Decreased collagen type III synthesis in skin fibroblasts is associated with parastomal hernia following colostomy.

Parastomal hernia (PH) is a common complication following stoma formation. Abnormal collagen synthesis has been suggested to be involved in PH. The aim of the present study is to explore the effect and mechanism of the collagen synthesis on PH. Data from 157 patients with rectal cancer who received permanent colostomy were retrospectively collected and analyzed to identify the risk factors for PH. Primary culture of skin fibroblasts from patients with or without PH were performed. Cell viability, migration and invasion levels were detected by Cell Counting Kit­8, and wound healing and Transwell assays, respectively. Reverse transcription quantitative polymerase chain reaction and western blot analysis assays were performed to measure the gene and protein expression levels, respectively. The risk factors of sex, body mass index, aperture size and collagen expression were closely associated with the occurrence of PH. α1 (III) procollagen expression levels were significantly increased in patients with PH, while no marked difference in α1 (I) procollagen mRNA expression levels were observed in patients with or without PH. The viability and motility of fibroblasts from the patients with hernia were suppressed. The expression levels of matrix metalloproteinase (MMP)­2 and MMP­9 were decreased while the levels of collagen III and metalloproteinase inhibitor 1 (TIMP­1) were increased in the fibroblasts from the patients with PH. Silencing TIMP­1 expression promoted fibroblast migration and invasion and reversed the patterns of MMP­2, MMP­9 and collagen III expression in fibroblasts from the patients with PH. Decreased collagen III may inhibit the development of PH, potentially through decreases in TIMP­1 expression. Therefore, the results from the present study may provide a novel target for PH therapy.

Age-Correlated Phenotypic Alterations in Cells Isolated From Human Degenerated Intervertebral Discs With Contained Hernias.

STUDY DESIGN: Human intervertebral disc (hIVD) cells were isolated from 41 surgically excised samples and assessed for their phenotypic alterations with age. OBJECTIVE: Toward the design of novel anti-aging strategies to overcome degenerative disc disease (DDD), we investigated age-correlated phenotypic alterations that occur on primary hIVD cells. SUMMARY OF BACKGROUND DATA: Although regenerative medicine holds great hope, much is still to be unveiled on IVD cell biology and its intrinsic signaling pathways, which can lead the way to successful therapies for IDD. A greater focus on age-related phenotypic changes at the cell level would contribute to establish more effective anti-aging/degeneration targets. METHODS: The study was subdivided in four main steps: i) optimization of primary cells isolation technique; ii) high-throughput cell morphology analysis, by imaging flow cytometry (FC) and subsequent validation by histological analysis; iii) analysis of progenitor cell surface markers expression, by conventional FC; and iv) statistical analysis and correlation of cells morphology and phenotype with donor age. RESULTS: Three subsets of cells were identified on the basis of their diameter: small cell (SC), large cell (LC), and super LC (SLC). The frequency of SCs decreased nearly 50% with age, whereas that of LCs increased nearly 30%. Interestingly, the increased cells size was due to an enlargement of the pericellular matrix (PCM). Moreover, the expression pattern for CD90 and CD73 was a reflexion of age, where older individuals show reduced frequencies of positive cells for those markers. Nevertheless, the elevated percentages of primary positive cells for the mesenchymal stem cells (MSCs) marker CD146 found, even in some older donors, refreshed hope for the hypothetical activation of the self-renewal potential of the IVD. CONCLUSION: These findings highlight the remarkable morphological alterations that occur on hIVD cells with aging and degeneration, while reinforcing previous reports on the gradual disappearance of an endogenous progenitor cell population. LEVEL OF EVIDENCE: N/A.

Neutrophil-to-Lymphocyte Ratio Predicts the Severity of Incarcerated Groin Hernia.

BACKGROUND The incarceration of a segment of bowel within a groin hernia can result in intestinal strangulation if hernia treatment is delayed. Once intestinal strangulation occurs, a bowel resection may be required, and there is an overall increased risk for postoperative complications. The aim of this study was to identify biomarkers to predict the severity of an incarcerated groin hernia. MATERIAL AND METHODS We retrospectively evaluated the records of 95 patients with incarcerated groin hernias who underwent emergency surgical correction of the hernias. The need for a bowel resection was regarded as an indicator of severity in incarcerated groin hernia patients. The patients were divided into 2 groups: patients with bowel resection surgery and patients without bowel resection surgery. RESULTS We discovered that leukocyte count (leukocyte count ≥10×10³/mm³), neutrophil-to-lymphocyte ratio (NLR, NLR ≥11.5), presentation of bowel obstruction, and duration of incarceration (duration of incarceration ≥26 h) were significantly associated with bowel resection in incarcerated groin hernia patients by using the chi-square test. Factors such as leukocyte count, NLR, presentation of bowel obstruction, and duration of incarceration were analyzed using multivariate logistic regression analysis. We found that NLR, presentation of bowel obstruction, and duration of incarceration were independently and significantly related to bowel resection in incarcerated groin hernia patients. CONCLUSIONS An elevated NLR can serve as a biomarker for the prediction of severity of incarcerated groin hernias. Additionally, incarcerated groin hernia patients who present with bowel obstruction or with duration of intestinal incarceration longer than 26 h have an increased risk for bowel resection.

Herniated Thoracic Spleen Mimicking Lung Metastasis on 68Ga-Labeled Prostate-Specific Membrane Antigen PET/CT in a Patient With Prostate Cancer.

We report a case of clinically asymptomatic patient of prostate cancer who was previously subjected to radical prostatectomy presenting with a rising serum prostate-specific antigen level of 6.6 ng/mL. Whole-body PET/CT with Ga-labeled prostate-specific membrane antigen ligand was performed to assess for disease recurrence, which revealed an intense tracer uptake in a soft tissue mass in left hemithorax mimicking lung metastasis; which later turned out to be splenic tissue.

In vitro cellular response to oxidized collagen-PLLA hybrid scaffolds designed for the repair of muscular tissue defects and complex incisional hernias.

Unique poly(l-lactic acid) (PLLA)-based scaffolds were constructed by embedding knitted PLLA yarns within a bioresorbable and differentially crosslinked three-dimensional (3D) oxidized collagen scaffold. The scaffolds were designed specifically for the repair of complex incisional abdominal wall hernias and the repair of defects within planar muscular tissues, such as the bladder. The chemical composition of the collagen matrix and the percentage of scaffold infiltration were compared for the different scaffold compositions. The results demonstrate that the incorporation of the collagen sponge within the PLLA scaffold facilitated bladder smooth muscle cell (bSMC) adhesion and proliferation. The highest dose of oxidized collagen (Oxicol) demonstrated better cell adhesion, resulting in the largest cell densities and most uniform distribution throughout the 3D collagen sponge. This formulation promoted the greatest α-smooth muscle actin (αSMA) expression detected through immunohistochemical staining and western blotting. For abdominal wall repair applications, the proliferation and differentiation of C2C12 myoblasts and myotube formation were studied. Following 7 days of myogenic induction, the greatest expression of mRNA of the myogenic markers myogenin and MRF4 was observed within the scaffolds with the highest dose of oxidized collagen, 1.5- and 3.85-fold greater expressions, respectively, compared to PLLA with unmodified collagen. Furthermore, in vitro myotube formation and MyMC expression were enhanced in the Oxicol scaffolds. We conclude that the Oxicol scaffold formulation with a high-dose oxidized collagen ratio provides enhanced myogenesis and αSMA, and the biological induction cues necessary to achieve better tissue integration, than standard PLLA scaffolds in the treatment of complex abdominal wall hernias. Copyright © 2013 John Wiley & Sons, Ltd.

Cistocele escrotal incidental. Signo de la mancuerna / Incidental finding of scrotal. Cystocele dumbbell sign

No disponible

Tamoxifen induces the development of hernia in mice by activating MMP-2 and MMP-13 expression.

Hernia is a disease with defects in collagen synthesis/metabolism. However, the underlying mechanisms for hernia formation have not been fully defined. Tamoxifen is a selective estrogen receptor modulator and used for patients with breast cancer. Tamoxifen also has pleiotropic and side effects. Herein, we report that tamoxifen treatment resulted in an appearance of a large bulge in the low abdomen between the hind legs in male but not in female mice. The autopsy demonstrated that the low abdominal wall was broken and a large amount of intestine herniated out of the abdominal cavity. Histological analysis indicated that tamoxifen caused structural abnormalities in the low abdominal wall which were associated with decreased type II collagen content. Furthermore, we determined increased matrix metalloproteinase-2 (MMP-2) and MMP-13 expression in the tissue. In vitro, tamoxifen induced MMP-2 and MMP-13 expression in fibroblasts. The promoter activity analysis and ChIP assay demonstrate that induction of MMP-13 expression was associated with activation of JNK-AP-1 and ERK1/2 signaling pathways while induction of MMP-2 expression was related to activation of the ERK1/2 signaling pathway. Taken together, our study establishes a novel murine hernia model, defines a severe side effect of tamoxifen, and suggests a caution to male patients receiving tamoxifen treatment.

The collagen turnover profile is altered in patients with inguinal and incisional hernia.

BACKGROUND: Disturbed metabolism in the extracellular matrix (ECM) contributes to formation of abdominal wall hernias. The aim of this study was to gain deeper insight into the ECM turnover in hernia patients by analyzing serum biomarkers specifically reflecting collagen synthesis and breakdown in the interstitial matrix (types I, III, and V collagens) and in the basement membrane (type IV collagen). MATERIAL AND METHODS: Patients with 3 different types of hernias were included: Primary unilateral inguinal hernia (n = 17), multiple hernias defined as ≥3 hernias (n = 21), and incisional hernia (n = 25). Patients without hernias scheduled to undergo elective operation for gallstones (n = 18) served as controls. Whole venous blood was collected preoperatively. Biomarkers for synthesis of interstitial matrix (PINP, Pro-C3, P5CP) and basement membrane (P4NP) as well as corresponding degradation (C1M, C3M, C5M, and C4M) were measured in serum by validated, solid-phase competitive assays. RESULTS: In inguinal hernia patients, the turnover of the interstitial matrix collagens type III (P < .042) and V (P < .001) was decreased compared with controls, whereas the turnover of the basement membrane collagen type IV was increased (P < .001). In incisional hernia patients, the turnover of type V collagen was decreased (P = .048) and the turnover of type IV collagen was increased compared with the hernia-free controls (P < .001). CONCLUSION: Hernia patients demonstrated systemically altered collagen metabolism. The serologic turnover profile of type IV collagens may predict the presence of inguinal and incisional hernia. Regulation of type IV collagen turnover may be crucial for hernia development.

Epidermal growth factor and active caspase-3 expression in the levator ani muscle of dogs with and without perineal hernia.

OBJECTIVES: To perform a histological and immunohistochemical study of epidermal growth factor, transforming growth factor-alpha and their receptor, as well as the apoptotic signal active caspase-3 in the levator ani muscle of dogs with and without perineal hernia. METHODS: Biopsy specimens of the levator ani muscle were obtained from 25 dogs with perineal hernia and 4 non-affected dogs and were processed for Masson and immunohistochemical staining. RESULTS: The affected dogs exhibited myopathological features, internalised nuclei, destruction and abnormal size of muscle fibres, which were replaced by collagen. The immunohistochemical study revealed active caspase-3, epidermal growth factor, transforming growth factor-alpha and epidermal growth factor receptor in the levator ani. Compared to the healthy muscle, transforming growth factor-alpha staining intensity was lower in the affected muscle, whereas epidermal growth factor receptor and active caspase-3 staining were higher. CLINICAL SIGNIFICANCE: Pelvic diaphragm muscle weakening is the leading cause of perineal hernia in the dog. Survival and death signals expressed in these muscles may contribute to the pathogenesis of this disease. This study reports epidermal growth factor, transforming growth factor-alpha and epidermal growth factor receptor immunohistochemical expression in the skeletal muscle and suggests that perineal hernia in the dog is accompanied by levator ani muscle atrophy, increased expression of epidermal growth factor receptor, caspase-3 activation, and decreased expression of transforming growth factor-alpha.

A structure-based approach for mapping adverse drug reactions to the perturbation of underlying biological pathways.

Adverse drug reactions (ADR), also known as side-effects, are complex undesired physiologic phenomena observed secondary to the administration of pharmaceuticals. Several phenomena underlie the emergence of each ADR; however, a dominant factor is the drug's ability to modulate one or more biological pathways. Understanding the biological processes behind the occurrence of ADRs would lead to the development of safer and more effective drugs. At present, no method exists to discover these ADR-pathway associations. In this paper we introduce a computational framework for identifying a subset of these associations based on the assumption that drugs capable of modulating the same pathway may induce similar ADRs. Our model exploits multiple information resources. First, we utilize a publicly available dataset pairing drugs with their observed ADRs. Second, we identify putative protein targets for each drug using the protein structure database and in-silico virtual docking. Third, we label each protein target with its known involvement in one or more biological pathways. Finally, the relationships among these information sources are mined using multiple stages of logistic-regression while controlling for over-fitting and multiple-hypothesis testing. As proof-of-concept, we examined a dataset of 506 ADRs, 730 drugs, and 830 human protein targets. Our method yielded 185 ADR-pathway associations of which 45 were selected to undergo a manual literature review. We found 32 associations to be supported by the scientific literature.

Stromal cell-derived factor-1 and vascular endothelial growth factor may play an important role in the process of neovascularization of herniated intervertebral discs.

Increased levels of stromal cell-derived factor (SDF)-1 occur in certain pathological situations, however the relationship between SDF-1alpha expression and human intervertebral disc herniation is unknown. Vascular endothelial growth factor (VEGF) plays an essential role in the formation of new blood vessels. The present study used immunohistochemistry to measure the expression of SDF-1alpha and VEGF in surgical specimens of human intervertebral discs to evaluate their role in neovascularization. The frequency of expression of SDF-1alpha and VEGF was found to be significantly higher in extruded and sequestrated herniated intervertebral discs compared with bulging, protruding and prolapsed herniated discs and control discs and there was high correlation between SDF-1alpha and VEGF expressions. It is concluded that SDF-1alpha and VEGF are expressed in human intervertebral discs and their interaction may be important in accumulating endothelial progenitor cells during the neovascularization processes in herniated intervertebral discs.

Tissue calcium content in piglets with inguinal or scrotal hernias or cryptorchidism.

Scrotal and inguinal hernias are of great economic importance to the pig industry. These lesions are thought to result from incomplete closure of the inguinal ring and/or a patent processus vaginalis. Impairment of programmed cell death (PCD) may be involved in these abnormalities. As tissue Ca(2+) overload may be used as a measure of cell death, the aim of this study was to determine the tissue Ca(2+) content in samples of hernia sac, peritoneum, cremaster muscle and aqueous fluid from newborn piglets with scrotal or inguinal hernias (n=18) or cryptorchidism (n=18). Control samples from healthy piglets (n=20) were also evaluated. Tissue Ca(2+) content was determined by atomic absorption spectrophotometry. Significantly less Ca(2+) was found in the sacs (0.005 mg/g wt), peritoneal tissue (0.100 mg/g wt) and cremaster muscles (0.008 mg/g wt) of piglets with inguinal or scrotal hernias compared with control tissues (0.184, 0.144 and 0.048 mg/g wt for sacs, peritoneal tissue and cremaster muscles, respectively). These findings suggest that there may be perturbation of the apoptotic pathway in the urogenital tissues of affected piglets.

[Hernias as medical disease]. / Hernier som medicinsk sygdom.

Abnormal systemic collagen metabolism is thought to dispose to the development of hernias. Studies have shown that a reduced type-I/III collagen ratio predisposes to the development of hernias. Patient groups with reduced type-I/III collagen ratio and consequently increased risk of herniation include patients with Ehlers-Danlos, Marfans syndrome, osteogenesis imperfecta, cutis laxa, and patients with abdominal aortic aneurysms, colonic diverticula or stress urinary incontinence. Looking ahead, the perspective may be individualization of the operative technique for patients with a hernia, depending on their collagen profile.

Reduction of the available area for aqueous humor outflow and increase in meshwork herniations into collector channels following acute IOP elevation in bovine eyes.

PURPOSE: To understand how hydrodynamic and morphologic changes in the aqueous humor outflow pathway contribute to decreased aqueous humor outflow facility after acute elevation of intraocular pressure (IOP) in bovine eyes. METHODS: Enucleated bovine eyes were perfused at 1 of 4 different pressures (7, 15, 30, 45 mm Hg) while outflow facility was continuously recorded. Dulbecco PBS + 5.5 mM glucose containing fluorescent microspheres (0.5 mum, 0.002% vol/vol) was perfused to outline aqueous outflow patterns, followed by perfusion-fixation. Confocal images were taken along the inner wall (IW) of the aqueous plexus (AP) in radial and frontal sections. Percentage effective filtration length (PEFL; IW length exhibiting tracer labeling/total length of IW) was measured. Herniations of IW into collector channel (CC) ostia were examined and graded for each eye by light microscopy. RESULTS: Increasing IOP from 7 to 45 mm Hg coincided with a twofold decrease in outflow facility (P < 0.0001), a 33% to 57% decrease in PEFL with tracer confined more to the vicinity of CC ostia, progressive collapse of the AP, and increasing percentage of CC ostia exhibiting herniations (from 15.6% +/- 6.5% at 7 mm Hg to 95% +/- 2.3% at 30 mm Hg [P < 10(-4)], reaching 100% at 45 mm Hg). CONCLUSIONS: Decreasing outflow facility during acute IOP elevation coincides with a reduction in available area for aqueous humor outflow and the confinement of outflow to the vicinity of CC ostia. These hydrodynamic changes are likely driven by morphologic changes associated with AP collapse and herniation of IW of AP into CC ostia.

Hernia disease and collagen gene regulation: are there clues for intervention?

Collagens belong to the most abundant proteins in the body. After tissue injury, a coordinated regulation of collagen gene expression guides the formation of a provisional matrix that subsequently evolves into a mature scar with tensile strength. In the following, knowledge regarding collagen gene regulation that may provide insight into how to specifically address the biological problem of soft tissue weakness and recurrent hernia disease is summarized.

Modification of collagen formation using supplemented mesh materials.

BACKGROUND: Formation of recurrent inguinal and incisional hernia shows an underlying defect in the wound healing process. Even following mesh repair an altered collagen formation and insufficient mesh integration has been found as main reason for recurrences. Therefore the development of bioactive mesh materials to achieve a local modification of the scar formation to improve patients outcome is advisable. METHODS: Thirty-six male Wistar rats were used within this study. A Mersilene (R) mesh sample was implanted after midline skin incision and subcutaneous preparation. Before implantation mesh samples were incubated for 30 minutes with either one of the following agents: doxycycline, TGF-beta 3, zinc-hydrogeneaspartate, ascorbic acid, hyaluronic acid. Incubation with a physiologic 0.9 % NaCl solution served as control. Seven and 90 days after mesh implantation 3 animals from each group (n = 6) were sacrificed for morphological observations. Collagen quantity and quality was analyzed measuring the collagen/protein as well as the collagen type I/III ratio. RESULTS: Following an implantation interval of 90 days supplementation with doxycycline (39.3 +/- 7.0 microg/mg) and hyaluronic acid (34.4 +/- 5.8 microg/mg) were found to have a significantly increased collagen/protein ratio compared to implantation of the pure Mersilene (R) mesh samples (28.3 +/- 1.9 microg/mg). Furthermore, an overall increase of the collagen type I/III ratio was found in all groups indicating scar maturation over time. However, no significant differences were found after 7 and 90 days of implantation comparing collagen type I/III ratio of supplemented mesh samples and control group. CONCLUSIONS: In summary, we found an influence of supplemented mesh materials on collagen deposition. However, the investigated bioactive agents with reported influence on wound healing were not associated with an improved quality in scar formation.

Collagenase and surgical disease.

Collagen types I, II, and III are the most abundant extracellular matrix (ECM) proteins. Collagenase is a member of the matrix metalloproteinase (MMP) family of enzymes, and is the principal enzyme involved with collagen degradation. Cellular-ECM interactions are vitally important to tissue structure and function. In this review, we summarize recent work that highlights the role of collagenase in ECM remodeling and repair, and further report that alterations of collagenase expression, function, and/or regulation are found in many diverse disease states, including aortic aneurysms, tumor invasiveness and their metastases, and hernias. Collagenase is intimately involved in many surgical diseases, and represents a potential target for therapy.

Expression of relaxin receptor LRG7, canine relaxin, and relaxin-like factor in the pelvic diaphragm musculature of dogs with and without perineal hernia.

OBJECTIVES: To compare the expression of canine relaxin, relaxin-like factor (RLF), and relaxin receptors within the muscles of the pelvic diaphragm of dogs with perineal hernia (PH) and clinically normal dogs. STUDY DESIGN: In vivo comparative study. ANIMALS: Fifteen client-owned intact male dogs with PH were studied. Four mature intact male dogs with no evidence of perineal pathology served as controls. METHODS: Biopsy samples from the levator ani, coccygeus, and internal obturator muscles were obtained. RNA samples were reverse transcribed and analyzed by real-time PCR for the expression of canine relaxin receptor LRG7, relaxin, and RLF. RESULTS: Significantly higher expression levels of canine relaxin receptors occurred in the musculature of the pelvic diaphragm and internal obturator muscle in dogs with PH compared with normal dogs. Expression of canine RLF revealed no significant difference between dogs with PH and controls. The difference in the expression of canine relaxin between groups was not statistically significant. CONCLUSIONS: Relaxin receptor up-regulation occurs in the coccygeus, levator ani, and internal obturator muscles of dogs with PH. CLINICAL RELEVANCE: The higher expression of relaxin receptors within the muscles of the pelvic diaphragm in dogs with PH suggests that relaxin might play a role in the pathogenesis of PH. Atrophy of these muscles, which predisposes to PH, may be attributable to increased relaxin activity.

Relaxin of prostatic origin might be linked to perineal hernia formation in dogs.

Perineal hernia occurs spontaneously in older male dogs after idiopathic weakening of the pelvic diaphragm. Hernias invariably contain cystic paraprostatic tissues. Castration reduces incidence and recurrence after surgical repair. Although cystic prostatic hypertrophy is a consistent feature in patients with perineal hernia, an endocrine link of the disease to steroid sex hormones has not been demonstrated. Employing immunohistochemistry, we found intense relaxin immunoreactivity in dogs with perineal hernia within the epithelia of hypertrophic prostates and in periprostatic tissues. The prostate of normal dogs exhibited similar but less intense relaxin staining. In neutered dogs with prostatic atrophy, relaxin immunostaining was weak or absent. Periprostatic cysts highly expressed relaxin precursors in the fluid phase as shown by SDS-gel electrophoresis. Relaxin of prostatic origin, therefore, is possibly a local factor in connective tissue weakening and subsequently in perineal hernia formation.

Impaired balance of type I and type III procollagen mRNA in cultured fibroblasts of patients with incisional hernia.

BACKGROUND: Recent findings of an impaired protein ratio of type I to type III procollagen showed a disturbed collagen metabolism in incisional hernia development. We analyzed the type I and type III procollagen messenger RNA to investigate whether these findings represent the altered extracellular matrix or a primary defect at the transcriptional level. METHODS: We examined cultured skin fibroblasts of patients with incisional or recurrent incisional hernia in comparison with those without any previous incision (control) and those with a skin scar without clinical appearance of a hernia (scar). Immunohistochemical detection of a lowered protein ratio of type I and type III collagen in the hernia skin tissue leads to mRNA expression analysis. The procollagen mRNA and the ratio of type I to type III procollagen mRNA are detected by reverse transcriptase-polymerase chain reaction and Northern blot analysis, the collagens type I and III by Western blot analysis. RESULTS: Reverse transcriptase-polymerase chain reaction revealed an increase of type I procollagen mRNA in the incisional and recurrent hernia (0.90 +/- 0.04 and 1.19 +/- 0.04, respectively) compared with stable scar (0.54 +/- 0.02) or healthy tissue (0.43 +/- 0.01). The obvious rise of type III procollagen mRNA to 4.13 +/- 0.04 for incisional, 6.02 +/- 0.03 for recurrent hernia, 2.29 +/- 0.04 for stable scar, and 1.72 +/- 0.03 for the healthy tissue showed a significantly decreased ratio of type I to type III procollagen mRNA in the hernia patients as compared with the controls (P <.01). By Western blot analysis, an increase of type I and type III collagen protein and a significant rise in the corresponding ratio in the recurrent hernia group were detected. CONCLUSIONS: The altered synthesis of type I and type III collagen in cultured skin fibroblasts suggests a disorder of collagen metabolism, at least in patients with recurrent hernia. Hence, a basically impaired wound healing process is likely to contribute to the unsatisfactory results of incisional hernia repair.