Retrospective analysis of open preperitoneal mesh repair of complex inguinal hernias.

PURPOSE: The open posterior approach in the form of either a Stoppa or Wantz operation may be a good alternative technique particularly in the repair of complex inguinal hernias. The term "complex inguinal hernia" designates hernias with a combination of arduous features including large hernia defects, large to giant hernia sacs, multiple recurrences, and bilaterality. In this retrospective analysis, we investigated our results of open posterior repair in view of its feasibility in patients with complex inguinoscrotal hernias. METHODS: From a series of 845 inguinal hernia patients, we retrospectively reviewed the records of 60 patients with complex inguinal hernias whom were directed to open preperitoneal repair by either a Stoppa or Wantz procedure. RESULTS: More than 80% of cases were males with large to giant inguinoscrotal hernias. One half of patients had bilateral hernias, and one fourth had recurrent hernias. Early postoperative complications occurred in almost half of patients; however, most of them were minor. The most important early complication in this series was the full recurrences we encountered in the very next morning in two patients. Eighty-three percent of patients left hospital in the first 2 days averaging 1.8 days of hospital stay. The mesh:defect area ratio is < 7 in recurrent hernias while it is > 9 in nonrecurrent cases. CONCLUSION: The open posterior approach to complex inguinal hernias facilitated both handling and repair of difficult hernias. It was very well tolerated by the patients, and yielded favorable postoperative results. We think the open posterior repair may be a method of choice in the repair of complex inguinal hernias.

Response of peripheral blood mononuclear cells from lupus patients to stimulation by CpG oligodeoxynucleotides.

OBJECTIVES: Increased levels of hypomethylated CpG-containing DNA in sera from patients with systemic lupus erythematosus (SLE) may contribute to the initiation and/or perpetuation of the disease. This study characterizes the in vitro response of peripheral blood mononuclear cells (PBMC) from SLE patients to CpG DNA. METHODS: Secretion of cytokines and IgM, cell proliferation and up-regulation of co-stimulatory molecules were evaluated in PBMC from SLE patients (n=24) and normal controls (n=24) after stimulation with synthetic oligodeoxynucleotides (ODN) containing CpG motifs. RESULTS: Up-regulation of co-stimulatory molecules and the secretion of interferon-alpha and interleukin-6 (IL-6) in response to CpG ODN was significantly reduced in monocytes and dendritic cells from SLE patients. Secretion of interferon-gamma by natural killer (NK) cells was also reduced. In contrast, the IgM and IL-10 response of B cells to CpG ODN was normal. CONCLUSION: Monocytes, dendritic cells and NK cells from SLE patients respond abnormally to CpG ODN stimulation, which may contribute to the cytokine imbalance observed in SLE.

Cutting edge: Role of Toll-like receptor 9 in CpG DNA-induced activation of human cells.

Unmethylated CpG motifs present in bacterial DNA stimulate a rapid and robust innate immune response. Human cell lines and PBMC that recognize CpG DNA express membrane-bound human Toll-like receptor 9 (hTLR9). Cells that are not responsive to CpG DNA become responsive when transfected with hTLR9. Expression of hTLR9 dramatically increases uptake of CpG (but not control) DNA into endocytic vesicles. Upon cell stimulation, hTLR9 and CpG DNA are found in the same endocytic vesicles. Cells expressing hTLR9 are stimulated by CpG motifs that are active in primates but not rodents, suggesting that evolutionary divergence between TLR9 molecules underlies species-specific differences in the recognition of bacterial DNA. These findings indicate that hTLR9 plays a critical role in the CpG DNA-mediated activation of human cells.

Sterically stabilized cationic liposomes improve the uptake and immunostimulatory activity of CpG oligonucleotides.

Immunostimulatory CpG oligonucleotides (ODN) show promise as immune adjuvants, anti-allergens, and immunoprotective agents. Increasing the bioavailability and duration of action of CpG ODN should improve their therapeutic utility. Encapsulating ODN in sterically stabilized cationic liposomes provides protection from serum nucleases while facilitating uptake by B cells, dendritic cells, and macrophages. In a pathogen challenge model, sterically stabilized cationic liposomes encapsulation doubled the duration of CpG ODN-induced immune protection. In an immunization model, coencapsulation of CpG ODN with protein Ag (OVA) magnified the resultant Ag-specific IFN-gamma and IgG responses by 15- to 40-fold compared with Ag plus CpG ODN alone. These findings support the use of sterically stabilized cationic liposomes to significantly enhance the therapeutic efficacy of CpG ODN.

Human peripheral blood cells differentially recognize and respond to two distinct CPG motifs.

Oligodeoxynucleotides (ODN) that contain unmethylated CpG dinucleotides trigger a strong innate immune response in vertebrates. CpG ODN show promise as vaccine adjuvants, anti-allergens, and immunoprotective agents in animal models. Their transition to clinical use requires the identification of motifs that are optimally stimulatory in humans. Analysis of hundreds of novel ODN resulted in the identification and characterization of two structurally distinct "clusters" of immunostimulatory CpG ODN. One cluster ("D") preferentially stimulates IFN-gamma production by NK cells, whereas the other ("K") stimulates cell proliferation and the production of IL-6 and IgM by monocytes and B cells. The distinct immunostimulatory properties of K and D ODN can improve the design of CpG-based products to achieve specific therapeutic goals.

Immunotherapeutic applications of CpG-containing oligodeoxynucleotides.

Bacterial DNA and synthetic oligodeoxynucleotides (ODN) expressing unmethylated CpG motifs stimulate the mammalian immune system to mount a rapid innate immune response. This response is characterized by the production of polyreactive IgM, immunomodulatory cytokines and chemokines. CpG ODN directly stimulate lymphocytes, natural killer cells and professional antigen-presenting cells (such as macrophages and dendritic cells). Owing to the strength and nature of this stimulation, CpG ODN are being harnessed for a variety of therapeutic uses. They are being tested for their ability to act as immune adjuvants, boosting the immune response elicited by conventional and DNA vaccines. As a result of their ability to activate a strong interferon gamma-dominated Th1 response while blocking the development of Th2-dependent allergies, CpG ODN are being examined for their antiallergic properties. Finally, CpG ODN are being used as "immunoprotective agents", since the innate immune response they elicit can protect the host from a variety of pathogenic bacteria, viruses and parasites.

[Acute pancreatitis and hyperlipidemia in females. Is pregnancy contraindicated? An analysis of two cases]. / Bayanlarda hiperlipidemi ve akut pankreatit: gebelik kontrendike midir? Iki olgunun incelenmesi.

Acute pancreatitis and hyperlipidemia during pregnancy is a rare but life-threatening condition for both mother and fetus. In this article, we reported two cases suffered from acute pancreatitis and hyperlipidemia; 24-year old pregnant women and 40 year old non-pregnant women. The risks of the pregnancy in this situation were also discussed.

Immunoadjuvant action of plasmid DNA in liposomes.

Bacterial DNA and oligodeoxynucleotides containing immunostimulatory sequences with a CpG motif stimulated a Th1 type response in vivo. The adjuvant action of a non-coding plasmid DNA derived from pRc/CMV HBS (encoding the S region of hepatitis B surface antigen, HBsAg) in mice was investigated. The role of methylation on the adjuvanticity of the plasmid as well as the effect of vaccine formulation employed on the outcome of antigen-specific humoral and cellular responses were also studied. The results demonstrated that plasmid DNA acted as a Th1 promoting adjuvant when mixed as such or co-entrapped in liposomes with a very low dose of antigen. However, the adjuvant activity was lost when separate liposome entrapped formulations of both the antigen and the plasmid DNA were mixed, indicating a necessity for the antigen and the plasmid DNA to contact the same APC for optimal immune activation. A decreased adjuvanticity of plasmid DNA upon methylation with HpaII methyltransferase was also demonstrated. A mechanism that may help partially explain the reduction in adjuvanticity after modification of C residues is also discussed.

The immunological co-adjuvant action of liposomal interleukin-2: the role of mode of localisation of the cytokine and antigen in the vesicles.

In experiments designed to study the co-adjuvant action of interleukin-2, a model antigen (tetanus toxoid) was passively entrapped in, or covalently coupled to multilamellar liposomes in the presence or absence of interleukin-2 (IL-2). When present, IL-2 was either co-entrapped with the toxoid, entrapped alone in liposomes with toxoid coupled to their surface, or coupled to the surface of liposomes with entrapped toxoid. The role of spatial localization of IL-2 within the liposomal structure (vis a vis that of the toxoid) was studied in terms of its immunoadjuvant action in vivo. Male CD-1 mice were injected intramuscularly twice with a variety of toxoid-containing liposomal preparations in the absence or presence of IL-2 incorporated in the same liposomes as above. In some experiments mice were immunized with liposomal toxoid mixed with separately entrapped IL-2. Results show that IL-2 augments significantly secondary immune responses (IgG1, IgGa, IgG2b subclasses) against the liposomal toxoid (up to 15-fold compared with the liposomal toxoid alone), regardless of cytokine and antigen mode of accommodation in the liposomal structure but only when both are present in the same vesicles. It is suggested that liposomal IL-2 may prove useful as a co-adjuvant for vaccines which are weak or ineffective.

Interleukin-15 acts as an immunological co-adjuvant for liposomal antigen in vivo.

The recently discovered interleukin-15 (IL-15) is known to bind to the receptor of interleukin-2 (IL-2) and to share several of the latter's immunological properties. In the present study, the first to our knowledge on IL-15 behaviour in vivo, we examined the possibility that IL-15 also shares the ability of IL-2 to enhance the immunological adjuvant property of liposomes by acting as a co-adjuvant. The cytokine and a model antigen (tetanus toxoid) were either co-entrapped by the dehydration rehydration method into, or covalently co-linked by diazotization to the surface of the same liposomes, or entrapped in different liposome populations. Intramuscular immunization of CD-1 mice with a variety of IL-15 and toxoid formulations revealed that IL-15 augments anti-toxoid IgG (IgG1, IgG2, IgG2b) responses well above (up to ten-fold) those achieved with liposomal toxoid alone (or with a mixture of free IL-15 and toxoid) when the cytokine and the antigen are associated with the same vesicles but not when in different vesicle populations that were mixed before injection. Higher responses were observed for all three subclasses studied only with liposomes where IL-15 and antigen were accommodated on their surface.

Influence of membrane components on the stability and drug release properties of reverse phase evaporation vesicles (REVs): light sensitive all-trans retinal, negatively charged phospholipid dicetylphosphate and cholesterol.

Incorporation of a negatively charged phospholipid, dicetylphosphate, initially increased encapsulation efficiency (from 12 to 24%) but beyond 5% (molar) a detrimental effect was observed. Rate of drug release from REVs was, for most cases, found to be bi-phasic implying partitioning between the lipid bilayer and the aqueous compartment. It was not possible to prepare liposomes with more than 1% (molar) all-trans retinal (ATR) as a membrane component. When ATR was reduced to 0.5% (molar), encapsulation efficiency increased to 7.76%. Upon exposure to long wave UV (365 nm), release from ATR containing REVs was increased and this was attributed to the formation of 13-cis isomer as indicated by HPLC and UV spectroscopy data.

A non-ionic surfactant vesicle-in-water-in-oil (v/w/o) system: potential uses in drug and vaccine delivery.

An aqueous dispersion of niosomes (non-ionic surfactant vesicles) emulsified in an external oil phase forms the vesicle-in-water-in-oil (v/w/o) system described in this paper. The properties of the surfactant used to form the vesicles, the surfactant or surfactant mixture used to stabilize the emulsion and the nature of the oil phase can be changed to provide systems of different capacities for drug or antigen and different release characteristics. The same nonionic surfactant is used as the principle amphipile to form the niosomes and to stabilize the w/o emulsion, thus promoting stability by decreasing transfer of surfactant between the stabilizing monolayers and the vesicle bilayers. The in vitro release of carboxyfluoroscein and 5-fluorouracil encapsulated within the niosomes of the v/w/o system has been investigated, the nature of the oil phase and surfactant-oil interactions being important in determining the rate of solute release. Initial studies of the system in vivo, as an adjuvant for tetanus toxoid, using cottonseed oil as the external oil phase, showed enhanced immunological activity over the free antigen or vesicles.