Hoffman's syndrome: muscle stiffness,pseudohypertrophy and hypothyroidism

Primary hypothyroidism is a chronic and insidious disease caused by failure of thyroid hormone production. We observed a 38-year-old woman admitted to our hospital due to progressive proximal weakness, muscle pain and fatigue during mild exercise. Laboratory tests showed features of rhabdomyolysis and hypothyroidism. After examination of the thyroid, we reached a diagnosis of Hashimoto's thyroiditis and hypothyroid myopathy. Hypothyroidism should be considered as a differential diagnosis of creatine kinase elevation; actually, neuromuscular symptoms and signs occur in most newly diagnosed patients with thyroid diseases. Hypothyroidism presenting as muscle stiffness and pseudohypertrophy is called 'Hoffman's syndrome'.     

Structure-guided residence time optimization of a dabigatran reversal agent

Novel oral anticoagulants are effective and safe alternatives to vitamin-K antagonists for anticoagulation therapy. However, anticoagulation therapy in general is associated with an elevated risk of bleeding. Idarucizumab is a reversal agent for the direct thrombin inhibitor, dabigatran etexilate (Pradaxa®) and is currently in Phase 3 studies. Here, we report data on the antibody fragment aDabi-Fab2, a putative backup molecule for idarucizumab. Although aDabi-Fab2 completely reversed effects of dabigatran in a rat model in vivo, we observed significantly reduced duration of action compared to idarucizumab. Rational protein engineering, based on the X-ray structure of aDabi-Fab2, led to the identification of mutant Y103W. The mutant had optimized shape complementarity to dabigatran while maintaining an energetically favored hydrogen bond. It displayed increased affinity for dabigatran, mainly driven by a slower off-rate. Interestingly, the increased residence time translated into longer duration of action in vivo. It was thus possible to further enhance the efficacy of aDabi-Fab2 based on rational design, giving it the potential to serve as a back-up candidate for idarucizumab.     

Donor-site morbidity of the pedicled rectus femoris muscle flap

The rectus femoris muscle flap is well known for its reliable anatomy, the ease with which it can be harvested, and its great versatility. As a pedicled or free flap, it is used to cover soft-tissue defects and to recreate motor function. Although the muscle is very reliable, it is not well respected because of its assumed donor-site morbidity, such as weakened knee extension force and decreased range of motion of the knee. To date, these clinical assumptions have only rarely been quantified in terms of objective scores, concerning force deficit and functional or aesthetic outcome. From 1995 to 2002, the authors treated 24 patients with pedicled rectus femoris muscle flaps. Fourteen patients were followed up. Follow-up time ranged from 3 to 56 months postoperatively. The results were evaluated by a standard questionnaire in which pain in relation to walking distance, subjective feeling of weakness, sensibility disorders, everyday function, and aesthetic aspects were assessed. Range of motion in the hip and the knee was measured. For objective verification of a decrease of maximal voluntary contraction force of the remaining quadriceps muscle and for detecting differences in true muscular capacity and voluntary activation, 10 patients with unilateral rectus femoris flaps were tested using the twitch interpolation technique. The authors' patients assessed the remaining function and the aesthetic result of the thigh as at least satisfactory. Two patients complained about pain and weakness in the thigh. Eight patients reported hypesthesia in the lateral suprapatellar region. The maximal voluntary contraction and true muscular capacity values were reduced by 21.8 percent and 18 percent, respectively, when compared with the healthy leg. The range of motion in the knee and hip was not influenced by muscle harvesting. The twitch interpolation technique revealed a mild voluntary activation deficit, probably caused by inhibitory regulation in the spinal cord. In conclusion, donor-site morbidity of the rectus femoris muscle flap is evident but well compensated. There is no decrease in active range of motion in the knee and hip. Patient satisfaction with the functional and aesthetic outcome was high.     

Electromuscular Incapacitation Current Induced Neuromuscular Tissue Injury

Electrical stun devices (ESDs) serve a basic role in law enforcement and provide an alternative to lethal options for target control by causing electromuscular incapacitation (EMI). A fundamental concern is the adverse health consequences associated with their use. The capability of EMI electric field pulses to disrupt skeletal muscle cells (i.e. rhabdomyolysis) was investigated over the operational range commonly used in commercial EMI devices. Functional and structural alteration and recovery of muscle and nerve tissue were assessed. In an anesthetized swine model, the left thigh was exposed to 2 min of electrical pulses, using a commercially available ESD or a custom-made EMI signal power amplifier. Serum creatinine phosphokinase (CPK), troponin, aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) levels were monitored intermittently for 6 h post-EMI exposure. A standard external cardiac defibrillator served as a positive control. Muscle and nerve tissue histology adjacent to the EMI contacts were examined. Post-EMI shock skeletal muscle function was evaluated by analyzing the compound muscle action potentials (CMAPs) of the rectus femoris muscle. Maximal energy cardiac defibrillator pulses resulted in rhabdomyolysis and marked elevation of CPK, LDH, and AST 6 h post-shock. EMI field pulses resulted in the animals developing transient acidosis. CMAP amplitudes decreased approximately 50% after EMI and recovered to near-normal levels within 6 h. Within 6 h post-EMI exposure, blood CPK was mildly increased, LDH was normal, and no arrhythmia was observed. Minimal rhabdomyolysis was produced by the EMI pulses. These results suggest that EMI exposure is unlikely to cause extremity rhabdomyolysis in normal individuals. Bioelectromagnetics. © 2020 Bioelectromagnetics Society     

Rhabdomyolysis after Withdrawal of Thyroid Hormone in a Patient with Papillary Thyroid Cancer

ObjectiveTo report a case of rhabdomyolysis presenting with severe hyperkalemia after withdrawal of thyroid hormone in a patient with differentiated thyroid cancer.MethodsWe describe the clinical and laboratory findings of the study patient and review the relevant literature.ResultsA 54-year-old man with progressive generalized weakness and myalgias presented with acute renal failure and hyperkalemia. He had undergone total thyroidectomy for papillary thyroid cancer 6 weeks earlier and had discontinued thyroid hormone 2 weeks before his current presentation in preparation for thyroid remnant ablation. He had a history of multiple colon and small-bowel resections for familial adenomatous polyposis and desmoid tumor. He was severely dehydrated on examination. Laboratory tests results included the following values: creatine phosphokinase, 5265 U/L (reference range, 52-336 U/L); creatinine, 2.1 mg/dL; potassium, > 8.0 mEq/L; and thyrotropin, 92.2 mIU/L. His condition was diagnosed as rhabdomyolysis, and his fluid deficit and hyperkalemia were treated aggressively. Cardiac status remained stable, and both acute renal failure and hyperkalemia improved. He then received remnant ablation, and thyroid hormone was restarted. His muscle complaints resolved over the following 3 months.ConclusionsHypothyroidism-induced rhabdomyolysis can occur during thyroid hormone withdrawal and can present with life-threatening hyperkalemia. Patients undergoing thyroid hormone withdrawal should be assessed for risk of rhabdomyolysis, and preventive strategies should be implemented, including prevention of dehydration.The use of recombinant thyrotropin, rather than thyroid hormone withdrawal, should be considered in those who are at high risk for such complications. (Endocr Pract. 2008;14:1023-1026)     

Acute Rhabdomyolysis (“Tying-Up”) in Standardbred Horses

LINDHOLM, A., H.-E. JOHANSSON & P. KJÆRSGAARD: Acute rhabdomyolysis (“tying-up”) in standardbred horses. A morphological and biochemical study. Acta vet. scand. 1974, 15, 325–339. — Morphological, biochemical and histochemical changes were studied in muscle needle biopsy specimens (gluteus medius) from 59 standardbred trotters with acute clinical symptoms of the “tying-up” disease. All horses had increased levels of serum enzymes SGOT and SCPK. The biopsy specimens were taken at various intervals after onset of clinical symptoms (1–4 hrs., 18–24 hrs. and 2–20 days). Ry light microscopy it was shown that the muscular alterations had a focal distribution and were of the hyalin degeneration type with insignificant inflammatory reaction and slight calcification. The ultrastructural changes apparently commenced with myofibrillar waving, mitochondrial and sarcotubular alterations and terminated with myofibrillar degeneration and necrosis with invasion of inflammatory cells. The inflammatory cells were ultrastructurally similar to monocytes and macrophages. The degenerative changes mainly comprised fast twitch (FT and FTH) fibres as histochemically evidenced by myofibrillar ATPase and alkaline phosphatase staining. Riopsies from diseased muscle 1–4 hrs. after the onset of “tyingup” contained a low muscle concentration of glycogen, ATP and CP and a high concentration of lactate and glucose. Hence it is suggested that the described muscular alterations may be caused by a deranged carbohydrate metabolism caused by a local hypoxia. It was found that the “tying-up” disease resembled idiopathic rhabdomyolysis in man and was thus designated “equine rhabdomyolysis”. histochemistry; horse; rhabdomyolysis; skeletal muscle; “tying-up”; ultrastructure.     

Piriform Syndrome

Among a variety of deep muscle trigger points, the piriform muscle trigger point is selected for individual scrutiny. This seems fully justified by the great potential for confusing this entity with discogenic disease and consequently having unnecessary surgical procedures carried out.The diagnosis can be made from findings on simple physical diagnostic tests and an appropriate history. Low back and hip pain with pain radiating down the back of the leg should suggest piriform syndrome as part of the differential diagnosis. This is especially true if a female patient has complaint of dyspareunia.Pain and weakness on resisted abduction-external rotation of the thigh is a sign of piriform syndrome. This is confirmed by tenderness and reproduction of the patient''s complaints by digital pressure over the belly of the piriform muscle, completing the diagnostic criteria.Local injection of the muscle belly is curative. There are no laboratory or x-ray findings leading to a diagnosis.     

Dabigatran ameliorates airway smooth muscle remodeling in asthma by modulating Yes‐associated protein

Accumulating evidence indicates that thrombin, the major effector of the coagulation cascade, plays an important role in the pathogenesis of asthma. Interestingly, dabigatran, a drug used in clinical anticoagulation, directly inhibits thrombin activity. The aim of this study was to investigate the effects and mechanisms of dabigatran on airway smooth muscle remodeling in vivo and in vitro. Here, we found that dabigatran attenuated inflammatory pathology, mucus production, and collagen deposition in the lungs of asthmatic mice. Additionally, dabigatran suppressed Yes‐associated protein (YAP) activation in airway smooth muscle of asthmatic mice. In human airway smooth muscle cells (HASMCs), dabigatran not only alleviated thrombin‐induced proliferation, migration and up‐regulation of collagen I, α‐SMA, CTGF and cyclin D1, but also inhibited thrombin‐induced YAP activation, while YAP activation mediated thrombin‐induced HASMCs remodeling. Mechanistically, thrombin promoted actin stress fibre polymerization through the PAR1/RhoA/ROCK/MLC2 axis to activate YAP and then interacted with SMAD2 in the nucleus to induce downstream target genes, ultimately aggravating HASMCs remodeling. Our study provides experimental evidence that dabigatran ameliorates airway smooth muscle remodeling in asthma by inhibiting YAP signalling, and dabigatran may have therapeutic potential for the treatment of asthma.     

Treatment of ischial pressure ulcers with a posteromedial thigh fasciocutaneous flap.

This study describes the use of the posteromedial thigh fasciocutaneous flap for the treatment of ischial pressure sores. The authors prefer this flap because it is the fasciocutaneous flap nearest to the ischial region, it is easy to raise, and it causes no donor-site morbidity. In this study, 11 ischial pressure sores in 10 paraplegic patients were closed using the posteromedial thigh fasciocutaneous flaps. All flaps survived, although two caused distal necrosis; after these same two flaps were readvanced, they survived. After an average follow-up time of 77 months, seven of the 10 patients have had no recurrence of ulcers.This fasciocutaneous flap was previously described by Wang et al. However, this study revealed that the arrangement of the vascular pedicle was different from that described by Wang et al. To reveal the vascular supply of this flap, anatomic dissections were conducted. The source of circulation to this flap was the suprafascial vascular plexus, in addition to the musculocutaneous perforator. The dominant pedicle was the musculocutaneous perforator from either the adductor magnus muscle or the gracilis muscle. The key to safe elevation of this flap was the accurate outlining of the skin island directly over the vascular pedicle and the preservation of the proximal fascial continuity. Of the 11 flaps, two viability problems occurred. These partial flap losses resulted from the failure to properly include the perforator. It is the authors' conclusion that the width of the flap should be greater than 5 cm. In addition, it is safe to make a flap within a 1:3 base-to-length ratio in a fatty, diabetic patient. This posteromedial thigh fasciocutaneous flap was found to be a valuable alternative for reconstruction of primary or recurrent ischial pressure ulcers.     

Therapeutic Effects of Procainamide on Endotoxin-Induced Rhabdomyolysis in Rats

Overt systemic inflammatory response is a predisposing mechanism for infection-induced skeletal muscle damage and rhabdomyolysis. Aberrant DNA methylation plays a crucial role in the pathophysiology of excessive inflammatory response. The antiarrhythmic drug procainamide is a non-nucleoside inhibitor of DNA methyltransferase 1 (DNMT1) used to alleviate DNA hypermethylation. Therefore, we evaluated the effects of procainamide on the syndromes and complications of rhabdomyolysis rats induced by lipopolysaccharide (LPS). Rhabdomyolysis animal model was established by intravenous infusion of LPS (5 mg/kg) accompanied by procainamide therapy (50 mg/kg). During the experimental period, the changes of hemodynamics, muscle injury index, kidney function, blood gas, blood electrolytes, blood glucose, and plasma interleukin-6 (IL-6) levels were examined. Kidneys and lungs were exercised to analyze superoxide production, neutrophil infiltration, and DNMTs expression. The rats in this model showed similar clinical syndromes and complications of rhabdomyolysis including high levels of plasma creatine kinase, acute kidney injury, hyperkalemia, hypocalcemia, metabolic acidosis, hypotension, tachycardia, and hypoglycemia. The increases of lung DNMT1 expression and plasma IL-6 concentration were also observed in rhabdomyolysis animals induced by LPS. Treatment with procainamide not only inhibited the overexpression of DNMT1 but also diminished the overproduction of IL-6 in rhabdomyolysis rats. In addition, procainamide improved muscle damage, renal dysfunction, electrolytes disturbance, metabolic acidosis, hypotension, and hypoglycemia in the rats with rhabdomyolysis. Moreover, another DNMT inhibitor hydralazine mitigated hypoglycemia, muscle damage, and renal dysfunction in rhabdomyolysis rats. These findings reveal that therapeutic effects of procainamide could be based on the suppression of DNMT1 and pro-inflammatory cytokine in endotoxin-induced rhabdomyolysis.     

Slow inactivation differs among mutant Na channels associated with myotonia and periodic paralysis.

Several heritable forms of myotonia and hyperkalemic periodic paralysis (HyperPP) are caused by missense mutations in the alpha subunit of the skeletal muscle Na channel (SkM1). These mutations impair fast inactivation or shift activation toward hyperpolarized potentials, inducing persistent Na currents that may cause muscle depolarization, myotonia, and onset of weakness. It has been proposed that the aberrant Na current and resulting weakness will be sustained only if Na channel slow inactivation is also impaired. We therefore measured slow inactivation for wild-type and five mutant Na channels constructed in the rat skeletal muscle isoform (rSkM1) and expressed in HEK cells. Two common HyperPP mutations (T698M in domain II-S5 and M1585V in IV-S6) had defective slow inactivation. This defect reduced use-dependent inhibition of Na currents elicited during 50-Hz stimulation. A rare HyperPP mutation (M1353V in IV-S1) and mutations within the domain III-IV linker that cause myotonia (G1299E) or myotonia plus weakness (T1306M) did not impair slow inactivation. We also observed that slow inactivation of wild-type rSkM1 was incomplete; therefore it is possible that stable membrane depolarization and subsequent muscle weakness may be caused solely by defects in fast inactivation or activation. Model simulations showed that abnormal slow inactivation, although not required for expression of a paralytic phenotype, may accentuate muscle membrane depolarization, paralysis, and sensitivity to hyperkalemia.     

Review of exertional rhabdomyolysis and a case in a rhesus monkey (Macaca mulatta)

This is the first confirmed report of exertional rhabdomyolysis in a non-human primate. The monkey was singly housed and presented with anorexia and reluctance to move. There was no external evidence of trauma. Clinicopathologic findings included mild azotemia, marked elevation in serum creatine phosphokinase (CPK), alanine aminotransferase, aspartate aminotransferase, and myoglobinuria. Two days post-incident, the peripheral skeletal muscle had marked multifocal myonecrosis and fibrillar disruption without an inflammatory reaction. Treatment included diuresis and pain relief, and urinary output was monitored. The monkey recovered over the next two weeks. The major significance of skeletal muscle damage is the potential of released myoglobin to cause acute renal failure in the presence of other co-factors such as hypovolemia, acidosis, or ischemia. CPK levels can be highly variable and are inconsistent with the degree of muscle damage; however, CPK is thought to be the most sensitive enzyme marker for muscle necrosis. Because of the potential life-threatening sequelae, exertional rhabdomyolysis should be included as a differential diagnosis when similar clinical and pathological signs are observed.     

Free anterolateral thigh flap for extremity reconstruction: clinical experience and functional assessment of donor site

From August of 1995 through July of 1998, 38 free anterolateral thigh flaps were transferred to reconstruct soft-tissue defects. The overall success rate was 97 percent. Among 38 anterolateral thigh flaps, four were elevated as cutaneous flaps based on the septocutaneous perforators. The other 34 were harvested as myocutaneous flaps including a cuff of vastus lateralis muscle (15 to 40 cm3), either because of bulk requirements (33 cases) or because of the absence of a septocutaneous perforator (one case). However, vastus lateralis muscle is the largest compartment of the quadriceps, which is the prime extensor of the knee. Losing a portion of the vastus lateralis muscle may affect knee stability. Objective functional assessments of the donor sites were performed at least 6 months postoperatively in 20 patients who had a cuff of vastus lateralis muscle incorporated as part of the myocutaneous flap; assessments were made using a kinetic communicator machine. The isometric power test of the ratios of quadriceps muscle at 30 and 60 degrees of flexion between donor and normal thighs revealed no significant difference (p > 0.05). The isokinetic peak torque ratio of the quadriceps and hamstring muscles, including concentric and eccentric contraction tests, showed no significant difference (p > 0.05), except the concentric contraction test of the quadriceps muscle, which revealed mild weakness of the donor thigh (p < 0.05). In summary, the functional impairment of the donor thighs was minimal after free anterolateral thigh myocutaneous flap transfer.     

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.     

Muscle weakness and atrophy-clinical and laboratory evaluation

A thorough family history, the age at the time of onset and detailed information regarding the rate, mode of progression and distribution of weakness is needed for evaluation of patients with weakness and atrophy. Associated findings such as dermal lesions, tenderness, myotonia and fasciculations should also be noted.The major diagnostically useful laboratory tests are electromyography, nerve conduction, serum enzyme levels and muscle biopsy.Each clinical and laboratory finding should be categorized in terms of its neuro-anatomical origin, since weakness may result from disturbances in the corticospinal pathways, the lower motor neuron, the myoneural junction and the muscle.     

Muscle Weakness and Atrophy—Clinical and Laboratory Evaluation

A thorough family history, the age at the time of onset and detailed information regarding the rate, mode of progression and distribution of weakness is needed for evaluation of patients with weakness and atrophy. Associated findings such as dermal lesions, tenderness, myotonia and fasciculations should also be noted.The major diagnostically useful laboratory tests are electromyography, nerve conduction, serum enzyme levels and muscle biopsy.Each clinical and laboratory finding should be categorized in terms of its neuro-anatomical origin, since weakness may result from disturbances in the corticospinal pathways, the lower motor neuron, the myoneural junction and the muscle.     

Estimation of the forces generated by the thigh muscles for transtibial amputee gait

The forces generated by the muscles with origin on the human femur play a major role in transtibial amputee gait, as they are the most effective of the means that the body can use for propulsion. By estimating the forces generated by the thigh muscles of transtibial amputees, and comparing them to the forces generated by the thigh muscles of normal subjects, it is possible to better estimate the energy output needed from prosthetic devices. The purpose of this paper is to obtain the forces generated by the thigh muscles of transtibial amputees and compare these with forces obtained from the same muscles in the case of normal subjects. Two transtibial amputees and four normal subjects similar in size to the amputees were investigated. Level ground walking was chosen as the movement to be studied, since it is a common activity that most amputees engage in. Inverse dynamics and a muscle recruitment algorithm (developed by AnyBody Technology^®) were used for generating the muscle activation patterns and for computing the muscle forces. The muscle forces were estimated as two sums: one for all posterior muscles and one for the anterior muscles, based on the position of the muscles of the thigh relative to the frontal plane of the human body. The results showed that a significantly higher force is generated by the posterior muscles of the amputees during walking, leading to a general increase of the metabolic cost necessary for one step.     

The expansive gluteus maximus flap

The rich vascular network of the gluteal and posterior thigh region provides for a larger range of flaps for reconstructive surgery than previously described. Facility with these flaps requires an appreciation of relevant anatomy, embryology, and anthropology. Structural changes in the gluteus maximus muscle are critical to the evolutionary advance toward an upright stance during walking. The superficial and deep segmentation of the gluteus maximus are best appreciated by phylogenic and ontogenetic study. Femoral arterial and gluteal arterial anastomotic hemodynamics are affected by the relative involution of the gluteal system in late embryogenesis. The gluteal thigh flap should include contributions from the femoral system when the cutaneous branch of the inferior gluteal artery cannot be identified. Huge sacral wounds can be closed with gluteus maximus myocutaneous flaps with maintenance of muscular function by detaching the entire origin, sliding the muscle medially, and reconstructing these attachments. By dissection between the divergent inserting fibers of the gluteus maximus, a long, superficial portion of the muscle can be raised that forms the basis of the extended gluteus maximus flap. The pedicle of the flap is at the level of the piriformis muscle and the skin paddle can be placed over the midportion of the posterior thigh. Finally, the first deep femoral perforating artery forms the basis of a posterolateral fasciae latae flap that is well suited for coverage of defects over the trochanter.     

Abnormal actin binding of aberrant β-tropomyosins is a molecular cause of muscle weakness in TPM2-related nemaline and cap myopathy

NM (nemaline myopathy) is a rare genetic muscle disorder defined on the basis of muscle weakness and the presence of structural abnormalities in the muscle fibres, i.e. nemaline bodies. The related disorder cap myopathy is defined by cap-like structures located peripherally in the muscle fibres. Both disorders may be caused by mutations in the TPM2 gene encoding β-Tm (tropomyosin). Tm controls muscle contraction by inhibiting actin-myosin interaction in a calcium-sensitive manner. In the present study, we have investigated the pathogenetic mechanisms underlying five disease-causing mutations in Tm. We show that four of the mutations cause changes in affinity for actin, which may cause muscle weakness in these patients, whereas two show defective Ca2+ activation of contractility. We have also mapped the amino acids altered by the mutation to regions important for actin binding and note that two of the mutations cause altered protein conformation, which could account for impaired actin affinity.