Synthesis of indolylalkoxyiminoalkylcarboxylates as leukotriene biosynthesis inhibitors

A series of substituted indolylalkoxyiminoalkylcarboxylates were found to be potent leukotriene biosynthesis inhibitors. The structure-activity relationships were investigated. Representative potent inhibitors identified were the quinolyl 3a (A-86885) and pyridyl 3b (A-86886) congeners with in vitro IC50s of 21 and 9 nM and in vivo leukotriene inhibition in the rat with oral ED50s of 0.9 and 1.7 mg/kg, respectively.     

Percutaneous dilational tracheostomy. Malposition leading to delayed weaning

We report a patient in whom delayed weaning from ventilatory support was caused by the malposition of a percutaneous dilational tracheostomy tube. A fold of mucosa, identified at tracheoscopy, was found to be the limiting factor, and the situation was resolved by removal of the tracheostomy and reintubation. We believe that the case supports the routine use of a bronchoscope to check the position of the tracheostomy tube.     

Immunohistochemistry of lymphocytes and macrophages in human celloidin-embedded temporal bone sections with acute otitis media

Immunohistochemical analyses were used to investigate the distribution of lymphocytes and macrophages in routine human temporal bone sections obtained from a subject with acute suppurative otitis media. Primary antibodies specific for human CD3 and CD43 (T-lymphocytes), CD20 (B-lymphocytes), CD45 (leukocyte common antigen), and CD68 (macrophages) were used. As a pretreatment, the sections were soaked in antigen retrieval solution (saturated sodium hydroxide-methanol solution in methanol at a ratio of 1:3). A second antigen retrieval procedure (microwave treatment in 1% zinc sulfate) was also employed for identifying CD3-positive cells. Then the avidin-biotin-peroxidase complex technique was performed. Positive reactions to all antibodies but anti-CD68 were observed in the mucosa of the eustachian tube, tympanic cavity, and mastoid air cells. Particularly, cells positive to anti-CD3 or anti-CD43 were making a diffuse invasion upon the lamina propria. CD68-positive cells were scattered only in the effusion of mastoid air cells. These results suggest that the retrospective immunohistochemical study of archival temporal bone sections is a promising approach to investigate the pathogenesis of otitis media.     

Metabolic responses of postmenopausal women to supplemental dietary boron and aluminum during usual and low magnesium intake: boron, calcium, and magnesium absorption and retention and blood mineral concentrations

The regulation by neuropeptide Y of alpha2-adrenoceptors in the nucleus tractus solitarii was evaluated in the adult normotensive Wistar Kyoto rat and the adult spontaneously hypertensive rat. The microinjection of a submaximal dose of l-noradrenaline (800 pmol in 50 nl) alone into the nucleus tractus solitarii produced a significant reduction in the mean arterial blood pressure in either strain. The threshold dose (1 pmol in 50 nl) of neuropeptide Y(1-36) for the vasodepressor response in the Wistar Kyoto rat was five times higher than that (0.2 pmol in 50 nl) in the spontaneously hypertensive rat. Furthermore, neuropeptide Y(1-36) at 0.2 pmol in 50 nl could significantly counteract the vasodepressor response to l-noradrenaline (800 pmol in 50 nl) in the spontaneously hypertensive rat, but not in the Wistar Kyoto rat, in which 1 pmol in 50 nl of neuropeptide Y(1-36) must be employed to counteract the vasodepressor response to l-noradrenaline (800 pmol in 50 nl), although the vasodepressor responses are of a similar magnitude. The in situ hybridization and quantitative receptor autoradiographical experiments showed that the alpha2A-adrenoceptor messenger RNA levels and the B(max) value of the alpha2-adrenoceptor agonist [3H]p-aminoclonidine binding sites measured in the nucleus tractus solitarii of the spontaneously hypertensive rat were substantially lower than those in the Wistar Kyoto rat. The quantitative receptor autoradiographical results were consistent with the cardiovascular results and showed that in the spontaneously hypertensive rat, neuropeptide Y(1-36) at 1 nM led to a significant increase in the K(d) value of [3H]p-aminoclonidine binding sites. In the Wistar Kyoto rat, neuropeptide Y(1-36) produced this effect only at 10 nM. The present study provides evidence for an increase of the potency of neuropeptide Y(1-36) to antagonistically modulate alpha2-adrenoceptors in the nucleus tractus solitarii of the spontaneously hypertensive rat. This enhanced antagonistic action may partly be related to a reduction in the number of alpha2A-adrenoceptors in the nucleus tractus solitarii of the spontaneously hypertensive rat, since a decrease has been observed in the alpha2A-adrenoceptor messenger RNA levels and the alpha2-adrenoceptor binding sites in the spontaneously hypertensive rat. This increased potency of neuropeptide Y(1-36) to antagonize alpha2-adrenoceptor function in the nucleus tractus solitarii of the spontaneously hypertensive rat may contribute to the development of high blood pressure in this hypertensive strain.     

Enhancement by hyperthermia of the in vitro cytotoxicity of mitomycin C toward hypoxic tumor cells

Mitomycin C and hyperthermia are both toxic to chronically hypoxic EMT6 tumor cells. Combinations of this drug and heat were tested in vitro in normally aerated and chronically hypoxic EMT6 mouse mammary tumor cells to establish whether greater than additive cytotoxicity could be achieved by combined treatment. Cell survival was measured at four concentrations of mitomycin C (0.01, 0.1, 1.0, and 10 microM) at 37 degrees or at elevated temperatures (41, 42, and 43 degrees) for durations of 1, 2, 3, and 6 hr. At 42 degrees, exposure to mitomycin C for 3 and 6 hr produced a 2- to 3-fold increase in hypoxic tumor cell kill at all drug concentrations over that expected for strict additivity. A 15-fold enhancement in the kill of hypoxic tumor cells was obtained at 1.0 and 10 microM mitomycin C at 43 degrees for 6 hr of exposure. Under most conditions, additivity was observed for the antibiotic and heat in oxygenated cells, except at 43 degrees with 0.01 and 0.1 microM mitomycin C following 3 and 6 hr of treatment, conditions under which a 5- to 10-fold potentiation of tumor cell kill was obtained. The rate of formation of reactive metabolites from mitomycin C under anaerobic conditions in EMT6 cell-free preparations was measured. A 30 to 50% increase in alkylating activity was observed at elevated temperatures, suggesting that the enhanced cytotoxicity of mitomycin C with heat toward hypoxic cells may, in part, be due to an increase in activation of the drug.     

Polymerase chain reaction in the diagnosis of tuberculosis. Comparison of two target sequences for amplification

Amplification of a 340 bp sequence of the 38 kDa protein gene of Mycobacterium tuberculosis by the polymerase chain reaction has been developed. The sensitivity of this PCR was shown to be 10 fg both by agarose gel electrophoresis and Southern blot hybridisation being equivalent to 2-3 organisms and highly specific to M. tuberculosis and excluding even M. tuberculosis H37Ra and Mycobacterium bovis BCG. Sputum samples from patients with pulmonary tuberculosis gave a positivity rate of 45%. PCR was also performed using pt8 and pt9 primers which amplified a 541 bp sequence of IS6110. 41% of the above samples gave positive amplification. Three samples that were positive for 38 kDa sequence were negative for IS6110.     

Pertussis in Massachusetts, 1981-1991: incidence, serologic diagnosis, and vaccine effectiveness

Massachusetts provides diphtheria-tetanus toxoid-pertussis (DTP) vaccine, and since 1980 has monitored pertussis with a statewide diagnostic service. The incidence of bacteriologically confirmed pertussis was 104.5 per 100,000 person-years in 1-month-old infants and declined progressively thereafter. Infants < 6 months old experienced disproportionate morbidity: 44% of bacteriologically confirmed pertussis, 64% of hospitalizations, and 71% of hospital days. Most children with pertussis had received < 3 DTP doses during childhood, whereas 87% of adolescents with pertussis had received > or = 4 doses. Serodiagnosis by single serum anti-pertussis toxin antibody ELISA increased the incidence of confirmed pertussis in persons 11-19 years old from 3.0 to 12.9 per 100,000 and in persons > or = 20 years old from 0.16 to 0.56 per 100,000. Bacteriologic methods underestimate pertussis incidence, but a single serum anti-pertussis toxin antibody ELISA is a practical method for population-based diagnosis in adolescents and adults.     

Clinical pharmacokinetics in the 21st century. Does the evidence support definitive outcomes?

In the last 30 years, few advances have been made in the management of tibial stress injuries such as tibial stress fracture and medial tibial stress syndrome (MTSS). Tibial overuse injuries are a recognised complication of the chronic, intensive, weight-bearing training commonly practised by athletic and military populations. Generally, the most effective treatment is considered to be rest, often for prolonged periods. This is a course of action that will significantly disrupt an active lifestyle, and sometimes end activity-related careers entirely. There is now considerable knowledge of the nature of tibial stress injuries, such that presently accepted management practices can be critically evaluated and supplemented. Most recent investigations suggest that tibial stress injuries are a consequence of the repetitive tibial strain imposed by loading during chronic weight-bearing activity. Evidence is presented in this article for an association between repeated tibial bending and stress injury as a function of: (i) strain-related modelling (in the case of MTSS), and (ii) a strain-related positive feedback mechanism of remodelling (in the case of stress fracture). Factors that influence the bending response of the tibia to loading are reviewed. Finally, a guide for injury prevention and management based on research observations is presented.