Cyclobutane carboxamide inhibitors of fungal melanin: biosynthesis and their evaluation as fungicides.

A new fungicide lead has been identified by enzyme screening of a focused combinatorial library. The lead compound 4, a potent inhibitor of scytalone dehydratase (SD), exhibits fungicidal activity upon foliar application but does not show systemic activity. The X-ray crystal structure of the enzyme-inhibitor complex and an appreciation for the relationship between physical properties and systemic activity enabled us to rapidly improve upon this initial lead. The geminal halogen-methyl group combination was found to be optimal for interaction with the bounding serine and asparagine side-chain residues. Replacement of CF3 with methyl was a key discovery, giving inhibitors with slightly diminished enzyme inhibition potency while significantly increasing systemic activity. Amides prepared from amines with 2,4-dichloro substitution on the phenyl ring gave the most potent enzyme inhibitors. Two compounds from this series showed systemic activity comparable to the commercial standard and were selected for outdoor testing in flooded plots which simulate rice paddies.

A new potent inhibitor of fungal melanin biosynthesis identified through combinatorial chemistry.

A new fungicide lead has been identified by in vitro screening of a focused combinatorial library. Amides (768) were synthesized in pools of four and assayed as inhibitors of scytalone dehydratase. Deconvolution of one of the most active pools led to the discovery of a potent inhibitor of the enzyme 3b (K(i) = 26 pM), which has fungicidal properties.

Accelerated acute rejection of an apparent A2 renal allograft in an O recipient: report of a case with flow cytometric analysis.

We report a case of accelerated acute rejection of a renal allograft from a presumed ABO histo-blood group A2 donor in an O recipient, in which all of the published criteria for compatibility had been met. Flow cytometric analysis of the A and H antigen expression on the kidney donor's erythrocytes suggested that this donor did not have an A2 phenotype, but rather another subgroup of A. Some of the reported cases of accelerated acute rejection of A2 renal allografts in O recipients may have resulted from misapplication of the results of standard lectin agglutination to the transplant setting. The current case suggests that a more sophisticated method of ABO phenotyping, such as erythrocyte flow cytometric analysis, may be necessary in the transplant setting.

Arthroscopically assisted reconstruction of the anterior cruciate ligament using a patella tendon bone autograft.

Techniques for anterior cruciate ligament (ACL) surgery have evolved from the traditional open procedures to arthroscopically assisted procedures. The rationale for arthroscopically assisted ACL reconstruction includes small incisions, no disruption of the extensor mechanism, shorter hospitalizations, reduced postoperative pain, and faster rehabilitation. A stepwise approach for ACL reconstructions is presented.

Magnetic resonance imaging of the knee.

Magnetic resonance imaging (MRI) is an accepted non-invasive modality for evaluation of soft tissue pathology without exposure to ionizing radiation. Current applications demonstrate excellent visualization of the anatomy and pathology of various organs. Preliminary studies in the knee reveal fine resolution of anatomy and pathology involving the meniscus. The purpose of this study is to determine a prospective correlation between MRI scans and actual meniscal pathology as documented at the time of arthroscopy. MRI scans were obtained in 155 patients, on 156 knees (one patient with bilateral scans), with 86 patients (87 knees) eventually undergoing diagnostic and operative videoarthroscopy performed by the same surgeon (DWJ). All images were obtained on the same high-resolution 1.5 Tesla GE Signa Magnetic Resonance Scanner with the same radiologist performing all readings (PEB). The knees were studied in the coronal and sagittal plane using a spin echo sequence and 5 mm slice thicknesses. The menisci were described as having Grade 1, 2, or 3 changes, with Grade 3 reserved for complete tears. Using arthroscopy as the diagnostic standard, the accuracy of MRI in diagnosing medial and lateral meniscal tears was 93.1% and 96.6%, respectively with a Grade 3 MRI reading. For tears of the ACL, the accuracy was 96.6% as confirmed at arthroscopy. Five tears of the PCL were also documented by MRI and correlated with clinical evaluation. Other abnormalities seen were articular cartilage and osteochondral defects, bone tumors, tibial plateau fractures, Baker's cysts, and meniscal cysts. The MRI scan is a highly accurate, noninvasive modality for documentation of meniscal pathology as well as cruciate ligament tears in the knee.