Clinically Differentiated Abnormalities of the Architecture and Expression of Myosin Isoforms of the Human Cremaster Muscle in Cryptorchidism and Retractile Testis.

AIM: To describe architecture and expression of myosin isoforms of the human cremaster muscle (CM) and to individuate changes in clinically differentiated abnormalities of testicular descent: cryptorchidism or undescended testis (UDT) and retractile testis (RT). BACKGROUND: The CM is a nonsomitic striated muscle differentiating from mesenchyme of the gubernaculum testis. Morphofunctional and molecular peculiarities linked to its unique embryological origin are not yet completely defined. Its role in abnormalities of testicular descent is being investigated. SUBJECTS AND METHODS: Biopsy samples were obtained from corrective surgery in cases of cryptorchidism, retractile testis, inguinal hernia, or hydrocele. Muscle specimens were processed for morphology, histochemistry, and immunohistology. RESULTS AND CONCLUSIONS: The CM differs from the skeletal muscles both for morphological and molecular characteristics. The presence of fascicles with different characterization and its myosinic pattern suggested that the CM could be included in the specialized muscle groups, such as the extrinsic ocular muscles (EOMs) and laryngeal and masticatory muscles. The embryological origin from the nonsomitic mesoderm is, also for the CM, the basis of distinct molecular pathways. In UDT, the histological alterations of CM are suggestive of denervation; the genitofemoral nerve and its molecular messengers directed to this muscle are likely defective. Compared with the other samples, RT has a distinct myosinic pattern; therefore, it has been considered a well-defined entity with respect to the other testicular descent abnormalities.

Endothelial CD40 Mediates Microvascular von Willebrand Factor-Dependent Platelet Adhesion Inducing Inflammatory Venothrombosis in ADAMTS13 Knockout Mice.

BACKGROUND: von Willebrand factor (vWF) plays an important role in platelet activation. CD40-CD40 ligand (CD40L) induced vWF release has been described in large vessels and cultured endothelium, but its role in the microcirculation is not known. Here, we studied whether CD40 is expressed in murine microvessels in vivo, whether CD40L induces platelet adhesion and leukocyte activation, and how deficiency of the vWF cleaving enzyme ADAMTS13 affects these processes. METHODS AND RESULTS: The role of CD40L in the formation of beaded platelet strings reflecting their adhesion to ultralarge vWF fibers (ULVWF) was analyzed in the murine cremaster microcirculation in vivo. Expression of CD40 and vWF was studied by immunohistochemistry in isolated and fixed cremasters. Microvascular CD40 was only expressed under inflammatory conditions and exclusively in venous endothelium. We demonstrate that CD40L treatment augmented the number of platelet strings, reflecting ULVWF multimer formation exclusively in venules and small veins. In ADAMTS13 knockout mice, the number of platelet strings further increased to a significant extent. As a consequence extensive thrombus formation was induced in venules of ADAMTS13 knockout mice. In addition, circulating leukocytes showed primary and rapid adherence to these platelet strings followed by preferential extravasation in these areas. CONCLUSION: CD40L is an important stimulus of microvascular endothelial ULVWF release, subsequent platelet string formation and leukocyte extravasation but only in venous vessels under inflammatory conditions. Here, the lack of ADAMTS13 leads to severe thrombus formation. The results identify CD40 expression and ADAMTS13 activity as important targets to prevent microvascular inflammatory thrombosis.

Heparanase-Dependent Remodeling of Initial Lymphatic Glycocalyx Regulates Tissue-Fluid Drainage During Acute Inflammation in vivo.

The glycocalyx is a dense layer of carbohydrate chains involved in numerous and fundamental biological processes, such as cellular and tissue homeostasis, inflammation and disease development. Composed of membrane-bound glycoproteins, sulfated proteoglycans and glycosaminoglycan side-chains, this structure is particularly essential for blood vascular barrier functions and leukocyte diapedesis. Interestingly, whilst the glycocalyx of blood vascular endothelium has been extensively studied, little is known about the composition and function of this glycan layer present on tissue-associated lymphatic vessels (LVs). Here, we applied confocal microscopy to characterize the composition of endothelial glycocalyx of initial lymphatic capillaries in murine cremaster muscles during homeostatic and inflamed conditions using an anti-heparan sulfate (HS) antibody and a panel of lectins recognizing different glycan moieties of the glycocalyx. Our data show the presence of HS, α-D-galactosyl moieties, α2,3-linked sialic acids and, to a lesser extent, N-Acetylglucosamine moieties. A similar expression profile was also observed for LVs of mouse and human skins. Interestingly, inflammation of mouse cremaster tissues or ear skin as induced by TNF-stimulation induced a rapid (within 16 h) remodeling of the LV glycocalyx, as observed by reduced expression of HS and galactosyl moieties, whilst levels of α2,3-linked sialic acids remains unchanged. Furthermore, whilst this response was associated with neutrophil recruitment from the blood circulation and their migration into tissue-associated LVs, specific neutrophil depletion did not impact LV glycocalyx remodeling. Mechanistically, treatment with a non-anticoagulant heparanase inhibitor suppressed LV HS degradation without impacting neutrophil migration into LVs. Interestingly however, inhibition of glycocalyx degradation reduced the capacity of initial LVs to drain interstitial fluid during acute inflammation. Collectively, our data suggest that rapid remodeling of endothelial glycocalyx of tissue-associated LVs supports drainage of fluid and macromolecules but has no role in regulating neutrophil trafficking out of inflamed tissues via initial LVs.

Dystrophin deficiency promotes leukocyte recruitment in mdx mice.

BACKGROUND: A growing body of evidence defines inflammation as a hallmark feature of disease pathogenesis of Duchenne muscular dystrophy. To tailor potential immune modulatory interventions, a better understanding of immune dysregulation in Duchenne muscular dystrophy is needed. We now asked whether dystrophin deficiency affects the cascade of leukocyte recruitment. METHODS: We performed intravital microscopy on the cremaster muscle of wild-type and dystrophin-deficient mdx mice. Recruitment was triggered by preparation alone (traumatic inflammation) or in combination with scrotal TNFα injections. Neutrophilic infiltration of the cremaster muscle was assessed on tissue sections. Integrin expression on circulating neutrophils and serum levels of pro-inflammatory cytokines were measured by flow cytometry. RESULTS: Mdx mice show increased rolling and adhesion at baseline (traumatic inflammation) and a more profound response upon TNFα injection compared with wild-type animals. In both models, neutrophilic infiltration of the cremaster muscle is increased. Upregulation of the integrins LFA-1 and Mac-1 on circulating leukocytes and pro-inflammatory cytokines IL-6 and CCL2 in the serum points toward systemically altered immune regulation in mdx mice. CONCLUSION: We are the first to show exaggerated activation of the leukocyte recruitment cascade in a dystrophin-deficient organism in vivo.

Detection of insulin-like growth factor receptor-1 in the human cremaster muscle and its role in the etiology of the undescended testis.

PURPOSE: Previous studies of undescended testis (UT) has focused on insulin-like hormone 3 (INSL3), the genitofemoral nerve, and androgens in the testicular descent. Leydig cells, which are under the control of insulin-like growth factor-1 (IGF1), produce both androgens and INSL3. We aimed to investigate whether insulin-like growth factor receptor-1(IGFR1) exists in the cremaster muscle (CM) complex and is associated with normally descended testis as well as UT cases in humans. METHODS: We studied 30 CM from 15 patients who comprised the UT group (UTG), and 15 patients with unilateral testicular torsion (Control group; CG). Muscles, nerves, and vessels within the CM specimen were examined to determine the presence of IGFR1. RESULTS: The mean staining score (MSS) of IGFR1 in CM and its nerves were higher in the CG than in the UTG. These results were statistically significant (p = 0.01 and p = 0.02). Although the MSS of IGF1R was higher in the vessels of CM in the CG than the UTG, this was not statistically significant (p = 0.48). CONCLUSIONS: IGFR1 with heterotetrameric receptor via IGF1, IGF2, insulin, and probably androgen, contribute to the remodeling and development of CM as well as the testis descent. In the current study, the presence of the IGFR1 in the CM was shown. Additionally, the IGFR1 density of the CM was lower in the UT cases than in the CG cases. Further evaluation of IGFR1 and other etiological factors can elucidate how they interact.

Association of abdominal muscle composition with prediabetes and diabetes: The CARDIA study.

AIM: To evaluate the relationship of abdominal muscle lean tissue and adipose tissue volumes with prediabetes and diabetes. RESEARCH DESIGN AND METHODS: We measured abdominal muscle composition in 3170 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study who underwent computed tomography (CT) at Year 25 of follow-up (ages, 43-55 years). Multinomial regression analysis was used to evaluate the associations of CT-measured intermuscular adipose tissue (IMAT), lean muscle tissue (lean) and visceral adipose tissue (VAT) volumes with diabetes at any point during the CARDIA study, newly detected prediabetes, prior history of prediabetes, and normal glucose tolerance. Models were adjusted for potential confounding factors: age, sex, race, height, smoking status, hypertension, hyperlipidaemia, cardiorespiratory fitness and study centre. RESULTS: Higher IMAT, lean and VAT volumes were all separately associated with a higher prevalence of prediabetes and diabetes. Inclusion of VAT volume in models with both IMAT volume and lean volume attenuated the association of IMAT with both prediabetes and diabetes, but higher lean volume retained its association with prediabetes and diabetes. Individuals in the highest IMAT quartile, coupled with VAT in its lower three quartiles, had a higher prevalence of diabetes, but not of prediabetes, than those with both IMAT and VAT in their respective lower three quartiles. Adjusting for cardiorespiratory fitness did not substantially change the findings. CONCLUSION: Higher IMAT volume was associated with a higher prevalence of diabetes even after adjustment for VAT volume. However, further study is warranted to understand the complicated relationship between abdominal muscle and adipose tissues.

Distinct Compartmentalization of the Chemokines CXCL1 and CXCL2 and the Atypical Receptor ACKR1 Determine Discrete Stages of Neutrophil Diapedesis.

Neutrophils require directional cues to navigate through the complex structure of venular walls and into inflamed tissues. Here we applied confocal intravital microscopy to analyze neutrophil emigration in cytokine-stimulated mouse cremaster muscles. We identified differential and non-redundant roles for the chemokines CXCL1 and CXCL2, governed by their distinct cellular sources. CXCL1 was produced mainly by TNF-stimulated endothelial cells (ECs) and pericytes and supported luminal and sub-EC neutrophil crawling. Conversely, neutrophils were the main producers of CXCL2, and this chemokine was critical for correct breaching of endothelial junctions. This pro-migratory activity of CXCL2 depended on the atypical chemokine receptor 1 (ACKR1), which is enriched within endothelial junctions. Transmigrating neutrophils promoted a self-guided migration response through EC junctions, creating a junctional chemokine "depot" in the form of ACKR1-presented CXCL2 that enabled efficient unidirectional luminal-to-abluminal migration. Thus, CXCL1 and CXCL2 act in a sequential manner to guide neutrophils through venular walls as governed by their distinct cellular sources.

6% Hydroxyethyl starch (HES 130/0.4) diminishes glycocalyx degradation and decreases vascular permeability during systemic and pulmonary inflammation in mice.

BACKGROUND: Increased vascular permeability is a pathophysiological hallmark of sepsis and results in increased transcapillary leakage of plasma fluid, hypovolemia, and interstitial edema formation. 6% hydroxyethyl starch (HES 130/0.4) is commonly used to treat hypovolemia to maintain adequate organ perfusion and oxygen delivery. The present study was designed to investigate the effects of 6% HES 130/0.4 on glycocalyx integrity and vascular permeability in lipopolysaccharide (LPS)-induced pulmonary inflammation and systemic inflammation in mice. METHODS: 6% HES 130/0.4 or a balanced electrolyte solution (20 ml/kg) was administered intravenously 1 h after cecal ligation and puncture (CLP) or LPS inhalation. Sham-treated animals receiving 6% HES 130/0.4 or the electrolyte solution served as controls. The thickness of the endovascular glycocalyx was visualized by intravital microscopy in lung (LPS inhalation model) or cremaster muscle (CLP model). Syndecan-1, hyaluronic acid, and heparanase levels were measured in blood samples. Vascular permeability in the lungs, liver, kidney, and brain was measured by Evans blue extravasation. RESULTS: Both CLP induction and LPS inhalation resulted in increased vascular permeability in the lung, liver, kidney, and brain. 6% HES 130/0.4 infusion led to significantly reduced plasma levels of syndecan-1, heparanase, and hyaluronic acid, which was accompanied by a preservation of the glycocalyx thickness in postcapillary venules of the cremaster (0.78 ± 0.09 µm vs. 1.39 ± 0.10 µm) and lung capillaries (0.81 ± 0.09 µm vs. 1.49 ± 0.12 µm). CONCLUSIONS: These data suggest that 6% HES 130/0.4 exerts protective effects on glycocalyx integrity and attenuates the increase of vascular permeability during systemic inflammation.

Plasminogen Activator Inhibitor-1 Promotes Neutrophil Infiltration and Tissue Injury on Ischemia-Reperfusion.

OBJECTIVE: Ischemia-reperfusion (I/R) injury significantly contributes to organ dysfunction and failure after myocardial infarction, stroke, and transplantation. In addition to its established role in the fibrinolytic system, plasminogen activator inhibitor-1 has recently been implicated in the pathogenesis of I/R injury. The underlying mechanisms remain largely obscure. APPROACH AND RESULTS: Using different in vivo microscopy techniques as well as ex vivo analyses and in vitro assays, we identified that plasminogen activator inhibitor-1 rapidly accumulates on microvascular endothelial cells on I/R enabling this protease inhibitor to exhibit previously unrecognized functional properties by inducing an increase in the affinity of ß2 integrins in intravascularly rolling neutrophils. These events are mediated through low-density lipoprotein receptor-related protein-1 and mitogen-activated protein kinase-dependent signaling pathways that initiate intravascular adherence of these immune cells to the microvascular endothelium. Subsequent to this process, extravasating neutrophils disrupt endothelial junctions and promote the postischemic microvascular leakage. Conversely, deficiency of plasminogen activator inhibitor-1 effectively reversed leukocyte infiltration, microvascular dysfunction, and tissue injury on experimental I/R without exhibiting side effects on microvascular hemostasis. CONCLUSIONS: Our experimental data provide novel insights into the nonfibrinolytic properties of the fibrinolytic system and emphasize plasminogen activator inhibitor-1 as a promising target for the prevention and treatment of I/R injury.

Influence of tobacco, alcohol and diabetes on the collagen of cremaster muscle in patients with inguinal hernias / Influência do tabaco, álcool e diabete sobre a interação célula-colágeno em músculo cremaster de humanos com hérnias inguinais

ABSTRACT Background: New findings point out that the mechanism of formation of the hernias can be related to the collagenous tissues, under activity of aggressive agents such as the tobacco, alcohol and diabetes. Aim: To analyze the collagen present in the cremaster muscle in patients with inguinal hernias, focusing the effect of tobacco, alcohol, and diabetes. Methods: Fifteen patients with inguinal hernia divided in three groups were studied: group I (n=5) was control; group II (n=5) were smokers and/or drinkers; and group III (n=5) had diabetes mellitus. All subjects were underwent to surgical repair of the inguinal hernias obeying the same pre, intra and postoperative conditions. During surgery, samples of the cremaster muscle were collected for analysis in polarized light microscopy, collagen morphometry and protein. Results: The area occupied by the connective tissue was higher in groups II and III (p<0.05). The collagen tissue occupied the majority of the samples analyzed in comparison to the area occupied by muscle cells. The content of total protein was higher in groups II and III compared to the control group (p<0.05). Conclusion: The tobacco, alcohol and diabetes cause a remodel the cremaster muscle, leading to a loss of support or structural change in this region, which may enhance the occurrences and damage related to inguinal hernias.

RESUMO Racional: Estudos recentes sinalizam que o mecanismo de formação das hérnias pode estar relacionado aos tecidos colagenosos, sob a ação de agentes agressores como o tabaco, o álcool e o diabete. Objetivo: Avaliar o colágeno presente no músculo cremaster em pacientes com hérnias inguinais enfocando o efeito do tabaco, álcool e diabete. Métodos: Foram estudados 15 pacientes com hérnias inguinais divididos em: grupo I (n=5) controles; grupo II (n=5) indivíduos fumantes e/ou etilistas; e grupo III (n=5) indivíduos que apresentavam diabete melito. Todos foram submetidos à correção cirúrgica das hérnias inguinais obedecendo às mesmas condições pré, intra e pós-operatórias. Durante o procedimento cirúrgico, amostras do músculo cremaster foram coletadas para análises em microscopia de luz polarizada, morfometria do colágeno e de proteínas. Resultados: A área ocupada por tecido conjuntivo foi maior nos grupos II e III (p<0,05). O tecido colágeno ocupou a maior parte das amostras analisadas, em comparação à área ocupada pelas células musculares. O conteúdo de proteínas totais foi maior nos grupos II e III, quando comparado com o grupo controle (p<0,05). Conclusão: O tabaco, o álcool e o diabete ocasionam remodelação no músculo cremaster, levando à perda de suporte ou alteração estrutural nesta região, podendo intensificar as ocorrências e os danos relacionados às hérnias inguinais.

Presence of Toxoplasma gondii in Pork Intended for Human Consumption in Tropical Southern Mexico.

BACKGROUND: Toxoplasmosis is caused by the protozoon Toxoplasma gondii, which is one of the most widespread parasites that infect animals and humans worldwide. One of the main routes of infection for humans is through the consumption of infected meat containing bradyzoites in tissue cysts. Pork is one of the foremost meat types associated with outbreaks of acute toxoplasmosis in humans. MATERIALS AND METHODS: Sixty blood samples were collected from finished pigs at slaughter and their sera was evaluated by an indirect-IgG ELISA. Matched muscle samples were obtained from the tongue and loin. Whole blood and tissue samples were evaluated to search for T. gondii DNA using a nested-polymerase chain reaction. RESULTS: Seroprevalence of T. gondii was 96.6% (58/60) of sampled pigs. Meanwhile, T. gondii DNA was present in 23.21% of tongue tissue samples (13/56), 7% of loin tissues (4/57), and 0% in blood samples (0/44), respectively. Two pigs were serologically indeterminate. CONCLUSION: This is the first report of the presence of T. gondii DNA in tissue samples obtained from finalized pigs. Results from the present study suggest a high exposure to T. gondii in pigs intended for human consumption from the tropical region of Mexico. Thus, the consumption of some undercooked pork meat meals typical from the southern region of Mexico could represent a significant risk for acquiring infection for the human population.

Congenital Partial Absence of Trapezius with Variant Pattern of Rectus Sheath.

Musculocutaneous pedicled/free flaps are an essential prerequisite for reconstructive surgery. Amongst the trunk muscles commonly harvested for flaps, the trapezius and rectus abdominis provide satisfactory coverage for cranial and trunk defects. unilateral/bilateral or partial congenital absence of trapezius muscle is well documented and may result in muscular imbalances compromising posture and limb movements. During routine cadaveric dissection, we encountered a case of bilateral partial absence of occipital part of the trapezius muscle. Concurrently, the ventral abdominal musculature displayed the aponeurosis of transversus abdominis muscle solely forming the posterior wall of the rectus sheath. These conjointly occurring anomalies advocate a compensatory strengthening of the anterior wall of rectus sheath in response to the congenital absence of occipital part of the trapezius, probably to counteract the postural instability. The present study focuses on recognition of compensatory mechanisms resulting from congenital variations as identification of such processes may prevent chronic debilitating conditions.

INFLUENCE OF TOBACCO, ALCOHOL AND DIABETES ON THE COLLAGEN OF CREMASTER MUSCLE IN PATIENTS WITH INGUINAL HERNIAS.

Background: New findings point out that the mechanism of formation of the hernias can be related to the collagenous tissues, under activity of aggressive agents such as the tobacco, alcohol and diabetes. Aim: To analyze the collagen present in the cremaster muscle in patients with inguinal hernias, focusing the effect of tobacco, alcohol, and diabetes. Methods: Fifteen patients with inguinal hernia divided in three groups were studied: group I (n=5) was control; group II (n=5) were smokers and/or drinkers; and group III (n=5) had diabetes mellitus. All subjects were underwent to surgical repair of the inguinal hernias obeying the same pre, intra and postoperative conditions. During surgery, samples of the cremaster muscle were collected for analysis in polarized light microscopy, collagen morphometry and protein. Results: The area occupied by the connective tissue was higher in groups II and III (p<0.05). The collagen tissue occupied the majority of the samples analyzed in comparison to the area occupied by muscle cells. The content of total protein was higher in groups II and III compared to the control group (p<0.05). Conclusion: The tobacco, alcohol and diabetes cause a remodel the cremaster muscle, leading to a loss of support or structural change in this region, which may enhance the occurrences and damage related to inguinal hernias.

Racional: Estudos recentes sinalizam que o mecanismo de formação das hérnias pode estar relacionado aos tecidos colagenosos, sob a ação de agentes agressores como o tabaco, o álcool e o diabete. Objetivo: Avaliar o colágeno presente no músculo cremaster em pacientes com hérnias inguinais enfocando o efeito do tabaco, álcool e diabete. Métodos: Foram estudados 15 pacientes com hérnias inguinais divididos em: grupo I (n=5) controles; grupo II (n=5) indivíduos fumantes e/ou etilistas; e grupo III (n=5) indivíduos que apresentavam diabete melito. Todos foram submetidos à correção cirúrgica das hérnias inguinais obedecendo às mesmas condições pré, intra e pós-operatórias. Durante o procedimento cirúrgico, amostras do músculo cremaster foram coletadas para análises em microscopia de luz polarizada, morfometria do colágeno e de proteínas. Resultados: A área ocupada por tecido conjuntivo foi maior nos grupos II e III (p<0,05). O tecido colágeno ocupou a maior parte das amostras analisadas, em comparação à área ocupada pelas células musculares. O conteúdo de proteínas totais foi maior nos grupos II e III, quando comparado com o grupo controle (p<0,05). Conclusão: O tabaco, o álcool e o diabete ocasionam remodelação no músculo cremaster, levando à perda de suporte ou alteração estrutural nesta região, podendo intensificar as ocorrências e os danos relacionados às hérnias inguinais.

The association between abdominal muscle and type II diabetes across weight categories in diverse post-menopausal women.

CONTEXT: Despite the key role of muscle in glucose regulation, little is known about the association between muscle area and prevalence of metabolic disorders, or the role low muscle may play in normal weight metabolic obesity. OBJECTIVE: The objective was to assess the independent associations between both abdominal muscle and fat depositions (measured by computed tomography) and the prevalence of type II diabetes, and to explore the modifying role of weight category. DESIGN: We conducted a cross-sectional analysis of the 2001-2002 visit for the Rancho Bernardo Study, Filipino Women's Health Study, and Health Assessment Study of African American Women. SETTING AND PARTICIPANTS: Participants were 392 community-dwelling older women (mean age = 64) free of clinical cardiovascular disease. MAIN OUTCOME MEASURE: The main outcome was prevalence of type II diabetes, defined as use of anti-diabetes medication, fasting plasma glucose ≥ 126 mg/dL, and/or OGTT ≥ 200 mg/dL. RESULTS: Adjusting for demographics, hypertension, estrogen use, lipids, smoking, physical activity, visceral fat area, and height, a greater muscle-to-total abdominal area ratio (MAR) was associated with lower odds of diabetes [OR = 0.63 per standard deviation, 95% CI (0.43-0.92), p = .02]. Higher visceral fat was associated with greater odds of diabetes in fully adjusted models including total muscle area [OR = 1.48, 95% CI (1.09, 2.01), p = .01]. Associations between MAR and diabetes were stronger for normal weight (BMI 18.5-24.9; OR = 0.32) than overweight/obese women (BMI ≥ 25, OR = 0.71, p-for-interaction = 0.046). Associations with visceral fat did not differ by BMI (p-for-interaction = 0.71). CONCLUSIONS: In older women, abdominal muscle area is inversely associated with type II diabetes independent of visceral adiposity, particularly for normal weight women.

Abdomen: normal variations and benign conditions resulting in uptake on FDG-PET/CT.

The increasing use of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in oncology has led to: improved sensitivity and specificity in detecting localized and metastatic disease, increased ability to target biopsies to the site of most aggressive disease, and development of a noninvasive biomarker to assess prognosis and effects of therapy. However, for correct interpretation of FDG-PET/CT studies, an understanding of both normal and abnormal imaging appearances commonly encountered in oncology patients is important. This article discusses commonly seen normal variations and benign findings on FDG-PET/CT of the abdomen.

Motor protein function in skeletal abdominal muscle of cachectic cancer patients.

Cachexia presents with ongoing muscle wasting, altering quality of life in cancer patients. Cachexia is a limiting prognostic factor for patient survival and health care costs. Although animal models and human trials have shown mechanisms of motorprotein proteolysis, not much is known about intrinsic changes of muscle functionality in cancer patients suffering from muscle cachexia, and deeper insights into cachexia pathology in humans are needed. To address this question, rectus abdominis muscle samples were collected from several surgical control, non-cachectic and cachectic cancer patients and processed for skinned fibre biomechanics, molecular in vitro motility assays, myosin isoform protein compositions and quantitative ubiquitin polymer protein analysis. In pre-cachectic and cachectic cancer patient samples, maximum force was significantly compromised compared with controls, but showed an unexpected increase in myofibrillar Ca(2+) sensitivity consistent with a shift from slow to fast myosin isoform expression seen in SDS-PAGE analysis and in vitro motility assays. Force deficit was specific for 'cancer', but not linked to presence of cachexia. Interestingly, quantitative ubiquitin immunoassays revealed no major changes in static ubiquitin polymer protein profiles, whether cachexia was present or not and were shown to mirror profiles in control patients. Our study on muscle function in cachectic patients shows that abdominal wall skeletal muscle in cancer cachexia shows signs of weakness that can be partially attributed to intrinsic changes to contractile motorprotein function. On protein levels, static ubiquitin polymeric distributions were unaltered, pointing towards evenly up-regulated ubiquitin protein turnover with respect to ubiquitin conjugation, proteasome degradation and de-ubiquitination.

Elevated concentration of oxidized LDL together with poor cardiorespiratory and abdominal muscle fitness predicts metabolic syndrome in young men.

BACKGROUND: Metabolic syndrome (MetS) is associated with increased oxidized LDL (ox-LDL), systemic inflammation, and poor cardiorespiratory fitness. We examined affiliations of these factors and the effect of muscular fitness on MetS in young healthy men. METHODS: Physical fitness, ox-LDL, tumor necrosis factor α (TNFα), interleukin-6 (IL-6) and serum lipids were measured in a nationally representative sample of Finnish young men with and without MetS. Participants (mean age 25.1years) performed tests of maximal oxygen uptake (VO2max) and muscle fitness, and were divided into MetS (n=54, IDF 2007 criteria) and non-MetS (n=790). Age, smoking and leisure-time physical activity were used as covariates (ANCOVA). RESULTS: The MetS group had lower results in VO2max and all of the muscular fitness tests (excluding grip strength) (P<0.0001, in all). Ox-LDL, ox-LDL/HDL-cholesterol, ox-LDL/LDL-cholesterol, TNFα and IL-6 were all higher in the MetS group than in the non-MetS group (P<0.01, in all). In stepwise multivariate logistic regression analysis (adjusted to MetS criteria), higher ox-LDL (OR 1.118, 95% CI 1.078-1.160), lower VO2max (OR 0.938, 95% CI 0.901-0.977) and lower sit-ups (OR 0.898, 95% CI 0.844-0.956) predicted MetS (p<0.05, in all). CONCLUSIONS: Young men with MetS possess significantly poorer cardiorespiratory and muscle fitness, together with elevated systemic levels of ox-LDL, TNFα and IL-6 compared to non-MetS young men. Of these variables, ox-LDL, VO2max and sit-ups predicted MetS. Based on these findings, poor physical fitness and elevated concentration of ox-LDL are significant predisposing factors in the development of MetS.

The effects of chronically increased intra-abdominal pressure on the rabbit diaphragm.

BACKGROUND: Diaphragmatic muscular remodeling is caused by various conditions and was mainly studied in pulmonary pathologies and chronic alterations of intra-thoracic pressure. We investigate the effect of the chronically increased intra-abdominal pressure (IAP) on the diaphragm by morphological and biochemical analysis. METHODS: Thirty rabbits were divided into control and study groups. IAP was increased in group B to 12 mmHg for 2 months. The left hemidiaphragm underwent morphological, while the right underwent biochemical analysis. RESULTS: In H&E, all fibers were normal. ATPase analysis demonstrated that type I fibers show no differences between groups. Type ΙΙ(Α) were decreased (p = 0.016) while type ΙΙ(Β/X) fibers were increased (p = 0.025) in group B. Fibers with resistance to fatigue were decreased in group B (p = 0.024). In group B, biochemical activity for glutathione reductase (p = 0.004), glutathione peroxidase (p = 0.021), protein carbonylation (0.029), lipid peroxidation (p = 0.005), and balance of preoxidative-antioxidative factors (p = 0.006) was increased. CONCLUSIONS: Chronically increased IAP induces alterations to the rabbit diaphragm. Adaptation, equivalent to strenuous contraction, transforms the diaphragm to be functionally more efficient toward workload but makes it vulnerable against oxidative stress.

Can chronic intra-abdominal hypertension cause oxidative stress to the abdominal wall muscles? An experimental study.

BACKGROUND: The aim of this study was to test the hypothesis that intra-abdominal hypertension alone could trigger such changes to the rectus abdominis muscle that would lead to an imbalance between oxidant production and antioxidant protection. MATERIALS AND METHODS: Forty-five New Zealand white rabbits were divided into three groups and a rubber bag was implanted into their peritoneal cavity. In group A (n = 15), the bag was empty. In group B (n = 15), it was filled with normal saline to achieve an intra-abdominal pressure of over 12 mm Hg. In group C (n = 15), it was filled with lead equiponderant to the mean weight of the normal saline injected in group B. After 8 weeks, we measured in rectus abdominis muscle biopsies the lipid peroxidation products, the protein carbonyl content, the total glutathione and superoxide dismutase (SOD) concentration, the activity of glutathione reductase and glutathione peroxidase, and the pro-oxidant-antioxidant balance. RESULTS: The lipid peroxidation products were significantly higher in group B compared with both group A (P = 0.026) and group C (P < 0.001). The total protein carbonyl content was significantly higher in group B compared with both group A (P = 0.006) and group C (P < 0.001). No difference was found between the three groups in total glutathione (P = 0.735) and SOD (P = 0.410) concentration. Glutathione peroxidase activity was higher in groups B and C compared with group A (P = 0.05 and P = 0.003, respectively). Glutathione reductase activity was higher in group B compared with group A (P = 0.005) and group C (P = 0.001). The pro-oxidant antioxidant balance was higher in group B compared with the group A (P = 0.012). CONCLUSIONS: Maintaining the IP over 12 mm Hg for 8 wk caused increased oxidative damage to both lipids and proteins with an increased pro-oxidant-antioxidant balance. In an attempt to compensate for this damage the muscle fibers increased their glutathione reductase and glutathione peroxidase activity.

Matrix metalloproteinase imbalance in inguinal hernia formation.

BACKGROUND: Emerging evidence supports the role of matrix metalloproteinases (MMPs) in hernia formation. However, the imbalance between the proteolytic activity of MMPs and their endogenous inhibitors (TIMPs) has not been investigated. The aim of the present study was to determine changes of MMP and TIMP levels in patients with inguinal hernia. METHODS: Two matrix metalloproteinases (MMP-9 and MMP-2) and their main inhibitors TIMP-1 and TIMP-2 were evaluated in consecutive patients undergoing inguinal hernia repair and control subjects. MMP/TIMP quantification was performed using ELISA in abdominal fascia tissue specimens and preoperative plasma samples. RESULTS: Tissue explants from hernia patients produced significantly higher levels of MMP-9 and MMP-2, and reduced TIMP-1 and TIMP-2 concentrations compared to those of controls. In plasma, a reverse correlation was found regarding the concentrations of MMPs; the circulating levels of MMP-9 and MMP-2 were significantly lower in patients with inguinal hernia than controls. Furthermore, hernia patients were found to have elevated plasma levels of TIMP-2 and reduced plasma levels of TIMP-1. CONCLUSIONS: The imbalance in MMP/TIMP activity indicates a dysregulation of the extracellular matrix degradation process in patients with inguinal hernia. The results of the present study suggest that impaired collagen metabolism may be an underlying pathophysiological mechanism of inguinal hernia formation.