Validation of a new patient-reported outcome instrument of health-related quality of life specific to patients with alcohol use disorder: the Alcohol Quality of Life Scale (AQoLS).

PURPOSE: The Alcohol Quality of Life Scale (AQoLS) is a new patient-reported outcome 34-item questionnaire measuring health-related quality of life (HRQOL), specific to patients with an alcohol use disorder, developed from the patients' perspective. This is the first report establishing evidence in support of measurement reliability and validity of the AQoLS. METHODS: A total of 285 randomly selected patients receiving interventions for alcohol use disorder in addiction specialised care settings in France were included in the study (response rate 80.1 %). Exploratory factor analysis was conducted to evaluate the hypothesised-during-development-stage dimensional structure of the AQoLS. Internal consistency of the total score and the dimensions subscores were assessed through Cronbach's alpha coefficients. Construct validity was tested through correlations with the Short-Form 36 Health Survey (SF-36) and EuroQol 5 dimensions (EQ-5D). RESULTS: Exploratory analysis indicated seven observed dimensions which differed slightly from the 7 dimensions defined a priori in the framework hypothesised during the scale development: activities, relationships, living conditions, negative emotions, self-esteem, control and sleep. A major common factor allows the summing of the 34 items to obtain a total score. All the 34 items were acceptable. Cronbach's alpha for the AQoLS total score was 0.96 and ranged from 0.8 to 0.9 for the dimensions subscores. Negative correlations between AQoLS and all dimensions of the SF-36, but general health and positive correlations between AQoLS and all items of the EQ-5D were shown. As expected, the correlations were mostly moderate in magnitude, low with scores referring to physical areas and the highest with the SF-36 MSC. CONCLUSION: This study provides evidence of the measure's psychometric properties in terms of construct validity and internal consistency. The "control" and "self-esteem" dimensions are of particular interest as these concepts are not captured in existing HRQOL. Further longitudinal validation of the scale is necessary to assess sensitivity to change.

Chromosomal patterns of diversity and differentiation in creepers: a next-gen phylogeographic investigation of Certhia americana.

With methods for sequencing thousands of loci for many individuals, phylogeographic studies have increased inferential power and the potential for applications to new questions. In songbirds, strong patterns of inter-chromosomal synteny, the published genome of a songbird and the ability to obtain thousands of genetic loci for many individuals permit the investigation of differentiation between and diversity within lineages across chromosomes. Here, we investigate patterns of differentiation and diversity in Certhia americana, a widespread North American songbird, using next-generation sequencing. Additionally, we reassess previous phylogeographic studies within the group. Based on ~30 million sequencing reads and more than 16,000 single-nucleotide polymorphisms in 41 individuals, we identified a strong positive relationship between genetic differentiation and chromosome size, with a negative relationship between genetic diversity and chromosome size. A combination of selection and drift may explain these patterns, although we found no evidence for selection. Because the observed genomic patterns are very similar between widespread, allopatric clades, it is unlikely that selective pressures would be so similar across such different ecological conditions. Alternatively, the accumulation of fixed differences between lineages and loss of genetic variation within lineages due to genetic drift alone may explain the observed patterns. Due to relatively higher recombination rates on smaller chromosomes, larger chromosomes would, on average, accumulate fixed differences between lineages and lose genetic variation within lineages faster, leading to the patterns observed here in C. americana.

The effect of delirium preventive measures on the occurrence of postoperative cognitive dysfunction in older adults undergoing cardiovascular surgery. The DelPOCD randomised controlled trial.

STUDY OBJECTIVE: This trial examines the effect of delirium preventive measures on the incidence of postoperative cognitive dysfunction in older adults. DESIGN: In a randomised approach, a delirium prevention and a standard care group were compared regarding manifestation of postoperative cognitive dysfunction at seven days, three and twelve months postoperatively (primary outcome). To correct for practice effects and age-depended cognitive decline, a control group of age-matched healthy subjects was included. SETTING: The trial was conducted at the University Medical Centre Hamburg between 2014 and 2018, data assessment took place in the Anaesthesia Outpatient Clinic and on the surgical ward. PATIENTS: A total of 609 patients ≥60 years scheduled for cardiovascular surgery were enrolled, allocated treatment was received by 284 patients in the delirium prevention and 274 patients in the standard care group. INTERVENTION: The intervention consisted of a delirium prevention bundle including reorientation measures, sleeping aids and early mobilisation. MEASUREMENTS: Cognitive functions were assessed via neuropsychological testing of attention, executive functions including word fluency, and verbal memory utilizing a computerised test of attentional performance, the trail making test, the digit span subtest from the Wechsler Adult Intelligence Scale-IV, the verbal learning and memory test, and the Regensburg Word Fluency Test. Assessments were performed preoperatively and at three time points postoperatively (one week, three months and 12 months). MAIN RESULTS: Postoperative cognitive dysfunction was defined as a clinically meaningful decline in at least two out of nine chosen test parameters compared to the preoperative level (reliable change index ≤ - 1.96). The rates of postoperative cognitive dysfunction were 25.9% (delirium prevention group, n = 284) vs. 28.1% (standard care group, n = 274) [X2(1,n = 433) = 0.245;p = 0.621] at postoperative day seven and declined to 7.8% vs. 6.8% [X2(1,n = 219) = 0.081;p = 0.775] and 1.3% vs. 5.6% (p = 0.215, Fisher's exact test) at three and 12 months following surgery, respectively. The postoperative delirium rates did not differ between the two groups (delirium prevention group: 13.4% vs. standard care group: 17.3%). Attentional performance was impaired shortly after surgery, whereas verbal delayed recall was most frequently affected over the whole postoperative period. CONCLUSION: These findings suggest that an intervention combining specific measures extracted from established postoperative delirium prevention programs did not reduce the rate of postoperative cognitive dysfunction in older adults.

Low doses of eriocitrin attenuate metabolic impairment of glucose and lipids in ongoing obesogenic diet in mice.

Eriocitrin is a citrus flavonoid with a high capacity to reduce the oxidative stress related to metabolic disorders and obesity. We assessed the effects of low doses of eriocitrin on the oxidative stress, inflammation, and metabolism of glucose and lipids of high-fat diet (HFD)-fed obese mice. Fifty male C57BL/6J mice were randomly assigned into five groups (n 10). The mice were fed an HFD (45 % kcal from fat, i.e. lard) for 4 weeks for obesity induction. After this period, the mice continued receiving the same HFD, but supplemented with eriocitrin at 10, 25 or 100 mg/kg body weight (bw) for an additional 4 weeks. Control groups were fed with standard diet (10 % kcal of fat, i.e. soy oil) or with HFD without eriocitrin, for eight consecutive weeks. At the end of the study, mice supplemented with eriocitrin showed lower levels of blood serum glucose and blood and liver triacylglycerols (P < 0⋅05). There was also improved levels of insulin, HOMA-IR, total-cholesterol, resistin and lipid peroxidation in the supplemented mice. It was concluded that the 25 mg dose of eriocitrin improved all the parameters studied and had positive effects on oxidative stress, systemic inflammation and metabolism of lipids and glucose in general.

Who receives treatment for alcohol use disorders in the European Union? A cross-sectional representative study in primary and specialized health care.

BACKGROUND: Alcohol use disorders (AUDs) are highly prevalent in Europe, but only a minority of those affected receive treatment. It is therefore important to identify factors that predict treatment in order to reframe strategies aimed at improving treatment rates. METHODS: Representative cross-sectional study with patients aged 18-64 from primary health care (PC, six European countries, n=8476, data collection 01/13-01/14) and from specialized health care (SC, eight European countries, n=1762, data collection 01/13-03/14). For descriptive purposes, six groups were distinguished, based on type of DSM-IV AUD and treatment setting. Treatment status (yes/no) for any treatment (model 1), and for SC treatment (model 2) were main outcome measures in logistic regression models. RESULTS: AUDs were prevalent in PC (12-month prevalence: 11.8%, 95% confidence interval (CI): 11.2-12.5%), with 17.6% receiving current treatment (95%CI: 15.3-19.9%). There were clear differences between the six groups regarding key variables from all five predictor domains. Prediction of any treatment (model 1) or SC treatment (model 2) was successful with high overall accuracy (both models: 95%), sufficient sensitivity (model 1: 79%/model 2: 76%) and high specificity (both models: 98%). The most predictive single variables were daily drinking level, anxiety, severity of mental distress, and number of inpatient nights during the last 6 months. CONCLUSIONS: Variables from four domains were highly predictive in identifying treatment for AUD, with SC treatment groups showing very high levels of social disintegration, drinking, comorbidity and functional losses. Earlier intervention and formal treatment for AUD in PC should be implemented to reduce these high levels of adverse outcomes.

Biological properties of citrus flavonoids pertaining to cancer and inflammation.

Citrus flavonoids encompass a diverse set of structures, including numerous flavanone and flavone O- and C-glycosides and methoxylated flavones. Each of these groups of compounds exhibits a number of in vitro and in vivo anti-inflammatory and anticancer actions. These biological properties are consistent with their effects on the microvascular endothelial tissue. Evidence suggests that the biological actions of the citrus flavonoids are possibly linked to their interactions with key regulatory enzymes involved in cell activation and receptor binding. The citrus flavonoids show little effect on normal, healthy cells, and thus typically exhibit remarkably low toxicity in animals. The citrus flavonoids extend their influence in vivo through their induction of hepatic phase I and II enzymes, and through the biological actions of their metabolites. Evidence clearly indicates to the potential health promoting properties of these dietary compounds.

Quantitative morphologic findings of the myocardium in idiopathic dilated cardiomyopathy.

This study assesses the relation between quantitative morphologic findings and left ventricular contractile function in patients with idiopathic dilated cardiomyopathy. Left ventricular endomyocardial catheter biopsy specimens were obtained from 73 patients during diagnostic heart catheterization. All patients had normal coronary arteriograms but abnormal electrocardiograms. Twenty-six patients had normal left ventricular function (ejection fraction greater than or equal to 55%), whereas 47 patients had contractile dysfunction (ejection fraction less than or equal to 54%). Myocardial fiber diameter, volume fraction of interstitial fibrosis, and intracellular volume fraction of myofibrils were determined by light microscopic morphometry. Results of light microscopic morphometry were confirmed by electron microscopic morphometry in 12 patients. The coefficient of variation (analysis of several biopsies from the same patient) was 6% for determination of fiber diameter, 43% for interstitial fibrosis, and 3% for volume fraction of myofibrils. Fiber diameter (r = -0.32, p less than 0.01) and fibrosis (r = -0.47, p less than 0.001) showed a negative correlation, the volume fraction of myofibrils (r = 0.55, p less than 0.001) and calculated myofibrillar mass per 100 g of myocardium (r = 0.64, p less than 0.001) a positive correlation with the ejection fraction. Thus, (1) sampling error is low for determination of fiber diameter and myofibrils but high for evaluation of fibrosis, and (2) a reduction in the volume fraction of myofibrils and an increase in fibrosis are morphologic correlates of left ventricular dysfunction in patients with idiopathic dilated cardiomyopathy.

Coronary dilatory capacity in idiopathic dilated cardiomyopathy: analysis of 16 patients.

Hemodynamic function and overall coronary blood flow (argon technique) were measured in 16 patients with idiopathic dilated cardiomyopathy (IDC) and in 12 patients without detectable heart disease (control subjects) referred for precordial pain. In patients with IDC, coronary blood flow was normal at rest (78 +/- 17 ml/100 g-min versus 78 +/- 9 in control subjects). During maximal inducible coronary vasodilation (dipyridamole, 0.5 mg/kg), coronary blood flow was significantly reduced (142 +/- 38 ml/100 g.min versus 301 +/- 64 in control subjects; p less than 0.001). Consequently, obtainable minimal coronary resistance was increased in IDC (0.54 +/- 0.20 mm Hg/ml/100 g.min versus 0.23 +/- 0.04 in control subjects; p less than 0.001). In patients with IDC, left ventricular (LV) end-diastolic pressure was significantly increased (19 +/- 11 mm Hg versus 6 +/- 3 in control subjects; p less than 0.005), and the LV ejection fraction was diminished (36 +/- 11% versus 72 +/- 3% in control subjects; p less than 0.001). In patients with IDC, LV end-diastolic pressure correlated significantly with the obtained minimal coronary resistance after application of dipyridamole (r = 0.85; p less than 0.001). LV catheter biopsy specimens revealed no alterations in myocardial microvasculature. Thus, coronary dilatory capacity is impaired in patients with IDC, due partially to an increase in extravascular component of coronary resistance.

Ramipril and captopril in patients with heart failure: effects on hemodynamics and vasoconstrictor systems.

Fifteen patients with congestive heart failure (New York Heart Association III) were randomly assigned to treatment with either captopril or ramipril, a newly developed angiotensin converting enzyme inhibitor. Both groups were similar with respect to baseline hemodynamic measurements and plasma levels of norepinephrine, renin and vasopressin. The group receiving ramipril showed hemodynamic changes comparable to the group receiving captopril on the seventh day of treatment. The stroke volume index increased by 20% versus 21%, respectively, and the total peripheral resistance decreased by 13% versus 20%, respectively. The decrease in blood pressure and the tendency to decrease heart rate were similar in both groups. All patients had reactive hyperreninemia during therapy with the converting enzyme inhibitor. The resting elevated plasma norepinephrine decreased in both groups significantly, whereas vasopressin did not change. The hemodynamic improvement was more pronounced and comparable in both groups during exercise. Thus, ramipril is equally effective compared with captopril in the treatment of patients with severe congestive heart failure.

Baroreceptor-mediated release of vasopressin in patients with chronic congestive heart failure and defective sympathetic responsiveness.

In patients with congestive heart failure (CHF), overactivity of the sympathetic nervous system may be accompanied by an impairment of the baroreflex control mechanism. To evaluate the reflex responses of the sympathetic nervous system, the renin-angiotensin system and vasopressin release to baroreceptor unloading, 38 patients with left ventricular dysfunction were studied. Hemodynamic data, and plasma norepinephrine, renin activity and vasopressin concentrations were measured before and 60 minutes after administration of high-dose hydralazine (0.4 mg/kg intravenously). On the basis of blood pressure response to vasodilator administration, patients were divided arbitrarily into those with a decrease in mean arterial blood pressure greater than or equal to 15 mm Hg (group A; n = 12) and those with a decrease less than 15 mm Hg (group B; n = 26) compared with control values. In response to hydralazine, heart rate decreased in group A from 100 to 92 beats/min (p less than 0.001) and increased in group B from 90 to 96 beats/min (p less than 0.05). In group A, hemodynamic changes induced by hydralazine were accompanied by a decrease in plasma norepinephrine from 822 to 518 pg/ml (p less than 0.01) and an increase in plasma vasopressin from 8.4 to 45.2 pg/ml (p less than 0.001). In group B, plasma norepinephrine and vasopressin did not change significantly (407 vs 447, and 8.4 vs 8.3 pg/ml, respectively). Plasma renin activity remained unchanged in group A and increased in group B (p less than 0.001). The data show that baroreceptor-mediated release of vasopressin is not impaired in patients with CHF and a defective sympathetic reflex control mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of successful thrombolytic therapy on right ventricular function in acute inferior wall myocardial infarction.

In 19 patients undergoing intracoronary fibrinolytic therapy for acute myocardial infarction, the site of coronary obstruction was in the proximal right coronary artery. Time between onset of symptoms and hospitalization was less than 4 hours. These patients were studied prospectively by radionuclide techniques immediately after admission, 48 hours and 4 weeks after AMI. Right and left ventricular (RV and LV) ejection fractions (EF) were calculated from gated blood pool scintigrams and the size of the LV perfusion defect was assessed by thallium-201 scintigraphy. Before the intervention, RV performance was significantly lower (RVEF 29 +/- 8%) than normal (53 +/- 7%). The size of the LV perfusion defect was relatively small (less than 25% of LV circumference), and as a consequence, LV pump function was only marginally impaired (LVEF 54 +/- 11%). Recanalization of the infarct artery was achieved in 12 patients (group A); in 7 patients the infarct artery remained occluded (group B). Early after the intervention (48 hours), RV performance in group A recovered significantly (RVEF: 30 +/- 9% vs 39 +/- 7%, p less than 0.01), and further improvement was noted at 4 weeks (RVEF 43 +/- 5%, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Intracoronary thrombolysis in acute myocardial infarction: an attempt to quantitate its effect by comparison of enzymatic estimate of myocardial necrosis with left ventricular ejection fraction.

The quantity of myocardium was estimated that can be salvaged by reperfusion of acute transmural myocardial infarction (MI). Serial analysis of serum creatine kinase (CK) activity was carried out in 41 consecutive patients with acute MI who underwent intracoronary thrombolysis. Enzymatic estimate of MI size was calculated using an average (method A) and an individually determined elimination constant (method B). Left ventricular ejection fraction 4 weeks after successful thrombolysis (cineangiogram) correlated inversely with MI size (method A: r = -0.85, method B: r = -0.76; both p less than 0.001). Patients with recanalization within 4 hours after the onset of symptoms were assembled in group A1 (n = 13, early reperfusion), and patients with successful recanalization after 4 hours in group A2 (n = 16, late reperfusion). Group B consisted of 12 patients without reperfusion. MI size in group A1 was 21 CK-g-Eq (method A) and 23 CK-g-Eq (method B), in group A2 50 CK-g-Eq (method A) and 54 CK-g-Eq (method B), and in group B 73 CK-g-Eq (method A) and 63 CK-g-Eq (method B). Mean values in group A1 were lower than in group A2 and group B (p less than 0.05). It is concluded that MI size was significantly reduced to about one third after early reperfusion as compared with no reperfusion. In contrast, MI size was not significantly reduced after late reperfusion.

Intracoronary thrombolysis in acute myocardial infarction: duration of ischemia as a major determinant of late results after recanalization.

To define the effect of duration of myocardial ischemia on the late results after successful thrombolysis in patients with acute transmural myocardial infarction, data on 39 patients treated with intracoronary infusion of streptokinase were analyzed. Patients with successful recanalization of infarct vessel and a time lag between onset of symptoms and reperfusion less than 4 hours were assembled in group A1 (n = 15), and patients with successful recanalization but a time lag of more than 4 hours (n = 17) in group A2. Group B consisted of 7 patients with unsuccessful thrombolysis. Coronary anatomy, left ventricular volume, ejection fraction, and regional ejection fraction of infarct area were determined before and 4 weeks after thrombolysis with cineangiography. Serum creatine kinase activity was serially measured. Before intervention, the groups were comparable with regard to age, Killip class, localization of infarction, incidence of previous infarction, Gensini score of coronary anatomy, left ventricular volume, ejection fraction, regional ejection fraction of infarct area, and serum creatine kinase activity. Four weeks after the intervention, patients in group A1 had a higher ejection fraction (59%) and regional ejection fraction of infarct area (39%) than patients in group A2 (ejection fraction: 49%, p less than 0.05; regional ejection fraction: 26%, p less than 0.05) and group B (ejection fraction: 44%, p less than 0.05; regional ejection fraction: 25%, p = 0.05). Peak serum creatine kinase activity measured during the acute illness was lower in group A1 (764 U/liter) than in group A2 (1,580 U/liter, p less than 0.05) and group B (2,106 U/liter, p less than 0.05). Thus, contraction of infarct area was improved and enzymatic estimate of infarct size was reduced after early as compared with late reperfusion in patients with acute myocardial infarction.

Acid-catalyzed hydrolysis of hesperidin at elevated temperatures.

Dilute sulfuric acid was used as a catalyst for hydrolysis of hesperidin suspensions in water at temperatures ranging from 25 to 180 degrees C. Significant acceleration of the reaction was observed at 120 degrees C and higher temperatures. This increase in the rate of hydrolysis can be attributed to increased solubilization of hesperidin in water at higher temperatures. Partial hydrolysis of hesperidin at 140 degrees C was used for the preparations of hesperetin-7-glucoside, which has a value in the synthesis of dihydrochalcone sweeteners. Simple separation of hesperetin and hesperetin-7-glucoside by extraction with dry acetone or lower alcohols has been developed.

Phenols in citrus peel byproducts. Concentrations of hydroxycinnamates and polymethoxylated flavones in citrus peel molasses.

In addition to the main flavanone glycosides (i.e., hesperidin and naringin) in citrus peel, polymethoxylated flavones and numerous hydroxycinnamates also occur and are major phenolic constituents of the molasses byproduct generated from fruit processing. Although a small number of the hydroxycinnamates in citrus occur as amides, most occur as esters and are susceptible to alkaline hydrolysis. This susceptibility to alkaline hydrolysis was used in measuring the concentrations of hydroxycinnamates in citrus peel molasses. The highest concentrations of hydroxycinnamates occurred in molasses of orange [C. sinensis (L.) Osbeck] and tangerine (C. reticulata Blanco.) compared to grapefruit (C. paradisi Macf.) and lemon [C. limon (L.) Burm.]. Concentrations of two phenolic glucosides, phlorin (phloroglucinol-beta-O-glucoside) and coniferin (coniferyl alcohol-4-beta-O-glucoside), were also measured. Measurements of the polymethoxylated flavones in molasses from several tangerine and orange varieties showed that these compounds occurred in the highest amounts in Dancy tangerine, whereas samples from two other tangerine molasses contained significantly lower levels, similar to those in the molasses samples from late- and early/mid-season oranges.

Purification and characterization of a beta-glucosidase from Citrus sinensis var. Valencia fruit tissue.

A preliminary survey demonstrated activity for alpha-D-glucosidase, alpha-D-mannosidase, alpha-L-arabinosidase, beta-D-glucosidase, beta-D-xylosidase, and beta-D-galactosidase in orange fruit flavedo and albedo tissue. alpha-L-Rhamnosidase was not detected. Subsequently, a beta-glucosidase was purified from mature fruit rag tissue (composed of intersegmental septa, squeezed juice sacs, and fruit core tissue) of Citrus sinensis var. Valencia. The beta-glucosidase exhibited low levels of activity against p-nitrophenyl-beta-D-fucopyranoside (13.5%) and p-nitrophenyl-alpha-D-glucopyranoside (7.0%), compared to its activity against p-nitrophenyl-beta-D-glucopyranoside (pNPG, 100%). The enzyme was purified by a combination of ion exchange (anion and cation) and gel filtration (Superdex and Toyopearl HW-55S) chromatography. It has an apparent molecular mass of 64 kDa by denaturing electrophoresis or 55 kDa by gel filtration chromatography (BioGel P-100). Hydrolysis of pNPG demonstrated a pH optimum between 4.5 and 5.5. At pH 5.0 the temperature optimum was 40 degrees C. At pH 5.0 and 40 degrees C the K(m) for pNPG was 0.1146 mM and it had a V(max) of 5.2792 nkatal x mg(-1) protein (katal = 0.06 International Units = the amount of enzyme that produces, under standard conditions, one micromol of product per min). Of the substrates tested, the enzyme was most active against the disaccharide cellobiose (1-->4), but was not active against p-nitrophenyl-beta-D-cellobioside. High levels of activity also were observed with the disaccharides laminaribiose (1-->3), gentiobiose (1-->6), and sophorose (1-->2). Activity greater than that observed with pNPG was obtained with the flavonoids hesperetin-7-glucoside and prunin (naringenin-7-glucoside), salicin, mandelonitrile-beta-D-glucoside (a cyanogenic substrate), and sinigrin (a glucosinolate). The enzyme was not active against amygdalin, coniferin, or limonin glucoside.

Purification of citrus peel juice and molasses.

Citrus peel juice and molasses are extremely bitter and unpalatable byproducts of orange and grapefruit juice production. Major components of interest are soluble sugars, glucose, fructose, and sucrose, which account for 60-70% of the dry solids. Analyses indicate that the remaining components are suspended tissue fragments, proteins, organic acids, mineral ions, phenolic compounds, and polyols. A purification sequence that removed a majority of bitter limonoids and phenolic compounds by adsorption on nonionic, macroporous resins was tested. Residual phenolic compounds were removed by adsorption on activated carbon or anion-exchange resin, which also removed anions of organic and inorganic acids. Taste panel results suggested that debittered products could be acceptable for food uses.

Genetic toxicity of a standardized mixture of citrus polymethoxylated flavones.

Flavonoids are a ubiquitous family of phytochemicals that display a variety of biological effects, both beneficial and adverse depending on the individual compound. Certain flavonoids are genotoxic while others inhibit the genotoxicity of other mutagens. In the present studies, the mutagenicity of a mixture of polymethoxylated flavones (PMFs) purified from citrus peel oil was evaluated. The mixture consisted of nobiletin (32.5%), 3,3',4',5,6,7,8-heptamethoxyflavone (25.0%), tangeretin (14.0%), trimethylscutellarein (9.1%), sinensetin (3.9%), 5-demethyl-nobiletin (2.8%), hexa-O-methylquercetagetin (3.3%), 5-demethyl-tetramethylscutellarein (0.7%), 5-hydroxy-3,3',4',6,7,8-hexamethoxyflavone (0.7%), and a small quantity of unidentified flavonoid compounds (3.9%). In vitro addition of the PMF mixture over a concentration range that spanned four log doses (0.0005-5.0 mg/plate) did not reveal any evidence of mutagenicity in five bacterial tester strains (Salmonella typhimurium TA98, TA100, TA102, TA1535 and TA1537) either in the absence or presence of S9 activation. The PMF mixture exhibited a statistically significant increase in mutagenicity of L5178Y tk(+/-) mouse lymphoma cells at 0.05 (38.5 x 10(-6); P<0.05) and 0.1 mg/ml (61 x 10(-6); P<0.01) compared with vehicle-treated controls (mutation frequency=19.7 x 10(-6)). However, these responses were within historical values observed in negative control cultures and extremely small compared to the positive control (EMS 0.5 microl/ml; 1685.3 x 10(-6)). Furthermore, in the presence of S9 there was no indication of genetic toxicity in L5178Y tk(+/-) cells. These results demonstrate that the PMF mixture is not genotoxic in in vitro assay systems.

Immunotoxicity of a standardized citrus polymethoxylated flavone extract.

Polymethoxylated flavones (PMFs) from citrus inhibit production of TNF-alpha and other pro-inflammatory cytokines. As TNF-alpha also modulates NK cell activity, the current studies were conducted to assess the potential for a standardized citrus PMF mixture to suppress humoral and innate immune functions. PMFs were isolated from orange peel oil using a procedure that obtained a consistent mixture of PMFs both in identity and proportion. The mixture consisted of nobiletin (30.7%), 3,3',4',5,6,7,8-heptamethoxyflavone (27.9%), trimethylscutellarein (14.5%), tangeretin (10.4%), sinensetin (5.8%), 5-demethyl-nobiletin (2.0%), hexa-O-methylquercetagetin (1.3%), 5-demethyl-tetramethylscutellarein (0.6%), and other flavonoids (2.7%). To assess the effect of the PMF mixture on humoral immune responses, female B(6)C(3)F(1) mice (n=8) were exposed to the PMF by gavage at 5, 50, 150 and 500 mg/kg/day for 28 days. On day 25, mice were sensitized to sRBC by tail vein injection and AFC response determined 4 days later. Humoral immunity was insensitive to suppression following exposure to all concentrations of the PMF mixture. Suppression of NK cell activity was observed only following 500 mg/kg/day for 28 days. Body weights were not affected by exposure to any concentration of the PMF mixture in sRBC immunized or non-immunized mice. However, in sRBC-immunized mice, higher concentrations of PMF were associated with a statistically insignificant increase in spleen weight (P>0.05). No change in spleen weight was observed in non-immunized mice. As anticipated, based on previously published in vitro observations, long-term, high-dose exposure to a standardized mixture of citrus PMFs caused a mild suppression of NK cell activity; however, humoral immunity was not sensitive to suppression at the same exposure levels.

Popliteal venous aneurysm with pulmonary and paradoxical embolization.

A 31-year-old woman was admitted with recurrent pulmonary emboli. The patient subsequently developed right sided hemiplegia. A mobile left atrial mass attached to the interatrial septum was detected and paradoxical embolization was assumed to be the underlying cause of the cerebral event. Leg phlebography and B-mode ultrasonographic imaging showed that the most probable source of embolization was a right popliteal venous aneurysm containing thrombi adherent to the vein wall. The immediate treatment was restricted to full dose heparin therapy and supportive measures. Thirteen days after admission, the aneurysm was excised. Recovery was rapid and the patient was discharged for further rehabilitation with an only minimal neurological deficit 3 weeks after admission.