Dobutamine stress echocardiography compared with dipyridamole thallium-201 single-photon emission computed tomography in detecting coronary artery disease

To compare the diagnostic value of dobutamine stress echocardiographywith dipyridamole thallium-201 single-photon emission computedtomography (SPECT) in detecting coronary artery disease (CAD),we performed both tests on 54 patients who also underwent coronaryarteriography. Dobutamine was infused at an incremental regimenof 5,10,20,30 and 40 µg. kg^-1. min^-1. Dipyridamole wasinfused at a rate of 0.14 mg. kg^-1. min^-1 over 4 min. Dobutaminestress echocardiography detected 40 (93%) and SPECT 42 (98%,P=ns) of the 43 patients with significant CAD, defined as (greaterthan or equal) 50% diameter stenosis. The specificity was 73%(8 of 11) for both tests. The sensitivity for detecting individualcoronary artery stenosis with dobutamine stress echocardiographywas 81% (30 of 37) for the left anterior descending artery,75% (24 of 32) for the right coronary artery, and 61% (17 of28) for the left circumflex artery. For SPECT it was 89%, 97%(P>0.05 vs dobutamine stress echocardiography) and 75%, respectively. Among the 97 stenotic coronary arteries, 17 had mild to moderatestenosis (50%-69% diameter stenosis) and 80 had severe stenosis($$70% diameter stenosis). With dobutamine stress echocardiography,53% of the arteries with mild to moderate stenosis were identifiedvs 78% of those with severe stenosis (P<0.05). With SPECT,the sensitivity was 82% (14 of 17) in mild to moderate stenosisand 89% (71 of 80) in severe stenosis (P=ns). No major sideeffects occurred during either test. Thus, both dobutamine stressand SPECT are highly sensitive for detection and localizationof CAD. However, the sensitivity of dobutamine stress is affectedby the level of stenosis severity.     

Current and novel therapies in acute GVHD

Despite improvements in our understanding of transplant immunology and clinical and supportive care, acute graft-versus-host disease (GVHD) remains a clinical challenge and a major cause of morbidity and mortality for patients after allogeneic hematopoietic stem-cell transplantation. While systemic corticosteroid is standard primary therapy for acute GVHD, there is no established standard treatment in the steroid-refractory setting. New generations of monoclonal antibodies, biologics, and chemotherapeutics with immunomodulatory effects have been developed over the past decade, and are being tested as novel therapies in this disease. Many of these agents - including, among others, mycophenolate mofetil, anti-tumor necrosis factor-alpha antibodies, denileukin diftitox, and anti-interleukin-2Ralpha-chain antibodies - have demonstrated promising activity in steroid-refractory acute GVHD. Despite the high response rates, however, long-term survival remains poor due to a high incidence of infections. The key to improving acute GVHD outcomes may, in fact, rest upon successful initial therapy, and timely taper of corticosteroids to promote healthier immune reconstitution. Clinical trials combining these newer agents with systemic corticosteroids as initial treatment are under way, and will determine whether fortifying initial therapy will indeed reduce the development of steroid-refractory GVHD and improve long-term outcomes. In this article, we review current and novel agents available for acute GVHD, and discuss newer investigational approaches - such as phototherapy and cellular therapies - in the management of this common transplant complication.     

Modulation by progestogens of the effects of oestrogen on hepatic endocrine function in postmenopausal women

OBJECTIVE: Oral but not transdermal oestrogen administration reduces IGF-I, and increases GH binding protein (GHBP) reflecting effects on hepatic endocrine function in postmenopausal women. As progestogens attenuate the effects of oestrogen on circulating lipid levels according to their androgenic properties, we have investigated the impact of progestogen types on the hepatic endocrine effects of oestrogen. DESIGN: Four progestogens differing in androgenicity were co-administered in a monthly cyclical regimen in random order to postmenopausal women receiving either oral (n = 9, premarin 1.25 mg) or transdermal (n = 10, Estraderm 100 microg patches twice weekly). The four progestogens were cyproterone acetate (CA 5 mg, antiandrogenic), dydrogesterone (20 mg, neutral), medroxyprogesterone acetate (MPA 10 mg, mildly androgenic), norethisterone (2.5 mg, androgenic). PATIENTS: Nineteen postmenopausal women (age 57 +/- 3 years, mean +/- SE) were studied. MEASUREMENTS: The effects of oestrogen alone and the combined effects with each progestogen type on IGF-I, GHBP, SHBG, cholesterol, triglycerides and lipoprotein(a) were investigated. RESULTS: Mean IGF-I fell while GHBP and SHBG levels increased with oral (P < 0.01) but not transdermal oestrogen administration. When the combined effects were examined, progestogens did not affect IGF-I, GHBP and SHBG during oral oestrogen treatment, while they significantly increased (P < 0.01) mean IGF-I levels during transdermal therapy. Among the progestogen types, only norethisterone prevented the fall in IGF-I induced by oral oestrogen. During transdermal therapy, MPA and norethisterone but not CA or dydrogesterone significantly increased (P < 0.005) IGF-I. The rise in GHBP induced by oral oestrogens tended to be lower during co-administration of MPA and norethisterone. The increase in SHBG induced by oral oestrogen was attenuated (P < 0.05) by norethisterone which was the only progestogen that lowered SHBG (P < 0.05) during transdermal oestrogen treatment. Mean IGF-I was higher (P < 0.001), GHBP and SHBG lower during co-administration of androgenic progestogens (MPA and norethisterone). CONCLUSIONS: Oestrogen effects on IGF-I, GHBP and SHBG are dependent on the route of administration with progestogens having variable effects. Among the progestogen types, norethisterone, the most androgenic, had the greatest effect, particularly on IGF-I. Progestogens modulate the effects of oestrogen on hepatic endocrine function in relation to their intrinsic androgenic properties. The modulatory effects of progestogens on IGF-I during oestrogen therapy may have long-term implications for lean body mass.     

Lipopolysaccharide‐induced cytokine and receptor expression and neutrophil infiltration in the liver of osteopetrosis (op/op) mutant mice

Abstract: Background/Aims: Mice homozygous for the osteopetrosis (op) mutation are genetically deficient in macrophage colony‐stimulating factor (M‐CSF/CSF‐1) and are characterized by defective differentiation and function of macrophages. The aim of this study is to assess the contribution of M‐CSF to lipopolysaccharide (LPS)‐induced cytokine expression and neutrophil infiltration in the liver. Methods: We investigated the effects of LPS administration in M‐CSF‐deficient op/op mutant mice. The expression of cytokines and receptors in the liver was studied by immunohistochemistry and RT‐PCR. Neutrophil infiltration in the liver was also examined. Results: After LPS administration, cytokine production and expression of LPS receptors, such as CD14 and scavenger receptor class A (MSR‐A), were induced at lower levels in op/op mice than those in littermate mice. Neutrophil infiltration in the liver of op/op mice did not differ significantly from that of littermate mice. Anti‐IL‐8 receptor homologue and anti‐C5a receptor antibody reduced the number of infiltrating neutrophils. Conclusions: These findings indicate that deficient macrophage activation following LPS injection in op/op mice is associated with decreased expression of CD14 and MSR‐A in the liver. Thus, M‐CSF plays a critical role in LPS‐induced macrophage activation but does not exert a dominant role in neutrophil infiltration in the liver.     

Prevalence and predictors of renal artery stenosis in Chinese patients with coronary artery disease

Abstract
Background:  Ischaemic nephropathy is currently a major public health issue in atherosclerotic populations. Although atherosclerotic cardiovascular disease in Asia has reached epidemic proportions over the last two decades, there is little published data on the prevalence of atherosclerotic renal artery stenosis (ARAS) in Oriental subjects. Because ARAS may be clinically silent until end-stage renal failure sets in, it is important to identify patients with significant but clinically unsuspected ARAS. ARAS and coronary artery disease (CAD) often coexist.
Aims:  The purpose of the present study was to evaluate the prevalence and predictors of ARAS among Chinese patients with CAD.
Methods:  A total of 230 consecutive Chinese patients with CAD confirmed by coronary angiography underwent an abdominal aortogram in the same sitting to screen for ARAS. Patient demographics and comorbid­ities were analysed for any association with ARAS.
Results:  A total of 34 (14.8%) patients was found to have significant ARAS. Age and multivessel CAD were independent predictors of ARAS. Hypertension, renal insufficiency, extracranial cerebrovascular disease and female gender were also associated with a higher risk of ARAS but did not independently predict ARAS.
Conclusion:  Clinically silent yet angiographically significant ARAS is common among CAD patients. The prevalence and predictors of ARAS among Chinese patients with CAD are similar to those reported for Caucasian subjects. Underlying ARAS should be suspected in CAD patients with such comorbidities as hypertension, renal insufficiency, extracranial cerebrovascular disease, and more so in the elderly and those with multivessel disease. (Intern Med J 2003; 33: 280−285)     

Local injection of stem cell factor (SCF) improves myocardial homing of systemically delivered c-kit + bone marrow-derived stem cells

AIMS: Recent studies have shown that stem cell therapy may alleviate the detrimental effects of myocardial infarction. Yet, most of these reports observed only modest effects on cardiac function, suggesting that there still is need for improvement before widespread clinical use. One potential approach would be to increase migration of stem cells to the heart. We therefore tested whether local administration of stem cell factor (SCF) improves myocardial homing of intravenously infused lin-/c-kit+ stem cells after myocardial infarction. METHODS AND RESULTS: Myocardial infarction was induced in mice via ligation of the left anterior descending artery and 2.5 microg of SCF were injected into the peri-infarct zone. Sham-operated mice and animals with intramyocardial injection of phosphate-buffered saline (PBS) served as controls. Twenty-four hours after myocardial infarction, lin-/c-kit+ stem cells were separated from murine bone marrow by magnetic cell sorting, labelled with the green fluorescent cell tracker CFDA or 111 Indium, and subsequently 750 000 labelled cells were systemically infused via the tail vein. Another 24 or 72 h later, respectively (i.e. 48 and 96 h after myocardial infarction), hearts were removed and analysed for myocardial homing of stem cells. Green fluorescent stem cells were exclusively detected in the peri-infarct zone of animals having prior SCF treatment. Radioactive measurements revealed that an intramyocardial SCF injection significantly amplified myocardial homing of lin-/c-kit+ stem cells compared to animals with PBS injections (3.58 +/- 0.53 vs. 2.28 +/- 0.23 cpm/mg/10(6)cpm, +60%, P < 0.05) and sham-operated mice without myocardial infarction (3.58 +/- 0.53 vs. 1.95 +/- 0.22 cpm/mg/10(6)cpm, +85%, P < 0.01). Similar results were obtained 72 h after stem cell injection. CONCLUSION: We demonstrate that intramyocardial administration of SCF sustainably directs more lin-/c-kit+ stem cells to the heart. Future studies will have to show whether higher levels of myocardial SCF (i.e. by virus-mediated gene transfer) can further improve homing of systemically delivered c-kit+ stem cells and thus favourably influence cardiac remodelling following myocardial infarction.     

Exposure to environmental tobacco smoke and urinary 1-hydroxypyrene levels in preschool children

Environmental tobacco smoke (ETS) contains relatively high concentrations of polycyclic aromatic hydrocarbons (PAHs). Urinary 1-hydroxypyrene (1-OHP), a metabolite of pyrene, is a good indicator of PAH exposure in occupational studies. In this study, we investigated the relationship between urinary 1-OHP concentration and ETS exposure in preschool children. Forty preschool children, aged 24-76 months, were studied during November and December, 1999. Two spot-urine specimens (one in the morning immediately after the subject woke up and the other at night before the subject went to bed) were collected 1 day after completion of a questionnaire, in order to determine 1-OHP concentrations by fluorescent spectrophotometry. Overall, urinary 1-OHP concentrations were relatively low but detectable (morning: median, 0.021 microg/g creatinine; range, 0.002-1.019 microg/g creatinine; night: median, 0.015 microg/g creatinine; range, 0.002-1.328 microg/g creatinine). Multiple linear regression analyses revealed that the total number of cigarettes smoked by the children's fathers during the 3 days prior to collection of the urine specimens was significantly associated with their urinary 1-OHP concentrations, after adjusting for other confounders. Each cigarette smoked by a child's father resulted in an average 9.6% increase in 1-OHP concentration in the morning urine specimen (95% confidence interval = 1.8-18.1%; p = 0.02). We did not find a significant increase in the 1-OHP concentration in night urine specimens (p = 0.19). Although the sample size was small, these findings indicate that urinary 1-OHP may be a suitable biomarker of ETS carcinogen exposure in children.     

Elevated levels of transforming growth factor-beta(1) in serum of patients with stable bronchiectasis

Bronchiectasis is a chronic inflammatory and infective airway disease characterized by irreversible dilatation of the bronchi and persistent purulent sputum. Transforming growth factor-beta(1) (TGF-beta(1)) has been found to be increased in the lungs or bronchoalveolar lavage fluid of patients with inflammatory lung diseases. However, little is known on the serum TGF-beta(1) levels in patients with bronchiectasis. We aimed to determine the serum TGF-beta(1) concentrations in 95 patients with stable bronchiectasis (63 women; mean+/-sd age, 58.9+/-14.1 years) and 68 control subjects (23 women; 48.9+/-12.8 years) by ELISA, and to correlate with clinical parameters. The serum TGF-beta(1) levels were significantly higher in bronchiectatic patients compared with control subjects (median [range], 1812.5 pg/ml [1226.4-4114.5 pg/ml] vs. 1342.4 pg/ml [940.3-2371.7 pg/ml]; P<0.001). There was, however, no correlation between serum TGF-beta(1) levels with FEV(1) (% predicted), FVC (% predicted), 24h sputum volume, the number of bronchiectatic lung lobes or total white blood cell count (P>0.05). Our findings support previous indications that TGF-beta(1) may contribute to bronchiectatic airway inflammation. Further studies on the potential mechanisms and pathogenesis implications of this elevation should also be pursued in future.     

Controlled, randomized trial of island flap anoplasty for treatment of trans–sphincteric fistula–in-ano: early results

Treatment of trans–sphincteric fistula is usually a compromise between recurrence and incontinence. Dermal island flap anoplasty has been found to be useful in the treatment of these fistulas. We performed a randomized trial to compare dermal island flap anoplasty with conventional treatment for trans–sphincteric fistula–in–ano. Seventy nine patients with fistula–in–ano were recruited; twenty patients with trans–sphincteric fistula confirmed by endoanal ultrasound were prospectively randomized to receive either dermal island flap anoplasty (IFA) or conventional treatment (CVN) for trans–sphincteric fistula–inano. Conventional treatment consisted of lay open fistulotomy or seton insertion if deemed unsuitable for fistulotomy. Dermal island flap anoplasty involved a cutaneous advancement flap into the rectum. Pain scores, fecal incontinence scores, operative complications, wound healing and recurrence rates were charted. Two patients in the CVN group required seton insertions, which were still intact at the 9–month follow–up. Two patients with similar high trans–sphincteric fistula in the IFA group avoided having a long–term seton. There were no differences in the postoperative pain score, incontinence score, complications, wound healing and recurrence rates between the two groups. IFA is a safe and useful method for treating transsphincteric fistula. It can be considered when a suprasphincteric extension is suspected, thus avoiding risk of incontinence or the discomfort of a long–term seton.