Serum levels of interferon-α and-γ in acute and chronic hepatitis B virus infection

To evaluate the potential implication ofin vivo interferon production in the pathogenesis of different forms of acute and chronic hepatitis B virus infection, serum levels of interferon- and- were measured using immunoassay techniques in 20 patients with acute hepatitis B who subsequently cleared the virus (group Ia), 8 patients with acute hepatitis B who became HBsAg carriers (group Ib), 55 patients with chronic hepatitis B (group II), and 15 healthy controls. None of the controls had interferon- or- detectable in serum, while 15% and 100% of group Ia patients, 25% and 100% of group Ib patients, and 22% and 15% of group II patients, had raised serum levels of interferon- and-, respectively. Serum interferon- was detected significantly more frequently in group Ia and Ib patients than in controls and in group II patients. Among patients with acute hepatitis B, serum levels of interferon- and- showed no significant difference between group Ia and group Ib patients. Among patients with chronic hepatitis B, interferon- was detected significantly more frequently in patients with serum HBV-DNA (31.4% or 11/35) than in those without (5% or 1/20), whereas interferon- was detected significantly more frequently in patients with chronic active hepatitis (28% or 7/25) than in those with chronic persistent hepatitis (3.3% or 1/30). In conclusion, in acute hepatitis B, serum levels of interferon- and- did not show a significant difference between patients who subsequently cleared the virus and those who became HBsAg carriers. In chronic hepatitis B, the raised serum levels of interferon- correlated with the presence of viral replication, while the raised serum levels of interferon- correlated with the presence of histological evidence of active hepatitis.     

Determination of flunarizine in rat brain by liquid chromatography-electrospray mass spectrometry

A rapid liquid chromatography-electrospray mass spectrometry (LC-ES-MS) assay for the determination of flunarizine (FZ) in rat brain has been developed. A C18 column and an isocratic elution were employed for the separation. Using post-column split, 64% of the eluent was introduced into the ES-MS system for detection. The [M+H]+ (m/z 406) and a fragmented ion (m/z 203) were detected using selected ion monitoring. The linear range of this assay was good, ranging from 0.05 to 5 microM (r2=0.99). The intra- and inter-day precisions showed relative standard deviations ranging from 1.4% to 2.0% and 1.3% to 2.9%, respectively. The application of this newly developed method was demonstrated by examining the pharmacokinetics of FZ in rat brain.     

Rhenium-188-Labeled DTPA: a new radiopharmaceutical for intravascular radiation therapy

Balloon angioplasty is a standard treatment for artherosclerotic coronary artery disease. However, its clinical value is reduced by a high restenosis rate. A new concept in preventing restenosis is the use of a liquid-filled balloon containing a beta-emitting radioisotope. In this study, we performed biodistribution studies of Re-188 perrhenate and Re-188 diethylenetriaminopentaacetate (DTPA) to assess the resulting organ dose values in the event of balloon rupture if these agents are used for the clinical inhibition of restenosis after percutaneous transluminal coronary angioplasty (PTCA). After injecting Re-188 preparations intravenously, rats were killed at 10 min, 30 min, 60 min, 2 h, and 6 h ( n =5 per group). Tissue concentrations were calculated and expressed as percent injected dose per gram or per milliliter (%ID/g or %ID/mL). In addition, urine excretion and thyroid gland uptake were evaluated in rats ( n=5 per group) with a gamma camera after administration of 37 MBq (1 mCi) of each agent. Our data showed that both agents were excreted primarily via urine. However, the excretion of Re-188 DTPA was much faster than that of Re-188 perrhenate via the urinary system. The biodistribution data revealed that radioactivity levels in the stomach and the thyroid gland were high in the perrhenate group but low in the Re-188 DTPA group. The concentration levels in other tissues including lung, liver, testis, muscle, and blood were low throughout this study for both agents. The thyroid radiation value in the Re-188 perrhenate group was 0.163 mGy/MBq, which was much higher than that of the Re-188 DTPA group (0.0167 mGy/MBq). The stomach radiation value was as high as 0.127 mGy/MBq for Re-188 perrhenate, compared with 0.013 mGy/MBq for Re-188 DTPA. In conclusion, in the event of balloon rupture, the release of Re-188 DTPA results in lower radiation doses than Re-188 perrhenate, especially to the thyroid gland and the stomach. Our data suggest that Re-188 DTPA is a useful radiopharmaceutical for endovascular irradiation.     

Design, synthesis, and biological evaluation of matrix metalloproteinase inhibitors derived from a modified proline scaffold

The synthesis and structure-activity relationship (SAR) studies of a series of proline-based matrix metalloproteinase inhibitors are described. The data reveal a remarkable potency enhancement in those compounds that contain an sp(2) center at the C-4 carbon of the ring relative to similar, saturated compounds. This effect was noted in compounds that contained a functionalized oxime moiety or an exomethylene at C-4, and the potencies were typically <10 nM for MMP-3 and <100 nM for MMP-1. Comparisons were then made against compounds with similar functionality where the C-4 carbon was reduced to sp(3) hybridization and the effect was typically an order of magnitude loss in potency. A comparison of compounds 14 and 34 exemplifies this observation. An X-ray structure was obtained for a stromelysin-inhibitor complex which provided insights into the SAR and selectivity trends observed within the series. In vitro intestinal permeability data for many compounds was also accumulated.     

Comparison of flomoxef with latamoxef in the treatment of sepsis and/or Gram-negative bacteremia in adult patients

The safety and efficacy of flomoxef and latamoxef were compared in the treatment of hospitalized patients with sepsis and/or Gram-negative bacteremia in a prospective, open-labelled clinical trial. Patients were randomized to receive 1 to 2 g intravenous doses of either flomoxef every 6 to 12 h, or latamoxef every 8 to 12 h. Data from 21 patients given flomoxef and 23 patients given latamoxef were included in the evaluation of efficacy. Flomoxef produced clinical cure and satisfactory microbiological responses in 85.7% and 100% of patients, respectively. These results were similar to those obtained with latamoxef (87% and 100%, respectively). In addition, no significant difference was found in mean age, sex, severity of infection, distribution of pathogens and focus of infection between the two groups. However, the flomoxef group included more patients with ultimately fatal diseases. Six patients given flomoxef and two patients given latamoxef developed superinfections caused by yeast, enterococci and Pseudomonas aeruginosa in the urinary tract. Mild and reversible adverse reactions probably related to flomoxef and latamoxef were noted in 14.3% and 13% of patients, respectively. The results of this study demonstrated that flomoxef is a safe and effective antimicrobial agent in the treatment of patients with sepsis and/or Gram-negative bacteremia.     

Maternal risk of breast cancer following multiple births: a nationwide study in Sweden

The association between multiple births and subsequent maternal breast cancer risk was explored in a nested case-control study in Sweden encompassing 19,368 parous women with breast cancer diagnosed up to age 65 years, and 100,459 parous controls. Among cases and controls, there were 329 and 2,031 women, respectively, with a history of at least one live multiple birth. Compared with singleton mothers, breast cancer risk was 12 percent lower (odds ratio=0.088, 95 percent confidence interval=0.78–0.99) in women who had had a multiple birth. After stratification for age at diagnosis, evidence of a significant inverse association was found only in women aged 54 years or younger. Birth order of the multiple pregnancy had no apparent risk-modifying effect. Age at earliest multiple birth was unrelated to breast cancer risk. The inverse association between twinning and breast cancer risk may reflect protective physiological features of twin pregnancies. Further research is needed to investigate the role, if any, of in creased levels of steroid hormone-binding globulins in mothers of twins and the proposed inhibitory effects of human chorionic gonadotropin and -fetoprotein, both of which are increased during multiple gestations, on breast carcinogenesis. Breast feeding patterns in mothers of twins also may modify their risk of developing breast cancer.Ambors are with the Department of Cancer Epidemiology (Drs Lambe Ekbom, Adami) and Department of Social Medicine (Lambe), University Hospital, Uppsala, Sweden: Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA (Drs Hsieb, Tsilib, Adami, Ekbom, Trichopoulos); UMASS Cancer Center, Worcester, MA, USA (Dr Hsieb). Address correspondece to Dr Lambe, Department of Cancer Epidemiology, University Hospital, S-751 85 Uppsala, Sweden. This project is funded by grants from the Swedish Cencer Societv. the Swedish Societv of Medicine. and the Wahlmarks Fund at Uppsala City Council.     

Doppler sonographic detection of reverse twin-twin transfusion after intrauterine death of the donor

We report a "stuck" twin, in which a reverse blood shunt from the recipient to the donor was detected by Doppler sonography after death of the donor. This acute reverse transfusion caused intrauterine fetal distress and severe neonatal anemia of the surviving recipient. We believe that acute hemodynamic change after death of one fetus, in addition to causing a derangement in coagulation, causes immediate danger or subsequent organ damage for the surviving co-twin.