Novel cationic copolymers of a polyasparthylhydrazide: synthesis and characterization

,β-poly(asparthylhydrazide) (PAHy), a water soluble synthetic polymer, was functionalized by using EDCI chemistry with 3-(carboxypropyl)trimethyl-ammonium chloride (CPTACl) obtaining carboxypropyltrimethyl ammonium copolymers (PAHy-CPTA). Three PAHy-CPTA copolymers at increasing derivatization degrees (38%, 48%, 58%) were chosen for subsequent investigations. The capability of these copolymers to bind, neutralize, and protect DNA against degradation by DNase II was evalued by gel retardation assay and DNA degradation test at pH 5.5. Zeta potential measurements show that all studied polymers are able to neutralize the anionic charge of DNA at polymer/DNA weight ratio in the range of 0.8/1-5/1. Polyplex dimensional distribution analyses in bistilled water, saline solution NaCl 0.9%, and HEPES pH 7 show that polyplex size is strongly affected by both presence and type of electrolyte and with time incubation.     

Combined analysis of 635 patients confirms an age-related association of the serotonin 2A receptor gene with tardive dyskinesia and specificity for the non-orofacial subtype

Tardive dyskinesia (TD) is an important limiting factor in the use of typical antipsychotic drugs. Genetic variability in the serotonin 2A (5-HT(2A)) receptor may influence risk for TD but the results of prior studies are not confirmatory. The objective of this study was to determine association of T102C and His452Tyr polymorphisms in the 5-HT(2A) receptor gene (HTR(2A)) with TD in a large, multicentre patient sample. The design employed case-control analysis controlling for possible confounders using pooled, original data from published and available unpublished samples and employing logistic regression, analysis of variance and meta-analysis. The study sample consisted of 635 patients with schizophrenia or schizoaffective disorder (256 with TD and 379 without TD) drawn from five research centres, divided into six groups based on population origin. The main outcome measure was association of a categorical diagnosis of TD based on the Research Diagnostic Criteria for TD with HTR(2A) T102C and His452Tyr genotypes and haplotypes. The findings indicate significant association of TD with HTR(2A) T102C genotype (p=0.002) over and above the effect of population group, also when controlling for age and gender (p=0.0008), but not with His452Tyr genotype. The T102C genotype was significantly associated with TD in older (>median age 47 yr, p=0.002) but not younger patients and in patients with non-orofacial (limb-truncal) (p=0.001) but not orofacial TD. By meta-analysis the Mantel-Haenszel (M-H) pooled odds ratio (OR) across all the available data was 1.64. A T102C-His452Tyr haplotype was significantly associated with TD (p=0.0008). These findings confirm that genetic variability in HTR(2A) contributes a small but significant degree of risk for the expression of TD, particularly in older patients and specifically for the non-orofacial (limb-truncal) type. Together with other genetic variants associated with TD the findings could be used to assess risk in patients who are candidates for treatment with typical antipsychotic medications.     

Dual role of VEGF in pretreated experimental ePTFE arterial grafts

BACKGROUND: Lack of endothelialization and abnormal smooth muscle cell (SMC) growth adversely affect the outcome of vascular synthetic grafts. The aims of our study were to investigate how a coating of extracellular matrix (ECM) and vascular endothelial growth factor (VEGF) might affect the endothelialization rate, smooth muscle cells (SMC) proliferation, and myointimal hyperplasia in experimental arterial ePTFE grafts. METHODS: In each of 30 male Lewis rats, a 1-cm-long ePTFE graft was inserted at the level of the abdominal aorta. Animals were randomized in five groups (six animals each): groups A and A1 received ePTFE grafts coated with a synthetic extracellular matrix (growth factor-reduced matrigel) containing VEGF; groups B and B1 received ePTFE grafts coated with synthetic ECM; and group C received ePTFE grafts alone. The grafts were explanted at 30 days from surgery for immunohistochemical analysis. RESULTS: Both endothelialization rate and myointimal hyperplasia were augmented in group A versus groups B and C, and these findings were statistically significant. SMC density resulted significantly higher in group A versus groups B and C, and this was associated with an altered expression of bFGF and TGFbeta. CONCLUSIONS: Pretreating ePTFE grafts with synthetic ECM and VEGF results in better endothelialization, but also in undesired higher SMC density and myointimal hyperplasia.     

Endometriosis of the abdominal wall (authors' experience)

Endometriosis is a very common gynecological disease, although the abdominal wall localization is a rare clinical problem in the everyday practice and this explains the incomplete reports in literature and the difficulty of a standard treatment. The authors report four cases of abdominal wall endometriosis, underlining how the surgical therapy represents the golden standard of decisive treatment, thanks also to prosthetic reconstruction techniques who allow more radical demolitions. On the contrary, the medical treatment should be reserved to selected cases such as especially the less symptomatic umbilical primitive diseases.     

Segmental embolization of the gastroduodenal artery in a case of a perforated pseudoaneurysm and gastrointestinal massive bleeding

We present the history of a woman suffering from an extensive gastrointestinal bleeding due to liver cirrhosis and chronic pancreatitis. Selective angiogram of the celiac artery revealed a pseudoaneurysm of the gastroduodenal artery caused by inflammatory wall penetration. The life-threatening hemorrhage was completely stopped by embolization with three stainless steel coils after microcatheter engagement of the gastroduodenal artery. The particularity of this case is the restricted embolization of the aneurysm vessel segment, so the collateral circulation of the gastroduodenal and pancreaticoduodenal artery could be preserved.     

Tardive dyskinesia and DRD2, DRD3, DRD4, 5-HT2A variants in schizophrenia: an association study with repeated assessment

We performed an association study between four candidate genes, DRD2, DRD3, DRD4 and 5-HT2A for the presence of tardive dyskinesia (TD) on 84 patients with residual schizophrenia. The sample was evaluated again for the presence of TD after an interval of 3 years. The first group did not exhibit TD in either observation (n=34) while in the second group of patients exhibited TD in at least one of the observations (n=20+18). The clinical and socio-demographic characteristics were not significantly different between the two groups; the genetic analysis revealed a significant correlation between the C/C genotype of 5-HT2A and TD (p=0.017). An association trend was observed between the 'short' variant of DRD4 and TD (p=0.022). We did not observe any significant association for the DRD2 and DRD3 polymorphisms.     

N-cadherin as an invasion promoter: a novel target for antitumor therapy?

Cell adhesion molecules of the cadherin superfamily are frequently altered during tumor progression. The loss of E-cadherin, in particular, has long been described in various epithelial cancers where it correlates with malignancy and metastasis. In addition, a subset of tumors show de novo expression or upregulation of N-cadherin, a cadherin that promotes cell motility and invasion. In spite of the accumulating evidence supporting the relationship between N-cadherin levels and cancer progression, the causal role of N-cadherin in tumor development has not yet been clearly demonstrated. This review will address this issue at three different levels: (i) the expression pattern of N-cadherin in cancer; (ii) the cellular events that are modulated by N-cadherin and could account for its pro-invasive role in tumorigenesis; and (iii) the signaling properties of N-cadherin, with particular emphasis on its cross-talk with cell surface partners such as fibroblast growth factor receptor and with intracellular cascades such as the antiapoptotic machinery. Taken together, the topics discussed in this review point to N-cadherin as an important player in tumor development and, therefore, a potential target for novel therapeutic approaches.     

Loss of neural cell adhesion molecule induces tumor metastasis by up-regulating lymphangiogenesis

Reduced expression of neural cell adhesion molecule (NCAM) has been implicated in the progression to tumor malignancy in cancer patients. Previously, we have shown that the loss of NCAM function causes the formation of lymph node metastasis in a transgenic mouse model of pancreatic beta cell carcinogenesis (Rip1Tag2). Here we show that tumors of NCAM-deficient Rip1Tag2 transgenic mice exhibit up-regulated expression of the lymphangiogenic factors vascular endothelial growth factor (VEGF)-C and -D (17% in wild-type versus 60% in NCAM-deficient Rip1Tag2 mice) and, with it, increased lymphangiogenesis (0% in wild-type versus 19% in NCAM-deficient Rip1Tag2 mice). Repression of VEGF-C and -D function by adenoviral expression of a soluble form of their cognate receptor, VEGF receptor-3, results in reduced tumor lymphangiogenesis (56% versus 28% in control versus treated mice) and lymph node metastasis (36% versus 8% in control versus treated mice). The results indicate that the loss of NCAM function causes lymph node metastasis via VEGF-C- and VEGF-D-mediated lymphangiogenesis. These results also establish Rip1Tag2;NCAM-deficient mice as a unique model for stochastic, endogenous tumor lymphangiogenesis and lymph node metastasis in immunocompetent mice.     

Segmental conduction abnormalities and myelin thickenings in Val102/fs null mutation of MPZ gene

The authors report in patients with Val102/fs null mutation a possibly age dependent variability of clinical and electrophysiologic phenotype, segmental conduction abnormalities mainly in ulnar nerves at the elbow, and excessive myelin foldings and thickenings. The authors hypothesize that myelin thickenings at the paranodal region, in concurrence with compression at usual entrapment sites or minor repetitive trauma, may induce segmental conduction abnormalities.