Total Perineal Prostatectomy: A Retrospective Study in Six Dogs

Perineal hernia refers to the herniation of pelvic and abdominal viscera into the subcutaneous perineal region through a pelvic diaphragm weakness: a concomitant prostatic disease is observed in 25–59% of cases. Prostatectomy involves the removal of the prostate, either partially (partial prostatectomy) or completely (total prostatectomy). In case of complicated perineal hernia, staged procedures are recommended: celiotomy in order to perform colopexy, vasopexy, cystopexy, and/or to treat the prostatic disease, and perineal access in order to repair the perineal hernia. Very few reports relate prostatectomy using a perineal approach and, to the extent of the author’s knowledge, this technique has not been thoroughly investigated in the literature. The aim of this article is to retrospectively describe the total perineal prostatectomy in dogs presenting perineal hernia with concomitant prostatic diseases which required the removal of the gland. The experience in six dogs (three dogs with the prostate within hernial contents and three dogs with intrapelvic prostate) is reported as well as advantages, disadvantages, and limitations of the surgical procedure. In the authors’ clinical practice, total perineal prostatectomy has been a useful surgical approach to canine prostatic diseases, proven to be safe, well tolerated, and effective.

Molecular Mechanisms of Diaphragm Myopathy in Humans With Severe Heart Failure

Rationale: Diaphragm weakness impairs quality of life, exercise capacity, and survival in patients with chronic heart failure (CHF) and reduced left ventricular ejection fraction. However, the underlying cellular mechanisms responsible in humans remain poorly resolved. Objectives: We prospectively evaluated clinical, functional (in vivo/in vitro), histological/ultrastructural, and molecular alterations of the diaphragm from patients with CHF receiving a left ventricular assist device compared with patients without CHF undergoing elective coronary bypass grafting (control) in the observational LIPAMUS-HF (Lipsia Diaphragm And Muscle Heart Failure). Methods and Results: Participants (controls=21, CHF=18) underwent cardiopulmonary exercise and spirometry/respiratory muscle testing alongside diaphragm and cardiac imaging. Diaphragm biopsies were phenotyped for mitochondrial respiration, muscle fiber function, histology/ultrastructure, and protein expression. In vivo respiratory muscle function and diaphragm thickness were reduced in CHF by 38% and 23%. Diaphragm biopsies revealed a fiber-type shift and severe fiber atrophy in CHF alongside elevated proteasome-dependent proteolysis (ie, MuRF1 [muscle-specific RING finger protein 1] expression, ubiquitination, ubiquitin-proteasome activity) and myofibrillar protein oxidation, which corresponded to upregulated Nox (NADPH [nicotinamide adenine dinucleotide phosphate oxidase] oxidase; Nox2/Nox4) signaling. Mitochondria demonstrated severe intrinsic functional and ultrastructural abnormalities in CHF characterized by accumulation of small mitochondria and inhibited autophagy/mitophagy. Single muscle fiber contractile function revealed reduced Ca 2+ sensitivity in CHF and there was evidence of RyR1 (ryanodine receptor 1) dysfunction indicating Ca 2+ leak from the sarcoplasmic reticulum. Mitochondrial and Ca 2+ measures corresponded to upregulated Nox4 isoform NADPH oxidase expression. Molecular markers correlated to whole-body exercise intolerance and diaphragm dysfunction/wasting. Conclusions: Patients with CHF demonstrate an obvious diaphragm myopathy independent of disuse or other confounding factors, such as aging, obesity, or hypertension. Diaphragm weakness in CHF was associated with intracellular abnormalities characterized by fiber atrophy, oxidative stress, mitochondrial dysfunction, impaired Ca 2+ homeostasis, elevated proteasome-dependent proteolysis, but inhibited autophagy/mitophagy, which we speculate offers a novel therapeutic molecular target regulated by a Nox-MuRF1/ubiquitin-proteasome-mitochondria-RyR1/Ca 2+ signaling axis. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02663115.

Late-onset Pompe disease (LOPD): may axial myopathy influence respiratory dysfunction?

Background Respiratory dysfunction in Late Onset Pompe Disease (LOPD) is attributed primarily to diaphragm weakness; it is not always proportional to skeletal muscle weakness. Beyond diaphragm and rib cage muscles, we know that posterior trunk muscles participate to inspiration, and abdominal wall muscles contribute to forced expiration. We aimed to investigate whether the involvement of axial muscles detected by muscle MRI may correlate with respiratory dysfunction or influence respiratory functional tests. Methods In 19 patients with LOPD in different stages of disease, we analyzed trunk muscle MRI and upright forced vital capacity FVC, postural drop in VC, and maximal inspiratory and expiratory pressures (MIP, MEP). Results While upright FVC did not correlate with trunk muscle involvement, postural drop in VC, reflecting diaphragm weakness, was strongly influenced by the severity of involvement of all posterior and anterior muscles. Conclusion Trunk muscles involvement in LOPD may reveal respiratory dysfunction and contribute to postural drop in VC. It is likely that axial muscle weakness may impair the compensatory mechanisms occurring in clinostatism, and mainly operated by the abdominal muscles. Detection of axial muscle damage by MRI may thus suggest the need of more extensive respiratory assessment, i.e. by polysomnography, even when upright VC is still within normal ranges.

M Mode Ultrasound and Tissue Doppler Imaging to Assess Diaphragm Feature in Late Onset Pompe Disease

Late-onset Pompe disease (LOPD) is an autosomal recessive lysosomal storage disease. Clinical features include skeletal muscle deficiency and diaphragm weakness. Clinical management relies on supportive treatment and mechanical ventilation in patients with chronic respiratory failure. M mode ultrasound and sniff tissue Doppler imaging can be used to assess and follow diaphragm function.

MitoTEMPOL, a mitochondrial targeted antioxidant, prevents sepsis-induced diaphragm dysfunction

Clinical studies indicate that sepsis-induced diaphragm dysfunction is a major contributor to respiratory failure in mechanically ventilated patients. Currently there is no drug to treat this form of diaphragm weakness. Sepsis-induced muscle dysfunction is thought to be triggered by excessive mitochondrial free radical generation; we therefore hypothesized that therapies that target mitochondrial free radical production may prevent sepsis-induced diaphragm weakness. The present study determined whether MitoTEMPOL, a mitochondrially targeted free radical scavenger, could reduce sepsis-induced diaphragm dysfunction. Using an animal model of sepsis, we compared four groups of mice: 1) sham-operated controls, 2) animals with sepsis induced by cecal ligation puncture (CLP), 3) sham controls given MitoTEMPOL (10 mg·kg−1·day−1 ip), and 4) CLP animals given MitoTEMPOL. At 48 h after surgery, we measured diaphragm force generation, mitochondrial function, proteolytic enzyme activities, and myosin heavy chain (MHC) content. We also examined the effects of delayed administration of MitoTEMPOL (by 6 h) on CLP-induced diaphragm weakness. The effects of MitoTEMPOL on cytokine-mediated alterations on muscle cell superoxide generation and cell size in vitro were also assessed. Sepsis markedly reduced diaphragm force generation. Both immediate and delayed MitoTEMPOL administration prevented sepsis-induced diaphragm weakness. MitoTEMPOL reversed sepsis-mediated reductions in mitochondrial function, activation of proteolytic pathways, and decreases in MHC content. Cytokines increased muscle cell superoxide generation and decreased cell size, effects that were ablated by MitoTEMPOL. MitoTEMPOL and other compounds that target mitochondrial free radical generation may be useful therapies for sepsis-induced diaphragm weakness.

SS31, a mitochondrially targeted antioxidant, prevents sepsis-induced reductions in diaphragm strength and endurance

Sepsis-induced diaphragm dysfunction contributes to respiratory failure and mortality in critical illness. There are no treatments for this form of diaphragm weakness. Studies show that sepsis-induced muscle dysfunction is triggered by enhanced mitochondrial free radical generation. We tested the hypothesis that SS31, a mitochondrially targeted antioxidant, would attenuate sepsis-induced diaphragm dysfunction. Four groups of mice were studied: 1) sham-operated controls, 2) sham-operated+SS31 (10 mg·kg−1·day−1), 3) cecal ligation puncture (CLP), and 4) CLP+SS31. Forty-eight hours postoperatively, diaphragm strips with attached phrenic nerves were isolated, and the following were assessed: muscle-field-stimulated force-frequency curves, nerve-stimulated force-frequency curves, and muscle fatigue. We also measured calpain activity, 20S proteasomal activity, myosin heavy chain (MHC) levels, mitochondrial function, and aconitase activity, an index of mitochondrial superoxide generation. Sepsis markedly reduced diaphragm force generation; SS31 prevented these decrements. Diaphragm-specific force generation averaged 30.2 ± 1.4, 9.4 ± 1.8, 25.5 ± 2.3, and 27.9 ± 0.6 N/cm2 for sham, CLP, sham+SS31, and CLP+SS31 groups ( P < 0.001). Similarly, with phrenic nerve stimulation, CLP depressed diaphragm force generation, effects prevented by SS31. During endurance trials, force was significantly reduced with CLP, and SS31 prevented these reductions ( P < 0.001). Sepsis also increased diaphragm calpain activity, increased 20S proteasomal activity, decreased MHC levels, reduced mitochondrial function (state 3 rates and ATP generation), and reduced aconitase activity; SS31 prevented each of these sepsis-induced alterations ( P ≤ 0.017 for all indices). SS31 prevents sepsis-induced diaphragm dysfunction, preserving force generation, endurance, and mitochondrial function. Compounds with similar mechanisms of action may be useful therapeutically to preserve diaphragm function in patients who are septic and critically ill. NEW & NOTEWORTHY Sepsis-induced diaphragm dysfunction is a major contributor to mortality and morbidity in patients with critical illness in intensive care units. Currently, there is no proven pharmacological treatment for this problem. This study provides the novel finding that administration of SS31, a mitochondrially targeted antioxidant, preserves diaphragm myosin heavy chain content and mitochondrial function, thereby preventing diaphragm weakness and fatigue in sepsis.