Bladder tissue regeneration using acellular bi-layer silk scaffolds in a large animal model of augmentation cystoplasty

Acellular scaffolds derived from Bombyx mori silk fibroin were investigated for their ability to support functional tissue regeneration in a porcine model of augmentation cystoplasty. Two bi-layer matrix configurations were fabricated by solvent-casting/salt leaching either alone (Group 1) or in combination with silk film casting (Group 2) to yield porous foams buttressed by heterogeneous surface pore occlusions or homogenous silk films, respectively. Bladder augmentation was performed with each scaffold group (6 × 6 cm²) in juvenile Yorkshire swine for 3 m of implantation. Augmented animals exhibited high rates of survival (Group 1: 5/6, 83%; Group 2: 4/4, 100%) and voluntary voiding over the course of the study period. Urodynamic evaluations demonstrated mean increases in bladder capacity over pre-operative levels (Group 1: 277%; Group 2: 153%) which exceeded nonsurgical control gains (144%) encountered due to animal growth. Similarly, elevations in bladder compliance were substantially higher in augmented animals from baseline (Group 1: 357%; Group 2: 147%) in comparison to controls (41%). Gross tissue evaluations revealed that both matrix configurations supported extensive de novo tissue formation throughout the entire original implantation site which exhibited ultimate tensile strength similar to nonsurgical counterparts. Histological and immunohistochemical analyses showed that both implant groups promoted comparable extents of smooth muscle regeneration and contractile protein (α-smooth muscle actin and SM22α) expression within defect sites similar to controls. Parallel evaluations demonstrated the formation of a transitional, multi-layered urothelium with prominent cytokeratin, uroplakin, and p63 protein expression in both matrix groups. De novo innervation and vascularization processes were evident in all regenerated tissues indicated by synaptophysin-positive neuronal cells and vessels lined with CD31 expressing endothelial cells. Ex vivo organ bath studies demonstrated that regenerated tissues supported by both silk matrices displayed contractile responses to carbachol, α,β-methylene-ATP, KCl, and electrical field stimulation similar to controls. Our data detail the ability of acellular silk scaffolds to support regeneration of innervated, vascularized smooth muscle and urothelial tissues within 3 m with structural, mechanical, and functional properties comparable to native tissue in a porcine model of bladder repair.     

Phenotypic and genotypic characterization of dengue virus isolates differentiates dengue fever and dengue hemorrhagic fever from dengue shock syndrome

Dengue viruses (DENV) cause 50-100 million cases of acute febrile disease every year, including 500,000 reported cases of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Viral factors have been proposed to influence the severity of the disease, but markers of virulence have never been identified on DENV. Three DENV serotype-1 isolates from the 2007 epidemic in Cambodia that are derived from patients experiencing the various clinical forms of dengue were characterized both phenotypically and genetically. Phenotypic characteristics in vitro, based on replication kinetics in different cell lines and apoptosis response, grouped isolates from DF and DHF patients together, whereas the virus isolate from a DSS patient showed unique features: a lower level of replication in mammalian cells and extensive apoptosis in mosquito cells. Genomic comparison of viruses revealed six unique amino acid residues in the membrane, envelope, and in non-structural genes in the virus isolated from the DSS patient.     

The prince and the pauper. A tale of anticancer targeted agents

Cancer rates are set to increase at an alarming rate, from 10 million new cases globally in 2000 to 15 million in 2020. Regarding the pharmacological treatment of cancer, we currently are in the interphase of two treatment eras. The so-called pregenomic therapy which names the traditional cancer drugs, mainly cytotoxic drug types, and post-genomic era-type drugs referring to rationally-based designed. Although there are successful examples of this newer drug discovery approach, most target-specific agents only provide small gains in symptom control and/or survival, whereas others have consistently failed in the clinical testing. There is however, a characteristic shared by these agents: -their high cost-. This is expected as drug discovery and development is generally carried out within the commercial rather than the academic realm. Given the extraordinarily high therapeutic drug discovery-associated costs and risks, it is highly unlikely that any single public-sector research group will see a novel chemical "probe" become a "drug". An alternative drug development strategy is the exploitation of established drugs that have already been approved for treatment of non-cancerous diseases and whose cancer target has already been discovered. This strategy is also denominated drug repositioning, drug repurposing, or indication switch. Although traditionally development of these drugs was unlikely to be pursued by Big Pharma due to their limited commercial value, biopharmaceutical companies attempting to increase productivity at present are pursuing drug repositioning. More and more companies are scanning the existing pharmacopoeia for repositioning candidates, and the number of repositioning success stories is increasing. Here we provide noteworthy examples of known drugs whose potential anticancer activities have been highlighted, to encourage further research on these known drugs as a means to foster their translation into clinical trials utilizing the more limited public-sector resources. If these drug types eventually result in being effective, it follows that they could be much more affordable for patients with cancer; therefore, their contribution in terms of reducing cancer mortality at the global level would be greater.     

Ovarian cyst fenestration via the laparoscope. A laparoscopic method for treatment of non-neoplastic ovarian cysts

A laparoscopic method of managing macroscopically benign, unilateral, unilocular, mobile, translucent, and smooth-walled ovarian cysts in women of reproductive age is described. The method requires the cutting of a window in the cyst wall through the laparoscope fenestration. In preference to aspiration at laparoscopy or removal at laparotomy, this method has the advantage of ensuring histologic material as well as permanent drainage by the use of atraumatic surgical technique. Nineteen cysts were fenestrated laparoscopically. Four cysts could not be classified, two owing to lack of histologic material, two owing to malpreparation of the selected cyst tissue. In one case an epithelial cyst--a mucinous cystadenoma, being laparoscopically unsuspected--was fenestrated. One cyst recurred. By observing the above criteria it is possible and tolerably safe to select non-neoplastic cysts, for which fenestration should be reserved.     

Pharmacological characterization of the novel nociceptin/orphanin FQ receptor ligand,ZP120: in vitro and in vivo studies in mice

1 This study reports on the pharmacological characterization of ZP120, a novel ligand of the nociceptin/orphanin FQ (N/OFQ) peptide receptor, NOP. ZP120 is a structure inducing probes modified NOP ligand: Zealand Pharma proprietary SIP technology was used to increase the enzymatic stability and half-life of peptide. 2 In vitro, ZP120 mimicked the inhibitory effects of N/OFQ in the electrically stimulated mouse vas deferens, showing however higher potency (pEC(50) 8.88 vs 7.74), lower maximal effects (E(max) 69+/-5% vs 91+/-2%), and slower onset of action. Like N/OFQ, the effects of ZP120 were not modified by 1 micro M naloxone, but they were antagonized by the NOP receptor selective antagonist J-113397 (pA(2) 7.80 vs ZP120, 7.81 vs N/OFQ). 3 In vivo, ZP120 mimicked the effects of N/OFQ, producing pronociceptive effects in the tail withdrawal assay and decreased locomotor activity after i.c.v., but not after i.v. administration in mice. ZP120 elicited similar maximal effects as N/OFQ, but it was about 10 fold more potent and its effects lasted longer. 4 In conclusion, the novel NOP receptor ligand ZP120 is a highly potent and selective partial agonist of the NOP receptor with prolonged effects in vivo.     

Structure-activity relationships of some 3-substituted-4-hydroxycoumarins as HIV-1 protease inhibitors

The screening of the HIV-1 protease (PR) inhibitory activity (IC-50) of various substituted 3-phenyl-4-hydroxycoumarins, 3-benzyl-4-hydroxycoumarins, 3-phenoxy-4-hydroxy-coumarins, 3-benzenesulfonyl-4-hydroxycoumarins and 3-(7-coumarinyloxy)-4-hydroxycoumarins was performed. The data indicate the importance of substituents at positions 5 and 7 of the coumarin ring on the inhibitory potency of the HIV-1-PR.     

Neoadjuvant gemcitabine therapy for breast cancer

Neoadjuvant chemotherapy has become a standard treatment in the management of locally advanced breast cancer. Patients with earlier-stage disease may also benefit from neoadjuvant treatment in terms of improved rates of breast-conserving surgery and thus better quality of life. Gemcitabine is a pyrimidine analogue that has shown activity in a variety of solid tumors, a good toxicity profile, and nonoverlapping toxicity with other chemotherapeutic agents. Several phase II/III studies are assessing gemcitabine combined with anthracyclines, taxanes, and/or vinorelbine both in the neoadjuvant and metastatic disease settings. This article reviews developments in neoadjuvant use of gemcitabine in combination with anthracyclines and taxanes. Several phase II trials of gemcitabine combined with doxorubicin/epirubicin or with doxorubicin/paclitaxel have been carried out. Preliminary findings demonstrate increased complete response rates and good tolerability of these regimens in patients with breast cancer.     

Intraarterially administered verapamil as adjunct therapy for cerebral vasospasm: safety and 2-year experience

BACKGROUND AND PURPOSE: Despite the widespread use of angioplasty, adjunct chemical therapy is often needed to treat patients with cerebral vasospasm. In this study, we examined the safety of intraarterial administration of verapamil to patients with cerebral vasospasm. We herein summarize our 2-year experience with this treatment. METHODS: We retrospectively reviewed the procedure reports, anesthesia records, clinical charts, and brain images of 29 patients who received intraarterially administered verapamil in 34 procedures for the treatment of vasospasm after subarachnoid hemorrhage from July 1998 to June 2000. The average changes in mean arterial pressure and heart rate were used to measure cardiovascular side effects. The neurologic effects were assessed by angiographic findings, the results of neurologic examinations performed before and after the procedure, and findings of CT of the head. RESULTS: The average dose of verapamil per patient was 3 +/- 0 mg or 44 +/- 5 mcg/kg. The average changes in mean arterial pressure at 10 and 20 minutes were -5 +/- 1 mm Hg and -2 +/- 1 mm Hg or -3.8 +/- 1.0% and -1.7 +/- 1.1%, respectively. No significant change of heart rate was observed at 10 minutes. The patients showed no sign of increased intracranial pressure by hemodynamic parameters, neurologic examination, or CT of the head. On 10 occasions, when the effect of verapamil infusion was assessed angiographically, there was 44 +/- 9% increase of vessel diameter in the spastic segment. Neurologic improvement was noted after five of 17 procedures when verapamil was used as the sole treatment. CONCLUSION: Low dose verapamil is safe when administered intraarterially to patients with cerebral vasospasm. Beneficial effects are achieved in some patients, prompting further study of its efficacy.     

Determinants of fruit and vegetable consumption among children and adolescents: a review of the literature. Part I: quantitative studies

Background  

In order to more effectively promote fruit and vegetable intake among children and adolescents, insight into determinants of intake is necessary. We conducted a review of the literature for potential determinants of fruit and vegetable intake in children and adolescents.