In the past few years there has been an increasing appreciation of the importance of Toll-like receptors (TLRs), not just in immunity, but also in autoimmune diseases. TLRs were first identified as sensors of viral and bacterial pathogens that form an integral part of the innate immune response. It was later discovered that these receptors can also respond to endogenous ligands that are produced as a result of tissue damage. This lead to the hypothesis that TLRs may be key contributors to the pathogenesis of chronic inflammatory conditions. A large body of data supporting the role of TLRs in autoimmunity has emerged from animal models and more data is increasingly being generated from human studies as further tools to examine these receptors have become available. Developing strategies to manipulate TLR function is of great interest in autoimmunity, as well as other diseases that include allergy and cancer. This review explores the evidence that points to a role for TLRs in autoimmunity and highlights some of the potential ways in which modulation of their action may yield clinical benefits.

Background: It is hypothesized that psoriasis is an autoimmune disease. The most recent therapeutic approach that proved to be more effective than earlier methods of treatment is the use of mAb/fusion proteins. Efforts nowadays are focused on investigating the antipsoriatic affect of small molecules that can be administered orally, some of which are capable of entering cells, and being selective in targeting intracellular pathways. Objective: Preclinical patented small molecules that are recommended for the treatment of psoriasis are reviewed. Emphasis is placed on their mechanism of action. Methods: http://ep.espacenet.com/, Pubmed, Scopus and Google websites were the main sources used for the patented small molecule search. A number of patents were poorly described and difficulties were faced in trying to figure out the patentee(s) explanation. Moreover, most patents were recommended for the treatment of a number of autoimmune diseases and cancer, and not only for psoriasis. Results/conclusions: Small molecules that inhibit the activation of T lymphocytes, leukocyte trafficking, leukotriene activity/production and angiogenesis, and promote apoptosis have been patented. Small molecules that have been patented for the treatment of other autoimmune diseases and could be used for treating psoriasis are described. Moreover, other possible mechanistic approaches using small molecules are discussed.

Abstract Background The role of streptococcal infection in the initiation of guttate psoriasis is well-recognized. But the treatment results with oral erythromycin and phenoxymethylpenicillin are conflicting. Objective Our purpose was to evaluate the effectiveness of these antibiotics in the treatment of streptococcus associated guttate psoriasis comparing with a control group. Methods A total of 43 male patients with serologic evidence of a recent streptococcal infection were studied. Their mean age was 21 years (ranged between 19 and 23 years). These 43 patients were randomly allocated into three groups (no treatment group n = 15, erythromycin group n = 14, phenoxymethylpenicillin group n = 14). Both the treatment groups were treated for 14 d. All the groups were followed up for additional 4 weeks. Results There were no statistically significant improvement in any group and among the groups. Conclusion There was no statistically significant improvement in streptococcus associated guttate psoriasis with or without a course of oral penicillin or erythromycin.

Psoriasis comprises a broad spectrum of different clinical courses among which the chronic stable psoriasis by far occurs most frequently. The clinical presentation ranges from mild disease to more serious forms involving large areas of skin and/or joint disease. A number of modifying factors may impact on treatment choice in individual cases (eg, location of the lesions, disease phase, treatment history, response to previous treatments, comorbidity). Aside from this consideration, there are special localizations that remain some of the most difficult regions to control. Such entities are the scalp, nails, and intertriginous areas. Topical treatment of such different-to-treat areas has to be considered as a first-line intervention strategy, at least in those patients who are presenting an exclusively isolated involvement. In some situations (eg, in severe psoriasis or in patients who are refractory to topical treatment), however, a systemic treatment is indicated. Most obvious difficulties in treating these locations are due to unrealistic expectations from the patients' perspectives, time-consuming applications, side effects, cosmetic injuries, and restricted bioavailability of active compounds. Aside from hair care, initial use of keratolytics for scalp psoriasis, corticosteroids, and vitamin D(3) and analogues are currently standard treatments. Recently developed new formulations of both active ingredients such as foam or gel appear to be more acceptable to patients than traditional creams or ointments. Current treatment options for nail psoriasis are very often poorly efficacious, associated with undesirable effects, or time consuming. Success has to be measured in terms of months. Topical treatments (eg, corticosteroids, vitamin D analogues, tazarotene) are mainly used, but impressive improvement rates mostly will be achieved by systemic treatment of conventional and biologic agents. Finally, the usefulness of corticosteroids, vitamin D and analogues, and calcineurin inhibitors in treating intertriginous psoriasis clearly is demonstrated. Especially the use of calcineurin inhibitors exhibits efficacy in intertriginous regions and therefore may be seen as a promising treatment option in the future. Besides the important innovations in the last years, there is a need for new effective and well-tolerated treatment modalities, especially for long-term use in the 3 difficult-to-treat locations, which encompass cosmetic acceptability.

Superantigens are powerful T lymphocyte-stimulating agents that are believed to contribute to the pathogenesis of certain diseases such as psoriasis. Toxins produced by Streptococcus pyogenes and Staphylococcus aureus are superantigens. The aim of this study was to detect genes that code for superantigens in Streptococcus and Staphylococcus aureus isolates from psoriatic patients. Primers to amplify streptococcal pyrogenic exotoxin A, B, and C and streptolysin O genes and staphylococcal enterotoxin A, B, C, and D genes were used. Streptococcal exotoxin B was detected in five streptococcal isolates. Staphyloccocus aureus enterotoxin A and/or C genes were detected in nine S. aureus isolates. Isolates from 13 of 22 patients possesed gene(s) that code for toxin(s)(superantigens). These results might support the role of superantigens in the exacerbation of psoriasis.

Recently, several reports have been pointing to a possible relationship between Helicobacter pylori infection of gastric mucosa and dermatological diseases. Association has been reported for urticaria, rosacea, sjogrens syndrome and Henoch-Schonlein purpura. It has also been suggested that Helicobacter pylori may be one of the organisms capable of triggering psoriasis. We did Helicobacter pylori serology in 50 clinically typical psoriatic patients presenting to the Department of Dermatology, SMHS Hospital, Srinagar to determine if antibodies to Helicobacterpylori could be found in them. These psoriatic patients were without any known gastrointestinal complaints. An equal number of healthy individuals constituted the control group. The prevalence of Helicobacterpylori sero-positivity in psoriatic patients was significantly higher (P< 0.05) than in control group.

BACKGROUND: The dogma in psoriasis is that due to pathogen-induced inflammatory responses, an autoreactive immune response is induced that leads to tissue destruction. However, this model might be too simplistic. Literature data suggest that the expression of enzymes crucial for fatty acid oxidation is upregulated in the skin of patients with psoriasis compared with healthy individuals. OBJECTIVES: To examine the influence of fatty acid oxidation on psoriasis with regard to expression and activity of the key enzyme in fatty acid oxidation, carnitine palmitoyltransferase-1 (CPT-1) and the effect of the CPT-1 inhibitor, Etomoxir. METHODS: Experiments were performed with homogenates of lesional and healthy skin, fibroblast cultures and a model of human psoriatic skin transplanted on immune-deficient BNX mice. RESULTS: CPT-1 was highly active in lesional skin. Etomoxir was able to block CPT-1 activity in skin, implying that this antagonist may have the potential to suppress psoriasis when administered topically. In the mouse model, Etomoxir had an antipsoriatic effect that was at least as good as that of betamethasone, as evidenced by reduction of epidermal thickness, keratinocyte proliferation and differentiation. CONCLUSIONS: We conclude that fatty acid metabolism and in particular CPT-1 may be an excellent target for treatment of psoriasis.

Toll-like receptors (TLR) are crucial players in the innate immune response to microbial invaders. These receptors are expressed on immune cells, such as monocytes, macrophages, dendritic cells, and granulocytes. Importantly, TLR are not only expressed by peripheral blood cells, but their expression has been demonstrated in airway epithelium and skin, important sites of host-pathogen interaction. Host cells expressing TLR are capable of recognizing conserved pathogen-associated molecular patterns, such as lipopolysaccharide and CpG DNA, and their activation triggers signaling pathways that result in the expression of immune response genes and cytokine production. As TLR are instrumental in both launching innate immune responses and influencing adaptive immunity, regulation of TLR expression at sites of disease such as in leprosy, acne, and psoriasis may be important in the pathophysiology of these diseases. Furthermore, since TLR are vital players in infectious and inflammatory diseases, they have been identified as potential therapeutic targets. Indeed, synthetic TLR agonists such as imiquimod have already established utility in treating viral pathogens and skin cancers. In the future, it seems possible there may also be drugs capable of blocking TLR activation and thus TLR-dependent inflammatory responses, providing new treatment options for inflammatory diseases.

At the Problem Psoriasis Clinic at the University of Tennessee, Memphis, we use an antimicrobial approach for the treatment of psoriasis. This method is described for patient history, physical examination, and laboratory tests as well as treatment.

The recent discovery that human epidermal cells themselves make and secrete the components necessary for activation of the alternative complement pathway appears to provide an explanation for how human skin is ordinarily able to avoid colonization by molds and other organisms. It also helps clarify the mechanisms underlying clinical and laboratory findings seen in chronic mucocutaneous candidiasis, dandruff, and psoriasis. Psoriasis seems best explainable as a visible, late stage of the inflammatory sequelae of activation of the alternative complement pathway in the epidermis.

Thirty-seven patients with seborrheic dermatitis were treated topically with a 2% ketoconazole cream or its vehicle control in a double-blind study. The subjects were studied for numbers of Malassezia ovalis (Pityrosporum ovale) cells in their scalp scale; changes in numbers of yeast cells and morphology of M. ovalis were tabulated along with clinical assessment of improvement. The 2% ketoconazole cream, but not the placebo cream, reduced the numbers of viable yeast cells on the scalp. The clinical effect of 2% ketoconazole cream was good (75%-95% improvement) or better in eighteen of twenty subjects; the placebo cream produced good results in only three of seventeen subjects treated. Results of this study are consistent with the view that M. ovalis plays a central role in the pathogenesis of seborrheic dermatitis.

The addition of 5 days of rifampin therapy to a 10- or 14-day course of penicillin or erythromycin therapy has been shown to reduce greatly the rate of chronic streptococcal carriage. The empiric use of rifampin in combination with penicillin or erythromycin in nine of nine patients with streptococcal-associated psoriasis appeared to coincide with a marked improvement in their skin.

Microbial findings were analyzed from a group of 167 patients with psoriasis in an attempt to discover specific associations. Positive findings include associations between Malassezia ovalis and scalp/ear/face psoriasis and between bacteria and bodyfold, nailfold, and gluteal/rectal psoriasis.

Infectious complications in severe acute pancreatitis are an important problem and determine outcome in patients who survived the first inflammatory hit of the disease. Timely diagnosis of infected pancreatic necrosis is often challenging, but should not delay adequate treatment, which consists of source control and antibiotic treatment. Prophylactic antibiotics are not effective in reducing the incidence of (peri)pancreatic infection in patients with severe acute pancreatitis (or necrotizing pancreatitis). The only rational indication for antibiotics at this moment is documented infection. The spectrum of empiric antibiotics should cover both Gram-negative, Gram-positive and anaerobic microorganisms (also keeping in mind exposure to nosocomial microorganisms), and local ecology should be taken into account. Fungal infections are often present, and antifungal coverage should be considered, especially if multiple risk factors for invasive candidiasis are present. Currently, no tools are available to guide antimicrobial treatment.

Alefacept is an LFA3-Ig fusion protein that binds to CD2 and is thought to inhibit T cell activation by antagonism of CD2 signaling or by lysis of CD2(+) cells. Alefacept is potential future therapeutic for organ transplant recipients or graft-vs-host disease and is an approved therapeutic for psoriasis vulgaris, which is a T cell-mediated inflammatory disease. However, alefacept improves psoriasis in only approximately 50% of patients treated for 12 wk. We studied the immunologic effects of alefacept in a group of psoriasis patients during treatment. We found that T cells, especially CD8(+) T cells, were rapidly decreased in the peripheral circulation. Decreases in circulating T cells were not associated with induced apoptosis. Unexpectedly, in addition to suppression of inflammatory genes, we found a marked induction of mRNAs for STAT1, IL-8, and monokine induced by IFN-gamma during the first day of treatment in PBMC. We confirmed the agonistic effects of alefacept in PBMC in vitro, which were similar to CD3/CD28 ligation on T cells. These data establish that alefacept activates gene expression programs in leukocytes and suggest that its therapeutic action may be as a mixed agonist/antagonist. Furthermore, responding patients to alefacept treatment show unique patterns of gene modulation. Whereas alefacept down-regulated TCRs CD3D and CD2 in responders, nonresponders reveal a higher expression of T cell activation genes such as CD69 in pretreatment PBMC. These finding suggest a potential basis for categorizing responders vs nonresponders at an early time point in treatment or before treatment of a broad range of proinflammatory diseases. This study 1) establishes alefacept as a novel CD2 agonist molecule for induction of leukocyte activation genes (prior work proposed its mechanism as a CD2 antagonist) and 2) that differential activation of genes may categorize clinical responders to this agent, critical for cost-effective use of this drug.

The role of inflammation in the aetiology of age-related macular degeneration (AMD) has become very topical as the discovery that genetic variation in complement pathway genes influences the risk of developing AMD. Complement factor H gene, an inhibitor of the alternative complement activation pathway along with other complement pathway genes factor F (BF) and C2 show significant contribution to the risk of AMD. The alternative complement pathway is activated by a trigger, which is often microbial in nature. One current model of AMD aetiology implicates aberrant regulation of the alternative pathway of complement, in combination with some unknown infectious agents. Chlamydia pneumoniae could be one such potential trigger of the alternative complement pathway and several investigations have linked C. pneumoniae to AMD. However, there are only a few studies to date and numbers in most studies are small. Also there are many difficulties in verifying laboratory techniques for the detection of C. pneumoniae chronic infection. As such we need to be cautious not to over interpret the current results. However, the findings certainly give impetus for further work on C. pneumoniae and AMD. This paper provides an overview of work in this area.

Hemolytic uremic syndrome (HUS) is an important cause of acute renal failure in children. Mutations in one or more genes encoding complement-regulatory proteins have been reported in approximately one-third of nondiarrheal, atypical HUS (aHUS) patients, suggesting a defect in the protection of cell surfaces against complement activation in susceptible individuals. Here, we identified a subgroup of aHUS patients showing persistent activation of the complement alternative pathway and found within this subgroup two families with mutations in the gene encoding factor B (BF), a zymogen that carries the catalytic site of the complement alternative pathway convertase (C3bBb). Functional analyses demonstrated that F286L and K323E aHUS-associated BF mutations are gain-of-function mutations that result in enhanced formation of the C3bBb convertase or increased resistance to inactivation by complement regulators. These data expand our understanding of the genetic factors conferring predisposition to aHUS, demonstrate the critical role of the alternative complement pathway in the pathogenesis of aHUS, and provide support for the use of complement-inhibition therapies to prevent or reduce tissue damage caused by dysregulated complement activation.

Analysis of the adequacy of the initial empiric antimicrobial treatment of patients with acute Chlamydia pneumoniae (CP) infection, admitted to the Infectious Diseases Clinic, Clinical Centre, Medical Faculty, Skopje, Republic of Macedonia, for community-acquired pneumonia. Material and methods: A total number of 407 patients with community-acquired pneumonia (CAP) hospitalized at the Clinic between September 1997 and June 2002, with an average age of x=46.44 years, of whom 53.56% were male. Acute Chlamydia pneumoniae infection was proven serologically with MIF assay in 54 (13.27%) patients. Results: Initial empiric treatment with antibiotics in patients with CP pneumonia was provided with antimicrobial agents with intracellular activity in 26 (48.15%) patients; with fluoroquinolones in 19 (35.19%); macrolides in 5 (9.26%) and tetracyclines in 2 (3.7%). The treatment was conducted as monotherapy in 6 patients (11.11%) and in 20 patients (37.04%) in combination with betalactams. For 28 (51.85%) patients who were treated only with betalactams, empiric treatment was re-evaluated and new therapy with fluoroquinolon was conducted in 16 (29.63%), with macrolides in 8 (14.81%) and with tetracyclines in 4 (7.41%) patients. Conclusion: Adequate empiric treatment with antimicrobial agents with intracellular activity was performed in only 48.15% of the patients with acute CP infection. Therefore, when designing the initial empiric treatment of patients hospitalized with pneumonia, attention should be paid to this atypical pathogen of CAP. Key words: community acquired pneumonia, Chlamydia pneumoniae, atypical pneumonia, antimicrobial therapy.

TolerRx Inc, under license from BTG plc, is developing TRX-4, an anti-CD3 humanized monoclonal antibody for the potential treatment of type 1 diabetes and psoriasis. Phase II trials of the therapeutic antibody in type 1 diabetes have been completed and the company is planning a pivotal phase III trial for this indication. TolerRx is also enrolling psoriasis patients in a phase Ib clinical study of TRX-4. TRX-4 has been awarded Orphan Drug status for recent-onset type 1 diabetes.

In this article we present the path that led to current concepts regarding antimicrobial treatment of endocarditis caused by viridans streptococci highly susceptible to penicillin. Early treatment trials indicate that some patients with subacute endocarditis can be cured with shorter treatment duration than currently advised by international guidelines. Also, high-dose antibiotics, as recommended today, have a predominantly pharmacokinetic and pharmacodynamic rationale that is based mostly on experimental animal studies. Shortening antimicrobial treatment in select patients with endocarditis would be of great benefit. As yet there are no predictors of cure that can be used to individualize treatment duration in patients with bacterial endocarditis.

OBJECTIVE:: To assess the risk and prognostic factors of ventilator-associated pneumonia in trauma patients, with an emphasis on the inflammatory response. DESIGN:: Case-control study. SETTING:: Trauma intensive care unit. PATIENTS:: Of 190 consecutive mechanically ventilated patients, those with microbiologically confirmed pneumonia (n = 62) were matched with 62 controls without pneumonia. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: Clinical, microbiological, and outcome variables were recorded. Cytokines were measured in serum and blind bronchoalveolar lavage specimens at onset of pneumonia. Multivariate analyses of risk and prognostic factors for ventilator-associated pneumonia were done. Increased severity of head and neck injury (odds ratio, 11.9; p <.001) was the only independent predictor of pneumonia. Among patients with pneumonia, serum levels of interleukin-6 (p =.019) and interleukin-8 (p =.036) at onset of pneumonia were higher in nonresponders to treatment. Moreover, serum levels of tumor necrosis factor-alpha (p =.028) and interleukin-6 (p =.007) at onset of pneumonia were higher in nonsurvivors. Mortality in the intensive care unit was 23% in cases and controls. Nonresponse to antimicrobial treatment (odds ratio, 22.2; p =.001) and the use of hyperventilation (p =.021) were independent predictors of mortality in the intensive care unit for patients with pneumonia. CONCLUSIONS:: Severe head and neck trauma is strongly associated with ventilator-associated pneumonia. A higher inflammatory response is associated with nonresponse to treatment and mortality among patients with pneumonia. Although pneumonia did not influence mortality, nonresponse to treatment independently predicted mortality among these patients.

In this study we aimed to determine the microorganisms found in perianal fistulas in Crohn's disease and whether treatment with ciprofloxacin affects these microorganisms. Thirteen patients (males/females, 7/6; median age, 34 years; range, 18-61 years) with fistulas were treated with infliximab, 5 mg/kg intravenously, at weeks 6, 8, and 12 and randomized to double-blind treatment with ciprofloxacin, 500 mg bd (n = 6), or placebo (n = 7) for 12 weeks. Samples were taken at baseline and at weeks 6 and 18. In the ciprofloxacin group 10 different genera of microorganisms were identified, while 13 genera could be identified in the placebo group. Gram-negative enteric floras were present in a small minority. The genera found in patients with perianal fistulas were predominantly gram-positive microorganisms. Therefore, antimicrobial treatment should be directed toward these microorganisms.

General dentists frequently encounter patients with aggressive periodontal disease and should be able to diagnose and manage this disease properly. Periodontal care in the absence of a comprehensive treatment plan and proper therapy can result in the rapid progression of the disease and, ultimately, tooth loss. It is important for the general dentist to diagnose, inform, and treat the periodontal patient accurately, using referral and nonsurgical, surgical, and antimicrobial/antibiotic therapy. This article provides a brief history of the classification of aggressive periodontal disease, describes the microorganisms associated with aggressive periodontal disease, discusses the selection and use of systemic antibiotics in therapy, and lists the various antibiotic regimens for treating aggressive periodontal disease.