Thermal and impact histories of 25143 Itokawa recorded in Hayabusa particles.

Understanding the origin and evolution of near-Earth asteroids (NEAs) is an issue of scientific interest and practical importance because NEAs are potentially hazardous to the Earth. However, when and how NEAs formed and their evolutionary history remain enigmas. Here, we report the U-Pb systematics of Itokawa particles for the first time. Ion microprobe analyses of seven phosphate grains from a single particle provide an isochron age of 4.64 ± 0.18 billion years (1σ). This ancient phosphate age is thought to represent the thermal metamorphism of Itokawa's parent body, which is identical to that of typical LL chondrites. In addition, the incorporation of other particles suggests that a significant shock event might have occurred 1.51 ± 0.85 billion years ago (1σ), which is significantly different from the shock ages of 4.2 billion years of the majority of shocked LL chondrites and similar to that of the Chelyabinsk meteorite. Combining these data with recent Ar-Ar studies on particles from a different landing site, we conclude that a globally intense impact, possibly a catastrophic event, occurred ca. 1.4 Ga ago. This conclusion enables us to establish constraints on the timescale of asteroid disruption frequency, the validity of the crater chronology and the mean lifetime of small NEAs.

Impact of symptomatic skeletal events on health-care resource utilization and quality of life among patients with castration-resistant prostate cancer and bone metastases.

BACKGROUND: Data regarding the impact of symptomatic skeletal events (SSEs) on health economics and patient-reported outcomes in men with castration-resistant prostate cancer (CRPC) and bone metastases from a clinical setting are lacking. Hence, this study aimed to quantify the effects of SSEs on health-care resource utilization (HRU), health-related quality of life (HRQoL) and pain in men with CRPC metastasized to bone. METHODS: This cohort study included men with CRPC and bone metastasis treated at a tertiary center during December 1996-July 2015. SSEs, including pathological fracture, radiation to bone, spinal cord compression and bone surgery, as well as HRU were identified retrospectively through medical records and clinical database. A subset of surviving patients completed Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Brief Pain Inventory-Short Form (BPI-SF) questionnaires. The incremental effect of SSEs on HRU was evaluated using multivariable generalized linear regression. Questionnaire scores were compared using effect sizes (ES); ES⩾0.33 indicated meaningful differences between SSE and non-SSE cohorts. Lower scores suggest lower HRQoL and pain. RESULTS: Of the 832 patients, 207 developed ⩾1 SSE (mean 1.5±0.8) during follow-up (median 2.1 years). Radiation to bone was the most common SSE (84.1%). SSE cohort had significantly higher emergency room (incidence rate ratio (IRR)=1.48; P=0.006), outpatient (IRR=1.17; P=0.005) and inpatient (IRR=1.74; P<0.001) visits. Of the 107 eligible survey patients, 103 (96.3%) responded. SSE cohort had lower mean FACT-P functional well-being (17.5 vs 19.8; P=0.158; ES=0.36), higher mean pain severity (2.5 vs 1.6; P=0.048; ES=0.47) and worst pain scores (3.6 vs 2.3; P=0.033; ES=0.50) compared with the non-SSE cohort, indicating meaningful differences between cohorts. CONCLUSIONS: This study demonstrated high economic and HRQoL burden of SSEs. The findings underscore the need for better supportive and disease-modifying treatments for these patients.

Predictors of duration of abiraterone acetate in men with castration-resistant prostate cancer.

BACKGROUND: Androgen receptor signaling remains important in castration-resistant prostate cancer (CRPC) as demonstrated by the efficacy of abiraterone acetate (henceforth abiraterone) in phase III trials. Given that heterogeneous patient responses are observed, we sought to identify clinical factors associated with duration of abiraterone. METHODS: We retrospectively identified patients with CRPC treated with abiraterone in our database. Patient characteristics and types and duration of prostate cancer (PC) therapies were analyzed. These parameters were analyzed with duration of abiraterone in univariate and multivariable analyses. RESULTS: We identified 161 patients who had received abiraterone. All had received primary androgen-deprivation therapy (ADT), 86% prior secondary hormone therapy (SHT) and 33% prior chemotherapy. The median duration of primary ADT was 23 months, duration of SHT (excluding abiraterone) was 17 months and duration of chemotherapy was 8 months. We demonstrated that lower PSA at abiraterone initiation, longer primary ADT duration, no prior ketoconazole, no prior chemotherapy and longer chemotherapy duration were associated with a longer duration on abiraterone in univariate analysis. In multivariable analysis, duration of primary ADT (duration of abiraterone 9 versus 13 months for ⩽12 versus >12 months, P=0.03) and no use of prior chemotherapy (duration of abiraterone 16 versus 7 months for no versus yes prior chemotherapy, P<0.01) were associated with duration of abiraterone. CONCLUSIONS: Several clinical parameters, including type and duration of prior therapy, are predictive of responsiveness to abiraterone. These parameters are logical and correlate with smaller disease burden or less exposure to PC therapies. This information can help physicians counsel patients about the potential durability of efficacy of abiraterone. Identifying predictive biomarkers that inform patient selection for therapy is critical to optimizing treatment outcomes.

Analysis of the correlation between endorectal MRI response to neoadjuvant chemotherapy and biochemical recurrence in patients with high-risk localized prostate cancer.

BACKGROUND: Intermediate end points are desirable to expedite the integration of neoadjuvant systemic therapy into the treatment strategy for high-risk localized prostate cancer. Endorectal magnetic resonance imaging at 1.5 Tesla (1.5T erMRI) response has been utilized as an end point in neoadjuvant trials but has not been correlated with clinical outcomes. METHODS: Data were pooled from two trials exploring neoadjuvant chemotherapy in high-risk localized prostate cancer. Trial 1 explored docetaxel for 6 months and Trial 2 explored docetaxel plus bevacizumab for 4.5 months, both before radical prostatectomy. erMRI was done at baseline and end of chemotherapy. 1.5T erMRI response, based upon T2W sequences, was recorded. Multivariable Cox regression was undertaken to evaluate the association between clinical parameters and biochemical recurrence. RESULTS: There were 53 evaluable patients in the combined analysis: 20 (33%) achieved a PSA response, 16 (27%) achieved an erMRI partial response and 24 (40%) achieved an erMRI minor response. Median follow-up was 4.2 years, and 33 of 53 evaluable (62%) patients developed biochemical recurrence. On multivariable analysis, PSA response did not correlate with biochemical recurrence (hazard ratio=0.58, 95% confidence interval (CI) 0.25-1.33) and paradoxically erMRI response was associated with a significantly shorter time to biochemical recurrence (hazard ratio=2.47, 95% CI 1.00-6.13). CONCLUSIONS: Response by 1.5T erMRI does not correlate with a decreased likelihood of biochemical recurrence in patients with high-risk localized prostate cancer treated with neoadjuvant docetaxel and may be associated with inferior outcomes. These data do not support the use of 1.5T erMRI response as a primary end point in neoadjuvant chemotherapy trials.

A mathematical model for predicting outcome in preterm labour.

OBJECTIVE: This study aimed to develop a model for predicting the outcome and evaluating the treatment of patients with threatened of preterm labour. METHODS: Clinical data from 236 patients at <32 weeks gestation who were in preterm labour were analysed to develop a discriminant function using multiple logistic regression to identify significant risk factors. The function was validated retrospectively in a further 501 patients and prospectively in 63 patients with premature labour. RESULTS: Factors that increased the risk of preterm birth were premature rupture of the membranes, intrauterine infection, dilatation of the cervix and uterine bleeding. Factors that decreased the risk of preterm birth were hospital admission after 28 weeks of gestation and intravenous administration of ritodrine. The predictive accuracy of the function was 75.4% in the 236 patients analysed, 84.8% in the further 501 retrospectively studied patients and 85.7% in the prospective group. CONCLUSIONS: The discriminant function described was clinically useful for predicting the outcome of threatened preterm labour before initiating treatment and for determining the medical care of patients, including maternal transfer to a high-level perinatal care centre.

Endovascular surgery as the first-choice treatment for ruptured cerebral aneurysms: how far has it come?

SUMMARY: One hundred and seventy patients with ruptured cerebral aneurysms were treated by coil embolization from September 1997 to December 2002. After January 2000, coil embolization was selected as the first-choice treatment for ruptured aneurysms. During this period, the authors investigated the number of aborted cases, the number of complications, and how many patients could be treated by coil embolization according to the locations of ruptured cerebral aneurysms. One hundred and ninety-five sessions were performed on 170 patients, and 13 sessions (6.7%) were aborted mainly because of the difficulty of the approach and the wide necks of the aneurysms. In four patients, although procedural perforation and haemorrhage occurred, the outcome was good or excellent. Eight poorgrade patients experienced haemorrhage after coil embolization and seven patients died. The volume embolization ratios of small and large aneurysms were 27% and 21%, and the recanalization of small and large aneurysms occurred in 9% and 38% of patients, respectively. From January 2000 to December 2002, 119 (66%) of 180 ruptured cerebral aneurysms were treated by coil embolization. According to the location of aneurysms, 89% vertebrobasilar, 87% anterior cerebral, 65% internal carotid and 24% middle cerebral artery aneurysms could be treated by coil embolization. Because the tight packing of large aneurysms was difficult, the recanalization rate of large aneurysms was high. However, the results of small aneurysms were satisfactory. Almost 90% of vertebrobasilar and anterior cerebral artery aneurysms could be treated by coil embolization.

HGF/NK4 inhibited VEGF-induced angiogenesis in in vitro cultured endothelial cells and in vivo rabbit model.

AIMS/HYPOTHESIS: As vascular endothelial growth factor (VEGF) plays a pivotal role in the development of diabetic retinopathy, inhibition of angiogenesis induced by VEGF is crucial to treat diabetic retinopathy. HGF (hepatocyte growth factor)/NK4, containing the N-terminal hairpin domain and the four subsequent kringle domains of HGF, is considered as a specific antagonist for HGF. Our aim was to explore the inhibitory effects of HGF/NK4 on angiogenesis induced by VEGF. METHODS: To analyze the in vivo angiogenesis, we used rabbit corneal micropocket assay. Proliferation and migration of human endothelial cells, expression of ets-1, an essential transcription factor for angiogenesis, and the phosphorylation of extracellular signal-regulated kinase (ERK) was examined with or without HGF/NK4. RESULTS: Using corneal micropocket assay, in vivo administration of HGF/NK4 inhibited angiogenesis induced by VEGF. HGF/NK4 inhibited proliferation and migration of human endothelial cells induced by VEGF in a dose-dependent manner. Interestingly, VEGF-mediated phosphorylation of ERK was significantly attenuated by HGF/NK4. Of importance, HGF/NK4 attenuated the increase in ets-1 protein stimulated by VEGF. Nevertheless, HGF/NK4 did not affect phosphorylation of VEGF receptor-2 [kinase domain region (KDR)/foetal liver kinase (Flk)-1]. Although tyrosine phosphatase inhibitor (Na(3)VO(4)), or okadaic acid, serine-threonin kinase inhibitor, did not prevent the inhibition of ERK phosphorylation by HGF/NK4, co-incubation of HGF/NK4 with VEGF significantly diminished mitogen-activated protein (MAP) ERK kinase (MEK) phosphorylation (p<0.01). CONCLUSIONS/INTERPRETATION: Overall, HGF/NK4 inhibited angiogenesis induced by VEGF through inhibition of phosphorylation of ERK and ets-1 expression in in vitro cultured endothelial cells and in vivo rabbit model.

Treatment of asthma patients with herbal medicine TJ-96: a randomized controlled trial.

Alternative medicine use has increased at a remarkable pace all over the world in recent years. Although herbal medicine for the treatment of asthma is becoming the focus of public attention, randomized studies had not been performed, even in Eastern countries including Japan. This study was designed to investigate whether one of the Japanese government approved herbal complexes Saiboku-to (TJ-96) is effective for the treatment of atopic asthma, and to investigate whether this protective activity is associated with a reduction in eosinophilic inflammation. A double-blind, randomized, crossover design was used. Subjects received 2.5 g of TJ-96 or placebo orally 3 times daily for 4 weeks and then, after a washout period of at least 4 weeks, crossed over to receive the alternative treatment. We assessed the effects of pretreatment with TJ-96 on bronchoconstriction precipitated by inhalation of methacholine. Furthermore, eosinophil counts and measurement of eosinophilic cationic protein (ECP) were performed. After 4 weeks of treatment with TJ-96, values of PC20 -methacholine significantly improved in the treatment with TJ-96. Also, patients' symptoms, blood eosinophils, serum ECP, sputum eosinophils, and sputum ECP were significantly decreased. Our results suggest that TJ-96 has an antiinflammatory effect on bronchial eosinophilic infiltration. This study raises further interesting therapeutic possibilities and argues for further trials of new approaches to the treatment of asthma.

Immediate prediction of recovery of consciousness after cardiac arrest.

OBJECTIVE: Short-latency somatosensory evoked potential (SSEP) monitoring has been reported to be useful in predicting neurological outcome in patients with cardiac arrest and hypoxic-ischemic encephalopathy. To obtain the immediate data of SSEP and evaluate the relationship between the presence of cortical activity and the recovery of consciousness, SSEP was recorded immediately after return of spontaneous circulation. DESIGN AND SETTING: Prospective observational study in an intensive care unit of a university general hospital. PATIENTS: The study included 30 patients resuscitated from out-of-hospital cardiac arrest. INTERVENTIONS: Basic and advanced cardiac life support, and intensive care. MEASUREMENTS AND RESULTS: SSEP were recorded between 40 and 170 min (median 65) after spontaneous circulation returned. In the initial study all 30 patients showed the Erb's point potential and the N11-13 component, while only 12 (40%) showed cortical activity. Patients were assessed neurologically for recovery of consciousness until 1 month after cardiac arrest. Of 12 these patients 8 recovered consciousness within 10 days, while all patients without cortical activity died without opening their eyes. CONCLUSION: Even immediately following resuscitation, absence of cortical activity in SSEP indicates unlikelihood of recovering consciousness, while the preservation of such activity suggests that consciousness is improved. The result promises further accumulation of patients to validate the predictive ability of SSEP in managing postresuscitated patients.

Cromolyn sodium suppresses eosinophilic inflammation in patients with aspirin-intolerant asthma.

BACKGROUND: Although administration of cromolyn sodium is one of the most useful drugs for the treatment of aspirin-intolerant asthma (AIA), both its pharmacologic mechanism of action and association with the pathogenesis remain obscure. OBJECTIVE: This study was designed to investigate the protective effect of cromolyn sodium on airway responsiveness to the sulpyrine provocation test, and to examine whether its activity is associated with a reduction in eosinophilic inflammation. METHODS: Patients were randomly assigned to receive cromolyn sodium (20 mg/2 mL, or 1 ampoule; Fujisawa, Osaka, Japan) or matching placebo (2 mL of saline) four times daily for 1 week. We evaluated the effects of pretreatment with cromolyn sodium on bronchoconstriction precipitated by inhalation of sulpyrine in 16 adult patients with mild or moderate AIA; those who were in stable clinical condition were allocated to this study. A double-blind, randomized, crossover design was used. Blood and sputum samples were taken in the morning on the sulpyrine provocation testing day. Eosinophil counting and measurement of eosinophilic cationic protein (ECP) were performed. RESULTS: Inhaled cromolyn sodium protect against aspirin-induced attacks of asthma through mechanisms not related to the bronchodilator property, but related to the improvement of the bronchial hypersensitivity, almost completely in all patients (P < 0.001). After 1 week's treatment with cromolyn sodium, patients' symptoms, blood and sputum eosinophils counts, and sputum ECP levels were significantly decreased compared with both placebo and baseline. CONCLUSIONS: Cromolyn sodium has a bronchial anti-inflammatory effect associated with decreased eosinophilic infiltration. This is the first report that cromolyn sodium reduces blood and sputum eosinophils counts and sputum ECP levels in AIA.

Endothelial apoptosis induced by oxidative stress through activation of NF-kappaB: antiapoptotic effect of antioxidant agents on endothelial cells.

Injury of endothelial cells has been assumed to be an initial trigger of the development of atherosclerosis. In this study, we investigated the molecular mechanisms of endothelial cell death induced by hypoxia, which leads to oxidative stress. To study the relation between hypoxia-induced cell death and activation of nuclear factor-kappaB (NF-kappaB) in a hypoxic state, we evaluated the effect of 2 antioxidant drugs, probucol and pyrrolidine dithiocarbamate (PDTC), on human endothelial apoptosis. Although hypoxic treatment of human aortic endothelial cells resulted in a significant decrease in cell number and a significant increase in apoptotic cells compared with that of cells under normoxia (P<0.01), treatment with probucol (50 micromol/L) or PDTC (100 micromol/L) significantly attenuated the decrease in cell number (P<0.01) and was accompanied by inhibition of NF-kappaB activation. Furthermore, downregulation of bcl-2 caused by hypoxia was inhibited by these drugs. We further investigated the translocation of bax protein from the cytoplasm to the mitochondrial heavy fraction membrane, as translocation of bax protein is considered to be a determinant of apoptosis. Interestingly, we found that antioxidant treatment inhibited the translocation of bax protein caused by hypoxia. Moreover, upregulation of p53, a proapoptotic molecule, was observed in hypoxia, whereas treatment with probucol attenuated the expression of p53 accompanied by suppression of NF-kappaB activation. These data suggest functional links between p53 and endothelial apoptosis through the activation of NF-kappaB. Overall, the current study demonstrated that oxidative stress induced apoptosis in human aortic endothelial cells through the downregulation of bcl-2, translocation of bax, and upregulation of p53, probably through NF-kappaB activation. Oxidative stress may play an important role in endothelial apoptosis mediated by hypoxia, through the activation of NF-kappaB.

Possible relevance of virus infection for development of analgesic idiosyncrasy.

Although it has been hypothesized that analgesic idiosyncrasy could be acquired by viral infection, there is no evidence that any virus can cause sporadic cases of aspirin-intolerant asthma. We report a case, which points to the possible relevance of herpes simplex virus (HSV) infection for development of analgesic idiosyncrasy. We examined the patient to evaluate whether analgesic idiosyncrasy might have been acquired by viral infection. Sulpyrine provocation testing was performed to confirm the patient's development of analgesic idiosyncrasy and methacholine provocation testing was performed to assess bronchial hyperresponsiveness. The titer of anti-HSV IgG antibody was measured to confirm viral infection. Sulpyrine provocation testing revealed that hypersensitivity to analgesics had appeared in this patient. In contrast, the marked improvement of her bronchial hyperresponsiveness was confirmed by a PC(20) methacholine of 0.63 mg/ml 1 week after sulpyrine provocation testing. The anti-HSV IgG antibody confirmed recent HSV infection. To the best of our knowledge, this is the first reported case of acquired analgesic idiosyncrasy following HSV infection.

Ischemic hypertension of pigeon eye.

PURPOSE: To determine the etiology of open-angle glaucoma in human eyes, we tested the hypothesis that ischemia of the endothelial cells lining Schlemm's canal alters the intraocular pressure (IOP) by affecting the transport of fluids out of the eye. METHODS: Experiments were conducted on pigeons. After blocking the two major arteries to the aqueous sinus artery of one eye by laser photocoagulation, the episcleral arteries of both eyes were cauterized. The IOP was measured with a Mentor pneumatonometer before, immediately, and several days after blocking the major arteries. RESULTS: After the episcleral cauterization, the IOP of the laser-treated eye rose significantly and was maintained for at least 3 hours. By day 2, the IOP had recovered to the pre-cauterization level. The IOP of the control eye remained unchanged throughout the experiment. CONCLUSION: These results strongly support the hypothesis that ischemia of the endothelial cells lining Schlemm's canal plays a role in the control of the IOP.

Inhibition of experimental choroidal neovascularization by overexpression of tissue inhibitor of metalloproteinases-3 in retinal pigment epithelium cells.

PURPOSE: To evaluate the feasibility of introducing exogenous tissue inhibitor of metalloproteinases-3 gene into the rat retinal pigment epithelium using hemagglutinating virus of Japan liposomes and to assess the effect of tissue inhibitor of metalloproteinases-3 overexpression in retinal pigment epithelium cells on the formation of experimental choroidal neovascularization. METHODS: Hemagglutinating virus of Japan liposomes containing hemagglutin epitope-tagged tissue inhibitor of metalloproteinases-3 gene were injected into the subretinal space in rat eyes. Localization of oligonucleotides was evaluated by fluorescence microscopy. Exogenous tissue inhibitor of metalloproteinases-3 mRNA expression was assessed by reverse transcribed polymerase chain reaction. Exogenous tissue inhibitor of metalloproteinases-3 protein expression was visualized by immunostaining with monoclonal antibody 12CA5 against the hemagglutin epitope. Three days after transfection of tissue inhibitor of metalloproteinases-3 gene into retinal pigment epithelium cells, intense laser photocoagulation was performed and the incidence of choroidal neovascularization was assessed by fluorescein fundus angiography. RESULTS: Exogenous tissue inhibitor of metalloproteinases-3 mRNA expression in the choroid and retina was detected on day 3. The efficiency of tissue inhibitor of metalloproteinases-3 gene transfection into retinal pigment epithelium cells was greatest on day 7 and decreased gradually thereafter. The incidence of choroidal neovascularization in tissue inhibitor of metalloproteinases-3 gene-transfected eyes was markedly decreased compared with controls. CONCLUSIONS: This study shows that tissue inhibitor of metalloproteinases-3 gene can be transferred into rat retinal pigment epithelium using the hemagglutinating virus of Japan-liposome method and that tissue inhibitor of metalloproteinases-3 gene overexpression can inhibit development of experimental choroidal neovascularization. This method may represent a future treatment modality for human macular degeneration associated with choroidal neovascularization.

Antithrombin therapy for severe preeclampsia: results of a double-blind, randomized, placebo-controlled trial. BI51.017 Study Group.

A double-blind, randomized, placebo-controlled trial was conducted to evaluate whether treatment with Antithrombin (AT) concentrates improved the clinical and perinatal outcome in patients with severe preeclampsia. Severe preeclamptic patients (24 to 35 weeks of gestation. Gestosis Index (GI) > or = 6 points) were randomized into two groups: 66 received AT and 67 received placebo. There were no statistical differences in the clinical profiles of the two groups. Study drugs were given intravenously once daily for 7 consecutive days. Maternal symptoms were evaluated from the difference of GI between before and after treatment, and fetal findings were evaluated from the changes of the biophysical profile score and the estimated fetal weight gain. Improvement was significantly greater in the AT group for both the GI (p = 0.020) and the estimated fetal weight gain (p = 0.029). The improvement of coagulation parameters was also evaluated. The D-dimer levels increased significantly in the placebo group (p = 0.026), but did not change in the AT group. Gestation was significantly prolonged (p = 0.007), and the number of low-birth weight infants was significantly smaller (p = 0.011) in the AT group. No adverse events related to AT were observed. It is revealed that AT concentrate therapy for preeclampsia is effective and safe, leading to an improved perinatal outcome.

Effect of pranlukast on bronchial inflammation in patients with asthma.

BACKGROUND: Pranlukast (8-[p-(4-phenylbutyloxy) benzol] amino-2-[tetrazol-5-yl]-4-oxo-4H-1-benzopyran hemihydrate), a selective cysteinyl leukotriene receptor antagonist, has been reported to exhibit not only antileukotrine activity but also pharmacological activity including antieosinophilic effects. OBJECTIVE: This study was designed to investigate whether the antiasthmatic activity of pranlukast is associated with a reduction in eosinophilic inflammation. METHODS: A double-blind, randomized, crossover design was used. Subjects received 225 mg of pranlukast or placebo orally twice daily for 4 weeks and then, after a washout period of at least 4 weeks, crossed over to receive the alternative treatment. We assessed the effects of pretreatment with pranlukast on bronchoconstriction precipitated by inhalation of methacholine in 32 adult patients with mild or moderate bronchial asthma; those who were in stable clinical condition were allocated to this study. Blood and sputum samples were taken the morning of the methacholine provocation test. Eosinophil counts and measurement of eosinophilic cationic protein (ECP) were performed. RESULTS: After the 4 weeks of treatment with pranlukast, patients' symptoms, blood eosinophils, serum ECP, sputum eosinophils, and sputum ECP were significantly decreased. Furthermore, values of PC20-methacholine significantly improved in the treatment with pranlukast. CONCLUSION: Our results suggest that pranlukast has an anti-inflammatory effect on bronchial eosinophilic infiltration. This study raises further interesting therapeutic possibilities and argues for further trials of new approaches to the treatment of bronchial asthma.

Clarithromycin suppresses bronchial hyperresponsiveness associated with eosinophilic inflammation in patients with asthma.

BACKGROUND: Although long-term administration of 14-membered macrolide antibiotics is a therapeutic alternative in asthma, both its pharmacologic mechanism of action and association with the pathogenesis of asthma remain obscure. OBJECTIVE: This study investigated the suppressive effect of clarithromycin on airway responsiveness to methacholine provocation testing and examined whether chrarithromycin's antiasthmatic activity is associated with a reduction in eosinophilic inflammation. METHODS: For 8 weeks, patients received 200 mg of clarithromycin or identical-appearing placebo twice daily. We assessed the effects of treatment with clarithromycin on bronchoconstriction precipitated by inhalation of methacholine in 17 adults with mild or moderate bronchial asthma who were in stable clinical condition. A double-blind, randomized, crossover design was used. Eosinophil counts and eosinophilic cationic protein (ECP) levels were determined in blood and sputum samples obtained on the morning of the methacholine provocation testing day. RESULTS: After 8 weeks of treatment with clarithromycin, patients' symptoms, blood and sputum eosinophils counts and sputum ECP levels were significantly decreased compared with both placebo and baseline. Furthermore, values of PC20 methacholine improved in all patients after clarithromycin treatment. CONCLUSIONS: Clarithromycin has a bronchial anti-inflammatory effect associated with decreased eosinophilic infiltration. This study suggests interesting therapeutic possibilities for bronchial asthma that warrant further trials.

Fixation patterns of idiopathic macular holes after vitreous surgery.

BACKGROUND: Evaluation of idiopathic macular holes with the scanning laser ophthalmoscope (SLO) has shown fixation to be located at or near the margin of the hole and above the horizontal meridian in most cases. However, changes between preoperative and postoperative fixation have not been well studied. METHOD: We used SLO microperimetry to determine scotomas and fixation points in 13 patients with idiopathic macular holes before and after vitreous surgery. The distance between preoperative and postoperative fixation points and the direction of movement were measured. RESULTS: Preoperatively, fixation was found to be at or near the margin of the macular hole in all eyes and was located above the horizontal meridian in most (84.6%) eyes. Postoperatively, there was a shift in the position of the fixation points. The distance between preoperative and postoperative fixation correlated with the degree of visual improvement (P = 0.032), but the direction of movement was variable. CONCLUSION: A shift in the position of fixation occurs after macular hole surgery, and the amount of shift correlates with visual improvement. From this observation, we define the term functional macular hole closure, characterized by centripetal movement of the neurosensory retina and improvement in vision, and the broader term anatomic macular hole closure, in which apparent hole closure may result from gliosis in the absence of movement of the neurosensory retina, not associated with visual improvement.

Enhancement of transgene expression by cotransfection of oriP plasmid with EBNA-1 expression vector.

We have attempted to develop a system for specific enhancement of transgene expression, which has been one of the most important issues in human gene therapy. When an Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA-1) expression vector, pCMV-trEBNA-1, was cotransfected with an origin of latent viral DNA replication (oriP)-harboring plasmid, poriP-CMV-luciferase, luciferase gene expression was up to 20 times greater than in the absence of EBNA-1. This enhancement was regulated mainly at the transcriptional level and was dependent on the oriP sequence and the amount of EBNA-1. However, cointroduction of poriP-CMV-luciferase with purified recombinant EBNA-1 inhibited luciferase gene expression whereas no inhibition was observed when pCMV-luciferase was cointroduced with recombinant EBNA-1. We also introduced poriP-CMV-luciferase into mouse liver via the use of HVJ (hemagglutinating virus of Japan)-liposomes. By 10 days after transfer, luciferase gene expression was decreased to low levels. We then introduced pCMV-trEBNA-1 to mouse liver via HVJ-liposomes on day 10. Luciferase gene expression was reactivated, whereas no reactivation was detected by the injection of EBNA-1 expression plasmid into liver injected with pCMV-luciferase lacking the oriP sequence. Thus, cotransfection of oriP-harboring expression vector with EBNA-1 expression plasmid should be promising for human gene therapy, although the safety of the system must be investigated thoroughly.