Micellar-type complexes of tailor-made synthetic block copolymers containing the HIV-1 tat DNA for vaccine application

A novel class of cationic block copolymers constituted by a neutral hydrophilic poly(ethylene glycol) (PEG) block and a positively charged poly(dimethylamino)ethyl methacrylate block was prepared for delivery of DNA. These block copolymers spontaneously assemble with DNA to give in aqueous medium micellar-like structures. Five of these novel block copolymers (K1-5), differing in the length of both the PEG chain and the linear charge density of the poly(dimethylamino)ethyl methacrylate block, were prepared and analyzed for gene delivery, gene expression and safety. All five block copolymers protected DNA from DNAse I digestion and delivered the DNA into the cell. However, only three of them (K1, K2 and K5) released the DNA at level allowing efficient gene expression into cells. No toxic effects of both the copolymers alone or their DNA complexes were observed in vitro or in mice. In addition, copolymers were scarcely immunogenic. These results indicate that this novel class of cationic block copolymers is safe and possesses the biological characteristics required for DNA delivery, thus, representing promising vehicles for DNA vaccination.     

Expression of 90K (Mac-2 BP) correlates with distant metastasis and predicts survival in stage I non-small cell lung cancer patients

90K, also known as Mac-2 binding protein, is a secreted glycoprotein that binds galectins, beta1-integrins, collagens, and fibronectin, and has some relevance in cell-cell and cell-extracellular matrix adhesion. Previous studies have shown that serum levels of 90K have prognostic value in several neoplasms. In the present study, the role of the expression of 90K as an adverse prognostic indicator in 72 pathological stage I non-small cell lung cancer patients was investigated immunohistochemically. All of the patients underwent complete surgical removal of the tumor. The median length of follow-up care was 54 months. High level of 90K expression (90K staining of > or =50% of the neoplastic cells) was observed in 20 of the 72 (28%) tumors. Expression of 90K was confirmed by ELISA. The results showed that a high expression of 90K correlates with adverse prognosis. Among patients with high 90K expression, the disease-free and overall survival rates were significantly lower than the same rates of those with low expression (P = 0. 0001 and P = 0. 0003, respectively). The incidence of distant metastases in the patients with high 90K expression (60%; 12 of 20 patients) was significantly higher than that of in the patients with low expression (21%; 11 of 53 patients; P = 0.0038). The results of multivariate analysis confirmed that a high 90K expression was a significant factor to predict poor prognosis. We suggest that 90K expression could be a useful prognostic factor in patients with stage I non-small cell lung cancer, likely as an indicator of the metastatic propensity of the tumor.     

Determining the sensitivity of transrectal ultrasonography on a consecutive series of prostate cancers in a clinical and screening setting

PURPOSE: To evaluate the sensitivity at transrectal ultrasonography (TRUS) for prostate cancer. MATERIAL: A consecutive series of 170 prostate cancers identified by matching local cancer registry and TRUS archives at the Centro per lo Studio e la Prevenzione Oncologica of Florence. METHOD: TRUS sensitivity was determined as the ratio of TRUS positive to total prostate cancers occurring at different intervals from TRUS date. Univariate and multivariate analyses of sensitivity determinants were performed. RESULTS: Sensitivity at 6 months, 1, 2 and 3 years after the test was 94.1% (95% CI, 90-98), 89.8% (95% CI, 85-95), 80.4% (95% CI, 74-87) and 74.1% (95% CI, 68-81%), respectively. A higher sensitivity (statistically significant) of TRUS was observed only if digital rectal examination was suspicious, whereas no association to sensitivity was observed for age, prostate-specific antigen or prostate-specific antigen density. CONCLUSIONS: The study provided a reliable estimate of TRUS sensitivity, particularly reliable being checked against a cancer registry: observed sensitivity was high, at least of the same magnitude of other cancer screening tests. TRUS, which is known to allow for considerable diagnostic anticipation and is more specific than prostate-specific antigen, might still be considered for its contribution to a screening approach.     

Salmonella pathogenicity island-2 and anticancer activity in mice

Salmonella enterica servovar Typhimurium is capable of targeting, colonizing, and eliciting growth suppression of tumors in mice. We examined the effects of mutations on this anticancer phenotype in two Salmonella virulence gene clusters. Salmonella pathogenicity island (SPI)-1 genes promote systemic invasion from the intestine, whereas SPI-2 genes support systemic survival within macrophages and other cells. Disabling SPI-1 (prgH(-)) strongly reduced invasion in vitro, but had no effect on tumor growth suppression in vivo. However, disabling SPI-2 (ssaT(-)) ablated tumor growth suppression. In addition to ssaT(-), mutations in SPI-2 genes sseA, sseB, sseC, sscA, and ssrA also eliminated antitumor activity, whereas mutations in sseF or sseG yielded partial loss of function. Impaired tumor amplification was seen in three SPI-2 mutants tested after intravenous or intratumoral injection. A SPI-2(-) strain was unable to suppress tumor growth in CD18-deficient mice with defective macrophages and neutrophils, suggesting that loss of tumor growth suppression in wild-type mice by SPI-2 mutants was not solely a function of increased susceptibility to immune attack. Thus, SPI-2 is essential for the Salmonella antitumor effects, perhaps by aiding bacterial amplification within tumors, and is the first identified genetic system for this Salmonella phenotype.     

Seizures after spontaneous supratentorial intracerebral hemorrhage

PURPOSE: To characterize seizures after intracerebral hemorrhage (ICH), evaluating the risk of occurrence and relapse, predisposing factors, and prognostic significance, and to assess the utility of antiepileptic drug (AED) therapy as used in clinical practice. METHODS: The study sample consisted of 761 patients with spontaneous, nonaneurysmal, supratentorial ICH. Seizures were classified as immediate (within 24 h of ICH) and early (within 30 days of ICH). Baseline variables and clinical events were compared in the seizure and nonseizure group by using a multivariate regression model of failure time data. RESULTS: Fifty-seven patients had one or more seizures. The 30-day actuarial risk of a post-ICH seizure was 8.1%. Lobar location and small volume of ICH were independent predictors of immediate seizures. Early seizures were associated with lobar location and neurologic complications, mainly rebleeding. In patients with lobar ICH, the risk of early seizures was reduced by prophylactic AED therapy. Among seizure patients, history of alcohol abuse increased the risk of status epilepticus. Immediate and early seizures were not independent predictors of in-hospital mortality. CONCLUSIONS: Patients with ICH are exposed to a substantial risk of seizures; however, short-term mortality was not affected, and the risk of epilepsy was lower than previously thought. The likelihood of immediate seizures is influenced by factors that are inherent characteristics of ICH, whereas the chance of developing early seizures is influenced not only by certain characteristics of ICH, but also by unpredictable events. A brief period of therapy soon after ICH onset may reduce the risk of early seizures in patients with lobar hemorrhage.     

Ictal pattern of EEG and muscular activation in symptomatic infantile spasms: a videopolygraphic and computer analysis

PURPOSE: To investigate ictal muscular phenomena characterizing symptomatic infantile spasms (ISs) and their relation to ictal EEG. METHODS: Four children with severe encephalopathy, neurologic impairment, and refractory ISs related to different dysplastic lesions, underwent videopolygraphic recordings collecting surface electromyogram (EMG) activity from several cranial and limb muscles to evaluate the pattern of muscular recruitment, duration, and side-to-side asymmetry of ISs. Acquired data were stored for off-line analysis by a computerized polygraphic system. RESULTS: Spasms were characterized by a complex pattern of muscular activation. A constant or rostrocaudal propagation pattern was lacking in all patients. Intervals between the onset of EMG activity in different muscles in each spasm were very long: 相似文献   

Mutational analysis of nicotinic acetylcholine receptor beta2 subunit gene (CHRNB2) in a representative cohort of Italian probands affected by autosomal dominant nocturnal frontal lobe epilepsy

Twenty-four autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) probands were analyzed for the presence of V287L and V287M mutations in the CHRNB2 gene, which have been recently associated with the disease. In all patients, the involvement of the two additional loci reported as being associated with ADNFLE (CHRNA4 gene and chromosome 15q24 region) had been previously excluded. Mutational screening was performed by sequencing a polymerase chain reaction-amplified CHRNB2 DNA fragment, spanning the whole exon 5, which contains the V287L and V287M mutations and codes for approximately 65% of the mature protein. In none of the patients were mutations in the analyzed region of CHRNB2 found. These data, obtained in the largest ADNFLE cohort so far analyzed, demonstrate the rarity of the identified CHRNB2 mutations in ADNFLE patients.     

Association between panic disorder,major depressive disorder and celiac disease: a possible role of thyroid autoimmunity

OBJECTIVE: To evaluate the association between celiac disease and specific anxiety and depressive disorders and to identify potential common pathogenetic links, with particular regard to thyroid function and autoimmunity. METHODS: Cases included 36 adult celiac patients, 25 females and 11 males, aged 18-64 years. Controls comprised 144 healthy subjects matched by sex and age with no clinical evidence or family history of celiac disease. Diagnosis of celiac disease was made on the basis of clinical history and serological criteria. Psychiatric diagnoses were formulated using the International Composite Diagnostic Interview, according to DSM-IV criteria. Thyroid was evaluated by palpation, echography and measurement of serum-free thyroid hormones (FT4, FT3), thyroid-stimulating hormone (TSH) and antithyroid autoantibodies (anti-TPO). RESULTS: Compared to controls, a significantly higher number of celiac patients met criteria for lifetime [15 (41.7%) versus 30 (29.8%), P < .01] and 6-month [7 (19.4%) versus 9 (6.2%), OR = 3.2, chi(2) = 5.2, P < .05] major depressive disorder (MDD) and lifetime [5 (13.9%) versus 3 (2.1%), P < .001] and 6-month [3 (8.1%) versus 2 (1.4%), P < .05] panic disorder (PD). Anti-TPO prevalence was significantly higher in celiac patients than in the control group (11/36 = 30.5% versus 14/144 = 9.7%, P < .001). A higher frequency of PD and MDD was found in celiac patients with positive anti-TPO when compared to negative anti-TPO patients (4/11 = 36.4% PD in TPO+ versus 1/25 = 4% PD in TPO-, P < .01; 9/11 = 81.8% MD in TPO+ versus 6/25 = 9.5% MD in TPO-, P < .01). CONCLUSION: Patients affected by celiac disease tend to show a high prevalence of PD and MDD and association with subclinical thyroid disease appears to represent a significant risk factor for these psychiatric disorders.