The synthesis and antibacterial activities of quinolones containing five- and six-membered heterocyclic substituents at the 7-position

A series of 6-fluoro-7-substituted-1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids were prepared. The substituents at the 7-position included five- and six-membered heterocyclic rings such as oxazoline and oxazine as well as five-membered heteroaromatic rings such as oxazoles and imidazoles. The structure--activity relationships (SAR) of these compounds indicated that oxazole substituents containing a 2-methyl group had the greatest in vitro potency. The compounds showed greater in vitro antibacterial activity against Gram-positive organisms than against Gram-negative organisms.     

Asbestos disease risk communication conducted by the New Jersey department of health

Since October 1985, the New Jersey Department of Health (NJDOH) has required hospitals to report all patients with a discharge diagnosis of asbestosis. As follow-up to a needs assessment survey of these patients, the NJDOH developed an educational packet including an information bulletin titled “Asbestos Disease: Medical and Legal Facts for Employees” and a pre-stamped postcard evaluation survey. The packet was sent to 1,418 patients reported by hospitals; 433 patients returned the evaluation questionnaire. The survey assessed attitudinal responses (were the materials helpful and easy to understand?) and behavioral responses (did the respondent plan on discussing the materials with a doctor or lawyer?) to the information in the packet. Of the postcard respondents, 85% found the materials helpful, and approximately half indicated that they would discuss the materials with a doctor or lawyer. Of the 33% who were proxy respondents, half appeared not to have understood that the materials had relevance to them as family members. Modifications to the protocol for the asbestos disease educational packet were made based on the evaluation data. Limitations of the evaluation survey and the value of process evaluations in risk communication projects are discussed. © 1993 Wiley-Liss, Inc.     

Stimulation of nerve growth factor and substance P expression in the iris–trigeminal axis of diabetic rats—involvement of oxidative stress and effects of aldose reductase inhibition

In rats with streptozotocin-induced diabetes, we measured increased (by 61%; P<0.05) mRNA for nerve growth factor (NGF) in the iris together with increased (by 82%; P<0.05) mRNA for preprotachykinin (the substance P precursor) in the trigeminal ganglion, suggesting that increased NGF was driving increased substance P gene expression. In other diabetic rats, these changes were prevented by treatment with either an antioxidant (butylated hydroxytoluene; 1% by diet) or an aldose reductase inhibitor (ARI) (sorbinil; 25 mg/kg/day p.o.) and the sorbinil treatment was associated with significant inhibition of polyol pathway intermediates in both lens and sciatic nerve. This suggests that polyol pathway activity in the lens may translate to oxidative stress-driving stimulation of NGF gene expression in the iris. The change is selective for NGF, because expression of the analogous neurotrophin, neurotrophin-3 (NT-3), was unaltered in the same irises. These changes suggest that oxidative stress and/or inflammation can drive up NGF expression in diabetes—a mechanism that might participate in iritis.     

The use of urine proteomic and metabonomic patterns for the diagnosis of interstitial cystitis and bacterial cystitis

The advent of systems biology approaches that have stemmed from the sequencing of the human genome has led to the search for new methods to diagnose diseases. While much effort has been focused on the identification of disease-specific biomarkers, recent efforts are underway toward the use of proteomic and metabonomic patterns to indicate disease. We have developed and contrasted the use of both proteomic and metabonomic patterns in urine for the detection of interstitial cystitis (IC). The methodology relies on advanced bioinformatics to scrutinize information contained within mass spectrometry (MS) and high-resolution proton nuclear magnetic resonance (1H-NMR) spectral patterns to distinguish IC-affected from non-affected individuals as well as those suffering from bacterial cystitis (BC). We have applied a novel pattern recognition tool that employs an unsupervised system (self-organizing-type cluster mapping) as a fitness test for a supervised system (a genetic algorithm). With this approach, a training set comprised of mass spectra and 1H-NMR spectra from urine derived from either unaffected individuals or patients with IC is employed so that the most fit combination of relative, normalized intensity features defined at precise m/z or chemical shift values plotted in n-space can reliably distinguish the cohorts used in training. Using this bioinformatic approach, we were able to discriminate spectral patterns associated with IC-affected, BC-affected, and unaffected patients with a success rate of approximately 84%.     

Cardiovascular and respiratory changes during acute pulmonary edema produced by nephrotoxic serum in the rat

The intravenous injection of rabbit anti-rat kidney serum in rats produces, with a latency of 30 to 60 seconds, the triad sinus bradycardia (or S-A blockade), systemic hypotension and apnea. Recordings of the intracardiac pressures showed a rise in the right and a simultaneous fall in the left ventricular pressure, 30 to 60 seconds after the serum injection. These initial effects were followed by pulmonary edema and death. Bilateral vagotomy prevented the bradycardia and apnea, but not the intracardiac changes, edema and death. Atropine also prevented the bradycardia, but not the apnea, edema and death. Experiments using alpha and beta adrenergic blocking agents seem to indicate that the edema is not caused by the release of catecholamines. It is suggested that the edema could be explained by a rise in the pulmonary capillary pressure, due to the antigen-antibody reaction. The triad bradycardia, systemic hypotension and apnea seems to be the first sign of the pulmonary edema, is reflex in nature, and is assumed to be due to stimulation of J receptors in the lungs, by a mechanical effect (edema). Phenylbutazone and acetylsalicylic acid give a partial protection against the pulmonary edema. Ultramorphological observations of lungs with edema were described.     

X-linked liver glycogenosis type II (XLG II) is caused by mutations in PHKA2, the gene encoding the liver alpha subunit of phosphorylase kinase

X-linked liver glycogenosis type II (XLG II) is a recently described X- linked liver glycogen storage disease, mainly characterized by enlarged liver and growth retardation. These clinical symptoms are very similar to those of XLG I. In contrast to XLG I patients, however, XLG II patients do not show an in vitro enzymatic deficiency of phosphorylase kinase (PHK). Recently, mutations were identified in the gene encoding the liver alpha subunit of PHK (PHKA2) in XLG I patients. We have now studied the PHKA2 gene of four unrelated XLG II patients and identified four different mutations in the open reading frame, including a deletion of three nucleotides, an insertion of six nucleotides and two missense mutations. These results indicate that XLG II is due to mutations in PHKA2. In contrast to XLG I, XLG II is caused by mutations that lead to minor structural abnormalities in the primary structure of the liver alpha subunit of PHK. These mutations are found in a conserved RXX(X)T motif, resembling known phosphorylation sites that might be involved in the regulation of PHK. These findings might explain why the in vitro PHK enzymatic activity is not deficient in XLG II, whereas it is in XLG I.      

Granulocyte precursors are the principal cells in bone marrow that stimulate allospecific cytolytic T-lymphocyte responses.

Mouse bone marrow cells were fractionated and enriched for functional activity as stimulators of allospecific cytolytic T-lymphocyte (CTL) responses in vitro. The relevant stimulator cells were enriched sequentially in the low-density fraction of bone marrow, its 2-hr adherent and 18-hr non-adherent fractions and in the FcR-negative fraction of 18-hr non-adherent cells. The functionally enriched cell population contained over 90% granulocyte precursors by ultrastructural analysis. The results indicate that granulocyte precursors are the principal cells in bone marrow that stimulate alloreactive T-cell responses.     

Distinct Leishmania braziliensis isolates induce different paces of chemokine expression patterns

Inflammatory events during Leishmania braziliensis infection in mice were investigated. Large lesions were directly correlated with the inflammatory reaction but not with parasite burden. Different L. braziliensis strains induce different paces of chemokine expression patterns, leading to diverse cell recruitment and differential inflammatory responses.     

The 4p- syndrome—An autopsy study

The autopsy of an infant with the 4p- or Wolf-Hirschhorn syndrome revealed visceral abnormalities not previously described, i.e., agenesis of the gallbladder and spleen. The parent's chromosomes were normal.