Mold and Human Health: a Reality Check.

There are possibly millions of mold species on earth. The vast majority of these mold spores live in harmony with humans, rarely causing disease. The rare species that does cause disease does so by triggering allergies or asthma, or may be involved in hypersensitivity diseases such as allergic bronchopulmonary aspergillosis or allergic fungal sinusitis. Other hypersensitivity diseases include those related to occupational or domiciliary exposures to certain mold species, as in the case of Pigeon Breeder's disease, Farmer's lung, or humidifier fever. The final proven category of fungal diseases is through infection, as in the case of onchomycosis or coccidiomycosis. These diseases can be treated using anti-fungal agents. Molds and fungi can also be particularly important in infections that occur in immunocompromised patients. Systemic candidiasis does not occur unless the individual is immunodeficient. Previous reports of "toxic mold syndrome" or "toxic black mold" have been shown to be no more than media hype and mass hysteria, partly stemming from the misinterpreted concept of the "sick building syndrome." There is no scientific evidence that exposure to visible black mold in apartments and buildings can lead to the vague and subjective symptoms of memory loss, inability to focus, fatigue, and headaches that were reported by people who erroneously believed that they were suffering from "mycotoxicosis." Similarly, a causal relationship between cases of infant pulmonary hemorrhage and exposure to "black mold" has never been proven. Finally, there is no evidence of a link between autoimmune disease and mold exposure.

The clinical relevance of complex regional pain syndrome type I: The Emperor's New Clothes.

The management of patients with chronic pain is a nearly daily challenge to rheumatologists, neurologists, orthopedic surgeons, pain specialists and indeed a issue in nearly every clinical practice. Among the myriad of causes of pain are often included a unique syndrome, generally referred to as complex regional pain syndrome type I (CRPS). Unfortunately CRPS I has become a catch all phase and there are serious questions on whether it exists at all; this has led to an extraordinary number of poorly defined diagnostic criteria. It has also led to an etiologic quagmire that includes features as diverse as autoimmunity to simple trauma. These, in turn, have led to overdiagnosis and often overzealous use of pain medications, including narcotics. In a previous paper, we raised the issue of whether CRPS type I reflected a valid diagnosis. Indeed, the diagnostic criteria for CRPS I, and therefore the diagnosis itself, is unreliable for a number of reasons: 1) the underlying pathophysiology of the signs and symptoms of CPRS I are not biologically plausible; 2) there are no consistent laboratory or imaging testing available; 3) the signs and symptoms fluctuate over time without a medical explanation; 4) the definitions of most studies are derived from statistical analysis with little consideration to required sample size, i.e. power calculations; 5) interobserver reliability in the assessment of the signs and symptoms are often only fair to moderate, and agreement on the diagnosis of "CRPS I" is poor. Even physicians who still believe in the concept of "CRPS I" admit that it is vastly overdiagnosed and has become a diagnosis of last resort, often without a complete differential diagnosis and an alternative explanation. Finally, one of the most convincing arguments that there is no clinical entity as "CRPS I" comes from the enormous heterogeneity in sign and symptom profiles and the heterogeneity of pathophysiological mechanisms postulated. This observation is underscored by the diversity of responses among "CRPS I" patients to essentially all treatment modalities. It has even led to the concept that the signs and symptoms of CRPS can spread throughout the body, as if it is an infectious disease, without any medical plausible explanation. If true progress is to be made in helping patients with pain, it will require entirely new and different concepts and abandoning CRPS I as a legitimate diagnosis.

The Basis of Structure/Function Claims of Nutraceuticals.

In the United States, as in most of the world, there are large numbers of nutraceuticals that are sold and which people take to boost their immune response. There are, in addition, almost an equal number of products sold to reduce allergies. However, very few consumers, and indeed physicians, are aware of what a structure/function claim is. Structure/function claims are labeling claims that can be used to describe the potential effects of a dietary ingredient or similar substance on the structure or function of the human body. This category of claims was created by legislation contained in the Dietary Supplement Health and Education Act. The intent was to supply consumers with reasonably substantiated information that would allow them to make educated choices about their diet and health. They were not intended to have the same weight and substantiation as the claims made for conventional prescription pharmaceuticals. Rather, they were proposed to fill the gap between consumer desire for over-the-counter supplements and foods, and rigorous and generally more potent and potentially "toxic" prescription medications. The legally mandated disclaimer, stating that the U.S. Food and Drug Administration has not evaluated the structure/function claim, often leads to misinterpretation. While there should be a biologic premise underlying the claim, there is not an absolute requirement for a conventional rigorous placebo-controlled dose response trial. While this may not be the clinical standard that a typical scientific oriented society might desire, it reflects the attempts of the FDA to find common grounds and to allow consumers to use products that are generally considered as safe based on historical use and biologic comparisons. The logic of, indeed need for, structure/function claims is straightforward; however, of equal importance is that nutraceuticals should be properly labeled, have accuracy in their ingredients, be free of contamination, be safe, and have a reasonable body of data that supports their efficacy.

Fibromyalgia: A Critical and Comprehensive Review.

Fibromyalgia is a disorder that is part of a spectrum of syndromes that lack precise classification. It is often considered as part of the global overview of functional somatic syndromes that are otherwise medically unexplained or part of a somatization disorder. Patients with fibromyalgia share symptoms with other functional somatic problems, including issues of myalgias, arthralgias, fatigue and sleep disturbances. Indeed, there is often diagnostic and classification overlap for the case definitions of a variety of somatization disorders. Fibromyalgia, however, is a critically important syndrome for physicians and scientists to be aware of. Patients should be taken very seriously and provided optimal care. Although inflammatory, infectious, and autoimmune disorders have all been ascribed to be etiological events in the development of fibromyalgia, there is very little data to support such a thesis. Many of these disorders are associated with depression and anxiety and may even be part of what has been sometimes called affected spectrum disorders. There is no evidence that physical trauma, i.e., automobile accidents, is associated with the development or exacerbation of fibromyalgia. Treatment should be placed on education, patient support, physical therapy, nutrition, and exercise, including the use of drugs that are approved for the treatment of fibromyalgia. Treatment should not include opiates and patients should not become poly pharmacies in which the treatment itself can lead to significant morbidities. Patients with fibromyalgia are living and not dying of this disorder and positive outlooks and family support are key elements in the management of patients.

Lyme disease: a rigorous review of diagnostic criteria and treatment.

Lyme disease was originally identified in Lyme, Connecticut, based upon an unusual cluster of what appeared to be patients with juvenile rheumatoid arthritis. It was subsequently identified as a new clinical entity originally called Lyme arthritis based on the observation that arthritis was a major clinical feature. However, Lyme arthritis is now called Lyme disease based upon the understanding that the clinical features include not only arthritis, but also potential cardiac, dermatologic and neurologic findings. Lyme disease typically begins with an erythematous rash called erythema migrans (EM). Approximately 4-8% of patients develop cardiac, 11% develop neurologic and 45-60% of patients manifest arthritis. The disease is transmitted following exposure to a tick bite containing a spirochete in a genetically susceptible host. There is considerable data on spirochetes, including Borrelia burgdorferi (Bb), the original bacteria identified in this disease. Lyme disease, if an organism had not been identified, would be considered as a classic autoimmune disease and indeed the effector mechanisms are similar to many human diseases manifest as loss of tolerance. The clinical diagnosis is highly likely based upon appropriate serology and clinical manifestations. However, the serologic features are often misinterpreted and may have false positives if confirmatory laboratory testing is not performed. Antibiotics are routinely and typically used to treat patients with Lyme disease, but there is no evidence that prolonged or recurrent treatment with antibiotics change the natural history of Lyme disease. Although there are animal models of Lyme disease, there is no system that faithfully recapitulates the human disease. Further research on the effector mechanisms that lead to pathology in some individuals should be further explored to develop more specific therapy.

Respiratory syncytial virus--a comprehensive review.

Respiratory syncytial virus (RSV) is amongst the most important pathogenic infections of childhood and is associated with significant morbidity and mortality. Although there have been extensive studies of epidemiology, clinical manifestations, diagnostic techniques, animal models and the immunobiology of infection, there is not yet a convincing and safe vaccine available. The major histopathologic characteristics of RSV infection are acute bronchiolitis, mucosal and submucosal edema, and luminal occlusion by cellular debris of sloughed epithelial cells mixed with macrophages, strands of fibrin, and some mucin. There is a single RSV serotype with two major antigenic subgroups, A and B. Strains of both subtypes often co-circulate, but usually one subtype predominates. In temperate climates, RSV infections reflect a distinct seasonality with onset in late fall or early winter. It is believed that most children will experience at least one RSV infection by the age of 2 years. There are several key animal models of RSV. These include a model in mice and, more importantly, a bovine model; the latter reflects distinct similarity to the human disease. Importantly, the prevalence of asthma is significantly higher amongst children who are hospitalized with RSV in infancy or early childhood. However, there have been only limited investigations of candidate genes that have the potential to explain this increase in susceptibility. An atopic predisposition appears to predispose to subsequent development of asthma and it is likely that subsequent development of asthma is secondary to the pathogenic inflammatory response involving cytokines, chemokines and their cognate receptors. Numerous approaches to the development of RSV vaccines are being evaluated, as are the use of newer antiviral agents to mitigate disease. There is also significant attention being placed on the potential impact of co-infection and defining the natural history of RSV. Clearly, more research is required to define the relationships between RSV bronchiolitis, other viral induced inflammatory responses, and asthma.

Lupus nephritis: a critical review.

Lupus nephritis remains one of the most severe manifestations of systemic lupus erythematosus associated with considerable morbidity and mortality. A better understanding of the pathogenesis of lupus nephritis is an important step in identifying more targeted and less toxic therapeutic approaches. Substantial research has helped define the pathogenetic mechanisms of renal manifestations and, in particular, the complex role of type I interferons is increasingly recognized; new insights have been gained into the contribution of immune complexes containing endogenous RNA and DNA in triggering the production of type I interferons by dendritic cells via activation of endosomal toll-like receptors. At the same time, there have been considerable advances in the treatment of lupus nephritis. Corticosteroids have long been the cornerstone of therapy, and the addition of cyclophosphamide has contributed to renal function preservation in patients with severe proliferative glomerulonephritis, though at the cost of serious adverse events. More recently, in an effort to minimize drug toxicity and achieve equal effectiveness, other immunosuppressive agents, including mycophenolate mofetil, have been introduced. Herein, we provide a detailed review of the trials that established the equivalency of these agents in the induction and/or maintenance therapy of lupus nephritis, culminating in the recent publication of new treatment guidelines by the American College of Rheumatology. Although newer biologics have been approved and continue to be a focus of research, they have, for the most part, been relatively disappointing compared to the effectiveness of biologics in other autoimmune diseases. Early diagnosis and treatment are essential for renal preservation.

Giant cell arteritis: a review of classification, pathophysiology, geoepidemiology and treatment.

Giant cell arteritis is a chronic vasculitis affecting large and medium-sized arteries, most commonly the temporal and other cranial arteries. Temporal artery biopsy has long been the gold standard for establishing the diagnosis of giant cell arteritis. There is growing evidence that simultaneous color Doppler and duplex ultrasonography of temporal arteries of GCA patients represents a valid alternative for this somewhat invasive procedure. Ultrasonography and other imaging modalities such as magnetic resonance imaging and positron emission tomography have also provided evidence that involvement of the aorta and its proximal branches is much more common in giant cell arteritis than previously appreciated; it will be important to clarify whether these patients need to be treated more aggressively. It has long been known that patients with giant cell arteritis face a markedly increased risk of developing aortic aneurysms and of dying from aortic dissection. This raises important questions as to whether patients should be screened regularly for extra-cranial large-vessel involvement and whether and how treatment of patients with positive screening results should be adjusted. In this review we discuss the pathophysiology of this disease and also the issues of epidemiology and sex differences.

Transverse myelitis.

Acute transverse myelitis (ATM) is an etiologically heterogeneous syndrome with acute or subacute onset, in which inflammation of the spinal cord results in neurologic deficits, manifesting as weakness, sensory loss and autonomic dysfunction. It is frequently associated with infectious or systemic autoimmune diseases, but its etiology remains unknown in a substantial portion of cases, which are classified as idiopathic. Unifying diagnostic criteria for idiopathic and disease-associated ATM were proposed in 2002. Although they have been applied to a few cohorts of patients, the limited information provided in the relevant publications has not yet yielded many new insights on the clinical characteristics, disease course, and outcome of adult patients with idiopathic ATM compared to older studies that did not always distinguish between the various etiologies of ATM. There is, however, some new epidemiological data indicating that the incidence of idiopathic ATM is considerably higher, and the female preponderance greater, than previously recognized. In addition, new data on children with ATM show that the prognosis in pediatric patients is not always as benign as previous studies had indicated. The combination of ATM and optic neuritis characterize Devic's syndrome or neuromyelitis optica (NMO). A seminal discovery was the identification of an antibody that is a specific marker not only for NMO, but also of some of its characteristic manifestations in isolation, including longitudinally extensive TM. This has resulted in the proposal that all of the disorders that are associated with NMO-IgG positivity constitute part of an NMO spectrum of disorders. This antibody recognizes aquaporin-4, which represents the most abundant water channel of the central nervous system. There is growing evidence that the antibodies targeting this channel protein have pathogenic potential, thereby providing insights into the possible pathogenetic mechanisms of at least one type of ATM.

Sociological differences between women and men: implications for autoimmunity.

There are an enormous number of incorrect stereotypes that characterize the differences between women and men. Indeed, nearly all of these stereotypes are based on cultural inaccuracies and faulty data without consideration of biology and the distinct sociological differences between genders. Sociological differences are those that relate to the development, structure, interaction and behavior of organized groups of human beings, or societies, and their values and beliefs. Gender is a social construct referring "to the culturally and historically based differences in the roles, attitudes and behaviors of men and women" ([1], p.1) as shaped by norms and stereotypes. Sex, on the other hand, serves to classify living things according to their reproductive organs and functions assigned by chromosomal complement (according to the US Institute of Medicine) and the physical and biological characteristics arising from these organs and functions. The two terms are generally viewed as dichotomous; however, they are closely intertwined in as yet hardly understood ways, and it is frequently difficult to distinguish between them since gendered life experiences can have profound effects on body structure and function [2]. In this review, we will examine to what extent gender roles and stereotypes shape the daily lives of women in their roles as students, employees, wives, and mothers and their health. These data have implications for the etiology of autoimmunity and also for differences in the natural history of disease.

Immune-mediated adverse effects of biologicals used in the treatment of rheumatic diseases.

Biological agents represent a major advance in the treatment of rheumatic diseases, most particularly in the prevention of irreversible structural damage. While generally well tolerated, their increasing use continues to reveal a variety of immune-mediated adverse effects. The most frequent adverse events are infusion reactions and injection site reactions, but despite their fairly common occurrence the precise mechanisms are not fully understood. Another adverse event that became appreciated early in the era of biologicals is the increased risk of Mycobacterium tuberculosis and other granulomatous infections in patients treated with tumor necrosis factor (TNFα) antagonists. Although it is evident that this enhanced susceptibility to intracellular infections must be due to immunosuppression arising from the blockade of TNFα, the mechanisms have not been fully elucidated; such an understanding is likely to provide important insights into the role of TNFα in granulomatous and other infectious diseases. In addition, the biologicals may paradoxically induce autoimmunity. The development of autoantibodies is seen in a considerable proportion of patients, but clinical autoimmune disease develops much less commonly, including systemic lupus erythematosus, multiple sclerosis and other demyelinating diseases, psoriasis, sarcoidosis, and interstitial lung disease. The mechanisms leading to their induction are very poorly understood, but an intriguing hypothesis is that interferon α provides a common link, at least for lupus, psoriasis and possibly sarcoidosis. Finally, the potential risk of infection with use of the biologicals is an issue that clinicians should always be aware of. These comments aside, the biologics are the most important advance in the treatment of rheumatic disease in the history of rheumatology and their usage has not only greatly helped patient care, but also provided key data on the immunobiology of the disease processes.

Idiopathic pulmonary fibrosis-an epidemiological and pathological review.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease (ILD) affecting the pulmonary interstitium. Other forms of interstitial lung disease exist, and in some cases, an environmental etiology can be delineated. The diagnosis of IPF is typically established by high-resolution CT scan. IPF tends to have a worse prognosis than other forms of ILD. Familial cases of IPF also exist, suggesting a genetic predisposition; telomerase mutations have been observed to occur in familial IPF, which may also explain the increase in IPF with advancing age. Alveolar epithelial cells are believed to be the primary target of environmental agents that have been putatively associated with IPF. These agents may include toxins, viruses, or the autoantibodies found in collagen vascular diseases. The mechanism of disease is still unclear in IPF, but aberrations in fibroblast differentiation, activation, and proliferation may play a role. Epithelial-mesenchymal transition may also be an important factor in the pathogenesis, as it may lead to accumulation of fibroblasts in the lung and a disruption of normal tissue structure. Abnormalities in other components of the immune system, including T cells, B cells, and dendritic cells, as well as the development of ectopic lymphoid tissue, have also been observed to occur in IPF and may play a role in the stimulation of fibrosis that is a hallmark of the disease. It is becoming increasingly clear that the pathogenesis of IPF is indeed a complex and convoluted process that involves numerous cell types and humoral factors.

The immune response in Coccidioidomycosis.

With the increasing use of biologics, clinical rheumatologists are becoming very well acquainted with opportunistic infections, including tuberculosis, histoplasmosis and Coccidiomycosis. In the great valleys of California as well as several other hot spots in the Southern areas of the United States and select pockets in South America, valley fever, also known as Coccidiomycosis, is an endemic infection. The vast majority of patients are asymptomatic following exposure, but are at risk for clinical disease in the case of immunosuppression. Additionally, although 60% of patients with infections are completely asymptomatic, nearly all patients have immunological evidence of exposure. Within some communities in the central valley of California, sero conversion approaches 100%, fortunately the vast majority remain asymptomatic. In this review we will place the context of the immune response to Coccidiomycosis in perspective and discuss not only the lymphoid response, but also recent data on antigenic analysis and bioinformatics of Coccidioides. This information is significant not only for a better understanding of Coccidiomycosis, but will also have utility in the management of patients within areas of the world who are treated with the biologics for autoimmune disease.

Public safety and dietary supplementation.

Approximately 6 in 10 Americans report regularly using some type of dietary supplement, and approximately 1 in 6 Americans reports using herbal remedies on a regular basis. The diversity of manufacturers, manufacturing processes, and quality control issues are enormous. As with all plant products, herbal products are complex mixtures of a variety of chemical constituents with considerable variation in the growth, harvesting, and storage conditions, including different extraction procedures. Furthermore, not only is there variation in batches, but also the potential for contamination. In addition, herbal products have the potential to interact with pharmaceuticals. These problems have led to consumer and physician confusion about the use of herbal products and have not been satisfactorily resolved, because the Food and Drug Administration has only very recently started to fulfill its mission of consumer protection in the realm of dietary supplements. More importantly, we provide a working plan for addressing this important issue.

The geoepidemiology of type 1 diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by absolute insulin deficiency resulting from the progressive immune-mediated destruction of pancreatic islet beta cells. It is thought to be triggered by as yet unidentified environmental factors in genetically susceptible individuals, the major genetic contribution coming from loci within the HLA complex, in particular HLA class II. The worldwide incidence of T1D varies by at least 100-fold, being highest in Finland and Sardinia (Italy) and lowest in Venezuela and China. The incidence has been increasing worldwide at an annual rate of approximately 3%. While genetic factors are thought to explain some of the geographic variability in T1D occurrence, they cannot account for its rapidly increasing frequency. Instead, the declining proportion of newly diagnosed children with high-risk genotypes suggests that environmental pressures are now able to trigger T1D in genotypes that previously would not have developed the disease during childhood. Although comparisons between countries and regions with low and high-incidence rates have suggested that higher socioeconomic status and degree of urbanization are among the environmental factors that play a role in the rising incidence of T1D, the findings are too inconsistent to allow firm conclusions. Morbidity and mortality as well as causes of death also show considerable geographic variation. While glycemic control has been identified as a major predictor of the micro- and macrovascular complications of T1D and shows considerable geographical variability, it does not appear to be the only factor involved in the regional differences in complication rates. The role of genetics in susceptibility to nephropathy, retinopathy and other diabetic complications largely remains to be explored.

The geoepidemiology of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with manifold clinical manifestations and immunological abnormalities, affecting primarily women. Although accurate current data on its incidence and prevalence are largely lacking, there are numerous indications that SLE is far less common in Europeans and their descendants compared to all other ethnicities. The clinical manifestations of the disease show geographic or ethnic variation, generally being less severe in patients of European ancestry than in African, Asian, certain "Hispanic" or mestizo, and various indigenous populations. In particular, renal involvement is far more common in non-European patients. Genetic as well as environmental, sociodemographic and sociocultural factors are likely to contribute to the differences in the incidence and clinical expression of SLE.

The implications of autoimmunity and pregnancy.

There are multiple epidemiological studies that document the potential adverse affects of autoimmunity on nearly every aspect of reproduction, even in the absence of clinically manifest autoimmune disease. Two decades ago, it was suggested that women with autoimmune diseases avoid pregnancy due to inordinate risks to the mother and the child. In contrast, newer epidemiological data demonstrated that advances in the treatment of autoimmune diseases and the management of pregnant women with these diseases have similarly improved the prognosis for mother and child. In particular, if pregnancy is planned during periods of inactive or stable disease, the result often is giving birth to healthy full-term babies without increased risks of pregnancy complications. Nonetheless, pregnancies in most autoimmune diseases are still classified as high risk because of the potential for major complications. These complications include disease exacerbations during gestation and increased perinatal mortality and morbidity in most autoimmune diseases, whereas fetal mortality is characteristic of the anti-phospholipid syndrome (APS). In this review, we will discuss these topics, including issues of hormones, along with potential long-term effects of the microchimerism phenomenon. With respect to pregnancy and autoimmune diseases, epidemiological studies have attempted to address the following questions: 1) Is it safe for the mother to become pregnant or are there acute or chronic effects of pregnancy on the course of the disease? 2) Does the disease alter the course and/or the outcome of a pregnancy and thereby represent an inordinate risk for the fetus and infant? And do new therapeutic and management approaches improve the pregnancy outcomes in women with autoimmune diseases? 3) Does passage of maternal autoantibodies represent a risk to the child? 4) Do pregnancy, parity, or other factors influencing hormonal status explain the female predominance of many autoimmune diseases, and is the pregnancy effect related to microchimerism? Answering these questions has taken on additional importance in recent decades as women in western countries now frequently choose to delay pregnancies and have some or all of their pregnancies after disease onset. In this paper, we primarily focus on APS, systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), and type 1 diabetes (T1D).

Lymphocyte recruitment and homing to the liver in primary biliary cirrhosis and primary sclerosing cholangitis.

The mechanisms operating in lymphocyte recruitment and homing to liver are reviewed. A literature review was performed on primary biliary cirrhosis (PBC), progressive sclerosing cholangitis (PSC), and homing mechanisms; a total of 130 papers were selected for discussion. Available data suggest that in addition to a specific role for CCL25 in PSC, the CC chemokines CCL21 and CCL28 and the CXC chemokines CXCL9 and CXCL10 are involved in the recruitment of T lymphocytes into the portal tract in PBC and PSC. Once entering the liver, lymphocytes localize to bile duct and retain by the combinatorial or sequential action of CXCL12, CXCL16, CX3CL1, and CCL28 and possibly CXCL9 and CXCL10. The relative importance of these chemokines in the recruitment or the retention of lymphocytes around the bile ducts remains unclear. The available data remain limited but underscore the importance of recruitment and homing.

Probiotics and immunity.

Probiotics are defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host, including the gastrointestinal tract. While this beneficial effect was originally thought to stem from improvements in the intestinal microbial balance, there is now substantial evidence that probiotics can also provide benefits by modulating immune functions. In animal models, probiotic supplementation is able to provide protection from spontaneous and chemically induced colitis by downregulating inflammatory cytokines or inducing regulatory mechanisms in a strain-specific manner. In animal models of allergen sensitization and murine models of asthma and allergic rhinitis, orally administered probiotics can strain-dependently decrease allergen-specific IgE production, in part by modulating systemic cytokine production. Certain probiotics have been shown to decrease airway hyperresponsiveness and inflammation by inducing regulatory mechanisms. Promising results have been obtained with probiotics in the treatment of human inflammatory diseases of the intestine and in the prevention and treatment of atopic eczema in neonates and infants. However, the findings are too variable to allow firm conclusions as to the effectiveness of specific probiotics in these conditions.

Stevens-Johnson syndrome and toxic epidermal necrolysis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but potentially life threatening, diseases characterized by widespread epidermal necrosis, and are predominantly medication-induced. Unfortunately, though they are often associated with long-term debilitating sequelae, there are currently no efficacious pharmaceutical interventions proven through large clinical trials. It has been well established that the epidermal damage in these diseases is due to keratinocyte apoptosis. Although drug-specific T cells are implicated in this process, our understanding of the immunopathology is far from complete. The scenario suggested by today's literature points towards drug-specific CD8+ cytotoxic T cells utilizing perforin/granzyme B trigger keratinocyte apoptosis. Subsequently, there may be an expansion of apoptosis involving the interaction of either membrane-bound or soluble Fas ligand (sFasL) with its receptor Fas. The cellular source of sFasL remains controversial, with both peripheral lymphocytes and keratinocytes themselves as potential candidates. Cytokines produced by T lymphocytes, macrophages or keratinocytes may participate by activating keratinocytes and enhancing their expression of Fas and FasL, or by promoting the skin recruitment of lymphocytes by upregulating adhesion molecules. A better understanding of the underlying immunological mechanisms is required to identify appropriate therapeutic interventions. Finally, clinicians must remain vigilant about drug hypersensitivity to prevent SJS/TEN.