Increased formation of distinct F2 isoprostanes in hypercholesterolemia

BACKGROUND: F2 isoprostanes are stable, free radical-catalyzed products of arachidonic acid that reflect lipid peroxidation in vivo. METHODS AND RESULTS: Specific assays were developed by use of mass spectrometry for the F2 isoprostanes iPF2alpha-III and iPF2alpha-VI and arachidonic acid (AA). Urinary excretion of the 2 F2 isoprostanes was significantly increased in hypercholesterolemic patients, whereas substrate AA in urine did not differ between the groups. iPF2alpha-III (pmol/mmol creatinine) was elevated (P<0.0005) in homozygous familial hypercholesterolemic (HFH) patients (85+/-5. 5; n=38) compared with age- and sex-matched normocholesterolemic control subjects (58+/-4.2; n=38), as were levels of iPF2alpha-VI (281+/-22 versus 175+/-13; P<0.0005). Serum cholesterol correlated with urinary iPF2alpha-III (r=0.41; P<0.02) and iPF2alpha-VI (r=0. 39; P<0.03) in HFH patients. Urinary excretion of iPF2alpha-III (81+/-10 versus 59+/-4; P<0.05) and iPF2alpha-VI (195+/-18 versus 149+/-20; P<0.05) was also increased in moderately hypercholesterolemic subjects (n=24) compared with their controls. Urinary excretion of iPF2alpha-III and iPF2alpha-VI was correlated (r=0.57; P<0.0001; n=106). LDL iPF2alpha-III levels (ng/mg arachidonate) were elevated (P<0.01) in HFH patients (0.32+/-0.08) compared with controls (0.09+/-0.02). The concentrations of iPF2-III in LDL and urine were significantly correlated (r=0.42; P<0.05) in HFH patients. CONCLUSIONS: Asymptomatic patients with moderate and severe hypercholesterolemia have evidence of oxidant stress in vivo.     

High-dose chemotherapy of metastatic breast carcinoma]

In order to evaluate satisfaction with, and recollection of, the consent process, we sent a postal questionnaire to 204 patients who had taken part in one of six clinical trials. Three trials were multicentre commercial studies and three were 'in house'. The readability of the different patient information sheets was compared. Seventy-seven per cent of patients responded, of whom 82% remembered having an information sheet. Most (99%) thought this was easy to read and understand. Five patients claimed that they had felt pressurised to take part in the trials. Nearly all patients (97%) realised that participation was voluntary and that other treatment would not be affected; 83% knew they could have changed their minds. There were no differences in the response patterns between the patients taking part in the different trials although the patient information sheets produced by pharmaceutical companies were longer and more complex than the 'in hospital' variety. We conclude that increasing the amount and complexity of information does not alter patient satisfaction. Taken overall, patients were content with the way they were approached when asked for consent for clinical trials.     

Group cognitive-behavioral treatment of binge eating disorder: a comparison of therapist-led versus self-help formats

A new enzymatic assay for selectively measuring conjugated bilirubin concentration in serum with use of bilirubin oxidase (BOD) has been developed. At pH 5.5 BOD can oxidize only conjugated bilirubin in the presence of reagents such as sodium fluoride and N-acetylcysteine which can decrease BOD reactivity to unconjugated bilirubin and bilirubin covalently bound to albumin (delta bilirubin). The resulting decrease in absorbance at 450 nm is linearly related to the concentration of conjugated bilirubin in serum. The BOD in this new assay was confirmed to oxidize conjugated bilirubin, and neither unconjugated nor delta bilirubin, based on both its reactivity to unconjugated bilirubin and HPLC results. This assay was found to give satisfactory results, such as in terms of the range of measurement, the reproducibility of the results, the lack of interference with coexisting substances in serum and the stability of the reagent solutions, in practical applications. The serum conjugated bilirubin concentrations determined using this assay correlate well with those determined by the HPLC analysis. This assay can be used for accurate monitoring of changes in the conjugated bilirubin concentration in patient sera. These findings suggest that the conjugated bilirubin assay is useful for fractional determination of bilirubin in icteric sera.     

Distribution of HIV type 1 (HIV-1) in blood components: detection and significance of high levels of HIV-1 associated with platelets

BACKGROUND: Although inactivation of enveloped viruses transmitted by plasma derivatives has been successful, no methods for virus inactivation or removal have been established for platelet concentrates or red cell (RBC) components. Relatively little is known regarding the extent or significance of virus interactions with the cellular constituents in these components. STUDY DESIGN AND METHODS: Units of whole blood were collected from six HIV type 1 (HIV-1)-positive, asymptomatic individuals and separated into peripheral blood mononuclear cells (PBMNCs), cell-free plasma, white cell-reduced platelet concentrate, and white cell-reduced RBCs. DNA and RNA polymerase chain reaction and virus culture methods were used to study the compartmentalization of HIV-1 immediately after component preparation and after storage. RESULTS: As expected, HIV DNA and infectious virus were detected in fresh blood and in PBMNCs, and virion-associated RNA was detected in fresh plasma from all six donors. The levels of viral nucleic acids in these preparations remained relatively stable with 4 degrees C storage, whereas infectivity of PBMNCs was rapidly lost. Washed RBCs tested negative for HIV in all assays at all time points. Platelets retained high levels of HIV RNA (but not infectivity) after extensive washing, as well as after storage at 4 and 22 degrees C. High-level platelet-associated HIV-1 was also demonstrated in samples collected during early seroconversion. Periseroconversion and postseroconversion levels of platelet-associated HIV-1 correlated with the level of plasma viremia and with the rate of progression to AIDS. Cell-free virus from donor plasma and tissue culture fluid rapidly and firmly attached to platelets from noninfected donors. Infectivity of tissue culture virus bound to platelets was demonstrated in vitro. CONCLUSION: Significant levels of HIV-1 are associated with platelets during all stages of infection. Platelet-associated HIV could either mediate virus clearance or facilitate virus dissemination and expanded tropism. Finally, virus inactivation research must address virus associations with platelets.     

Scaling of movement velocity: a measure of neuromotor retardation in individuals with psychopathology

The combination of ifosfamide, carboplatin and etoposide (modified ICE), was evaluated for its toxicity and activity in relapsed or refractory aggressive non-Hodgkin's lymphoma. Twenty patients, 14-69 years of age, with relapsed (19 cases) or refractory (one case) aggressive non-Hodgkin's lymphoma were treated with modified ICE therapy, consisting of ifosfamide 6 g/m2 (1.2 g/m2 day 1-5), carboplatin 400 mg/m2 (day 1) and etoposide 500 mg/m2 (100 mg/m2 day 1-5). The regimen was repeated at approximately 28-day intervals. All patients had undergone a doxorubicin-containing regimen before modified ICE therapy. Median total dose of previously received doxorubicin was 406 mg/m2 (range: 200-825 mg/m2). The median interval from diagnosis to modified ICE therapy was 9.4 months (range: 3.6-121 months). Two patients achieved CR and five achieved PR out of 16 patients with measurable lesions (response rate 43.8%; 95% confidence interval 19.0-68.6%). Median overall survival was 227 days (range: 41-552 days) from the start of modified ICE therapy. Myelosuppression was the most serious toxicity, namely 16 patients (80%) and 11 patients (55%) showed grade 4 neutropenia and grade 4 thrombocytopenia after the first course, respectively. Modified ICE therapy might be an active regimen with acceptable toxicity as a salvage chemotherapy in aggressive non-Hodgkin's lymphoma.     

Arterial blood pressure response to transient arousals from NREM sleep in nonapneic snorers with sleep fragmentation

STUDY OBJECTIVES: To assess the hemodynamic effects of graded arousals during nonrapid eye movement (NREM) sleep in patients with partial upper airway obstruction during sleep without obstructive sleep apnea/hypopnea, overnight beat-to-beat BP was recorded in six patients. SETTING: At the end of each nonapneic obstructive event, EEG responses were graded as follows: grade 2, grade 1, and grade 0 were defined as increased high-frequency EEG lasting >15 s, 3 to 15 s, and no EEG arousals according to the American Sleep Disorders Association, respectively. MEASUREMENTS AND RESULTS: The following were observed during grade 0, 1, and 2 EEG patterns (mean+/-SD): systolic pressure increased by 7.1+/-1.5, 11.7+/-1.9, and 14.2+/-3.4 (p<0.005), respectively; diastolic pressure increased by 4.6+/-0.6, 6.7+/-1.7, and 9.4+/-3.0 (p<0.005), respectively; heart rate increased by 2.9+/-0.4, 3.9+/-2.2, and 8.6+/-4.6 (p<0.005), respectively. CONCLUSIONS: We conclude that nonapneic-nonhypopneic obstructive events are followed by arterial systemic pressure increases whose magnitude varies with the grade of the arousal.     

Clinical case of the month. Metastatic endocarditis: clinical observation and review of the literature

The authors describe a case of metastatic endocarditis associated with a gastric carcinoma. The diagnosis was made early and the treatment by surgery and chemotherapy allowed a survival of 18 months, which is unusually long. The differential diagnosis is discussed and includes nonbacterial thrombotic endocarditis, infectious endocarditis and primary tumors of the heart.     

Vav regulates peptide-specific apoptosis in thymocytes

Homologies between vertebrate forebrain subdivisions are still uncertain. In particular the identification of homologs of the mammalian neocortex or the dorsal ventricular ridge (DVR) of birds and reptiles is still a matter of dispute. To get insight about the organization of the primordia of the main telencephalic subdivisions along the anteroposterior axis of the neural tube, a fate map of the dorsal prosencephalon was obtained in avian chimeras at the 8- to 9-somite stage. At this stage, the primordia of the pallium, DVR and striatum were located on the dorsal aspect of the prosencephalon and ordered caudorostrally along the longitudinal axis of the brain. Expression of homeobox-containing genes of the Emx, Dlx and Pax families were used as markers of anteroposterior developmental subdivisions of the forebrain in mouse, chick, turtle and frog. Their expression domains delineated three main telencephalic subdivisions in all species at the onset of neurogenesis: the pallial, intermediate and striatal neuroepithelial domains. The fate of the intermediate subdivisions diverged, however, between species at later stages of development. Homologies between forebrain subdivisions are proposed based on the conservation and divergence of these gene expression patterns.     

Cartilage destruction in small joints by rheumatoid arthritis: assessment of fat-suppressed three-dimensional gradient-echo MR pulse sequences in vitro

In this study the small-intestine phenotype in rat colonic tumors was investigated in terms of sucrase and intestinal-type alkaline phosphatase (I-ALP) activity. F344 rats were given intraperitoneal injections of methylazoxymethanol acetate at a dose level of 25 mg/kg body weight once a week for 8 weeks and were killed 40 weeks after the first injection. Sucrase and I-ALP activities in proximal and distal colon adenocarcinomas were significantly higher than those in the normal colon epithelium. In the jejunum, by contrast, normal tissue had significantly higher levels than tumors. Immunohistochemical staining of I-ALP was also strong in striated cell borders of colon adenocarcinoma cells. These data suggest that, whereas absorptive cells of the small intestine lose their own traits with tumor development, colonocytes acquire phenotypic features of the small intestine. Intestinal enzymes associated with the striated-cell border, such as sucrase and I-ALP, may be useful markers for malignant phenotypic expression in colonocytes.     

Effects of methyltestosterone on insulin secretion and sensitivity in women

The frequent coexistence of hyperandrogenism and insulin resistance is well established; however, whether a cause and effect relationship exists remains to be established. In this study we tested the hypothesis that short-term androgen administered to women would induce insulin resistance. To test this hypothesis, regularly menstruating, nonobese women were studied before and during methyltestosterone administration (5 mg tid for 10-12 days) by the hyperglycemic (n=8) and euglycemic, hyperinsulinemic (n=7) clamp techniques. Short-term methyltestosterone administration had no significant effects on the fasting levels of glucose, insulin, c-peptide, glucagon, or glucose turnover. During the hyperglycemic clamp studies, the mean glucose level during the final hour was 203+/-2 and 201+/-1 mg/dL in the methyltestosterone and control studies, respectively. The insulin response to this hyperglycemic challenge was slightly but not significantly greater during methyltestosterone treatment (first phase 59+/-8 vs. 50+/-8 microU/mL in controls; second phase 74+/-9 vs. 67+/-9 microU/mL in controls; total insulin response 133+/-16 vs. 117+/-15 microU/mL in controls). In spite of this, glucose uptake was reduced from the control study value of 10.96+/-1.11 to 7.3+/-0.70 mg/kg/min by methyltestosterone (P < 0.05). The ratio of glucose uptake per unit of insulin was also significantly reduced from a control study value of 14.3+/-1.4 to 9.4+/-1.3 mg/kg/min per microU/mL x 100 during methyltestosterone administration. In the euglycemic hyperinsulinemic clamp studies, insulin was infused at rates of 0.25 and 1.0 mU/kg/min to achieve insulin levels of approximately 25 and 68 microU/mL, respectively. During low-dose insulin infusion, rates of endogenous hepatic glucose production were equivalently suppressed from basal values of 2.37+/-0.29 and 2.40+/-0.27 mg/kg/min to 0.88+/-0.25 and 0.77+/-0.26 mg/kg/min in the methyltestesterone and control studies respectively. Whole body glucose uptake during low-dose insulin infusion was minimally affected. During the high-dose insulin infusion, endogenous hepatic glucose production was nearly totally suppressed in both groups. However, whole body glucose uptake was reduced from the control value of 6.11+/-0.49 mg/kg/min to 4.93+/-0.44 mg/kg/min during methyltestosterone administration (P < 0.05). Our data demonstrate that androgen excess leads to the development of insulin resistance during both hyperglycemic and euglycemic hyperinsulinemia. These findings provide direct evidence for a relationship between hyperandrogenemia and insulin resistance, and its associated risk factors for cardiovascular disease.