Morphological differences of the fallopian tube ampoule in young and old age

Работа основана на морфологическом исследовании ампул маточных труб 130 рожавших женщин молодого и старческого возраста. Применены макрометрический, гистологический, иммуногистохимический и микрометрический методы исследования. Выявлены закономерности возрастной морфологической изменчивости ампулы маточной трубы, проявляющиеся в уменьшении параметров их длины, а также наружных диаметров в середине ампулы и в местах перехода перешейка в ампулу и ампулы в воронку от молодого возраста к старческому возрасту. Гистоархитектоника ампул маточных труб у женщин в старческом возрасте характеризуется уплощением эпителия слизистой оболочки, образующей обилие близлежащих утолщенных складок, формирующих неравномерное сужение просвета ампулы. Определяется истончение мышечной оболочки с разрастанием вместо нее соединительной ткани и скоплением адипоцитов в подсерозной основе. В старческом возрасте отмечается более выраженная экспрессия виментина, прослеживающаяся не только в эндотелии и субэндотелиальном слое кровеносных сосудов, включая капилляры, но и в отдельных фибробластах. Установлено, что особенности микрометрических характеристик ампул маточных труб заключаются в уменьшении внутреннего периметра эпителиальной выстилки и площади просвета, наряду с увеличением площади их стенки при срединном сечении, в старческом возрасте в сравнении с молодым. The work is based on a morphological study of ampoules of the fallopian tubes of 130 young and senile women who gave birth. Macrometric, histological, immunohistochemical and micrometric methods of investigation were applied. The regularities of age-related morphological variability of the fallopian tube ampoule are revealed, which are manifested in a decrease in the parameters of their length, as well as external diameters in the middle of the ampoule and at the places of transition of the isthmus into the ampoule and ampoule into the funnel from young age to old age. Histoarchitectonics of ampoules of the fallopian tubes in women in old age is characterized by flattening of the epithelium of the mucous membrane, which forms an abundance of nearby thickened folds that form an uneven narrowing of the lumen of the ampoule. The thinning of the muscle membrane is determined with the growth of connective tissue instead of it and the accumulation of adipocytes in the subserose base. In old age, there is a more pronounced expression of vimentin, which can be traced not only in the endothelium and subendothelial layer of blood vessels, including capillaries, but also in individual fibroblasts. It was found that the features of the micrometric characteristics of the fallopian tube ampoules consist in a decrease in the inner perimeter of the epithelial lining and the lumen area, along with an increase in the area of their wall at the median cross-section in old age compared with young age.

Depletion of essential fatty acids in muscle is associated with shorter survival of cancer patients undergoing surgery-preliminary report

Emerging studies are reporting associations between skeletal muscle abnormalities and survival in cancer patients. Cancer prognosis is associated with depletion of essential fatty acids in erythrocytes and plasma in humans. However the relationship between skeletal muscle membrane fatty acid composition and survival is unknown. This study investigates the relationship between fatty acid content of phospholipids in skeletal muscle and survival in cancer patients. Rectus abdominis biopsies were collected during cancer surgery from 35 patients diagnosed with cancer. Thin-layer and gas chromatography were used for quantification of phospholipid fatty acids. Cutpoints for survival were defined using optimal stratification. Median survival was between 450 and 500 days when patients had arachidonic acid (AA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in muscle phospholipid below the cut-point compared to 720–800 days for patients above. Cox regression analysis revealed that low amounts of AA, EPA and DHA are risk factors for death. The risk of death remained significant for AA [HR 3.5 (1.11–10.87), p = 0.03], EPA [HR 3.92 (1.1–14.0), p = 0.04] and DHA [HR 4.08 (1.1–14.6), p = 0.03] when adjusted for sex. Lower amounts of essential fatty acids in skeletal muscle membrane is a predictor of survival in cancer patients. These results warrant investigation to restore bioactive fatty acids in people with cancer.

The Dysferlin Transcript Containing the Alternative Exon 40a is Essential for Myocyte Functions

Dysferlinopathies are a group of muscular dystrophies caused by recessive mutations in the DYSF gene encoding the dysferlin protein. Dysferlin is a transmembrane protein involved in several muscle functions like T-tubule maintenance and membrane repair. In 2009, a study showed the existence of fourteen dysferlin transcripts generated from alternative splicing. We were interested in dysferlin transcripts containing the exon 40a, and among them the transcript 11 which contains all the canonical exons and exon 40a. This alternative exon encodes a protein region that is cleaved by calpains during the muscle membrane repair mechanism. Firstly, we tested the impact of mutations in exon 40a on its cleavability by calpains. We showed that the peptide encoded by the exon 40a domain is resistant to mutations and that calpains cleaved dysferlin in the first part of DYSF exon 40a. To further explore the implication of this transcript in cell functions, we performed membrane repair, osmotic shock, and transferrin assay. Our results indicated that dysferlin transcript 11 is a key factor in the membrane repair process. Moreover, dysferlin transcript 11 participates in other cell functions such as membrane protection and vesicle trafficking. These results support the need to restore the dysferlin transcript containing the alternative exon 40a in patients affected with dysferlinopathy.

Therapeutic Benefit of Galectin-1: Beyond Membrane Repair, a Multifaceted Approach to LGMD2B

Two of the main pathologies characterizing dysferlinopathies are disrupted muscle membrane repair and chronic inflammation, which lead to symptoms of muscle weakness and wasting. Here, we used recombinant human Galectin-1 (rHsGal-1) as a therapeutic for LGMD2B mouse and human models. Various redox and multimerization states of Gal-1 show that rHsGal-1 is the most effective form in both increasing muscle repair and decreasing inflammation, due to its monomer-dimer equilibrium. Dose-response testing shows an effective 25-fold safety profile between 0.54 and 13.5 mg/kg rHsGal-1 in Bla/J mice. Mice treated weekly with rHsGal-1 showed downregulation of canonical NF-κB inflammation markers, decreased muscle fat deposition, upregulated anti-inflammatory cytokines, increased membrane repair, and increased functional movement compared to non-treated mice. Gal-1 treatment also resulted in a positive self-upregulation loop of increased endogenous Gal-1 expression independent of NF-κB activation. A similar reduction in disease pathologies in patient-derived human cells demonstrates the therapeutic potential of Gal-1 in LGMD2B patients.

Inherited Muscle Disorders

Inherited muscular disorders can manifest at any age, from prenatal life to adulthood. The broad differential diagnosis includes muscular dystrophies, congenital myopathies, disorders of glycogen and lipid metabolism, channelopathies, and mitochondrial disorders. Muscular dystrophies may present at any age, are inherited, and involve progressive degeneration of muscle, which is often replaced by connective tissue. Muscular dystrophies result from defects in the sarcolemmal proteins of muscle, including dystrophin-associated muscle membrane protein complex, muscle intracellular proteins (eg, nuclear envelope proteins), and extracellular matrix proteins (eg, collagen VI).

Leg pain in neuropathic postural tachycardia syndrome is associated with altered muscle membrane properties

Purpose In neuropathic postural tachycardia syndrome, peripheral sympathetic dysfunction leads to excessive venous blood pooling during orthostasis. Up to 84% of patients report leg pain and weakness in the upright position. To explore possible pathophysiological processes underlying these symptoms, the present study examined muscle excitability depending on body position in patients with neuropathic postural tachycardia syndrome and healthy subjects. Methods In ten patients with neuropathic postural tachycardia syndrome and ten healthy subjects, muscle excitability measurements were performed repeatedly: in the supine position, during 10 min of head-up tilt and during 6 min thereafter. Additionally, lower leg circumference was measured and subjective leg pain levels were assessed. Results In patients with neuropathic postural tachycardia syndrome, muscle excitability was increased in the supine position, decreased progressively during tilt, continued to decrease after being returned to the supine position, and did not completely recover to baseline values after 6 min of supine rest. The reduction in muscle excitability during tilt was paralleled by an increase in lower leg circumference as well as leg pain levels. No such changes were observed in healthy subjects. Conclusions This study provides evidence for the occurrence of orthostatic changes in muscle excitability in patients with neuropathic postural tachycardia syndrome and that these may be associated with inadequate perfusion of the lower extremities. Insufficient perfusion as a consequence of blood stasis may cause misery perfusion of the muscles, which could explain the occurrence of orthostatic leg pain in neuropathic postural tachycardia syndrome.

Unilateral Cauda Equina Syndrome Due to Cancer Metastasis Diagnosed with Electromyography: A Case Report

Background: Typical cauda equina syndrome (CES) presents as low back pain, bilateral leg pain with motor and sensory deficits, genitourinary dysfunction, saddle anesthesia and fecal incontinence. In addition, it is a neurosurgical emergency, which is essential to diagnose as soon as possible, and needs prompt intervention. However, unilateral CES is rare. Here, we report a unique case of a patient who had unilateral symptoms of CES due to cancer metastasis and was diagnosed through electromyography. Methods: A 71-year-old man with diffuse large B cell lymphoma (DLBCL) suffered from severe pain, motor weakness in the right lower limb and urinary incontinence, and hemi-saddle anesthesia. It was easy to be confused with lumbar radiculopathy due to the unilateral symptoms. Lumbar spine magnetic resonance imaging (MRI) showed suspected multifocal bone metastasis in the TL spine, including T11-L5, the bilateral sacrum and iliac bones, and suspected epidural metastasis at L4/5, L5/S1 and the sacrum. PET CT conducted after the third R-CHOP showed residual hypermetabolic lesions in L5, the sacrum, and the right presacral area. Results: Nerve conduction studies (NCS) revealed peripheral neuropathy in both hands and feet. Electromyography (EMG) presented abnormal results indicating development of muscle membrane instability following neural injury, not only on the right symptomatic side, but also on the other side which was considered intact. Overall, he was diagnosed with cauda equina syndrome caused by DLBCL metastasis, and referred to neurosurgical department. Conclusions: Early diagnosis of unilateral CES may go unnoticed due to its unilateral symptoms. Failure to perform the intervention at the proper time can impede recovery and leave permanent complications. Therefore, physicians need to know not only the typical CES, but also the clinical features of atypical CES when encountering a patient, and further evaluation such as electrodiagnostic study or lumbar spine MRI have to be considered.

Inflammation in Duchenne Muscular Dystrophy–Exploring the Role of Neutrophils in Muscle Damage and Regeneration

Duchenne muscular dystrophy (DMD) is a severe and progressive, X-linked, neuromuscular disorder caused by mutations in the dystrophin gene. In DMD, the lack of functional dystrophin protein makes the muscle membrane fragile, leaving the muscle fibers prone to damage during contraction. Muscle degeneration in DMD patients is closely associated with a prolonged inflammatory response, and while this is important to stimulate regeneration, inflammation is also thought to exacerbate muscle damage. Neutrophils are one of the first immune cells to be recruited to the damaged muscle and are the first line of defense during tissue injury or infection. Neutrophils can promote inflammation by releasing pro-inflammatory cytokines and compounds, including myeloperoxidase (MPO) and neutrophil elastase (NE), that lead to oxidative stress and are thought to have a role in prolonging inflammation in DMD. In this review, we provide an overview of the roles of the innate immune response, with particular focus on mechanisms used by neutrophils to exacerbate muscle damage and impair regeneration in DMD.

MG53 Preserves Neuromuscular Junction Integrity and Alleviates ALS Disease Progression

Respiratory failure from progressive respiratory muscle weakness is the most common cause of death in amyotrophic lateral sclerosis (ALS). Defects in neuromuscular junctions (NMJs) and progressive NMJ loss occur at early stages, thus stabilizing and preserving NMJs represents a potential therapeutic strategy to slow ALS disease progression. Here we demonstrate that NMJ damage is repaired by MG53, an intrinsic muscle protein involved in plasma membrane repair. Compromised diaphragm muscle membrane repair and NMJ integrity are early pathological events in ALS. Diaphragm muscles from ALS mouse models show increased susceptibility to injury and intracellular MG53 aggregation, which is also a hallmark of human muscle samples from ALS patients. We show that systemic administration of recombinant human MG53 protein in ALS mice protects against injury to diaphragm muscle, preserves NMJ integrity, and slows ALS disease progression. As MG53 is present in circulation in rodents and humans under physiological conditions, our findings provide proof-of-concept data supporting MG53 as a potentially safe and effective therapy to mitigate ALS progression.