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PubMedDate not supplied

Physiotherapy treatment of sexual pain disorders.

Physiotherapists provide treatment to restore function, improve mobility, relieve pain, and prevent or limit permanent physical disabilities of patients suffering from injuries or disease. Women with vulvar pain, dyspareunia, or vaginismus have limited ability to function sexually and often present with musculoskeletal and neurological findings appropriately addressed by a trained physiotherapist. Although pelvic floor surface electromyography (sEMG) biofeedback has been studied, the inclusion of physiotherapy in the team approach to treating women with sexual pain disorders is a relatively recent advancement, and its exact role is not widely understood by doctors, mental health professionals, or laypersons. This article will examine the supportive and often primary role of the physiotherapist in the overlapping conditions of vaginismus and dyspareunia.

Biofeedback, Psychology↗
PubMed2002

Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice.

Familial hypertrophic cardiomyopathy (FHC) is an inherited autosomal dominant disease caused by mutations in sarcomeric proteins. Among these, mutations that affect myosin binding protein-C (MyBP-C), an abundant component of the thick filaments, account for 20% to 30% of all mutations linked to FHC. However, the mechanisms by which MyBP-C mutations cause disease and the function of MyBP-C are not well understood. Therefore, to assess deficits due to elimination of MyBP-C, we used gene targeting to produce a knockout mouse that lacks MyBP-C in the heart. Knockout mice were produced by deletion of exons 3 to 10 from the endogenous cardiac (c) MyBP-C gene in murine embryonic stem (ES) cells and subsequent breeding of chimeric founder mice to obtain mice heterozygous (+/-) and homozygous (-/-) for the knockout allele. Wild-type (+/+), cMyBP-C(+/-), and cMyBP-C(-/-) mice were born in accordance with Mendelian inheritance ratios, survived into adulthood, and were fertile. Western blot analyses confirmed that cMyBP-C was absent in hearts of homozygous knockout mice. Whereas cMyBP-C(+/-) mice were indistinguishable from wild-type littermates, cMyBP-C(-/-) mice exhibited significant cardiac hypertrophy. Cardiac function, assessed using 2-dimensionally guided M-mode echocardiography, showed significantly depressed indices of diastolic and systolic function only in cMyBP-C(-/-) mice. Ca2+ sensitivity of tension, measured in single skinned myocytes, was reduced in cMyBP-C(-/-) but not cMyBP-C(+/-) mice. These results establish that cMyBP-C is not essential for cardiac development but that the absence of cMyBP-C results in profound cardiac hypertrophy and impaired contractile function.

Actin Cytoskeleton↗
PubMed2005

Drug-associated mitochondrial toxicity and its detection.

Mitochondrial dysfunction is a fundamental mechanism in the pathogenesis of several significant toxicities in mammals, especially those associated with the liver, skeletal and cardiac muscle, and the central nervous system. These changes can also occur as part of the natural aging process and have been linked to cellular mechanisms in several human disease states including Parkinson's and Alzheimer's, as well as ischemic perfusion injury and the effects of hyperglycemia in diabetes mellitus. Our knowledge of the effects of xenobiotics on mitochondrial function has expanded to the point that chemical structure and properties can guide the pharmaceutical scientist in anticipating mitochondrial toxicity. Recognition that maintenance of the mitochondrial membrane potential is essential for normal mitochondrial function has resulted in the development of predictive cell-based or isolated mitochondrial assay systems for detecting these effects with new chemical entities. The homeostatic role of some uncoupling proteins, differences in mitochondrial sensitivity to toxicity, and the pivotal role of mitochondrial permeability transition (MPT) as the determinant of apoptotic cell death are factors that underlie the adverse effects of some drugs in mammalian systems. In order to preserve mitochondrial integrity in potential target organs during therapeutic regimens, a basic understanding of mitochondrial function and its monitoring in the drug development program are essential. Toward this end, this review focuses on two topics, (1) the specific effects of xenobiotics on mitochondrial structure and function and (2) a summarization of current methods for quantifying these changes in a preclinical toxicology laboratory.

Animals↗
PubMed1998

[Analgetic treatment and rehabilitation in osteoporosis].

Osteoporosis seems to be a component of body aging process. Through the years, muscles, ligaments, and fasciae loose their natural elasticity; degenerative changes form in joints; also, mechanical resistance of bones reduces. Involutive changes in central nervous system (CNS) cause disturbances in reciprocal transmission of impulses between CNS and muscles. This changes normal motion pattern, leading, consequently, to lasting stress of ligaments, muscles, joints and bones, what becomes a source of strong nociceptive impulses. One of first symptoms of this is pain, localized particularly in spine region. Pain is another cause of increased, abnormal tension of muscles and, thus, of their stress. Proper treatment of above situation must be necessarily consisted of simultaneous analgesia, correcting of muscle tension and relaxation. Therefore, guideline for the rehabilitation program needs to be supported by thorough clinical, biomechanical, roentgenographic and densitometrical case analysis. Rehabilitation works as prophylactics of formation and fixing of deformities. Therefore, this must be aimed to: pain relief, maintaining of proper patient's stance, rebuilding of normal muscle force, maintaining of normal motion range and increasing of daily motion activity, what would stimulate skeletal system. For practical reasons, forming of dysfunctions in motion system in course of osteoporosis is classified into three stages--I--early, II--advanced osteoporosis and III--late.

Aging↗
PubMed2002

Microvascular protection induced by late preconditioning was abolished in STZ-induced acute diabetic rats.

The authors attempted to determine whether ischemic preconditioning (IPC) can provide microvascular protection in skeletal muscle of diabetic rats against injury from a subsequent (24 hr later) prolonged period of ischemia and reperfusion. Male Sprague Dawley rats weighting 80 to 100 g were injected intraperitoneally with either streptozotocin (STZ, 65 mg/kg) or vehicle (sodium citrate, pH 4.5). Rats with a fasting blood glucose level over 300 mg/dl 1 week after injection of STZ were considered acute diabetic. The cremaster muscle of the rats underwent 45 min of IPC and 24 hr later, 4 hr of warm ischemia followed by reperfusion (I/R). Four groups were compared: IPC in normal rats (n=8); sham IPC in normal rats (n=8); IPC in diabetic rats (n=6); and sham IPC in diabetic rats (n=4). Microvascular responses in the cremaster muscle to IPC were determined by measuring the diameter of feeding, terminal arterioles and capillary perfusion using intravital microscopy, and by the evaluation of the endothelium-dependent nitric oxide system in the terminal arterioles. The average diameter of the feeding and terminal arterioles, as well as capillary perfusion, were significantly decreased in diabetic animals, compared to normal animals. There was a significant endothelial dysfunction detected in the terminal arterioles of diabetic rats. Ischemic preconditioning provided significant microvascular protection against prolonged ischemia/reperfusion in normal rats, but not in diabetic rats. IPC-induced microvascular protection in the normal skeletal muscle was abolished in STZ-induced acute diabetic rats.

Animals↗
PubMed2002

Intramuscular force transmission.

The architectural form of skeletal muscle, the pattern of activity/usage between neighbouring fibres, and the pathways for lateral and lengthwise tension delivery are all of interest in understanding muscle function and dysfunction. We have attempted to contribute to understanding of intramuscular force transmission by investigating the functional relationships between coactive motor units, and by examining the detailed molecular and morphological features at sites of tension transfer. We found that tension delivery is modulated by interaction between active and inactive fibres, that many muscle fibre terminations feature structural coupling between fibres, and that sites of tension delivery feature a variety of proteins including acetylcholinesterase, NCAM, dystrophin and two splice variants of the alpha7 integrins. We conclude that structural and molecular pathways exist to deliver force within, along, and between muscle fibres, and that the quality/quantity of tension delivered from any single fibre is at least partly a consequence of whether its neighbouring fibres are synchronously coactive.

Animals↗
PubMed2002

Involvement of nitric oxide in myotoxicity produced by diisopropylphosphorofluoridate (DFP)-induced muscle hyperactivity.

Oxidative stress, as determined by increased lipid peroxidation, has been implicated in the pathology of myotoxicity. As a model system to study the response of muscle to oxidative insults, we have studied the effects of diisopropylphosphorofluoridate (DFP)-induced muscle hyperactivity on levels of nitric oxide (NO) and energy metabolites in rat skeletal muscles. In in vivo experiments, citrulline levels as indicators of NO and NO synthase (NOS), and ATP and phosphocreatine (PCr) as indicators of mitochondrial dysfunction, were determined using HPLC methods 15 min, 30 min, 60 min, 2 h, and 24 h after intoxication. Within 15 min of DFP exposure, with onset of fasciculations, citrulline levels were significantly elevated in all three muscles [soleus, extensor digitorum longus (EDL), and diaphragm]. Maximum increases in citrulline (272-288%) were noted 60 min after DFP injection. At this time point, acetylcholinesterase activity was reduced by 90-96% (soleus < diaphragm < EDL). The levels of ATP and PCr were maximally reduced (30-43%), and total adenine nucleotides, and total creatine compounds showed declines. The findings revealed that the increase in NOS activity and NO was greater than the decrease of ATP and PCr. Since memantine (MEM) has been shown to reduce nerve and muscle hyperactivity, we have studied the possible protective effect of MEM on the DFP-induced biochemical changes. Pretreatment with MEM (18 mg/kg s.c.) and atropine sulfate (16 mg/kg s.c.), 60 min and 15 min, respectively, before DFP injection prevented the increase in citrulline and muscle hyperactivity and the decrease in ATP and PCr. These data suggest that free radical reactions by depleting high-energy phosphates may be initiating the cascade of events leading to myotoxicity during DFP-induced muscle hyperactivity.

Acetylcholinesterase↗
PubMed2006

Adipose tissue dysfunction in obesity and lipodystrophy.

The primary function of adipose tissue is to store energy in the form of triglycerides during periods of energy excess and to release the energy during fasting or starvation as free fatty acids and glycerol. Adipose tissue secretes a variety of peptides called adipocytokines (eg, leptin, adiponectin, tumor necrosis factor-alpha, interleukin-6, resistin, visfatin) that have endocrine, autocrine, and paracrine effects on the brain, liver, and skeletal muscles. These peptides play an important role in the regulation of energy homeostasis and intermediary metabolism. Adipose tissue also aromatizes androgens to estrogens, and some adipose tissue depots (mechanical fat) serve a protective or cushioning function. Dysfunction of adipose tissue can result in insulin resistance and its metabolic complications in patients with excess body fat (obesity) or markedly reduced body fat (lipodystrophy). Alterations in free fatty acid and adipocytokine release from adipose tissue may underlie metabolic complications.

Adipose Tissue↗
PubMed2002

Tissue factor deficiency causes cardiac fibrosis and left ventricular dysfunction.

Exposure of blood to tissue factor (TF) activates the extrinsic (TF:FVIIa) and intrinsic (FVIIIa:FIXa) pathways of coagulation. In this study, we found that mice expressing low levels of human TF ( approximately 1% of wild-type levels) in an mTF(-/-) background had significantly shorter lifespans than wild-type mice, in part, because of spontaneous fatal hemorrhages. All low-TF mice exhibited a selective heart defect that consisted of hemosiderin deposition and fibrosis. Direct intracardiac measurement demonstrated a 30% reduction (P < 0.001) in left ventricular function in 8-month-old low-TF mice compared with age-matched wild-type mice. Mice expressing low levels of murine FVII ( approximately 1% of wild-type levels) exhibited a similar pattern of hemosiderin deposition and fibrosis in their hearts. In contrast, FIX(-/-) mice, a model of hemophilia B, had normal hearts. Cardiac fibrosis in low-TF and low-FVII mice appears to be caused by hemorrhage from cardiac vessels due to impaired hemostasis. We propose that TF expression by cardiac myocytes provides a secondary hemostatic barrier to protect the heart from hemorrhage.

Animals↗
PubMed2002

Mitochondrial dysfunction in patients with hypotonia, epilepsy, autism, and developmental delay: HEADD syndrome.

A group of 12 children clinically presenting with hypotonia, intractable epilepsy, autism, and developmental delay, who did not fall into previously described categories of mitochondrial encephalomyopathy, were evaluated for mitochondrial respiratory enzyme activity levels, mitochondrial DNA, and mitochondrial structural abnormalities. Reduced levels in specific respiratory activities were found solely in enzymes with subunits encoded by mitochondrial DNA in seven of eight biopsied skeletal muscle specimens evaluated. Five cases exhibited increased levels of large-scale mitochondrial DNA deletions, whereas pathogenic point mutations previously described in association with mitochondrial encephalomyopathies were not found. Mitochondrial structural abnormalities were present in three of four patients examined. Our findings suggest that mitochondrial dysfunction, including extensive abnormalities in specific enzyme activities, mitochondrial structure, and mitochondrial DNA integrity, may be present in children with a clinical constellation including hypotonia, epileptic seizures, autism, and developmental delay. The acronym HEADD is presented here to facilitate pursuit of mitochondrial defects in patients with this clinical constellation after other causes have been excluded.

Adolescent↗
PubMed2004

Mitochondrial dysfunction measured in vivo.

AIMS: Mitochondria are responsible for meeting the majority of the energetic demand of most tissues. They also play a major role in regulating cell survival. These dual roles of mitochondria place them at the centre of many pathologies leading to tissue degeneration and disruption of energy balance. The prominent role of mitochondria in ageing and disease has led to a tremendous growth in mitochondrial research at the cellular and molecular level. We describe below a new non-invasive approach to measure mitochondrial function that will bridge the gap between our understanding of mitochondrial function in vitro and that in the intact organism. METHODS AND RESULTS: This approach uses optical and magnetic resonance spectroscopy to measure in vivo O2 consumption and ATP synthesis rates, respectively, from skeletal muscle. These values lead to a quantitative assessment of the mitochondrial ATP/O2 or P/O. The P/O represents the efficiency of coupling between phosphorylation and oxygen consumption in the mitochondria, which is a measure of mitochondrial dysfunction. CONCLUSIONS: This work represents a significant advance in research on the role of mitochondria in degenerative disease and ageing because it allows a quantitative measure of mitochondrial pathology in vivo. The non-invasive nature of this approach also enables repeated measures of mitochondrial function on the same individual, thereby making this a potentially useful diagnostic technique. The results from this work have led to insights into the coupling of ATP synthesis to oxidation and the regulation of oxidative phosphorylation by intracellular PO2.

Adenosine Triphosphate↗
PubMed2003

Gene transfer establishes primacy of striated vs. smooth muscle sarcoglycan complex in limb-girdle muscular dystrophy.

Limb-girdle muscular dystrophy types 2E and F are characterized by skeletal muscle weakness and often cardiomyopathy and are due to mutations in the genes encoding beta- and delta-sarcoglycan. We previously demonstrated that loss of sarcoglycans in smooth muscle leads to constrictions of the microvasculature that contributes to the cardiac phenotype. It is unclear how vasculature abnormalities affect skeletal muscle. We injected recombinant beta- or delta-sarcoglycan adenoviruses into skeletal muscles of corresponding null mice. We hypothesized that the adenoviruses would not transduce vascular smooth muscle, and we would only target skeletal muscle. Indeed, sustained expression of intact sarcoglycan-sarcospan complex was noted at the sarcolemma, neuromuscular junction, myotendinous junction, and in peripheral nerve, but not in vascular smooth muscle. Gene transfer of the corresponding deleted sarcoglycan gene preserved sarcolemmal integrity, prevented pathological dystrophy and hypertrophy, and protected against exercised-induced damage. We conclude that vascular dysfunction is not a primary cause of beta- and delta-sarcoglycan-deficient muscular dystrophy. In addition, we show successful functional rescue of entire muscles after adenovirus-mediated gene delivery. Thus, virus-mediated gene transfer of sarcoglycans to skeletal muscle in combination with pharmacological prevention of cardiomyopathy constitute promising therapeutic strategies for limb-girdle muscular dystrophies.

Adenoviridae↗
PubMed1994

Liver cytochrome c oxidase deficiency in a case of neonatal-onset hepatic failure.

In the last few years, inborn errors of oxidative phosphorylation have been recognized as possible causes of hepatic failure in infancy and respiratory enzyme deficiencies have been described in several tissues of affected individuals. Here, we report on cytochrome c oxidase deficiency in the liver but not in the skeletal muscle of a 5-month-old girl who presented hepatic failure in early infancy. Persistent hyperlactatemia (> 4 mM, normal < 2.4) with high lactate/pyruvate (L/P) molar ratios in plasma, and their further elevation in the post-absorptive period were suggestive of an inborn error of oxidative phosphorylation. However, no mutation in the coding sequences of the liver-specific subunits of cytochrome c oxidase (VIa and VIIa) has been detected and no major rearrangement or depletion of the mitochondrial DNA has been observed. Based on this observation we suggest that inborn errors of oxidative phosphorylation be considered in the diagnosis of severe hepatocellular dysfunction of unknown origin, especially when an abnormal oxidation-reduction status is found in the plasma and even if normal respiratory enzyme activities are found in peripheral tissues. The findings of normal respiratory enzyme activities in skeletal muscle, circulating lymphocytes or cultured skin fibroblasts does not rule out this diagnosis. Instead, the negativity of these tests should prompt one to carry out the specific enzyme assays in the tissue which expresses the disease, namely the liver.

Cytochrome-c Oxidase Deficiency↗
PubMed2006

Reversible disruption of dynactin 1-mediated retrograde axonal transport in polyglutamine-induced motor neuron degeneration.

Spinal and bulbar muscular atrophy (SBMA) is a hereditary neurodegenerative disease caused by an expansion of a trinucleotide CAG repeat encoding the polyglutamine tract in the androgen receptor (AR) gene. To elucidate the pathogenesis of polyglutamine-mediated motor neuron dysfunction, we investigated histopathological and biological alterations in a transgenic mouse model of SBMA carrying human pathogenic AR. In affected mice, neurofilaments and synaptophysin accumulated at the distal motor axon. A similar intramuscular accumulation of neurofilament was detected in the skeletal muscle of SBMA patients. Fluoro-gold labeling and sciatic nerve ligation demonstrated an impaired retrograde axonal transport in the transgenic mice. The mRNA level of dynactin 1, an axon motor for retrograde transport, was significantly reduced in the SBMA mice resulting from pathogenic AR-induced transcriptional dysregulation. These pathological events were observed before the onset of neurological symptoms, but were reversed by castration, which prevents nuclear accumulation of pathogenic AR. Overexpression of dynactin 1 mitigated neuronal toxicity of the pathogenic AR in a cell culture model of SBMA. These observations indicate that polyglutamine-dependent transcriptional dysregulation of dynactin 1 plays a crucial role in the reversible neuronal dysfunction in the early stage of SBMA.

Analysis of Variance↗
PubMed2001

Pulmonary endothelinergic system in experimental congestive heart failure.

OBJECTIVES: Endothelin-1 (ET-1), plays an important role in the pathophysiology of CHF and the pulmonary endothelium is an early hemodynamic target in diastolic left ventricular dysfunction. Therefore we hypothesized that the lung is a main source of humoral endothelin in CHF and that its secretion is proportional to the degree of heart failure. METHODS AND RESULTS: We used rats with coronary artery ligation as an experimental model of either compensated or decompensated heart failure, depending on infarct size. Reverse transcriptase polymerase chain reaction (RT-PCR) revealed that in the lung, the expression of preproET-1 mRNA was higher in decompensated HF than in control and compensated HF rats (P<0.001). Run-on assay demonstrated that ET-1 overexpression is regulated at a transcriptional level (P<0.01). In contrast, there was no change in ET-1 mRNA expression in aortae, left ventricular myocardium and skeletal muscle. The expression of endothelin-converting enzyme (ECE)-1 mRNA was not modified and the expression of ET(B) receptor mRNA in the congestive lung was significantly lower than in control and compensated HF rats (P<0.0001), while the expression of ET(A) receptor mRNA did not differ between groups. The lung and plasma ET-1 peptide levels were respectively 4.2 and 9 fold higher in the rats with decompensated HF than in control rats (P<0.05; P<0.0001). Organoculture experiments showed that the lung ET-1 peptide secretion level in rats with decompensated HF was higher than that in control rats (P<0.01). In contrast, there was no change in ET-1 peptide secretion by the left ventricular myocardium and skeletal muscle. In plasma of rats with decompensated HF, the rate of bigET-1 conversion to ET-1 was 22%. ET-1 peptide was also present in the pleural effusion of decompensated heart failure. Plasma ET-1 concentration was significantly correlated with upstream markers of left ventricular diastolic dysfunction, with the expression of preproET-1 mRNA in the lung, with lung and pleural ET-1 concentration and with the expression ratio of ET-1/ET(B) receptor mRNA. CONCLUSION: Taken together, these data suggest that overexpression of ET-1 and down-regulation of ET(B) receptors in the lung are determinants of circulating endothelin in CHF. As a corollary, increased plasma endothelin may provide evidence of pulmonary endothelial dysfunction in CHF.

Analysis of Variance↗
PubMedDate not supplied

Maternally inherited mitochondrial cardiomyopathy associated with a C-to-T transition at nucleotide 3303 of mitochondrial DNA in the tRNA(Leu(UUR)) gene.

Disorders associated with mitochondrial DNA (mtDNA) mutations are usually dominated by involvement of the nervous system and skeletal muscle (hence the term "mitochondrial encephalomyopathies"). However, considering the high dependence of the heart on oxidative metabolism, it is not surprising that myocardial dysfunction is often a prominent feature in these disorders, either as isolated cardiomyopathy or as part of a multisystem mitochondrial syndrome. We report an infant with a maternally inherited C-to-T transition at nucleotide 3303 of mtDNA in the tRNA(Leu(UUR)) gene; this is the second kindred with cardiomyopathy identified to have this mutation of mitochondrial DNA. A brief review of other mitochondrial DNA defects is also included.

Cardiomyopathy, Hypertrophic↗