Antigenic and immunologic characterization of an allogeneic colon carcinoma vaccine

In the present prospective, census-based study we have investigated the prevalence of organ-specific and non-organ-specific autoantibodies (AAb) in 152 unselected Cameroonians aged 60 years and older living in the community. AAb were detected in 49% of the participants. Non-organ-specific AAb (47%) predominated over organ-specific AAb (7%). Anti-TPO, anti-Tm, anti-Tg and anti-PC AAb were completely absent. RF was the most frequent AAb, being found in 57 (38%) cases. The prevalences of anti-SMA and RF were significantly higher in women than in men (respectively, P=0.023 and P=0.016). Higher serum concentrations of gammaglobulins were accompanied by a higher prevalence of RF (P < 0.0001) and a lower prevalence of ANA (P=0.036). The overall prevalence of AAb was higher in the filaria-infected (60%) compared to the non-infected (42%) participants (P=0.046). There was no significant influence of the vitamin D status, number of pregnancies, physical activity or medication use on the prevalence of AAb. In this study a heterogeneous pattern for the presence of the various AAb was found. Some AAb, which are commonly encountered in other studies on elderly subjects, were completely absent in this population. This diversified pattern of AAb prevalence therefore argues in favour of exogenous influences in the occurrence of AAb in elderly populations.     

Viral load,CD4 percentage,and delayed-type hypersensitivity in subjects receiving the HIY-1 Immunogen and antiviral drug therapy

Two trials of subjects inoculated with the inactivated, gp120-depleted HIV-1 Immunogen are reported. In one study, in which 19 subjects received ZDV and 8 subjects received ddI, treatment with the HIV-1 Immunogen did not affect the pharmacokinetic parameters of the antiviral drugs. In another study, 65 subjects who were previously immunized with the HIV-1 Immunogen over a mean period of 4.0 years (range, 1.2–5.4 years) received inoculations at 0 and 6 months. At some point during this 48-week study, 72% of the subjects (47/65) were receiving antiviral drug therapy. The HIV-1 DNA load in CD4 cells and CD4 percentage were found to be stable over the 48-week period. Delayed-type hypersensitivity to HIV-1 antigens increased after two inoculations with the HIV-1 Immunogen. In these two trials, no serious treatment-related adverse events were documented in the subjects. The two studies presented herein are the first to suggest that an immune-based therapy such as the HIV-1 Immunogen can be combined safely with antiviral drugs, supporting further study to evaluate the clinical utility of this approach.     

Detergent-resistant membrane microdomains facilitate Ib oligomer formation and biological activity of Clostridium perfringens iota-toxin

Clostridium perfringens iota-toxin consists of two separate proteins identified as a cell binding protein, iota b (Ib), which forms high-molecular-weight complexes on cells generating Na(+)/K(+)-permeable pores through which iota a (Ia), an ADP-ribosyltransferase, presumably enters the cytosol. Identity of the cell receptor and membrane domains involved in Ib binding, oligomer formation, and internalization is currently unknown. In this study, Vero (toxin-sensitive) and MRC-5 (toxin-resistant) cells were incubated with Ib, after which detergent-resistant membrane microdomains (DRMs) were extracted with cold Triton X-100. Western blotting revealed that Ib oligomers localized in DRMs extracted from Vero, but not MRC-5, cells while monomeric Ib was detected in the detergent-soluble fractions of both cell types. The Ib protoxin, previously shown to bind Vero cells but not form oligomers or induce cytotoxicity, was detected only in the soluble fractions. Vero cells pretreated with phosphatidylinositol-specific phospholipase C before addition of Ib indicated that glycosylphosphatidyl inositol-anchored proteins were minimally involved in Ib binding or oligomer formation. While pretreatment of Vero cells with filipin (which sequesters cholesterol) had no effect, methyl-beta-cyclodextrin (which extracts cholesterol) reduced Ib binding and oligomer formation and delayed iota-toxin cytotoxicity. These studies showed that iota-toxin exploits DRMs for oligomer formation to intoxicate cells.     

Wagner vitreoretinal degeneration with genetic linkage refinement on chromosome 5q13-q14

· Background: It has been previously described that Wagner disease is linked to chromosome 5q13-q14. This study was carried out to describe the ophthalmological aspects and report the results of genetic linkage analysis in a large pedigree affected by Wagner disease. · Methods: Fourty members of one same family agreed to be examined. · Results: Twenty patients presented vitreoretinal degeneration in both eyes without any extra-ocular abnormalities. In young patients, visual acuity was usually normal after correction of frequent mild myopia. Presenile cataracts progressed by the third decade and required removal for visual rehabilitation. The primary disorder involved an abnormal vitreous. A few avascular vitreous bands were usually the only optical feature in the mostly empty vitreous cavity. A circumferential vitreous condensation formed in contact with the retina on many spots. Less common retinal findings included retinal detachment, abnormal retinal pigmentation, progressive atrophy of the RPE simulating choroideremia and lattice degeneration. Genetic analysis revealed a highly significant linkage (lod score >5.0) between the disease and 10 markers of the chromosome 5q13-q14 region. Two recombination events allowed us to refine the linked interval to 20 cM between the D5S650 and D5S618 markers. · Conclusion: Ophthalmological aspects of Wagner’s disease appear to progress with age. Regular ophthalmological examination is important for detecting retinal abnormalities. The gene involved in Wagner’s disease lies in a 20 cM interval on chromosome 5q13-q14. Received: 30 June 1998 Revised version received: 5 October 1998 Accepted: 6 October 1998     

Micelles in anticancer drug delivery

In recent years, the development of micelle-based carriers for cancer chemotherapy has been the object of growing scientific interest, both in academia and the pharmaceutical industry. Micelles have attracted attention in drug formulation and targeting, given that they provide a set of unique features. The core/shell structure accounts for their qualities as efficient drug delivery systems. The core provides a reservoir where hydrophobic drugs can be dissolved, and the corona confers hydrophilicity to the overall system. Sequestration of anticancer drugs in the inner core can protect them from premature degradation and allow their accumulation at tumoral sites. Micelles can be subdivided into two different groups according to their molecular weights: low-molecular-weight surfactant micelles and polymeric micelles. Although surfactant micelles such as polyethoxylated castor oil (e.g. Cremophor® EL) are commonly used to solubilize hydrophobic anticancer drugs such as paclitaxel, they have often been associated with serious adverse effects. Polymeric micelles may offer several advantages over surfactant micelles in terms of drug loading, adverse effects, stability, and targeting of tumors. Indeed, polymeric micelles can increase the circulation time of cytostatics and induce substantial changes in their biodistribution, including tumor accumulation via the enhanced permeation and retention effect. In addition, some recent studies have demonstrated that amphiphilic block copolymers (e.g. poloxamers) used for the preparation of polymeric micelles could increase the activity of several cytostatics by reversing multidrug resistance. This review first describes and compares surfactant micelle and polymeric micelle systems, already commercialized or under investigation, used to administer cytostatics. Secondly, their in vitro interactions with neoplastic cells and tissues are discussed in terms of cellular uptake and pharmacologic activity. In particular, the pharmacokinetics and biodistribution of micelles, along with the factors affecting their delivery to tumoral sites, are thoroughly discussed. Finally, in vivo studies reporting the anticancer activity and toxicity of drugs associated with micelles are reviewed.     

Impact of medical practice guidelines on the assessment of patients with acute coronary syndrome without persistent ST segment elevation.

OBJECTIVE: To assess the impact of introducing clinical practice guidelines on acute coronary syndrome without persistent ST segment elevation (ACS) on patient initial assessment. DESIGN: Prospective before-after evaluation over a 3-month period. SETTING: The emergency ward of a tertiary teaching hospital. PATIENTS: All consecutive patients with ACS evaluated in the emergency ward over the two 3-month periods. INTERVENTION: Implementation of the practice guidelines, and the addition of a cardiology consultant to the emergency team. MAIN OUTCOME MEASURES: Diagnosis, electrocardiogram interpretation, and risk stratification after the initial evaluation. RESULTS: The clinical characteristics of the 328 and 364 patients evaluated in the emergency ward for suspicion of ACS before and after guideline implementation were similar. Significantly more patients were classified as suffering from atypical chest pain (39.6% versus 47.0%; P = 0.006) after guideline implementation. Guidelines availability was associated with significantly more formal diagnoses (79.9% versus 92.9%; P < 0.0001) and risk stratification (53.7% versus 65.4%, P < 0.0001) at the end of initial assessment. CONCLUSION: Guidelines implementation, along with availability of a cardiology consultant in the emergency room had a positive impact on initial assessment of patients evaluated for suspicion of ACS. It led to increased confidence in diagnosis and stratification by risk, which are the first steps in initiating effective treatment for this common condition.     

An association of pleuropulmonary blastoma and cystic nephroma: possible genetic association.

The association of pleuropulmonary blastoma and cystic nephroma is an uncommon entity, with only 4 cases of such an association in the same patient described in English literature. We report a 5th histologically documented case in a 32-month-old boy. The boy underwent a pulmonary biopsy that showed a pleuropulmonary blastoma and a nephrectomy that showed a cystic nephroma. The pleuropulmonary mass showed an important regression with postbiopsy chemotherapy, allowing subsequent tumorectomy. To date very little is known about this rare entity, and a genetic link between these 2 tumors is hypothesized.     

Is a prophylactic treatment by erythropoietin relevant to reduce red blood cell transfusion in the pediatric intensive care unit?

OBJECTIVE: An adult trial reported the efficacy of recombinant human erythropoietin in critically ill patients with a 19% decrease in red blood cell transfusion. Our aim was to evaluate the relevance of this prophylactic treatment in children hospitalized in a pediatric intensive care unit (PICU). DESIGN: Cohort study from January 1995 to December 2004. SETTING: University hospital PICU. PATIENTS: Children between 1 month and 18 yrs of age. INTERVENTIONS: We searched through a prospective databank for all children hospitalized in the PICU for > or =4 days (potential recipients of erythropoietin, as proposed in the adult trial) and transfused with red blood cells after day 7 following PICU entry (in whom erythropoietin might prevent anemia, according to results of the adult trial). MEASUREMENTS AND MAIN RESULTS: We found that 799 of 2,578 children (31%) were hospitalized for > or =4 days. The study group comprised 787 patients who were hospitalized for > or =4 days in the PICU and for whom full records were available. One hundred eighty-three children in this study group were transfused during their stay in the PICU (median age, 7 months; weight, 6.60 kg). Hemoglobin levels before transfusion (mean +/- sd) were 7.7 +/- 1.5 g/dL. These transfused children represented 23% of the study group and 7% of the total PICU admissions. Forty-seven children (6% of the study group, 2% of the total PICU admissions) were transfused with red blood cells after 7 days of hospitalization and could have benefited from a prophylactic treatment with erythropoietin. Relative risk to benefit of a prophylactic treatment by erythropoietin was higher in cases of mechanical ventilation (relative risk, 1.18) and inotropic treatment (relative risk, 1.72) and if the main diagnosis involved dermatological (relative risk, 3.03) or oncologic disease (relative risk, 3.94). CONCLUSIONS: If we applied the results of the adult trial to our PICU, we would have to treat 31% of the children with prophylactic erythropoietin and thereby expect a reduction of one red blood cell transfusion for every 17 treated patients.