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The 4-trifluoromethyl analog 4c shown moderate activity against Pim-1, but was surprisingly effective when tested against Pim-3 (residual activities 51% and 24%, respectively) The overall yield for the preparation of the C8 methyl derivative 17 from the common aldehyde starting material was 18%

The number of specimens originally collected from each patient during the 2001C2002 dengue outbreak varied; thus, the number of serum samples from each patient tested for leptospirosis also varied, ranging from 1 to 4. been diagnosed with dengue fever during the outbreak: rash (p 0.0001), chills (p = 0.05), and petechiae (p = 0.0005). Laboratory-positive leptospirosis infections were identified in persons exposed on each of the 5 most populous islands and illness onsets spanned a 10-month period, reflecting an endemic pattern of disease. If added TCF3 to the figures obtained via routine passive surveillance, the number of leptospirosis infections identified through this study would more than double the annual incidence GYKI-52466 dihydrochloride rate for Hawaii during 2001. These findings indicate that many leptospiral infections in Hawaii go undiagnosed. Physicians should maintain a high index of suspicion for leptospirosis when assessing patients presenting with acute febrile illness among residents and visitors to Hawaii. The disease is maintained in nature through the chronic renal infection of host animals and the bacterium is shed in their urine. Human infection GYKI-52466 dihydrochloride results from either direct contact with the urine of an infected animal or indirectly through contact with contaminated water or soil. Leptospires can affect many different human tissues, producing a wide array of clinical manifestations, ranging from a mild undifferentiated febrile illness to severe multiorgan failure and death (Bharti et al. 2003). As a consequence, leptospirosis infection may be clinically indistinguishable from many febrile illnesses including typhus, influenza, viral encephalitis, and dengue fever (Flannery et al. 2001). Furthermore, laboratory confirmation of leptospirosis by the gold standard microscopic agglutination test (MAT) is technically challenging because of the need to maintain panels of live leptospires in culture for long periods, and time consuming as paired acute and convalescent serum samples need to be tested together. Leptospirosis has a global distribution but is most common in tropical regions where warm, wet conditions promote the survival of the leptospires (Levett 2001, McBride et al. 2005). Within the United States, the annual incidence rates of leptospirosis in Hawaii are consistently much higher than those reported from the U.S. mainland (Effler et al. 2002). Still the challenges associated with recognizing and confirming infection suggest leptospirosis may be underdiagnosed among patients presenting with clinically compatible febrile illness in Hawaii. To assess this possibility, we used a commercially available leptospirosis IgM enzyme-linked immunosorbent assay (ELISA) to retrospectively test serum samples originally collected from patients being evaluated for dengue fever during an outbreak of dengue in 2001C2002. Materials and Methods In September 2001, the Hawaii State Department of Health (HDOH) contacted all licensed physicians in Hawaii requesting that they report any patients presenting with a dengue-like illness (DLI). DLI was defined as fever or chills and 2 or more of the following symptoms: myalgia, headache, arthralgia, retro-orbital pain, rash, or any hemorrhagic symptom (Effler et al. 2005). In addition, active surveillance for DLI was implemented in all acute care hospitals and major clinics throughout the state between September 12, 2001 and April 30, 2002. Clinical and travel histories for each patient with DLI were reviewed by HDOH staff, and whenever possible, serologic specimens were obtained and forwarded to the HDOH State Laboratories Division (SLD) for anti-dengue IgM and/or IgG antibodies, as previously described (Effler et al. 2005). Of the 1644 persons tested during the outbreak, 122 patients had confirmed dengue infection and the remainder (1522) lacked serologic evidence of recent GYKI-52466 dihydrochloride dengue infection. Following the outbreak, aliquots of sera were linked via a unique number to limited patient demographic and clinical information and stored at ?20C. Resources did not permit testing all of the 1522 patients who lacked serologic evidence of acute dengue infection for anti-IgM antibodies; instead a sample of 1206 (79%) patients was compiled by selecting stored sera without prior knowledge of patient characteristics. The number of specimens originally collected from each patient during the 2001C2002 dengue outbreak varied; thus, the number of serum samples from each patient tested for leptospirosis also varied, ranging from 1 to 4. The serum set tested for leptospirosis ultimately consisted of 1681 serum specimens from 1206 patients. This study was approved by the Institutional Review Board of the University of Hawaii. All serum samples were tested using the PAN-BIO IgM DIP-S-TICKS leptospirosis test (PAN-BIO, Inc., Columbia, MD) according to the.