Interferon-α induced remission in three patients with eosinophilic granulomatosis and polyangiitis. A case study.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic small vessel vasculitis associated with asthma and eosinophilia. Optimal therapy for maintenance of remission is yet to be defined. We present a case-series of three patients with EGPA in whom IFN-α, an immunomodulatory cytokine induced remission, which was maintained even after discontinuation of the drug. In all patients (ages 60, 51, and 50 years), remission was associated with normalisation of eosinophil counts and IgE-levels. Moreover, the patients remained in remission for one to four years. Two patients did not need further immunosuppression, one patient required low dose maintenance therapy. Although reversible side effects occur, IFN-α-therapy induces long-term remission of EGPA even after discontinuation of treatment.

[Airway complications following lung transplantation - clinic, diagnosis, and interventional management]. / Atemwegskomplikationen nach Lungentransplantation - Klinik, Diagnose und interventionelle Behandlung.

Tracheobronchial complications following lung transplantation are defined as local structural or infectious alterations of the airways, which occur early or several months after lung transplantation (LTx). They preferentially develop in the region of the bronchial anastomosis. The most frequently reported complications are bronchial stenosis, bronchial dehiscence, exophytic excessive granulation tissue formation, tracheo-bronchomalacia, bronchial fistulas, and endobronchial infections. Airway complications are mainly attributed to ischaemia of the donor bronchus during the immediate post-transplant period. The most relevant risk factors for the development of airway complications include local infections, surgical techniques, and the immunosuppressive regimen. Thus, management of post-transplant bronchial complications requires early interventional bronchoscopic procedures including balloon bronchoplasty, cryotherapy, laser photoresection, endobronchial brachytherapy, and bronchial stents. In addition, antibiotic treatment, or non-invasive positive-pressure ventilation may be necessary. The procedures required depend on the time of occurrence, the type, and clinical relevance of the airway complication. This review summarises clinical presentation, risk factors, the diagnostic methods as well as management options for the most common LTx-associated airway complications.

[Interferon-alpha as treatment option in severe persistent uncontrolled bronchial asthma: an open label study]. / Interferon-alpha als Therapieoption bei der Behandlung des schwergradig persistierenden, unkontrollierten Asthma bronchiale: Eine offene Studie.

BACKGROUND: The purpose of this study was to evaluate the long-term safety and therapeutic effects of IFN-alpha in patients with severe persistent uncontrolled asthma on long-term oral glucocorticoid (GC) treatment. PATIENTS AND METHODS: The study included 16 patients (2 male, 14 female; age 39 years [range: 24 - 63]) with severe persistent asthma. Diagnosis and severity classification of asthma were established according to the guidelines of the "Deutsche Atemwegsliga". Eight patients stopped the therapy within 7 months due to side effects (n = 3), costs not covered by health insurance (n = 2), non-compliance (n = 2), and change of residence (n = 1). 8 patients (8 female, age 49 years [range: 35 - 68], duration of disease 16 years [range: 5 - 24]) were treated for at least 12 months with IFN-alpha (9 microg) 3 times/week. All patients were on oral glucocorticoids (GCs) for more than 5 years (average dose 17.5 [range: 5.0 - 64.0] mg/d). Clinical signs, lung function, need for reliever medication, number of emergency visits and hospitalisations and diary were assessed prior to and after 12 months of treatment. Data are given as percent of normal or median [range]. RESULTS: IFN-alpha improved lung function after 12 months: FEV1 64 vs. 75 %; FEV1/IVC 76 vs. 89 %; RV 153 % vs. 129 %; Rtot 193 vs. 111 % and morning PEF by 50 - 190 L/min. IFN-alpha also significantly reduced the use of reliever medication (10 [2 - 20] vs. 1 [0 - 3] puffs/d), nocturnal awakening (11 [4 - 30] vs. 1 [0 - 5]/month), emergency visits (7 [2 - 15] vs. 0 [0 - 5]/month) and hospitalisations (4 [1 - 8] vs. 0 [0 - 5]/year). In 5 patients the asthma attacks and nightly disturbances disappeared completely. The improvements were achieved despite a tapering of the oral GCs in all patients from 17.5 (5.0 - 64.0) to 2 (0 - 16) mg/d. In 5 patients GC treatment could be discontinued. The number of blood eosinophils decreased from 0.46 to 0.28 Gpt/L. Adverse events were transient and usually decreased within 3 to 4 weeks. Two patients developed an autoimmune thyreoiditis. CONCLUSION: In severe persistent, uncontrolled, and GC-dependent asthma, treatment with IFN-alpha leads to sustained clinical improvement and allows the reduction or discontinuation of oral GCs. Severe side effects may occur in isolated cases.

Metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in mice.

The metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP), a heterocyclic amine carcinogen detected in cooked meats, was investigated in mice. In 3-methylcholanthrene-induced mice administered 0.1, 1.0 and 10 mg/kg [14C]PhIP (i.p.), urinary and fecal excretion over 24 h accounted for 16% and 42-56% of the dose respectively. Urinary excretion of unchanged parent compound accounted for only 0.5-0.8% of the administered dose. At all doses, the major urinary metabolite was identified as 4'-(2-amino-1-methylimidazo[4,5-b]pyrid-6-yl)phenyl sulfate and this metabolite comprised approximately 5% of the dose. Uninduced mice excreted greater than 13% of a 10 mg/kg dose as the sulfate conjugate. Urinary excretion of both 2-amino-1-methyl-6-(4'-hydroxy)-phenylimidazo[4,5-b]pyridine (4'-hydroxy-PhIP) and a glucuronide conjugate of 2-hydroxyamino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (N-hydroxy-PhIP) was also higher (4-fold) in uninduced versus induced mice. The decreased urinary excretion of P450-derived metabolites via induction contrasted with increased metabolite formation by hepatic microsomal preparations. 4'-Hydroxy-PhIP and N-hydroxy-PhIP were produced in amounts nearly 7- and 3-fold higher respectively by induced versus uninduced microsomal incubations at 50 microM [3H]PhIP. At concentrations less than 10 microM, PhIP was almost exclusively converted by the induced preparations to an unidentified metabolite that was not retained by the C18 column. This metabolite, which also was formed in incubations with either 4'-hydroxy-PhIP or N-hydroxy-PhIP, was produced by microsomes from uninduced animals at a much slower rate. Covalent binding to microsomal protein in incubations with [3H]PhIP was concentration-dependent and 2- to 4-fold higher in induced than uninduced preparations. Covalent binding in liver and kidney of induced mice administered [14C]PhIP was dose dependent. At 10 mg/kg PhIP, adducts were produced at 1.7-fold higher levels in livers of induced versus uninduced mice, but renal binding was higher in uninduced animals. These studies indicate the importance of cytochrome P450 and other xenobiotic enzymes in the metabolism, disposition and activation of PhIP.

Optical absorption at 1.06 microm in highly deuterated potassium dihydrogen phosphate.

We have determined the relationship between residual proton (hydrogen) concentration and optical absorption at 1.06 microm in highly deuterated potassium dihydrogen phosphate (KDP). The proton concentration was determined by nuclear magnetic resonance (NMR) spectroscopy and the absorbance was measured by calorimetry. We obtained a hydrogen concentration dependence of 396 +/- 55 parts in 10(6) (ppm) cm(-1)/% hydrogen for the o- (ordinary-) polarized absorbance at 1.064 microm, and 45 +/- 7 ppm cm(-1)/% hydrogen for the e- (extraordinary) polarization. In addition, the KDP crystals we tested have residual (hydrogen-independent) o- and e-polarized absorbances of 958 +/- 228 ppm cm(-1) and 343 +/- 28 ppm cm(-1), respectively, whose origin is unknown. We also found that the crystal deuterium-hydrogen (D-H) ratio can be related to the D-H ratio of the growth solution by a simple ideal mixture model with a segregation coefficient of 0.684 +/- 0.044.

The identification of a new heterocyclic amine mutagen from a heated mixture of creatine, glutamic acid and glucose.

A new heterocyclic amine mutagen was isolated from a dry-heated reaction of the natural meat components creatine, glutamic acid and glucose. Heating creatine and glutamic acid alone had only one seventh of the Ames/Salmonella mutagenic activity of the glucose, creatine and glutamic acid mixture. The major mutagenic compound was purified by HPLC using the Ames/Salmonella test to guide the purification. The mutagen has a molecular weight of 244 and a composition of C12H12N4O2 as determined by high-resolution mass spectrometry. NMR and IR spectral data suggest the structure is a 2,6-diamino-3,4-dimethyl-7-oxo-pyrano[4,3-g]benzimidazole. Mutagenic activity in strains TA1538, TA98 and TA100, was approximately 7000, 5200, and 550 revertants per microgram, respectively. The formation of this mutagen from natural meat components suggests that it may be present in cooked food. The preferential formation of this mutagen with glucose shows that glucose can be important in dry-heated mutagen-forming reactions.

Peripheral venous monitoring with acute blood volume alteration: cuff-occluded rate of rise of peripheral venous pressure.

We investigated the use of a new peripheral hemodynamic monitoring technique, the cuff-occluded rate of rise of peripheral venous pressure (CORRP), in the assessment of volume status in fluid overload. Seven adult mongrel dogs were given a general anesthetic, and monitoring lines were inserted. The animals were then subjected to an incremental volume overload of approximately 13% of estimated initial blood volume at 5-min intervals until a total volume infusion nearly equal to the animal's initial blood volume was reached. Comparison of the various monitoring techniques (e.g., cardiac output, CVP, systemic BP, pulmonary wedge pressure) demonstrated that the peripheral measurement of CORRP had better correlation with known administered volume (r = .96) than any of the other variables. The sensitivity of each of the variables in assessing small amounts of volume overload was also studied. The volume of crystalloid infusion necessary to cause a clinically significant change (defined as greater than 2 SD above the baseline mean) was compared for each of the monitoring variables. CORRP was equivalent to the other variables in sensing early volume overload. In summary, in the anesthetized animal model CORRP appears to be a sensitive, minimally invasive method of assessing volume status in acute volume overload. The efficacy of CORRP in a canine hemorrhagic shock and reperfusion model had previously been demonstrated. This technique could be clinically applicable in situations such as trauma with hemorrhagic shock, intraoperative volume changes, and in the assessment of intravascular volume after resuscitation.

The metabolism of 4,8-DiMeIQx in conventional and germ-free rats.

The aromatic amine mutagen, [14C]2-amino-3,4-8-trimethyl-imidazo[4,5-f]quinoxaline (4,8-DiMeIQx), which is derived from cooked food, was administered to conventional and germ-free AGUS rats previously fed either a semi-synthetic diet containing the cytochrome P-450 inducer beta-naphthoflavone (BNF) or a control diet without BNF. The germ-free animals had longer fecal transit times and lower induction of 7-ethoxyresorufin-O-deethylase activity than conventional rats. Induction with BNF caused a greater percentage of the radioactivity to be excreted in the feces of both germ-free and conventional rats. Feeding BNF also caused a 4-fold induction in germ-free and a 24-fold induction in conventional rat intestinal enzyme levels. Analysis of the urinary and fecal metabolites showed no consistent differences between conventional and germ-free rats in the metabolite profile. Major metabolites were identified as 8-hydroxymethyl-DiMeIQx, N-acetyl-8-hydroxymethyl-DiMeIQx, and 3-N-dimethyl-4-hydroxy-methyl-DiMeIQx. The data from this study indicate that intestinal microflora do not play a major role in the metabolism of 4,8-DiMeIQx, but the induction of intestinal enzymes does not affect the route and rate of excretion.

Identification of the mutagenic quinoxaline isomers from fried ground beef.

Two mutagens isolated from fried-beef patties were compared to a series of synthetic structural isomers of 2-aminodimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-aminotrimethylimidao[4,5-f]quinoxaline (DiMeIQx). Comparison by NMR spectrometry and HPLC coelution showed that one beef mutagen (molecular weight of 213) was identical to the 8-MeIQx isomer not the 7-Me isomer. Another quinoxaline beef mutagen, having 3 methyl groups (molecular weight of 227), had an NMR spectrum different from the 5,8- or 7,8-DiMeIQx isomers, but not clearly distinguishable from the 4,8- or 4,7-DiMeIQx isomers. The HPLC separation of the DiMeIQx isomers and subsequent addition of the beef mutagen showed the beef-derived compound to coelute with the 4,8-DiMeIQx and not with the 4,7-DiMeIQx. The number and position of methyl groups was responsible for a 7-fold range of mutagenic response in the Ames/Salmonella assay. In conclusion, the major quinoxaline mutagens isolated from fried beef were identified as 8-MeIQx and 4,8-DiMeIQx isomers.

The isolation and identification of a new mutagen from fried ground beef: 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).

A new mutagenic compound has been isolated from ground beef which was fried at 300 degrees C for 5.5 min on each side. The new mutagen was purified using an aqueous acid extraction, XAD-2 adsorption-solvent elution, a series of preparative and analytical h.p.l.c. purification steps, and monitored with the Ames/Salmonella assay. This study reveals a new mutagen member of the amino-imidazoazaarene class of aromatic amines, having a mol. w of 224, and a formula of C13H12N4 as determined by high-resolution mass spectrometry. N.m.r. spectrometry supports the structure, 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP), for the new mutagen. The 1-methyl and 3-methyl synthesized isomers of PhIP were compared to the purified mutagen. The two isomers had identical mass spectra to the purified compound, but only the 1-methyl isomer showed similar u.v. and n.m.r. spectra. The two synthetic isomers were separable by h.p.l.c. and the beef derived component co-eluted with the 1-methyl-PhIP isomer. PhIP has a specific activity in the Ames/Salmonella assay of 1950 revertants/microgram. Although it is not as mutagenic as other compounds isolated from fried beef (e.g. MeIQx, 58 000 revertants/microgram) it is the most abundant mutagenic compound by mass in fried beef. PhIP is present at approximately 15 p.p.b. of the original weight of uncooked beef (accounting for 75% of the mass of genotoxic material) and contributes 18% of the total mutagenicity of the fried beef.