30% (P < 0.05) and approximately 60% (P < 0.05) higher, respectively, in diaphragm homogenates from CHF rats than from sham-operated rats. The present study demonstrates diaphragm weakness at the single-fiber level in a myocardial infarct model of CHF. The reduced maximal force generation can be explained by a loss of myosin content in all fiber types and is associated with activation of caspase-3 and the proteasome. Furthermore, CHF decreases myofibrillar Ca(2+) sensitivity and slows cross-bridge cycling kinetics in diaphragm fibers.     

Juvenile dermatomyositis: medical,social and economic status in adulthood.

Eighteen adults were studied an average of 18.5 years after the diagnosis of juvenile dermatomyositis had been made. Persistent weakness was found in six patients and recurrent rash in the classic distribution in seven. Other clinical features present were Raynaud''s phenomenon, arthritis and subcutaneous nodules. Minor increases in the serum creatine phosphokinase level were noted in seven patients and did not correlate with the presence of weakness or rash. Educational achievement and employment status were better in this group than in a group of adults with juvenile rheumatoid arthritis or the general adult population of British Columbia. Significant residual disability related to calcinosis and flexion contractures was present in only three of the patients.     

Anti-C5 antibody treatment ameliorates weakness in experimentally acquired myasthenia gravis

Myasthenia gravis (MG) is a neuromuscular transmission disorder in which damage to acetylcholine receptors (AChR) on motor endplates by autoantibody-induced complement attack causes muscle weakness. To determine whether and, if so, to what extent, blockade of complement cascade at the C5 step ameliorates disease, we evaluated the effect of administering a functionally blocking anti-C5 mAb in passive experimental MG in Lewis rats induced with AChR Ab McAb-3. In contrast to uniform severe weakness at 24 h requiring euthanasia in untreated animals, anti-C5 mAb-pretreated rats showed no weakness at 48 h. Anti-C5 mAb treatment 24 h after disease induction restored strength in two-thirds of the rats. Immunofluorescence staining of endplates from the treated animals showed that C9 deposition at AChR was reduced and ultrastructural analyses showed that endplates were intact. The results argue that targeting C5 may warrant testing in MG patients and that this approach may be particularly valuable for myasthenic crisis.     

Biomechanical consequences of running with deep core muscle weakness

The deep core muscles are often neglected or improperly trained in athletes. Improper function of this musculature may lead to abnormal spinal loading, muscle strain, or injury to spinal structures, all of which have been associated with increased low back pain (LBP) risk. The purpose of this study was to identify potential strategies used to compensate for weakness of the deep core musculature during running and to identify accompanying changes in compressive and shear spinal loads. Kinematically-driven simulations of overground running were created for eight healthy young adults in OpenSim at increasing levels of deep core muscle weakness. The deep core muscles (multifidus, quadratus lumborum, psoas, and deep fascicles of the erector spinae) were weakened individually and together. The superficial longissimus thoracis was a significant compensator for 4 out of 5 weakness conditions (p < 0.05). The deep erector spinae required the largest compensations when weakened individually (up to a 45 ± 10% increase in compensating muscle force production, p = 0.004), revealing it may contribute most to controlling running kinematics. With complete deep core muscle weakness, peak anterior shear loading increased on all lumbar vertebrae (up to 19%, p = 0.001). Additionally, compressive spinal loading increased on the upper lumbar vertebrae (up to 15%, p = 0.007) and decreased on the lower lumbar vertebrae (up to 8%, p = 0.008). Muscular compensations may increase risk of muscular fatigue or injury and increased spinal loading over numerous gait cycles may result in damage to spinal structures. Therefore, insufficient strength of the deep core musculature may increase a runner’s risk of developing LBP.     

Biochemical studies on monoamine contents in spinal cord of patients with multiple system atrophy

Monoamine contents were measured in the cervical spinal cord of patients with multiple system atrophy (MSA) by high-performance liquid chromatography with electrochemical detection. The concentrations of noradrenaline (NA) and its metabolite 4-methyl-4-hydroxyphenylglycol (MHPG) were highest in ventral horn compared with other regions of the spinal cord in controls. Both NA and MHPG contents were reduced in all regions in 4 MSA patients. But in one case (case 5), which did not show an autonomic dysfunction, NA as well as MHPG level was similar to controls. Similarly, the concentrations of 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were highest in ventral horn and reduced in all regions in 4 MSA patients who showed mild motor weakness. In one case (case 5), which revealed clinical motor weakness associated with fasciculation and areflexia and pathological degeneration of ventral horn, 5-HT content showed higher values than controls whereas the 5-HIAA level was lower than controls. These results probably indicate that the cell loss of supraspinal monoaminergic nuclei may be one of the causes responsible for neurological dysfunction such as autonomic failures and motor weakness in MSA.     

Vitamin C deficiency in captive nonhuman primates fed commercial primate diet

Scurvy was diagnosed in 19 rhesus monkeys (Macaca mulatta) and four squirrel monkeys (Saimiri sciureus) from a colony of nonhuman primates maintained on a commercial diet. Signs of weakness, reluctance to move, gingival hemorrhage, bruising, proximal and distal metaphyseal fractures, weight loss and anemia appeared in juvenile and young adult rhesus monkeys over a 2 week period. Clinical signs subsided after 5 days of vitamin C therapy. At the same time, cephalohematomas and weakness developed in squirrel monkeys, which failed to respond to treatment. These cases were associated with manufacturer's admitted error in preparation of the commercially prepared monkey diet.     

A Novel Syndrome of Episodic Muscle Weakness Maps to Xp22.3

We describe a family with a novel disorder characterized by episodic muscle weakness and X-linked inheritance. Eight males in three generations demonstrate the characteristic features of the disorder. Episodes of severe muscle weakness are typically precipitated by febrile illness and affect the facial and extraocular musculature, as well as the trunk and limbs, and resolve spontaneously over a period of weeks to months. Younger members of the family are normal between episodes but during relapses show generalized weakness, ptosis, and fluctuations in strength. In some cases, fatigability can be demonstrated. The proband has late-onset chronic weakness and fatigability. The clinical phenotype has features suggestive both of the congenital myasthenic syndromes and of ion-channel disorders such as the periodic paralyses. We have localized the responsible gene to chromosome Xp22.3, with a maximum two-point LOD score of 4. 52 at a recombination fraction of.0, between OACA2 and DXS9985.     

The skeletal muscle phenotype of children with Neurofibromatosis Type 1 – A clinical perspective

Neurofibromatosis type 1 (NF1) can affect multiple systems in the body. An under recognised phenotype is one of muscle weakness. Clinical studies using dynamometry and jumping mechanography have demonstrated that children with NF1 are more likely to have reduced muscle force and power. Many children with NF1 are unable to undertake physical activities to the same level as their peers, and report leg pains on physical activity and aching hands on writing. Children and adolescents with NF1 reporting symptoms of muscle weakness should have a focused assessment to exclude alternative causes of muscle weakness. Assessments of muscle strength and fine motor skills by physiotherapists and occupational therapists can provide objective evidence of muscle function and deficits, allowing supporting systems in education and at home to be implemented. In the absence of an evidence base for management of NF1-related muscle weakness, we recommend muscle-strengthening exercises and generic strategies for pain and fatigue management. Currently, trials are underway involving whole-body vibration therapy and carnitine supplementation as potential future management options.     

Regulatory and adaptive capacities of children with different temperaments afflicted with a functional weakness of the sinus node

One hundred and twenty children with sinus node weakness were examined. The presence of functional pathology was diagnosed in most children using the cardiorespiratory synchronism test. It was also found that, in children with the sinus node weakness syndrome, their regulatory and adaptive capacities depended on their temperamental type and, hence, were predetermined genetically. This manifests itself in different degrees of weakening of the central link of the heart rhythmogenesis in the hierarchical system of the formation of the heart rhythm in the whole body, which determines the changes in the synchronization parameters when the cardiorespiratory synchronism test is performed in these patients.     

Neurotoxicity in Snakebite—The Limits of Our Knowledge

Snakebite is classified by the WHO as a neglected tropical disease. Envenoming is a significant public health problem in tropical and subtropical regions. Neurotoxicity is a key feature of some envenomings, and there are many unanswered questions regarding this manifestation. Acute neuromuscular weakness with respiratory involvement is the most clinically important neurotoxic effect. Data is limited on the many other acute neurotoxic manifestations, and especially delayed neurotoxicity. Symptom evolution and recovery, patterns of weakness, respiratory involvement, and response to antivenom and acetyl cholinesterase inhibitors are variable, and seem to depend on the snake species, type of neurotoxicity, and geographical variations. Recent data have challenged the traditional concepts of neurotoxicity in snake envenoming, and highlight the rich diversity of snake neurotoxins. A uniform system of classification of the pattern of neuromuscular weakness and models for predicting type of toxicity and development of respiratory weakness are still lacking, and would greatly aid clinical decision making and future research. This review attempts to update the reader on the current state of knowledge regarding this important issue.