Causative and contributive factors to asthma severity and patterns of medication use in patients seeking specialized asthma care

STUDY OBJECTIVES: (1) To assess the prevalence of specific factors considered causative or contributive to asthma in a population of patients seen in a specialized asthma clinic, and to determine whether any of these factors were associated with more severe disease; and (2) to assess the utilization of inhaled steroids by asthma severity in this population and compare it with published guidelines of the National Heart, Lung, and Blood Institute (NHLBI). DESIGN, SETTING, AND PATIENT POPULATION: We conducted a retrospective chart review of new patients seen in a specialized asthma treatment center over a 2.5-year period and recorded the prevalence of 14 causative or contributive factors, the severity of asthma, and the intensity of treatment with inhaled corticosteroids in each patient. Patients were grouped as mild asthma vs moderate/severe asthma and compared by chi(2) analysis and stepwise logistic regression to determine whether certain factors were associated with more severe asthma. MEASUREMENTS AND RESULTS: The average number of factors recorded was 2.9 +/- 1.8 in the mild group (+/- SD) and 3.5 +/- 1.6 in the moderate/severe asthma group. This difference was statistically significant (p = 0.014). Increasing age, male gender, symptomatic gastroesophageal reflux disease (GERD), and chronic sinusitis were independently associated with more severe asthma. Suboptimal use of inhaled corticosteroids was more common in patients with mild persistent asthma, but suboptimal dosing of inhaled corticosteroids was equally common in mild and moderate/severe asthma. No relationship was found between allergen sensitization combined with exposure to cats, dogs, dust mite, or molds and more severe asthma. CONCLUSIONS: This study confirms earlier studies showing that symptomatic GERD and chronic sinusitis are important comorbid conditions in patients with asthma, both being associated with greater asthma severity. This study further shows that the doses of inhaled corticosteroids used for treatment of asthma fall short of NHLBI guidelines in the majority of patients regardless of asthma severity.     

Neuroprotective effects of coenzyme Q10 at rostral ventrolateral medulla against fatality during experimental endotoxemia in the rat

Coenzyme Q10 (CoQ10, ubiquinone) is a highly mobile electron carrier in the mitochondrial respiratory chain that also acts as an antioxidant. We evaluated the neuroprotective efficacy of CoQ10 against fatality in an experimental model of endotoxemia that mimics systemic inflammatory response syndrome using a novel water-soluble formulation of this quinone derivative. Experiments were conducted in adult male Sprague-Dawley rats that were maintained under propofol anesthesia. Intravenous administration of Escherichia coli lipopolysaccharide (LPS; 30 mg/kg) induced progressive hypotension, with death ensuing within 4 h. The sequence of cardiovascular events during this LPS-induced endotoxemia can be divided into a reduction (Phase I), followed by an augmentation (Phase II; "pro-life" phase) and a secondary decrease (Phase III; "pro-death" phase) in the power density of the vasomotor components (0-0.8 Hz) of systemic arterial pressure signals. Pretreatment by microinjection bilaterally of CoQ10 (1 or 2 microg) into the rostral ventrolateral medulla (RVLM), the medullary origin of sympathetic vasomotor tone, significantly diminished mortality, prolonged survival time, and reduced the slope or magnitude of the LPS-induced hypotension. CoQ10 pretreatment also significantly prolonged the duration of and augmented the total power density of the vasomotor components of systemic arterial pressure signals in Phase II endotoxemia. The increase in superoxide anion production induced by LPS at the RVLM during Phases II and III endotoxemia was also significantly blunted. We conclude that CoQ10 provides neuroprotection against fatality during experimental endotoxemia by reducing superoxide anion production at the RVLM, whose neuronal activity is intimately related to the "life-and-death" process.     

Chromosomal gain of 3q and loss of 11q often associated with nodal metastasis in early stage cervical squamous cell carcinoma.

BACKGROUND/PURPOSE: Cervical cancer remains a health problem among women worldwide. Delineation of genetic changes is critical to understanding the molecular basis of tumor progression, as well as for identifying genetic markers for early identification of patients at high risk for a poor outcome. METHODS: To provide comparative genomic hybridization data for cervical squamous cell carcinoma in Taiwan, and to gain further insight into genetic markers associated with lymph node metastasis of this disease, we performed comparative genomic hybridization analysis of 30 consecutive cases of cervical squamous cell carcinoma (24 stage IB and 6 stage IIB). RESULTS: The results disclosed that higher staged tumors or those with lymph node metastasis had more chromosomal imbalances. The commonly recurrent chromosomal imbalances were gains of 3q (46.7%), 1q (36.7%) and 8q (20.0%) and losses of 11q (36.7%), 3p (33.3%), 6q (23.3%), and 2q (20.0%). The frequencies of these chromosomal imbalances in stage IB and IIB tumors did not differ significantly. However, when compared with tumors without lymph node metastasis, the loss of 11q14-q22 (5/9 vs. 3/21, p = 0.019) and gains of 3q11-q22 and 3q26-qter (6/9 vs. 5/21, p = 0.026) were significantly more prevalent in tumors with lymph node metastasis. CONCLUSION: The results suggest that certain tumor-associated genes residing on 3q and 11q warrant further investigation to elucidate their role in the progression of this disease.     

Increased chromosome-type chromosome aberration frequencies as biomarkers of cancer risk in a blackfoot endemic area

To examine whether biomarkers such as sister chromatid exchanges (SCEs) and chromosome aberrations (CAs) can predict cancer development, a nested case-control study was performed in a blackfoot endemic area with a known high cancer risk. A cohort of 686 residents was recruited from three villages in the blackfoot endemic area. Personal characteristics were collected, and venous blood was drawn for lymphocyte culture and stored in a refrigerator. The vital status and cancer development were followed using the National Death Registry, Cancer Registry, and Blackfoot Disease Registry. The follow-up period was from August 1991 to July 1995. During this 4-year period, 31 residents developed various types of cancer. Blood culture samples from nine of these subjects were unsuitable for experiments due to improper storage. Finally, a total of 22 cancer cases had cytogenetic samples that could be analyzed. Twenty-two control subjects were selected from those who did not develop cancer in the study period, and these subjects were matched to cases by sex, age, smoking habits, and residential area. The results showed that there was no significant difference in the frequencies of SCE and chromatid-type CAs between the case and control groups. However, the frequencies of chromosome-type CAs, e.g., chromosome-type gaps, chromosome-type breaks, chromosome-type breaks plus exchanges, total chromosome-type aberrations, and total frequencies of CAs in the case group, were significantly higher than those in the control group (P < 0.05). The odds ratio of cancer risk in subjects with more than zero chromosome-type breaks was 5.0 (95% confidence interval = 1.09-22.82) compared to those with zero chromosomal breaks. The odds ratios for more than zero chromosome-type breaks plus exchanges and a frequency of total chromosome-type aberrations of >1.007% were 11.0 and 12.0, respectively (P < 0.05). Subjects with a total CA frequency of >4.023% had a 9-fold increase for cancer risk. These results indicate that chromosome-type CAs are good biomarkers for the prediction of cancer development, whereas SCEs and chromatid-type CAs cannot predict cancer risk.     

Vanidipinedilol: a vanilloid-based beta-adrenoceptor blocker displaying calcium entry blocking and vasorelaxant activities

Calcium channel and beta-adrenoceptor blockade have proved highly useful in antihypertensive therapy. Studies of the mechanisms of action of vanidipinedilol that combine these effects within a single molecule are described here. Intravenous injection of vanidipinedilol (0.1, 0.25, 0.5, 1.0, and 2.0 mg/kg) produced dose-dependent hypotensive and bradycardic responses, significantly different from nifedipine-induced (0.5 mg/kg, i.v.) hypotensive and reflex tachycardic effects in pentobarbital-anesthetized Wistar rats. A single oral administration of vanidipinedilol at doses of 10, 25, and 50 mg/kg dose-dependently reduced blood pressure with a decrease in heart rate in conscious spontaneously hypertensive rats (SHRs). In the isolated Wistar rat atrium, vanidipinedilol (10(-7), 10(-6), and 10(-5) M) competitively antagonized the (-)isoproterenol-induced positive chronotropic and inotropic effects and inhibited the increase in heart rate induced by Ca2+ (3.0-9.0 mM) in a concentration-dependent manner. The parallel shift to the right of the concentration-response curve of (-)isoproterenol and CaCl2 suggested that vanidipinedilol possessed beta-adrenoceptor-blocking and calcium entry-blocking activities. On tracheal strips of reserpinized guinea pig, cumulative doses of vanidipinedilol (10(-10) to 3x10(-6) M) produced dose-dependent relaxant responses. Preincubating the preparation with ICI 118,551 (10(-10), 10(-9), 10(-8) M), a beta2-adrenoceptor antagonist, shifted the vanidipinedilol concentration-relaxation curve significantly to a region of higher concentrations. These results implied that vanidipinedilol had a partial beta2-agonist activity. In the isolated thoracic aorta of rat, vanidipinedilol had a potent effect inhibiting high-K+-induced contractions. KCI-induced intracellular calcium changes of blood vessel smooth muscle cell (A7r5 cell lines) determined by laser cytometry also was decreased after administration of vanidipinedilol (10(-8), 10(-7), 10(-6) M). Furthermore, the binding characteristics of vanidipinedilol and various antagonists were evaluated in [3H]CGP-12177 binding to ventricle and lung and [3H]nitrendipine binding to cerebral cortex membranes in rats. The order of potency of beta1- and beta2-adrenoceptor antagonist activity against [3H]CGP-12177 binding was (-)propranolol (pKi, 8.59 for beta1 and 8.09 for beta2) > vanidipinedilol (pKi, 7.09 for beta1 and 6.64 for beta2) > atenolol (pKi, 6.58 for beta1 and 5.12 for beta2). The order of potency of calcium channel antagonist activity against [3H]nitrendipine binding was nifedipine (pKi, 9.36) > vanidipinedilol (pKi, 8.07). The ratio of beta1-adrenergic-blocking/calcium entry-blocking selectivity is 0.1 and indicated that vanidipinedilol revealed more in calcium entry-blocking than in beta-adrenergic-blocking activities. It has been suggested that vanidipinedilol-induced smooth muscle relaxation may involve decreased entry of Ca2+ and partial beta2-agonist activities. In conclusion, vanidipinedilol is a nonselective beta-adrenoceptor antagonist with calcium channel blocking and partial beta2-agonist associated vasorelaxant and tracheal relaxant activities. Particularly, the vasodilator effects of vanidipinedilol are attributed to a synergism of its calcium entry blocking and partial beta2-agonist activities in the blood vessel. A sustained bradycardic effect results from beta-adrenoceptor blocking and calcium entry blocking, which blunts the sympathetic activation-associated reflex tachycardia in the heart.     

Modulation of protein kinase A activation by fibronectin matrix proteins at developing neuromuscular synapses in Xenopus laevis cell cultures.

Extracellular matrix proteins, such as fibronectin, laminin, and collagen, have been implicated in a wide variety of cellular properties, which include cell adhesion, migration, differentiation, and proliferation. In this study, we investigated the modulation of protein kinase A (PKA) activity by matrix proteins at developing motoneurons. The cultures of spinal neurons and myotomal cells were prepared from 1-day-old Xenopus laevis embryos. Spontaneous synaptic currents (SSC) were recorded from innervated myocytes of natural synapses by whole-cell voltage-clamped recordings (V(h) = -60 to approximately -65 mV). Bath application of agents, which directly or indirectly activate PKA, such as forskolin (20 microM), dibutyryl cAMP (DBcAMP) (1 mM), isoproterenol (10 microM), or albuterol (10 microM), significantly increased SSC frequency in cultures grown on fibronectin (FN)-coated substratum, but not on laminin- or collagen-coated glasses. The evoked synaptic currents increased in response to forskolin in neurons grown on FN substratum. Triflavin, an Arg-Gly-Asp-dependent disintegrin, inhibited potentiating action of isoproterenol in neurons grown on FN substratum, suggesting that integrin is involved in the potentiation of the PKA pathway in the regulation of acetylcholine (ACh) release. There is collaboration of neurotrophic factors and the FN matrix in regulating synaptic transmission in response to DBcAMP. Chronic treatment with neurotrophic factors, such as ciliary neurotrophic factor (150 ng/ml), glial cell line-derived neurotrophic factor (30 ng/ml), or neurotrophin-3 (50 ng/ml), enhanced the SSC-increasing action of DBcAMP in neurons grown on FN-coated glasses. These results suggest that the FN matrix potentiates synaptic transmission in response to PKA activation. Neurotrophic factors may collaborate with FN to regulate spontaneous ACh secretion at developing motoneurons, which may play an important role in the maturation of embryonic neuromuscular synapses.     

Levels of alpha- and gamma-tocopherol in human eyes: evaluation of the possible role of IRBP in intraocular alpha-tocopherol transport

Alpha-tocopherol was distributed almost equally between the retina and its underlying pigmented layers (pigment epithelium and choroid). Only 8.4% of the total alpha-tocopherol occurred in the iris and ciliary body. Alpha-tocopherol content was expressed as amount per eye, per cm2, and per 100 g wet weight. The combined retina and pigment epithelium-choroid contained 2.9 +/- 1.0 mg/100 g wet weight (means +/- SD, n = 30 donors). Gamma-tocopherol represented 20.9 +/- 12.2 mol % of the alpha-tocopherol. The anterior tissues contained 0.4 +/- 0.2 mg/100 g (n = 19 donors). No significant correlation with age was found. Purified bovine interstitial retinol-binding protein (IRBP) bound exogenous 3H-alpha-tocopherol, which could be displaced by unlabeled all-trans retinol (KD = 10(-6) M). Much higher concentrations of unlabeled alpha-tocopherol were required to achieve a partial displacement of bound 3H-all-trans retinol. No endogenous alpha-tocopherol could be detected in bovine interphotoreceptor matrix.     

Enzymatic phosphorylation of the antiherpetic agent 9-[(2,3-dihydroxy-1-propoxy)methyl]guanine

The antiherpetic agent 9-[(2,3-dihydroxy-1-propoxy)methyl]guanine (iNDG) is phosphorylated by HSV1 thymidine kinase, and its phosphorylated products inhibit DNA polymerase activity. iNDG exists in two enantiomeric forms, each with a primary and a secondary hydroxyl; thus, a number of possibilities for preferential phosphorylation exist, which were explored in this study. HSV1 thymidine kinase phosphorylates the primary hydroxyl of both the R and the S isomers of iNDG. This was established by comparison with analogues in which either the primary or the secondary hydroxyl was replaced by fluorine or hydrogen and also by a study of the NMR spectrum of the monophosphate. GMP kinase phosphorylates the R and the S monophosphates to the respective diphosphates. Further phosphorylation, however, is much more efficient with the S than with the R isomer. Furthermore, (S)-iNDG triphosphate is a more potent inhibitor of HSV1 DNA polymerase than (R)-iNDG triphosphate. These differences in the biochemical specificities of the two isomers account for the observed higher antiviral potency of (S)-iNDG as compared to that of (R)-iNDG.