Synthesis, metabolism and in vitro cytotoxicity studies on novel lavendamycin antitumor agents.

A series of lavendamycin analogues with two, three or four substituents at the C-6, C-7 N, C-2', C-3' and C-11' positions were synthesized via short and efficient methods and evaluated as potential NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor agents. The compounds were prepared through Pictet-Spengler condensation of the desired 2-formylquinoline-5,8-diones with the required tryptophans followed by further needed transformations. Metabolism and toxicity studies demonstrated that the best substrates for NQO1 were also the most selectively toxic to NQO1-rich tumor cells compared to NQO1-deficient tumor cells.

Lavendamycin antitumor agents: structure-based design, synthesis, and NAD(P)H:quinone oxidoreductase 1 (NQO1) model validation with molecular docking and biological studies.

A 1H69 crystal structure-based in silico model of the NAD(P)H:quinone oxidoreductase 1 (NQO1) active site has been developed to facilitate NQO1-directed lavendamycin antitumor agent development. Lavendamycin analogues were designed as NQO1 substrates utilizing structure-based design criteria. Computational docking studies were performed using the model to predict NQO1 substrate specificity. Designed N-acyllavendamycin esters and amides were synthesized by Pictet-Spengler condensation. Metabolism and cytotoxicity studies were performed on the analogues with recombinant human NQO1 and human colon adenocarcinoma cells (NQO1-deficient BE and NQO1-rich BE-NQ). Docking and biological data were found to be correlated where analogues 12, 13, 14, 15, and 16 were categorized as good, poor, poor, poor, and good NQO1 substrates, respectively. Our results demonstrated that the ligand design criteria were valid, resulting in the discovery of two good NQO1 substrates. The observed consistency between the docking and biological data suggests that the model possesses practical predictive power.

Hepatic, ocular, and cutaneous sarcoidosis.

Sarcoid affecting the skin, eye, or liver can be symptomatic of or cause significant morbidity. When disease is sever, alternative therapies may be needed.

Endobronchial capillary hemangioma: case report and review of the literature.

A 66-year-old man with mitral stenosis on coumadin presents with hemoptysis caused by a capillary hemangioma of the proximal airways. Argon plasma coagulation was utilized to treat the lesions resulting in resolution of hemoptysis. Tracheobronchial capillary hemangiomas are rare in adults, but are easily discovered and treated with bronchoscopic intervention. The literature to date is reviewed pertaining to adult tracheobronchial capillary hemangiomas.

Blastomycosis in indiana: digging up more cases.

BACKGROUND: The endemic region of blastomycosis historically has included the state of Indiana. However, few published reports of blastomycosis exist to substantiate this distinction. A surge of patients with blastomycosis in central Indiana (Indianapolis and surrounding counties) beginning in 2005 prompted us to review our local experience. We propose that this surge was related to major highway construction around Indianapolis. METHODS: We reviewed all microbiologically confirmed cases from four hospitals serving central Indiana. Chart review was completed for adult patients, and data were collected on clinical presentations, methods of diagnosis, comorbidities, radiologic findings, treatment, and outcomes. We plotted patient residence addresses with sites of highway construction. RESULTS: Fifty-nine patients were identified from laboratory results and physician referral. Interestingly, a surge of blastomycosis incidence occurred in 34 patients between 2005 and 2008 during which time major highway projects were under way around the Indianapolis metropolitan area. The majority of these patients presented acutely and with pulmonary involvement. Fungal culture and antigen testing were the most sensitive means to diagnosis. Antifungal therapy was highly effective. CONCLUSIONS: This urban outbreak of blastomycosis in Indianapolis should prompt clinicians to consider blastomycosis in this highly endemic area of histoplasmosis.

Surgical management of pulmonary and mediastinal sequelae of histoplasmosis: a challenging spectrum.

BACKGROUND: Histoplasmosis may result in a spectrum of complications that require thoracic surgical intervention. We reviewed our 17-year experience in the management of histoplasmosis to determine outcomes as well as gain insight into the distribution of complications requiring surgical intervention. METHODS: The hospital records of patients who underwent surgical treatment for complications related to histoplasmosis from 1991 to 2008 were reviewed. Based on the predominant presentation, patients were categorized with complications secondary to broncholithiasis, granulomatous disease, or fibrosing mediastinitis. Patients who underwent diagnostic surgery and were found to have histoplasmosis were excluded. RESULTS: Of the 49 patients who underwent surgery for histoplasmosis-related complications, 27 (55%) had granulomatous disease, 13 (27%) had broncholithiasis, and 9 (18%) had fibrosing mediastinitis. The most common clinical presentations were recurrent pneumonia (n = 16) and hemoptysis (n = 13); less common presentations included dysphagia (n = 3) and superior vena cava syndrome (n = 1). Two patients required cardiopulmonary bypass for resection; 1 of these died postoperatively (series mortality 2%). Seven patients (14%) had complications. Relief of symptoms was achieved in all surviving patients. CONCLUSIONS: Complications of histoplasmosis requiring thoracic surgical intervention are diverse with pulmonary complications predominating. Although surgically challenging, excellent short- and long-term outcomes may be expected.

Bronchoalveolar lavage as a research tool.

Researchers over the past 40 years have utilized bronchoalveolar lavage (BAL) as a tool to help expand our knowledge of pulmonary medicine. Many reports have documented BAL as a safe procedure for research subjects. New technologies, such as flow cytometry, have provided much needed insight into the mechanisms behind several pulmonary diseases. The concept of the lung as an easily accessible mucosal site to monitor local immune responses and treatment effects is evolving. Future BAL research with human subjects, aided by new technology, will undoubtedly yield clinically relevant information regarding biomarkers of disease and new therapeutic targets.