A high affinity binding site for [3H]-Dofetilide on human leukocytes

Certain Class III anti-arrhythmic agents have been shown to interact with human leukocytes and after antigenic and mitogenic activation. We hypothesized that a binding site for the Class III anti-arrhythmic agent, dofetilide, would exist on human leukocytes. Analysis of binding isotherms defined the presence of a single high affinity binding site on mononuclear cells and neutrophils: Kd 26+/-4 nm, Bmax 61+/-14 fmol/10( 6) cells and Kd 33+/-14 nm, Bmax 163+/-45 fmol/10(6) cells, respectively. Other Class III drugs inhibited [3H]-dofetilide binding at physiologically relevant concentrations, but the IC50 values of E4031 and quinidine were significantly higher for leukocytes than for cardiac myocytes. Interestingly, verapamil inhibited [3H]-dofetilide binding to leukocytes, but not to cardiac myocytes at physiologic concentrations (10 microM). Charybdotoxin and tetraethlyammonium inhibited [3H]-dofetilide binding to leukocytes at microM mm concentrations, respectively, however, apamin did not inhibit binding even at 1 microM concentrations. These data suggest that a Ca2+-activated K+ channel, like K(Ca) mini (apamin-insensitive isoform), is a candidate for the leukocyte [3H]-dofetilide binding site. To assess the functional significance of defetilide binding to leukocyte biology, we evaluated fMLP-stimulated superoxide production in the presence or absence of dofetilide. Dofetilide, at 30 nm suppressed of superoxide production. In conclusion, dofetilide binds to human leukocytes at physiologic concentrations and this binding alters leukocyte function possibly through interaction with a Ca2+-activated K+ channel.     

Primary ciliary dyskinesia (the immotile cilia syndrome)

OBJECTIVE: The purpose of this review is to familiarize the reader with the genetic aspects, clinical manifestations, diagnostic techniques and management of the primary ciliary dyskinesia syndrome. Further, this article illustrates some unusual features of this syndrome and discusses some speculative hypotheses concerning its pathogenesis and clinical presentation. DATA SOURCES: The bibliography includes references in English as well as some references of historical interest in German. Both human and veterinary literature are quoted. Sources included computerized bibliographic searches of recent literature and reviews of literature. STUDY SELECTION: Selection of papers was made based on their historic importance in the definition and characterization of the disease, and on reviews of large bodies of novel or interesting information. Some review papers were not included to avoid repetition. RESULTS: Although the incidence of primary ciliary dyskinesia is low, the inclusion of this condition in the differential diagnosis of chronic and recurrent sinobronchial disease in children and older individuals is very common. Primary ciliary dyskinesia should be suspected in individuals who present chronic respiratory symptoms already in the neonatal period, develop profuse, chronic mucopurulent rhinorrhea, and chronic otitis media and sinusitis. Chronic cough, obstructive lung disease, and bronchorrhea associated with the aforementioned manifestations should also make clinicians suspect this syndrome. Male sterility is almost universally present and situs inversus is present in 50% of affected persons. The diagnosis of primary ciliary dyskinesia is clinical and is confirmed by studies of ciliary motility and ultrastructure of the respiratory mucosa. Management is directed to microbial suppression by frequent antibiotic administration, and to clearing of retained secretions. CONCLUSIONS: The diagnosis of primary ciliary dyskinesia requires familiarity with the clinical picture and the specific techniques of identification. Although the basic mechanism of disease is known, the molecular genetics of primary ciliary dyskinesia and the causes for the phenotypic variability remain to be explained. Future research should be directed to the identification of the gene(s) responsible for the manifestations of the disease and to effective methods of activation, in vivo, of dysfunctional cilia.     

The development and morphofunctional characteristics of the human lateral pterygoid muscle

Peculiarities of the development of superior and inferior heads of lateral pterygoid muscle (LPM) as well as their micro- and ultramicroscopic structure were studied as related to the temporomandibular joint elements in human fetuses and newborns. As a result, heterogeneity and asynchronism of the development of myogenic elements of certain LPM heads were demonstrated. The process of muscle fibres differentiation in LPM superior head leads to more mature structural organization and runs faster than in the inferior head. By the moment of birth average section area of superior head muscle fibres is significantly higher than the inferior head similar parameter.     

A high deuterium abundance at redshift z = 0.7

Of the light elements, the primordial abundance of deuterium relative to hydrogen, (D/H)p, provides the most sensitive diagnostic for the cosmological mass density parameter, omegaB. Recent high-redshift D/H measurements are highly discrepant, although this may reflect observational uncertainties. The larger primordial D/H values imply a low omegaB (requiring the Universe to be dominated by non-baryonic matter), and cause problems for galactic chemical evolution models, which have difficulty in reproducing the steep decline in D/H to the present-day values. Conversely, the lower D/H values measured at high redshift imply an omegaB greater than that derived from 7Li and 4He abundance measurements, and may require a deuterium-abundance evolution that is too low to easily explain. Here we report the first measurement of D/H at intermediate redshift (z = 0.7010), in a gas cloud selected to minimize observational uncertainties. Our analysis yields a value of D/H ((2.0 +/- 0.5) x 10[-4]) which is at the upper end of the range of values measured at high redshifts. This finding, together with other independent observations, suggests that there may be inhomogeneity in (D/H)p of at least a factor of ten.     

Tracing the spread of methicillin-resistant Staphylococcus aureus by Southern blot hybridization using gene-specific probes of mec and Tn554

In a community hospital in Brooklyn, New York, over a 3-year period, 79 methicillin-resistant Staphylococcus aureus (MRSA) isolates from five different case clusters were subtyped by Southern blot hybridization with two previously characterized gene probes, mec and Tn554. Together, the genotyping enabled the hospital infection control team to differentiate simultaneous MRSA clusters in the surgical intensive care unit (type I:A) and the open heart unit (type II:J), document the spread of one strain (type I:A) between roommates, identify an endemic strain (type II:J) from cardiac monitors and medical personnel, and identify an unrelated outbreak strain (type II:NH) in the labor and delivery unit. On the basis of this investigation it is clear that the routine DNA fingerprinting of MRSA in health care facilities, to monitor their spread and identify cases of nosocomial infections, is an important infection control measure.     

Changes in drug-metabolizing enzymes of rats in ciprofibrate-induced hepatic nodules

1. Premalignant rat liver nodules produced in the resistant hepatocyte model, by exposure to carcinogenic chemicals (diethyl nitrosamine and 2-acetamidofluorene), and partial hepatectomy, exhibit decreased xenobiotic hydroxylase activities and increased conjugase activities, which are considered responsible for increased resistance to xenobiotic toxicity. 2. However, premalignant rat liver nodules generated by feeding the hypolipidaemic, peroxisomal proliferating drug, ciprofibrate, in a hypolipidaemic model, exhibit decreased hydroxylase activities but decreased conjugase activities also. 3. It is considered that reactive oxygen species (ROS) are generated in both the resistant hepatocyte model and in the hypolipidaemic model, resulting in lipid peroxidation, loss of haem, cytochromes and hydroxylase activities. 4. However, whereas there is a rebounding compensation of conjugase enzymes in the resistant hepatocyte model, this does not occur with the hypolipidaemic model, as peroxidation is probably persistent and the conjugases are continuously destroyed.     

Influence of energy supplementation on grazing ruminants: requirements and responses

Energy requirements of grazing livestock seem to be poorly defined. Requirements generated from measurements in pen-fed animals present both theoretical and practical concerns when they are applied to grazing situations. In mature ruminants a majority of energy used for maintenance seems to be consumed by visceral tissues. Moreover, factors that affect visceral energy use are poorly understood. Energy supplementation to meet requirements and production demands is often practiced during periods of summer dormancy and in winter months. Source of supplemental energy varies widely and includes grains, readily digestible fiber sources, and high-quality forages. Intake and digestibility can be reduced or unaffected by energy supplementation. In some cases, lower levels of energy supplementation have been shown to increase utilization of grazed forage. Reductions in ruminal pH, often cited as the major cause of reduced fiber digestion, may not always explain reductions in intake and digestibility associated with energy supplementation. Livestock production is usually either enhanced or unaffected by energy supplementation. Additional research regarding energy requirements of grazing ruminants, visceral energy use, and mechanisms associated with reductions in intake and digestibility of grazed forage resulting from energy supplementation is warranted.