Collagen matricryptin promotes cardiac function by mediating scar formation.

AIMS: A peptide mimetic of a collagen-derived matricryptin (p1159) was shown to reduce left ventricular (LV) dilation and fibrosis after 7 days delivery in a mouse model of myocardial infarction (MI). This suggested p1159 long-term treatment post-MI could have beneficial effects and reduce/prevent adverse LV remodeling. This study aimed to test the potential of p1159 to reduce adverse cardiac remodeling in a chronic MI model and to elucidate p1159 mode-of-action. MATERIALS AND METHODS: Using a permanent occlusion MI rodent model, animals received p1159 or vehicle solution up to 28 days. We assessed peptide treatment effects on scar composition and structure and on systolic function. To assess peptide effects on scar vascularization, a cohort of mice were injected with Griffonia simplicifolia isolectin-B4. To investigate p1159 mode-of-action, LV fibroblasts from naïve animals were treated with increasing doses of p1159. KEY FINDINGS: Matricryptin p1159 significantly improved systolic function post-MI (2-fold greater EF compared to controls) by reducing left ventricular dilation and inducing the formation of a compliant and organized infarct scar, which promoted LV contractility and preserved the structural integrity of the heart. Specifically, infarcted scars from p1159-treated animals displayed collagen fibers aligned parallel to the epicardium, to resist circumferential stretching, with reduced levels of cross-linking, and improved tissue perfusion. In addition, we found that p1159 increases cardiac fibroblast migration by activating RhoA pathways via the membrane receptor integrin α4. SIGNIFICANCE: Our data indicate p1159 treatment reduced adverse LV remodeling post-MI by modulating the deposition, arrangement, and perfusion of the fibrotic scar.

Dopamine receptor D3 agonist (Pramipexole) reduces morphine-induced cardiac fibrosis.

Morphine is routinely used for pain management in heart failure patients. However, extended morphine exposure associates with major adverse cardiovascular events. Reports link the dopamine receptor D2-family with morphine-induced nociception modulation. This study first assessed whether morphine induces cardiac remodeling in healthy mice, then whether DRD3 agonist (DRD3ag, D2-family member) adjunct therapy prevents morphine-induced cardiac remodeling. Mice received morphine (2 mg/kg/day i. p.) for 7 days (D7) and were either euthanized at D7 or kept 7 more days without morphine (i.e. withdrawal period, D8-D14): G1, morphine; G2, morphine/DRD3ag; G3, morphine + withdrawal; G4, morphine/DRD3ag + withdrawal; G5, morphine + withdrawal/DRD3ag. A separate cohort of animals were used as naïve tissues. We evaluated functional and molecular parameters of cardiac remodeling. Although we did not observe significant differences in systolic function, morphine induced both interstitial fibrosis and cardiomyocyte hypertrophy. Interestingly, DRD3ag abolished these effects. Compared to naïve tissues, collagen 1 increased after withdrawal in G3 and G4 and collagen 3 increased in G1-G4 but at higher levels in G1 and G2. Only G5 did not show collagen differences compared to naïve, suggesting DRD3ag treatment during withdrawal may be beneficial and prevent morphine-induced fibrosis. Smad2/3 phosphorylation increased during withdrawal, indicating a likely upstream pathway for the observed morphine-induced fibrosis. Overall, our data suggest that DRD3ag adjunct therapy decreases morphine-induced adverse cardiac remodeling.

Age- and sex-dependent differences in extracellular matrix metabolism associate with cardiac functional and structural changes.

Age-related remodeling of the heart causes structural and functional changes in the left ventricle (LV) that are associated with a high index of morbidities and mortality worldwide. Some cardiac pathologies in the elderly population vary between genders revealing that cardiac remodeling during aging may be sex-dependent. Herein, we analyzed the effects of cardiac aging in male and female C57Bl/6 mice in four age groups, 3, 6, 12, and 18 month old (n = 6-12 animals/sex/age), to elucidate which age-related characteristics of LV remodeling are sex-specific. We focused particularly in parameters associated with age-dependent remodeling of the LV extracellular matrix (ECM) that are involved in collagen metabolism. LV function and anatomical structure were assessed both by conventional echocardiography and speckle tracking echocardiography (STE). We then measured ECM proteins that directly affect LV contractility and remodeling. All data were analyzed across ages and between sexes and were directly linked to LV functional changes. Echocardiography confirmed an age-dependent decrease in chamber volumes and LV internal diameters, indicative of concentric remodeling. As in humans, animals displayed preserved ejection fraction with age. Notably, changes to chamber dimensions and volumes were temporally distinct between sexes. Complementary to the traditional echocardiography, STE revealed that circumferential strain rate declined in 18 month old females, compared to younger animals, but not in males, suggesting STE as an earlier indicator for changes in cardiac function between sexes. Age-dependent collagen deposition and expression in the endocardium did not differ between sexes; however, other factors involved in collagen metabolism were sex-specific. Specifically, while decorin, osteopontin, Cthrc1, and Ddr1 expression were age-dependent but sex-independent, periostin, lysyl oxidase, and Mrc2 displayed age-dependent and sex-specific differences. Moreover, our data also suggest that with age males and females have distinct TGFß signaling pathways. Overall, our results give evidence of sex-specific molecular changes during physiological cardiac remodeling that associate with age-dependent structural and functional dysfunction. These data highlight the importance of including sex-differences analysis when studying cardiac aging.

High Fat Diet Dysregulates Hypothalamic-Pituitary Axis Gene Expression Levels which are Differentially Rescued by EPA and DHA Ethyl Esters.

SCOPE: Dietary fat composition can modulate gene expression in peripheral tissues in obesity. Observations of the dysregulation of growth hormone (GH) in obesity indicate that these effects extend to the hypothalamic-pituitary (H-P) axis. The authors thus determine whether specific high fat (HF) diets influence the levels of Gh and other key gene transcripts in the H-P axis. METHODS AND RESULTS: C57BL/6 mice are fed a lean control diet or a HF diet in the absence or presence of OA, EPA, or DHA ethyl esters. Comparative studies are conducted with menhaden fish oil. The HF diet lowered pituitary Gh mRNA and protein levels, and cell culture studies reveal that elevated insulin and glucose can reduce Gh transcripts. Supplementation of the HF diet with OA, EPA, DHA, or menhaden fish oil do not improve pituitary Gh levels. The HF diet also impaired the levels of additional genes in the pituitary and hypothalamus, which are selectively rescued with EPA or DHA ethyl esters. The effects of EPA and DHA are more robust relative to fish oil. CONCLUSION: A HF diet can affect H-P axis transcription, which can be mitigated in some genes by EPA and DHA, but not fish oil in most cases.

Mechanisms of cardioprotection via modulation of the immune response.

Both morbidity and mortality as a result of cardiovascular disease remain significant worldwide and account for approximately 31% of annual deaths in the US. Current research is focused on novel therapeutic strategies to protect the heart during and after ischemic events and from subsequent adverse myocardial remodeling. After cardiac insult, the immune system is activated and plays an essential role in the beginning, development, and resolution of the healing cascade. Uncontrolled inflammatory responses can cause chronic disease and exacerbate progression to heart failure and therefore, constitute a major area of focus of cardiac therapies. In the present overview, we share novel insights and promising therapeutic cardioprotective strategies that target the immune response.

Soluble guanylyl cyclase-activated cyclic GMP-dependent protein kinase inhibits arterial smooth muscle cell migration independent of VASP-serine 239 phosphorylation.

Coronary artery disease (CAD) accounts for over half of all cardiovascular disease-related deaths. Uncontrolled arterial smooth muscle (ASM) cell migration is a major component of CAD pathogenesis and efforts aimed at attenuating its progression are clinically essential. Cyclic nucleotide signaling has long been studied for its growth-mitigating properties in the setting of CAD and other vascular disorders. Heme-containing soluble guanylyl cyclase (sGC) synthesizes cyclic guanosine monophosphate (cGMP) and maintains vascular homeostasis predominantly through cGMP-dependent protein kinase (PKG) signaling. Considering that reactive oxygen species (ROS) can interfere with appropriate sGC signaling by oxidizing the cyclase heme moiety and so are associated with several CVD pathologies, the current study was designed to test the hypothesis that heme-independent sGC activation by BAY 60-2770 (BAY60) maintains cGMP levels despite heme oxidation and inhibits ASM cell migration through phosphorylation of the PKG target and actin-binding vasodilator-stimulated phosphoprotein (VASP). First, using the heme oxidant ODQ, cGMP content was potentiated in the presence of BAY60. Using a rat model of arterial growth, BAY60 significantly reduced neointima formation and luminal narrowing compared to vehicle (VEH)-treated controls. In rat ASM cells BAY60 significantly attenuated cell migration, reduced G:F actin, and increased PKG activity and VASP Ser239 phosphorylation (pVASP·S239) compared to VEH controls. Site-directed mutagenesis was then used to generate overexpressing full-length wild type VASP (FL-VASP/WT), VASP Ser239 phosphorylation-mimetic (FL-VASP/239D) and VASP Ser239 phosphorylation-resistant (FL-VASP/239A) ASM cell mutants. Surprisingly, FL-VASP/239D negated the inhibitory effects of FL-VASP/WT and FL-VASP/239A cells on migration. Furthermore, when FL-VASP mutants were treated with BAY60, only the FL-VASP/239D group showed reduced migration compared to its VEH controls. Intriguingly, FL-VASP/239D abrogated the stimulatory effects of FL-VASP/WT and FL-VASP/239A cells on PKG activity. In turn, pharmacologic blockade of PKG in the presence of BAY60 reversed the inhibitory effect of BAY60 on naïve ASM cell migration. Taken together, we demonstrate for the first time that BAY60 inhibits ASM cell migration through cGMP/PKG/VASP signaling yet through mechanisms independent of pVASP·S239 and that FL-VASP overexpression regulates PKG activity in rat ASM cells. These findings implicate BAY60 as a potential pharmacotherapeutic agent against aberrant ASM growth disorders such as CAD and also establish a unique mechanism through which VASP controls PKG activity.

AMP-activated protein kinase inhibits vascular smooth muscle cell proliferation and migration and vascular remodeling following injury.

Vascular smooth muscle cell (VSMC) activation promotes a synthetic phenotype that underlies many vessel growth disorders. In this regard it has been suggested that the metabolic sensor adenosine 5'-monophosphate-activated protein kinase (AMPK) has significant antigrowth and antimetastatic properties and may serve as a viable therapeutic target. In the current study we hypothesized that AMPK reduces neointima formation following balloon injury and that this occurs through reduction in VSMC proliferation and migration. Data reveal that local or systemic dosing with the AMPK agonist 5-aminoimidazole-4-carboxamide-1-ß-d-ribofuranoside (AICAR) significantly increased AMPK activity in vivo and inhibited neointima formation in rat carotid arteries 2 wk after injury. In primary VSMCs, AICAR inhibited migration and induced cytostatic growth arrest through increased protein phosphatase 2A-mediated inhibition of mitosis-promoting cyclin B. AICAR also significantly enhanced AMPK-specific T278 phosphorylation of the actin anticapping vasodilator-activated serum phosphoprotein, increased G- to F-actin ratios and stress fiber formation, and abrogated PDGF-stimulated S397 autophosphorylation of focal adhesion kinase, promigratory cytoplasmic accumulation of paxillin, and extracellular matrix proteolysis by matrix metalloproteinase-9. Together, these results provide compelling evidence that AMPK serves to inhibit vascular smooth muscle migration and proliferation through regulation of cytoskeletal/focal adhesion/ECM stability, increasing our knowledge of this important metabolic regulator and providing support for its continued investigation in the treatment of vascular growth disorders.

Giant condyloma acuminatum quickly growing: case report.

BACKGROUND: Giant Condyloma Acuminatum (GCA) is a rare, slow growing, large cauliflower tumor of the penile foreskin and perianal region with benign histologic appearance but high propensity for local invasion and recurrences. GCA is associated with Human Papilloma Virus (HPV) types 6 and 11 and it also has considerable risk of neoplastic transformation into fully invasive squamous cell carcinoma into about 5 years. OBJECTIVE: Because of the rarity of perianal GCA, to date there is no general agreement on the best method for treatment. We wanted to know if surgical approach only was a good method to treat our case. CASE REPORT: A 28 years old man, HIV-negative, with a 4 years history of perianal GCA quickly growing underwent full tickness local excision at least 0,7 cm margin of normal tissue with skin grafting taken from the thighs. Fecal contamination was avoided by diet and loperamide per os. At two years follow-up no recurrence was detected. CONCLUSION: Surgical approach with full tickness excision and immediate skin-grafting and regular follow-up demonstrated effective to treat GCA and to minimize disease recurrence.

A randomized pilot study of systemic immunosuppression in the treatment of age-related macular degeneration with choroidal neovascularization.

BACKGROUND: Age-related macular degeneration remains the leading cause of irreversible blindness in the United States and the developed world. Intravitreal injections of anti­vascular endothelial growth factor (VEGF) medications have become standard of care for the treatment of the wet form of the disease. Recent reports have demonstrated an association with various immune factors. We aimed to investigate the effect of immunosuppressive therapy in the clinical course of the wet form of the disease. We compared anti-VEGF therapy plus one of three systemic immunosuppressive therapies versus anti-VEGF therapy alone for recurrent choroidal neovascularization associated with age-related macular degeneration. METHODS: This was a pilot, Phase I/II, prospective, randomized, unmasked, single-center trial. Patients with subretinal exudation secondary to recurrent choroidal neovascularization associated with age-related macular degeneration were included in the study. Patients were randomized to 1 of 3 systemic arms immunosuppressive agents (daclizumab, rapamycin, or infliximab) for 6 months plus intraocular anti-VEGF therapy if indicated, compared with a group who received only anti-VEGF therapy if indicated. RESULTS: The number of anti-VEGF injections per group, visual acuity, retinal thickness, and safety measures were assessed in all groups. Thirteen patients were randomized; comparing anti-VEGF injections before and during the study, a decrease in the number of injections from 0.73 injections per month to 0.42 for daclizumab and from 0.67 to 0.34 for sirolimus was seen, while no apparent decrease was seen for either infliximab or observation. Visual acuities were maintained in all groups. CONCLUSION: These preliminary data suggest that some immunosuppressive agents given systemically can alter the clinical course of the wet form of the disease and support the notion that more definitive clinical trials of immune mediation of age-related macular degeneration are indicated.

Fissurectomy combined with anoplasty and injection of botulinum toxin in treatment of anterior chronic anal fissure with hypertonia of internal anal sphincter: a pilot study.

BACKGROUND: In patients affected by anterior chronic anal fissure (CAAF) with hypertonia of the internal anal sphincter (IAS), the role of IAS hypertonia remains unclear. The aim of this study was to evaluate the efficacy of fissurectomy combined with advancement flap and IAS injection of botulinum toxin in healing the CAAF with hypertonia of IAS resistant to medical therapy. METHODS: Ten consecutive patients were enrolled. Anorectal manometry was performed preoperatively and at 6 months. CAAF with hypertonia was defined as those associated with maximum resting pressure (MRP) values higher than 85 mmHg. All patients underwent fissurectomy and anoplasty with advancement skin flap combined with the intrasphincter injection of 30 UI of botulinum toxin. Complete healing, MRP changes, relief of symptoms and immediate and long-term complications were recorded. RESULTS: Complete healing was observed in all patients within 30 days of the operation. The intensity and duration of pain post-defecation was reduced significantly starting from the first defecation. In all subjects, the preoperative MRP values were significantly reduced at 6 months. One month after surgery, three patients reported anal incontinence, two of them had complained preoperatively. The only postoperative complications were minor. CONCLUSIONS: Fissurectomy combined with advancement flap and intrasphincter injection of botulinum toxin results in complete healing, significant MRP reduction and full relief of symptom in all patients, thus it represents a valid procedure in preventing the occurrence of anal incontinence.

Fissurectomy and anal advancement flap for anterior chronic anal fissure without hypertonia of the internal anal sphincter in females.

AIM: Lateral internal sphincterotomy is considered the surgical treatment of choice for chronic anal fissure after failure of medical therapy but it risks continence. The aim of the study was to evaluate fissurectomy with advancement flap for anterior chronic anal fissure (CAAF) resistant to medical therapy. METHOD: Sixteen women with CAAF without hypertonia of the internal anal sphincter, unresponsive to previous medical treatment, were included in the study. Absence of hypertonia was defined as a maximum anal resting pressure (MRP) of less than 85 mmHg. All patients underwent fissurectomy with an advancement skin flap. RESULTS: Complete healing occurred in all patients within 30 days. The intensity and the duration of pain after defecation reduced from the first postoperative defecation. MRP before surgery and at 6 months showed no significant difference. At 1 month, four patients experienced a continence disturbance, two of whom had it preoperatively. At 12 months, two (12.5%) patients continued to experience a continence disturbance. CONCLUSION: Fissurectomy with skin advancement flap resulted in complete healing and full relief of symptoms in all patients. There was a low incidence of continence disturbance.

Describing saline-lock usage patterns on a telemetry unit: a retrospective study.

PURPOSE/OBJECTIVES: The purpose of this study was to describe saline-lock (SL) usage patterns of patients admitted with high-frequency medical diagnoses to a telemetry unit and to determine the acceptability of constructing a decision tree stratifying SL insertion decisions. DESIGN: A quantitative, descriptive study using retrospective chart reviews was used. SETTING: The study was conducted within a 48-bed telemetry unit of a large, urban, teaching hospital. SAMPLE: The sample was composed of the medical records of patients admitted to the telemetry unit from April 2007 through June 2007. Charts were included in the sample if the patient was admitted to the telemetry unit with one of the 4 highest-frequency admitting diagnoses, specifically myocardial infarction, congestive heart failure, syncope, and chest pain. METHODS: Data were collected via patient chart review using an electronic database by a team of 4 registered nurses, including 1 clinical nurse specialist. Data collection steps included a verification process that involved a random audit of the most recently collected chart data. FINDINGS: More than one-third of SLs were not used, and more than half that were used were accessed for the nonurgent delivery of medications. Saline locks were most frequently used for urgent medication delivery when patients were admitted with a diagnosis of heart failure. CONCLUSIONS: Findings suggest that most patients admitted to telemetry units do not require an immediate intravenous access for drug delivery. IMPLICATIONS: Clinical nurse specialists should consider that an evidence-based algorithm for determining SL need may improve patient outcomes and reduce SL-associated complication and infection rates.

[Bilateral testicular lymphoma. Case report]. / Linfoma primitivo testicolare bilaterale: a proposito di un caso clinico.

A case of bilateral testicular lymphoma with involvement of skin and oropharynx was described. After a review of literature, the Authors underline the clinical features focusing the diagnostic approaches and the therapeutics options.

Randomized clinical trial of botulinum toxin injection for pain relief in patients with thrombosed external haemorrhoids.

BACKGROUND: Thrombosed external haemorrhoids are one of the most frequent anorectal emergencies. They are associated with swelling and intense pain. Internal sphincter hypertonicity plays a role in the aetiology of the pain. This study evaluated the efficacy and safety of an intrasphincteric injection of botulinum toxin for pain relief in patients with thrombosed external haemorrhoids. METHODS: Thirty patients with thrombosed external haemorrhoids who refused surgical operation were randomized into two groups. Patients received an intrasphincteric injection of either 0.6 ml saline or 0.6 ml of a solution containing 30 units botulinum toxin. Anorectal manometry was performed before treatment and 5 days afterwards. RESULTS: After 5 days of treatment, the maximum resting pressure fell in both groups, but was significantly lower in the botulinum toxin group (P = 0.004). Pain intensity was significantly reduced within 24 h of botulinum toxin treatment (P < 0.001), but only after 1 week in the placebo group (P = 0.019). CONCLUSION: A single injection of botulinum toxin into the anal sphincter seems to be effective in rapidly controlling the pain associated with thrombosed external haemorrhoids, and could represent an effective conservative treatment for this condition. REGISTRATION NUMBER: NCT00717782 (http://www.clinicaltrials.gov).

Impact of different texture of polypropylene mesh on the inflammatory response.

Over the past decade, hernia surgery has undergone a considerable transformation with the use of prosthetic materials. The most used polypropylene meshes induce a rapid acute inflammatory response followed by chronic foreign body reaction. Many factors influence this response such as density, size, physical characteristics, different texture and porosity of each biomaterial. The aim of this study is to assess whether the implant of monofilament or multifilament meshes, in the inguinal hernioplasty, determine a different inflammatory response. Thirty-two male patients were included in the study and were randomly divided into two groups. In the first group (MO) inguinal hernioplasty was performed using monofilament polypropylene mesh, while in the second one (MU) multifilament prosthesis was used. Peripheral venous blood samples were collected 24 hours before surgery and then 6, 24, 48 and 168 hours post-operatively. Modifications in leukocyte count, C-reactive protein (CRP), alpha-1 antitrypsin (alpha1-AT), interleukin (IL)-1, IL-6, IL-1 ra and IL-10 serum levels were recorded at all sampling times. We present evidence that serum levels of CRP, (alpha1-AT), leukocytes and cytokines were significantly increased post-operatively in both groups, returning to basal values 168 hours afterwards. In particular, the production of all pro-inflammatory mediators was higher in the MU group, whereas the anti-inflammatory cytokine (IL-10, IL-1ra) production was higher in MO patients. Our results indicate that polypropylene multifilament mesh allows a higher intense acute inflammatory response as compared to monofilament mesh implantation.

Intramedullary spinal cord tumor presenting as the initial manifestation of metastatic colon cancer: case report and review of the literature.

STUDY DESIGN: Case reports and review of the literature. OBJECTIVE: Intramedullary spinal cord metastases (ISCMs) are rare type of central nervous system (CNS) involvement of systemic malignant tumors. Since the advent of new neuroradiological techniques, their detection have become increasingly diagnosed in recent years and, although somewhat controversial, surgical treatment has been considered a valid option. SETTING: Neurosurgical Clinic, Department of Clinic Neuroscience, University of Palermo, Italy. METHOD: The authors describe the case of a 61-year-old woman who was admitted presenting with progressive tetraplegia. Investigations revealed an intramedullary spinal cord lesion at the cervical level. Magnetic resonance imaging of the brain did not reveal other CNS metastatic lesions. RESULT: Patient underwent surgical treatment. The tumor was resected and the patient's neurologic deficits slowly improved. Histological examination of the lesion showed the typical features of a colon carcinoma metastasis. Patient was referred for proper oncological treatment but, unfortunately, she died of disseminated disease within 2 months. CONCLUSION: Although uncommon, spinal cord metastases should be considered in the differential diagnosis of ISCM in order to rationalize the decisional-making process and improve the quality of life for these patients.