The chemokines, members of a large family of chemotactic cytokines, act as directional cues for sorting inflammatory cell subsets to sites of inflammation or lymphoid microenvironments. In addition to their effects on migration, chemokines can also activate effector function in leukocytes and are involved in cell proliferation and angiogenesis. Therefore, it is not surprising that chemokines play important roles in a wide range of human diseases, including genetic immunodeficiencies, infections, autoimmune diseases, and malignant tumors. In this report, we have reviewed recent developments (since mid 2003) in chemokines in renal diseases. In animal models, chemokines are produced at the site of injury, leading to inflammatory cell recruitment. The therapeutic impact of the blockade of CCR1, CCR2, CCR4, CCR5, or the corresponding ligands has been further studied in various renal disease models. Recent studies on the role of the chemokine receptors in human diseases have demonstrated the expression of CXCR1, CXCR3, CCR2, and CCR5 on different subsets of inflammatory cells. The number of CCR5- and CXCR3-positive interstitial infiltrating cells (mainly T cells) correlates with renal function and proteinuria in glomerular diseases. Polymorphisms of chemokines and chemokine receptors are of impact on renal disease courses and allograft survival. Chemokine receptor blockade has approached clinical applications in nonrenal diseases and awaits the application in patients with kidney diseases.

Stephan Segerer

Peter J. Nelson

Chemokines in Renal Diseases

(+)-Discodermolide was isolated in 1990 by Gunasekera et al. from the deep-water Caribbean sponge Discodermia dissoluta. It attacks cancer cells in a similar way to the successful cancer drug Taxol&#x00AE; that has become the best-selling anticancer drug in history. Taxol is also the first natural product described that stabilizes the microtubules involved in many aspects of cellular biology and that represent an important target of anticancer chemotherapeutics. However, (+)-discodermolide appears to be far more potent than Taxol&#x00AE; against tumors that have developed multiple-drug resistance, with an IC50 in the low nanomolar range. Due to these excellent results, this natural product was licensed to Novartis Pharmaceutical Corporation in early 1998. The present review covers the history, biological activity, total synthesis, and synthetic analogs of (+)-discodermolide.

Marcus Vin&#xED;us Nora De Souza

(+)-Discodermolide: A Marine Natural Product Against Cancer

Onychomycosis is a common nail disease responsible for approximately 50% of diseases of the nail. It occurs more in the elderly, though several cases have been reported among children. Several factors influence, such as climate, geography, and migration. The two dermatophytes most commonly implicated in onychomycosis are Trichophyton rubrum and T. mentagrophytes, accounting for more than 90% of onychomycoses. Nonetheless, several other toxigenic molds have been implicated. For convenience, onychomycosis is divided into four major clinical presentations: distal subungal, which is the most common form of the disease; proximal subungal, which is the most common form found in patients with human immunodeficiency virus infection; superficial; and total dystrophic onychomycosis. Epidemiology of onychomycosis in adults and children is evaluated and the most common clinical symptoms addressed. Although the risk factors are discussed, the multifactorial nature of onychomycosis makes this inexhaustible. The diagnosis and treatments are difficult and the choice of appropriate antifungal drugs complex and require the knowledge of the chemical structures of the metabolites of the molds that cause onychomycosis and their interaction with the antifungal drugs. This is true because most of the antifungal drugs are derived from mold/fungal metabolism. Treatment with griseofulvin and amphotericin is displaced by the use of newer drugs from azole compounds, pyrimidines, and allylamines derivatives. Amorolfine, itraconazole, and ciclopirox nail lacquer solution 8 have gained support globally, but the side effects, drug resistance, and persistence of the disease are still a serious concern to the patients, just as economics and quality of life. Hence, the search for safer and more efficacious drug treatments are continuing.

Andrew W. Campbell

Ebere C. Anyanwu

Mohammed Morad

Evaluation of the Drug Treatment and Persistence of Onychomycosis

Proteinuria is common in diabetic patients and usually reflects the presence of diabetic glomerulosclerosis. This paper reviews the differential diagnosis of proteinuria in diabetic patients and discusses the role of renal biopsy examination in identification and management of minimal change disease in this cohort. Identification of nondiabetic glomerular disease requires careful correlation of clinical history and renal biopsy findings and may have important implications for prognosis and therapy.

M. Barry Stokes

The Diagnosis of Minimal Change Disease in Diabetic Nephropathy

Andrew R. Clamp

Gordon C. Jayson

Profiling Heparan Sulfate Proteoglycans in Ovarian Carcinoma

Differentiating between clear cell neuroendocrine tumor (NET) of the pancreas and renal cell carcinoma (RCC) metastatic to the pancreas can be challenging in patients with von Hippel-Lindau disease (VHL). The clear cell features of both NET and RCC in VHL patients may lead to misdiagnosis, inaccurate staging, and alternative treatment. We present a patient in which this occurred. As clear cell NETs closely resembling metastatic RCC are distinctive neoplasms of VHL and metastatic RCC to the pancreas in the VHL population is rare, careful pathologic examination should be performed prior to subjecting patients to definitive surgical or medical therapies.

Christopher Williams

McClellan Walther

Metastatic Renal Cell Carcinoma versus Pancreatic Neuroendocrine Tumor in von Hippel-Lindau Disease: Treatment with Interleukin-2

Krishnankutty Sudhir

Julie Nigro

Narin Osman

Peter Little

Androgens: New Effects on Proteoglycan Biosynthesis and Its Consequences for Atherosclerosis

Alzheimer�s dementia (AD) is the most common degenerative disorder of the central nervous system. Although the onset of dementia is above 65 years of age in the majority of the patients (late-onset AD, LOAD), a small subgroup of patients develops AD before 65 years of age (early-onset AD, EOAD).  To date 3 genes responsible for EOAD have been identified: the amyloid precursor protein gene (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). PSEN1 is the most frequently mutated EOAD gene with a mutation frequency of 18 to 50% in autosomal dominant EOAD. In addition, the e4 allele of the gene encoding apolipoprotein E (APOE) was identified as a risk factor for both LOAD and EOAD.  Many studies reported other susceptibility genes, but the APOE?4 alelle has been the only risk factor that was consistently replicated in all AD populations. Extensive cell biology research in the past ten years led to the hypothesis that the 4 EOAD genes lead to AD through a common biological pathway resulting in abnormal APP processing by subtle different mechanisms. Now, transgenic mice are produced to study the influence of EOAD mutations in vivo, eventually leading to the development of novel therapeutic strategies.

Rosa Rademakers

Marc Cruts

Christine Van Broeckhoven

Genetics of Early-Onset Alzheimer Dementia

A 76-year-old man with prostate cancer T3N0M0 and increasing PSA was treated with goserelin three times in a half year. As soon as the first treatment, he described subjective muscle weakness. After the third treatment, he developed complex motoric symptoms and atypical central pain with a likely association to goserelin. His left arm had signs of spastic movement; pain deteriorated after relaxation. The right hand showed muscle cramps under passive movements of the left arm that were not typical for rigor. He felt aching and partial burning pain in his whole body. There were few allodynic areas, mainly in the left arm. Several treatment approaches failed and the patient died some weeks after the first contact with our pain clinic due to pneumonia.

G. Ernst

A. Gericke

P. Berg

Central Pain and Complex Motoric Symptoms after Gosarelin Therapy of Prostate Cancer

Schizophrenia is a major mental disorder with no clearly identified pathophysiology. A variety of theories has been proposed to explain the pathophysiology of schizophrenia. One approach that is finding empirical support is the investigation of membrane composition and function. Evidence to date suggests that there are defects in phospholipid metabolism and cell signaling in schizophrenia. Specifically, low levels of arachidonic acid (AA)&#x2013;enriched phospholipids have been observed in both central and peripheral tissues. It is well known that changes in membrane composition are associated with a variety of functional consequences. Since AA has many key roles in neural functioning, understanding its significance for the pathophysiology of schizophrenia may lead to novel approaches to improving treatment of schizophrenia. The purpose of this review is thus to explore some of the roles of AA signaling in biological, physiological, and clinical phenomena observed in schizophrenia.

Jeffrey K. Yao

Ravinder K. Reddy

Membrane Pathology in Schizophrenia: Implication for Arachidonic Acid Signaling

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