The Novel Triad of Dorsal Agenesis of the Pancreas with Concurrent Pancreatic Ductal Adenocarcinoma and Nonalcoholic Chronic Calcific Pancreatitis: A Case Series and Review of the Literature

Introduction  

Dorsal agenesis of the pancreas (DAP) is a rare congenital anomaly, with only 44 cases having been reported in the English literature since 1966.     

Local tolerance and systemic safety of pegaptanib sodium in the dog and rabbit.

PURPOSE: To evaluate the local tolerance, systemic toxicity, and toxicokinetics in dogs and rabbits of pegaptanib sodium, an aptamer that targets vascular endothelial growth factor (VEGF(165)). METHODS: Dogs received biweekly, bilateral, intravitreous (IVT) injections of pegaptanib sodium for 9 months at doses of 0.3 (n = 10), 1 (n = 10), or 3 mg (n = 14); 14 control dogs received phosphate-buffered saline (PBS). In rabbits, pegaptanib sodium was administered by IVT injection biweekly for 6 months at doses of 0.2 (n = 14), 0.67 (n = 14), or 2 mg (n = 18); 18 rabbits received PBS. The systemic and ocular safety of pegaptanib sodium was assessed. Assessments in both dogs and rabbits included complete ophthalmologic examinations, serum chemistry, hematology, urinalysis, and coagulation assessments, as well as gross and microscopic pathologic examination. In addition, dogs were assessed by electroretinography and electrocardiography. In a cardiovascular safety study, loading intravenous boluses and maintenance infusions of pegaptanib sodium or PBS were administered to dogs (n = 4) in an ascending dose design, with each dose level separated by 2-3 days. The pegaptanib dosing regimens were designed to achieve pegaptanib plasma concentrations of approximately 90, 270, or 900 ng/mL. RESULTS: There were no pegaptanib sodium-associated clinical, ophthalmologic, pathologic, or cardiovascular abnormalities at doses of pegaptanib that achieved systemic and ocular exposure levels in excess of those associated with the recommended pegaptanib IVT dosing regimen of 0.3 mg per study eye in patients with age-related macular degeneration. CONCLUSION: These studies, together with data from clinical trials, provide strong evidence that inhibition of VEGF(165) by pegaptanib in the eye is a safe therapy for the treatment of ocular neovascular disease.     

In vitro antibacterial activity of gemifloxacin and comparator compounds against common respiratory pathogens

This study investigated the in vitro potency of the novel quinolone agent gemifloxacin (SB-265805), in comparison with other quionolones, beta-lactams, macrolides and trimethoprim- sulphamethoxazole, against a panel of common respiratory pathogens. This panel comprised recent clinical isolates of Streptococcus pneumoniae (n = 347), Haemophilus influenzae (n = 256) and Moraxella catarrhalis (n = 184). Overall, the quinolones were highly active against H. influenzae and were the most potent agents against M. catarrhalis. Gemifloxacin was the most potent quinolone tested against all three species and was four- to 512-fold more potent against pneumococci than trovafloxacin, grepafloxacin, levofloxacin, ciprofloxacin, ofloxacin, gentamicin, cefuroxime, penicillin, ampicillin, clarithromycin, azithromycin or trimethoprim- sulphamethoxazole. Against 19 ofloxacin-intermediate and 52 ofloxacin-resistant strains of S. pneumoniae, gemifloxacin retained activity, and was the only agent tested with MICs of < or =0.5 mg/L. The results of this study demonstrate the excellent in vitro antibacterial activity of gemifloxacin against pathogens commonly associated with respiratory tract infections and suggest that gemifloxacin has significant potential in the treatment of such infections, including those caused by pneumococci considered resistant to other quinolones.     

Thrombolytic therapy for delayed occlusion of knitted Dacron bypass grafts in the axillofemoral, femoropopliteal and femorotibial positions

Selective intra-arterial streptokinase therapy successfully reopened ten axillofemoral and lower extremity Dacron bypass grafts that had undergone delayed closure from two to 47 months after implantation. In four, completion arteriograms revealed no runoff obstruction acquired since implantation; additional runoff obstruction had developed in the remaining six. All of the grafts without obstruction have remained open from two to 11 months. Three of the six grafts with obstruction have remained open from two and one-half to four months after specific surgical correction of the obstructive lesion. We conclude that intra-arterial streptokinase therapy is an effective means to reopen knitted Dacron grafts that have undergone delayed closure in the axillofemoral and above-knee femoropopliteal positions.     

Discovery of aminopyridine-based inhibitors of bacterial enoyl-ACP reductase (FabI)

Bacterial enoyl-ACP reductase (FabI) catalyzes the final step in each cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. Our efforts to identify potent, selective FabI inhibitors began with screening of the GlaxoSmithKline proprietary compound collection, which identified several small-molecule inhibitors of Staphylococcus aureus FabI. Through a combination of iterative medicinal chemistry and X-ray crystal structure based design, one of these leads was developed into the novel aminopyridine derivative 9, a low micromolar inhibitor of FabI from S. aureus (IC(50) = 2.4 microM) and Haemophilus influenzae (IC(50) = 4.2 microM). Compound 9 has good in vitro antibacterial activity against several organisms, including S. aureus (MIC = 0.5 microg/mL), and is effective in vivo in a S. aureus groin abscess infection model in rats. Through FabI overexpressor and macromolecular synthesis studies, the mode of action of 9 has been confirmed to be inhibition of fatty acid biosynthesis via inhibition of FabI. Taken together, these results support FabI as a valid antibacterial target and demonstrate the potential of small-molecule FabI inhibitors for the treatment of bacterial infections.     

IgA With altered carbohydrate structure as a tumor-associated marker in serum of cancer patients

Serum IgA₁ contains O-linked carbohydrate structures, whereas other immuno-globulins contain only N-linked structures. An assay was developed which detects IgA₁ by measuring the DGalβ(1–3) DGalNAc structures O-linked to the IgA₁ hinge region. Fifty percent of the serum specimens from cancer patients tested were elevated compared to 1% of the total normal serum specimens tested by this assay. The assay combines antibody (anti-human IgA) and lectin and measures the DGalβ(1–3)DGalNAc structure in the IgA₁ molecule accessible to lectin binding. Three lectins were compared–the lectins from Bauhinia purpurea alba, Maclura pomifera, and peanut agglutinin (PNA). PNA in the assay discriminated best between serum specimens from normal subjects and cancer patients and was chosen as the lectin component in the assay. The anti-IgA-PNA enzyme immunoassay was evaluated in a retrospective study of cancer patients. A panel of 845 serum specimens was tested and the results analyzed at three cutoff R values. The R value of a specimen is the ratio of the assay absorbance obtained for that test specimen with respect to the assay absorbance obtained for a pool of normal human sera. At a cutoff R value of 2.38, 1% normals and 26% benigns were elevated. The following cancer specimens had elevated R values: 52% lung, 60% colon, 43% head and neck, 35% breast, 64% kidney, 38% bladder, 43% prostate, 8% ovarian, and 67% pancreas. Further testing showed a significant percentage of serum specimens from patients with cirrhosis, pancreatitis, or ulcerative colitis also had elevated R values. No correlation of this assay was observed with CEA levels. The results suggest that the carbohydrate structure of serum IgA₁ is altered by malignancies and that measurement of this altered IgA may supplement CEA testing.     

Regional myocardial dysfunction: evaluation of patients with prior myocardial infarction with fast CT

A prototype ultrafast cine computed tomographic (CT) scanner, designed specifically for cardiac imaging, was used to evaluate a preliminary series of patients with prior myocardial infarction (n = 21) and a control group without coronary artery disease (n = 5). Multilevel 50-msec CT scan exposures were obtained during peripheral intravenous bolus injections of contrast medium. A comparison was made between cine-CT scans and standard left ventriculographic images in assessing segmental left ventricular motion. Results indicate that cine CT, performed at sufficiently rapid speeds (20 scans per second) to allow useful analysis of regional ventricular wall motion, can provide adequate image quality. Analysis of 110 segments revealed a good correlation (90.9%) between the two techniques in characterizing normal from abnormal regional wall motion. Cine CT, based on this initial study, demonstrates considerable potential for evaluating not only cardiac chamber dimensions but also segmental wall dynamics.