The role of the human acetylation polymorphism in the metabolic activation of the food carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ).

The metabolic activation of the heterocyclic food carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) by two human cytochrome P450 monoxygenases (P4501A1 and P4501A2) and two human N-acetyltransferases (NAT1 and NAT2) was investigated. Various combinations of these enzymes were functionally expressed in COS-1 cells. DNA adducts resulting from the activation of IQ were assayed quantitatively by the 32P-postlabeling procedure. The highest adduct frequency was observed in cells expressing both CYP1A2 and NAT2. CYP1A2 in combination with NAT1 was 3-6 times less active. When expressed alone these enzymes gave rise to low adduct frequencies. Experiments with N-acetyl-IQ as substrate suggest that NAT1 and NAT2 in addition to their known role in N-acetylation display arylhydroxamic acid N, O-acetyltransferase (AHAT) activity. Quantitative differences in adduct formation between IQ and N-acetyl-IQ indicated that metabolic activation of these arylamines preferentially occurs by P4501A2-catalyzed N-hydroxylation followed by O-acetylation mediated through NAT1 and/or NAT2. These data, in combination with the known genetic polymorphism of NAT2, may explain the clinical observation that the acetylation polymorphism constitutes a risk factor in the carcinogenic activation of environmental mutagens.     

Tapering dose of inhaled budesonide in subjects with mild-to-moderate persistent asthma treated with montelukast: a 16-week single-blind randomized study

Pharmacological therapy with inhaled steroids (IS) is currently considered the gold-standard of treatment for mild-persistent asthma. Leukotriene receptor antagonist drugs (LTRAs) play an important role associated with IS, allowing dose tapering and maintaining control of asthma symptoms. The aim of this study was to determine the effectiveness of montelukast (MON) to allow tapering of the inhaled dose of budesonide (BUD) in patients with mild-moderate persistent asthma. This 16-wk single-blind randomized study included 40 asthmatic patients divided in 2 treatment groups. After a run-in period (4 wk), in which all patients inhaled 400 microg of BUD twice daily (bid), group A (20 patients) received MON (oral, 10 mg/day) combined with inhaled BUD (400 microg/bid), while group B (20 patients) was treated with BUD for the whole period of the study. In both groups, at every 4 wk the dose of BUD was halved. After 12 wk of treatment the mean value of forced expiratory volume during the first sec (FEV1, as % of predicted value) was significantly greater in group A compared with group B (94 +/- 7.5 vs 83.1 +/- 6.9; p<0.005). The mean values of peak expiratory flow (PEF), the percentages of asthmatic exacerbations, and the use of beta2-short-acting agonist (SABA) were similar in the 2 groups at 4, 8, and 12 wk. In conclusion, in patients with mild-moderate persistent asthma, MON therapy is useful in tapering the dose of IS in order to reduce its side effects and to maintain the clinical stability of the disease.     

Role of Th1 and Th2 cells in anterior chamber-associated immune deviation.

The immunological privilege of the anterior chamber (AC) of the eye is due, at least in part, to a selective antigen-specific down-regulation of delayed-type hypersensitivity (DTH) and a normal induction of antibody responses: a phenomenon that has been termed anterior chamber-associated immune deviation (ACAID). This dichotomy in the systemic immune responses is suggestive of a T-helper type-2 (Th2)-dominated immune phenotype in which a Th2 cell population is preferentially activated and cross-regulates T-helper type-1 (Th1) effector elements. This hypothesis was tested by comparing the cytokine pattern of antigen-pulsed spleen cells from mice primed in the anterior chamber with antigens that induce ACAID with responses in hosts primed with antigens that do not induce ACAID. The results indicated that CD4+ spleen cells from hosts primed in the AC with antigens that induce ACAID produced significant quantities of interleukin-10 (IL-10) but insignificant levels of IL-2, IL-4 and interferon-gamma (IFN-gamma). In contrast, hosts primed in the AC with antigens that do not induce ACAID, but instead elicit normal DTH, displayed cytokine patterns indicative of a Th1 response significant quantities of IL-2 and IFN-gamma were produced while IL-4 and IL-10 secretion was insignificantly different from normal controls. The immunological phenotype of the AC-primed hosts could be altered by systemic treatment with antibodies against either a Th1 cytokine (IFN-gamma) or a Th2 cytokine (IL-10). Hosts treated with anti-IL-10 antibody and subsequently primed in the AC with ACAID-inducing antigens developed normal DTH responses, while hosts treated with anti-IFN-gamma antibody and primed in the AC with antigens that normally produce positive DTH responses failed to develop positive DTH collectively the results support the proposition that immune privilege in the AC of the eye is due to the selective activation of a Th2 population that cross-regulates Th1 responses.     

Management of Facial Nerve in Surgical Treatment of Previously Untreated Fisch Class C Tympanojugular Paragangliomas: Long-Term Results

The aim of this study was to evaluate the long-term facial nerve outcome according to management of the facial nerve in patients undergoing surgery for Fisch class C tympanojugular paragangliomas. The study population consisted of 122 patients. The infratemporal type A approach was the most common surgical procedure. The facial nerve was left in place in 2 (1.6%) of the 122 patients, anteriorly rerouted in 97 (79.5%), anteriorly rerouted with segmental resection of the epineurium in 7 (5.7%), and sacrificed and reconstructed in 15 (12.3%). One patient underwent cross-face nerve grafting. At last follow-up, House-Brackmann grade I to II was achieved in 51.5% of patients who underwent anterior rerouting and in 28.5% of those who underwent anterior rerouting with resection of the epineurium. A House-Brackmann grade III was achieved in 73.3% of patients who underwent cable nerve graft interposition. The two patients in whom the facial nerve was left in place experienced grade I and grade III, respectively. The patient who underwent cross-face nerve grafting had grade III. Gross total resection was achieved in 105 cases (86%). Management of the facial nerve in tympanojugular paraganglioma surgery can be expected to ensure satisfactory facial function long-term outcome.     

Bronchial hyperresponsiveness and quality of life in asthmatics

BACKGROUND: Quality of Life (QoL) measurements are more responsive to clinically significant changes that are not evaluated by conventional clinical measures. OBJECTIVE: The objective of this study is to examine the relationship between bronchial hyperresponsiveness (BHR) and QoL in asthmatic patients. PATIENTS AND METHODS: 394 patients underwent clinical follow-up, pulmonary function tests and the methacholine challenge test (MCHt), and completed the Asthma Quality of Life Questionnaire (AQLQ). RESULTS: 200 patients had a positive MCHt and in 194 it was negative. For all 32 items, asthmatic patients had a median value of 4.7 (4.2-5.9) compared to 5.6 (4.7-6.3) in patients with negative MCHt (p < 0.01). For physical activities, patients with positive MCHt showed a median value of 5.0 (4.5-6.0) compared to 5.7 (4.8-6.3) in patients with negative MCHt (p < 0.05). Median scores of 12 items of symptoms and 5 items of emotions were significantly lower in patients with positive MCHt [4.5 (3.7-5.8) and 5.1 (4.2-6.1)] than in patients with negative MCHt [5.5 (4.4-6.1) and 6.3 (5.2-6.9), respectively, (p < 0.01)]. For items of environmental stimuli the median score was 4.7 (3.7-5.9) in patients with positive MCHt, being significantly lower than in patients with negative MCHt [5.4 (4.2-6.4), p < 0.05]. Patients with positive MCHt had lower values of QoL than patients with negative MCHt. CONCLUSIONS: QoL changes may be more sensitive than evaluation of BHR. The measurement of Qol may be important because it enables us to characterize patients who could be candidates eventually to a pharmacological treatment for BHR because they have an impaired QoL.     

Meta-analysis of randomized trials on access site selection for percutaneous coronary intervention in ST-segment elevation myocardial infarction

Introduction

Superior outcomes with transradial (TRPCI) versus transfemoral coronary intervention (TFPCI) in the setting of acute ST-segment elevation myocardial infarction (STEMI) have been suggested by earlier studies. However, this effect was not evident in randomized controlled trials (RCTs), suggesting a possible allocation bias in observational studies. Since important studies with heterogeneous results regarding mortality have been published recently, we aimed to perform an updated review and meta-analysis on the safety and efficacy of TRPCI compared to TFPCI in the setting of STEMI.

Material and methods

Electronic databases were searched for relevant studies from January 1993 to November 2012. Outcome parameters of RCTs were pooled with the DerSimonian-Laird random-effects model.

Results

Twelve RCTs involving 5,124 patients were identified. According to the pooled analysis, TRPCI was associated with a significant reduction in major bleeding (odds ratio (OR): 0.52 (95% confidence interval (CI) 0.38–0.71, p < 0.0001)). The risk of mortality and major adverse events was significantly lower after TRPCI (OR = 0.58 (95% CI: 0.43–0.79), p = 0.0005 and OR = 0.67 (95% CI: 0.52–0.86), p = 0.002 respectively).

Conclusions

Robust data from randomized clinical studies indicate that TRPCI reduces both ischemic and bleeding complications in STEMI. These findings support the preferential use of radial access for primary PCI.     

Has arteriography gotten a bad name? Current accuracy and morbidity of diagnostic contrast arteriography for aortoiliac and lower extremity arterial disease

Recently, contrast arteriography has been challenged as the diagnostic test of choice for lower extremity arterial disease because of its associated morbidity and questionable accuracy in identifying suitable distal outflow arteries. The purpose of this report was to analyze our experience to determine if these concerns were justified. We reviewed 500 consecutive contrast arteriograms performed at our hospital for aortoiliac and lower extremity arterial disease between November 1994 and November 1998. Arteriograms performed in conjunction with therapeutic procedures such as balloon angioplasty, stent placement, and thrombolysis were excluded, leaving 244 diagnostic cases for analysis. Forty-six percent (112) of patients had diabetes mellitus, 14% (34) had an elevated baseline serum creatinine (> or =1.5 mg/dL), and an additional 7% (17) were dialysis dependent. Radiologists limited contrast volume by imaging only the symptomatic extremity when appropriate and using digital subtraction techniques as indicated. Our results showed that diagnostic contrast arteriography is associated with an acceptably low morbidity, has an accuracy that is unlikely to be surpassed by other modalities, and remains the diagnostic test of choice for lower extremity arterial disease.