In vitro evaluation of BRL 42715, a novel beta-lactamase inhibitor.

The penem BRL 42715, C6-(N1-methyl-1,2,3-triazolylmethylene)penem, is a potent inhibitor of a broad range of bacterial beta-lactamases, including the plasmid-mediated TEM, SHV, OXA, and staphylococcal enzymes, as well as the chromosomally mediated enzymes of Bacteroides, Enterobacter, Citrobacter, Serratia, Morganella, Escherichia, Klebsiella, and Proteus species. The concentration of BRL 42715 needed to reduce the initial rate of hydrolysis of most beta-lactamase enzymes by 50% was less than 0.01 micrograms/ml, which was 10- to 100-fold lower than for other beta-lactamase inhibitors. These potent inhibitory activities were reflected in the low concentrations of BRL 42715 needed to potentiate the antibacterial activity of beta-lactamase-susceptible beta-lactams. Concentrations of 0.25 micrograms/ml or less considerably enhanced the activity of amoxicillin against many beta-lactamase-producing strains. The MIC50 (MIC for 50% of strains tested) of amoxicillin for 412 beta-lactamase-producing members of the family Enterobacteriaceae fell from greater than 128 to 2 micrograms/ml in the presence of 1 microgram of BRL 42715 per ml, whereas 5 micrograms of clavulanic acid per ml brought the MIC50 down to 8 micrograms/ml. Among these 412 strains were 73 Citrobacter and Enterobacter strains, and 1 microgram of BRL 42715 per ml reduced the MIC50 of amoxicillin from greater than 128 to 2 micrograms/ml for the 48 cefotaxime-susceptible strains and from greater than 128 to 8 micrograms/ml for the 25 cefotaxime-resistant strains.     

Positron emission tomography with 2-deoxy-2-[(18)F]fluoro-D-glucose for evaluating local and distant disease in patients with cervical cancer.

PURPOSE: To assess the accuracy of positron emission tomography (PET) with 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) for evaluating local and distant disease in patients with cervical cancer. METHODS: The PET imaging database maintained at our institution was used to identify patients who received FDG-PET scans for the clinical indication of cervical cancer for the past four years. Patients were followed for a minimum of six months following the PET study. Results of the FDG-PET studies were correlated with surgical pathology, biopsy results, and/or clinical follow up to assess the accuracy of FDG-PET in evaluating local and distant disease. RESULTS: A total of 61 FDG-PET studies performed in 41 patients were included in this retrospective study. Nine FDG-PET studies were performed for initial staging of cervical cancer, and 52 PET scans were performed in 35 different patients as restaging studies following therapy. For the initial staging, the local primary disease was identified in all nine FDG-PET studies, and PET distinguished the patients which had localized disease (four patients) from those with distant metastases on follow-up (five patients) with 100% accuracy. For restaging cervical cancer, FDG-PET had a sensitivity of 0.82 and specificity of 0.97 (accuracy 0.92) for evaluation of local recurrence. For evaluating distant disease in these patients, PET had a sensitivity of 1.00 and specificity of 0.90 (accuracy 0.94). In the evaluation of local disease, focal rectal activity caused false-positive results in two cases. Three false-positive studies for distant disease were caused by inflammatory adenopathy. CONCLUSION: FDG-PET is an accurate modality both for initial staging and restaging of patients with cervical cancer. PET is particularly sensitive for detecting distant metastases, allowing stratification of patients into those with locally confined disease and those with distant disease. These results were achieved by using a standardized PET imaging protocol without the use of bowel preparations, lasix administration, or Foley catheter drainage. Evaluation of local disease can be challenging due to adjacent rectal and bladder activity, and the use of hybrid PET/computed tomography (CT) scanners in the future may further improve evaluation of local disease.     

Pacemaker Lead Fracture Due to Twiddler's Syndrome

The authors report a case of pacemaker twiddler's syndrome that led to lead fracture and loss of consciousness. The role of chest X rays in the diagnosis of pacemaker twiddler's syndrome as well as the management of the syndrome is discussed.     

Cardiovascular effects of intravenous indoramin hydrochloride in man

Haemodynamic effects of intravenous indoramin (5-20 mg) were measured in ten healthy volunteers. Slight falls in arterial and central venous blood pressures were noted but no significant changes in heart rate, right atrial pressure, cardiac output or derived values occurred, except for a fall in peripheral vascular resistance in three cases. An increase in skin blood flow to the feet was observed. An attempt was made to determine the mechanisms of these responses and it was concluded that the drug was an alpha adrenoceptor blocking agent which appeared to act preferentially on those receptors controlling blood flow to the skin of extremities.     

Two missense mutations in the beta-globin gene can cause severe beta thalassemia. Hemoglobin Medicine Lake (beta 32[B14]leucine-->glutamine; 98 [FG5] valine-->methionine).

We studied the molecular basis of transfusion-dependent hemolytic anemia in an infant who rapidly developed the phenotype of beta thalassemia major. DNA sequence of one beta-globin gene of the proband revealed two mutations, one for the moderately unstable hemoglobin (Hb) Köln and another for a novel codon 32 cytosine-thymidine-guanine-->cytosine-adenine-guanine transversion encoding a leucine-->glutamine mutation. A hydrophilic glutamine residue at beta 32 has an uncharged polar side chain that could potentially distort the B helix and provoke further molecular instability. This new hemoglobin was called Hb Medicine Lake. Biosynthesis studies showed a deficit of beta-globin synthesis with early loss of beta-globin chains. An abnormal unstable hemoglobin, globin chain, or tryptic globin peptide was not present, demonstrating the extreme lability of this novel globin. Hb Medicine Lake mRNA was present, but an aberrantly spliced message was not. Absence of an abnormal beta-globin gene in the mother makes it likely that a de novo mutation occurred in the proband. The molecular pathogenesis of Hb Medicine Lake illustrates a mechanism whereby the phenotype of a genetic disorder, like the mild hemolytic anemia associated with a hemoglobinopathy, can be modulated by a coincident mutation in the same gene.     

Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of excess liver triacylglycerol (TAG), inflammation, and liver damage. The goal of the present study was to directly quantify the biological sources of hepatic and plasma lipoprotein TAG in NAFLD. Patients (5 male and 4 female; 44 +/- 10 years of age) scheduled for a medically indicated liver biopsy were infused with and orally fed stable isotopes for 4 days to label and track serum nonesterified fatty acids (NEFAs), dietary fatty acids, and those derived from the de novo lipogenesis (DNL) pathway, present in liver tissue and lipoprotein TAG. Hepatic and lipoprotein TAG fatty acids were analyzed by gas chromatography/mass spectrometry. NAFLD patients were obese, with fasting hypertriglyceridemia and hyperinsulinemia. Of the TAG accounted for in liver, 59.0% +/- 9.9% of TAG arose from NEFAs; 26.1% +/- 6.7%, from DNL; and 14.9% +/- 7.0%, from the diet. The pattern of labeling in VLDL was similar to that in liver, and throughout the 4 days of labeling, the liver demonstrated reciprocal use of adipose and dietary fatty acids. DNL was elevated in the fasting state and demonstrated no diurnal variation. These quantitative metabolic data document that both elevated peripheral fatty acids and DNL contribute to the accumulation of hepatic and lipoprotein fat in NAFLD.     

Susceptibility of Candida dubliniensis to salivary histatin 3

Candida dubliniensis is a recently described Candida species associated with oral candidiasis in human immunodeficiency virus (HIV)-infected patients and patients with AIDS. The majority of C. dubliniensis clinical isolates tested to date are susceptible to the commonly used antifungal drugs, including fluconazole, ketoconazole, itraconazole, and amphotericin B. However, the appearance of fluconazole-resistant C. dubliniensis strains in this patient group is increasing. Histatins are a family of basic histidine-rich proteins present in human saliva which have therapeutic potential in the treatment of oral candidiasis. The mechanism of action of histatin is distinct from that of commonly used azole and polyene drugs. Characterization of the antifungal activity of histatin has mainly been carried out using C. albicans but it is also effective in killing C. glabrata and C. krusei. Here we report that C. dubliniensis is also susceptible to killing by histatin 3. The concentration of histatin 3 giving 50% killing (the IC(50) value) ranged from 0.043 to 0.196 mg/ml among different strains of C. dubliniensis. The least-susceptible C. dubliniensis strain, P9224, was found to internalize histatin at a lower rate than the C. albicans reference strain CA132A. The dissociation constant (K(d)) for the least-susceptible strain (C. dubliniensis 9224) was ninefold higher than that for the C. albicans reference strain. These results suggest that histatin 3 may have potential as an effective antifungal agent, particularly in the treatment of oral candidiasis in HIV-infected patients and patients with AIDS in which resistance to the commonly used antifungal drug fluconazole has emerged.