Beneficial effects of aggressive low-density lipoprotein cholesterol lowering in women with stable coronary heart disease in the Treating to New Targets (TNT) study

OBJECTIVE: To examine by secondary analysis of the Treating to New Targets (TNT) study whether the benefits of intensive versus standard levels of lipid lowering are equally applicable to women. METHODS: A total of 10 001 patients (1902 women) with stable coronary heart disease (CHD) were randomised to double-blind treatment with atorvastatin 10 or 80 mg/day for a median follow-up of 4.9 years. RESULTS: In women and men, intensive treatment with atorvastatin 80 mg significantly reduced the rate of major cardiovascular events compared with atorvastatin 10 mg. Among women, the relative and absolute reductions were 27% and 2.7%, respectively (hazard ratio (HR) = 0.73, 95% confidence interval (CI) 0.54 to 1.00, p = 0.049). In men, the corresponding rate reductions were 21% and 2.2% (HR = 0.79, 95% CI 0.69 to 0.91, p = 0.001). The number needed to treat value (to prevent one cardiovascular event over 4.9 years compared with patients treated with atorvastatin 10 mg) for atorvastatin 80 mg was 29 for women and 30 for men. Rates of death of non-cardiovascular origin in the atorvastatin 80 mg and atorvastatin 10 mg were 3.6% and 1.6%, respectively (p = 0.004) among women, and 2.8% and 3.1% (p = 0.47) among men. CONCLUSION: Intensive lipid-lowering treatment with atorvastatin 80 mg produced significant reductions in relative risk for major cardiovascular events compared with atorvastatin 10 mg in both women and men with stable CHD.

Experimental models of CNS infections. Contributions to concepts of disease and treatment

Lessons learned from studies of experimental meningitis and brain abscess in animal models of infection represent major, highly significant contributions to our understanding of the pathogenesis and antimicrobial chemotherapy of these infections. For example, studies of experimental meningitis in rabbits demonstrated that the subarachnoid space is deficient in local host defenses, a finding that explains why only bactericidal antibiotic regimens are effective in treating this disease; studies of the efficacy of corticosteroids as adjunctive therapy for meningitis yielded data indicating that both beneficial and detrimental effects on the host are imparted by these compounds. These and a number of other key investigations of experimental meningitis and brain abscess, the results of these investigations, and the clinical significance of these results are presented in this article.

Age dependency of intrarenal resistance index (RI) in healthy adults and patients with fatty liver disease

BACKGROUND: Our aim was to investigate the influence of age and gender on intrarenal resistance index (RI) measurements in 78 healthy subjects (46 males, 32 females; group 1) and 35 subjects (group 2) with fatty liver disease (28 males and 7 females). SUBJECTS AND METHODS: First, each subject underwent a conventional abdominal ultrasound examination. Then, intrarenal RI values were determined from three distinct interlobar and cortical arteries respectively on both kidneys. The correlation of intrarenal RI with age and gender as a variable was statistically evaluated by linear regression. RESULTS: In group 1, the variables gender, kidney region and comparison of right versus left kidney had no significant effect on intrarenal RI (p>0.05). The variable age, on the other hand, showed a significant positive correlation on all four defined measuring points (p<0.01) with linear correlation coefficients of r = 0.26 (left kidney, central) to r = 0.37 (right kidney, cortical). Therefore normal RI values at ages 25, 45, 65 years could be defined as 0.59, 0.61 and 0.63, respectively. Age dependency can thus be expressed as a function with the formula y = 0.565 + 0.001.x. Patients with fatty liver disease showed age dependency on renal RI (p<0.01) as well. CONCLUSION: In accordance with other studies, the influence of age on intrarenal RI measurement is significant in healthy subjects. Intrarenal RI values from subjects with a fatty liver disease showed age dependency as well. Therefore it is necessary to consider the age of the examined person to interpret RI values correctly.

10-year follow-up of a prospective randomized trial comparing bare-metal stenting with internal mammary artery grafting for proximal, isolated de novo left anterior coronary artery stenosis the SIMA (Stenting versus Internal Mammary Artery grafting) trial

OBJECTIVES: This study was designed to compare the long-term clinical outcome of coronary artery bypass grafting (CABG) with intracoronary stenting of patients with isolated proximal left anterior descending coronary artery. BACKGROUND: Although numerous trials have compared coronary angioplasty with bypass surgery, none assessed the clinical evaluation in the long term. METHODS: We evaluated the 10-year clinical outcome in the SIMA (Stent versus Internal Mammary Artery grafting) trial. Patients were randomly assigned to stent implantation versus CABG. RESULTS: Of 123 randomized patients, 59 underwent CABG and 62 received a stent (2 patients were excluded). Follow-up after 10 years was obtained for 98% of the randomized patients. Twenty-six patients (42%) in the percutaneous coronary intervention group and 10 patients (17%) in the CABG group reached an end point (p < 0.001). This difference was due to a higher need for additional revascularization. The incidences of death and myocardial infarction were identical at 10%. Progression of the disease requiring additional revascularization was rare (5%) and was similar for the 2 groups. Stent thrombosis occurred in 2 patients (3%). Angina functional class showed no significant differences between the 2 groups. CONCLUSIONS: Both stent implantation and CABG are safe and highly effective in relieving symptoms in patients with isolated, proximal left anterior descending coronary artery stenosis. Stenting with bare-metal stents is associated with a higher need for repeat interventions. The long-term prognosis for these patients is excellent with either mode of revascularization.

Biolimus-eluting stent with biodegradable polymer versus sirolimus-eluting stent with durable polymer for coronary revascularisation (LEADERS): a randomised non-inferiority trial

BACKGROUND: A novel stent platform eluting biolimus, a sirolimus analogue, from a biodegradable polymer showed promising results in preliminary studies. We compared the safety and efficacy of a biolimus-eluting stent (with biodegradable polymer) with a sirolimus-eluting stent (with durable polymer). METHODS: We undertook a multicentre, assessor-blind, non-inferiority study in ten European centres. 1707 patients aged 18 years or older with chronic stable coronary artery disease or acute coronary syndromes were centrally randomised by a computer-generated allocation sequence to treatment with either biolimus-eluting (n=857) or sirolimus-eluting (n=850) stents. The primary endpoint was a composite of cardiac death, myocardial infarction, or clinically-indicated target vessel revascularisation within 9 months. Analysis was by intention to treat. 427 patients were randomly allocated to angiographic follow-up, with in-stent percentage diameter stenosis as principal outcome measure at 9 months. The trial is registered with ClinicalTrials.gov, number NCT00389220. FINDINGS: We analysed all randomised patients. Biolimus-eluting stents were non-inferior to sirolimus-eluting stents for the primary endpoint at 9 months (79 [9%] patients vs 89 [11%], rate ratio 0.88 [95% CI 0.64-1.19], p for non-inferiority=0.003, p for superiority=0.39). Frequency of cardiac death (14 [1.6%] vs 21 [2.5%], p for superiority=0.22), myocardial infarction (49 [5.7%] vs 39 [4.6%], p=0.30), and clinically-indicated target vessel revascularisation (38 [4.4%] vs 47 [5.5%], p=0.29) were similar for both stent types. 168 (79%) patients in the biolimus-eluting group and 167 (78%) in the sirolimus-eluting group had data for angiographic follow-up available. Biolimus-eluting stents were non-inferior to sirolimus-eluting stents in in-stent percentage diameter stenosis (20.9%vs 23.3%, difference -2.2% [95% CI -6.0 to 1.6], p for non-inferiority=0.001, p for superiority=0.26). INTERPRETATION: Our results suggest that a stent eluting biolimus from a biodegradable polymer represents a safe and effective alternative to a stent eluting sirolimus from a durable polymer in patients with chronic stable coronary artery disease or acute coronary syndromes. FUNDING: Biosensors Europe SA, Switzerland.

Ambulatory arterial stiffness index is increased in hypertensive childhood disease

Arterial hypertension in adults is often associated with an increased arterial stiffness, which correlates with the ambulatory arterial stiffness index (AASI) as derived from ambulatory blood pressure (BP) measurements. The purpose of this study was to demonstrate whether children with diagnosed hypertension have an increased AASI as in hypertensive adults. AASI was calculated from 185 ambulatory BP measurements of 114 hypertensive and 71 normotensive, healthy children. Hypertensive children had higher AASI values compared with their normotensive healthy counterparts (0.370 +/- 0.120 versus 0.204 +/- 0.199, p < 0.0001). Children with longer duration of hypertension or a history of primary or secondary aortic coarctation displayed even more elevated AASI values. A receiver operator curve derived cut-off of AASI set at 0.301 distinguished (p < 0.0001) hypertensive from normotensive children with an odds ratio of 8.2, a sensitivity of 81%, and a specificity of 65%. Moreover, AASI correlated with pulse and systolic BP. In conclusion, AASI is elevated in hypertensive children and correlates with the duration and the origin of hypertension in childhood.

Bacterial colitis increases susceptibility to oral prion disease

Dietary exposure to prion-contaminated materials has caused kuru and variant Creutzfeldt-Jakob disease in humans and transmissible spongiform encephalopathies (TSEs) in cattle, mink, and felines. The epidemiology of dietary prion infections suggests that host genetic modifiers and possibly exogenous cofactors may play a decisive role in determining disease susceptibility. However, few cofactors influencing susceptibility to prion infection have been identified. In the present study, we investigated whether colitis might represent one such cofactor. We report that moderate colitis caused by an attenuated Salmonella strain more than doubles the susceptibility of mice to oral prion infection and modestly accelerates the development of disease after prion challenge. The prion protein was up-regulated in intestines and mesenteric lymph nodes of mice with colitis, providing a possible mechanism for the effect of colitis on the pathogenesis of prion disease. Therefore, moderate intestinal inflammation at the time of prion exposure may constitute one of the elusive risk factors underlying the development of TSE.

MR colonography: 1.5T versus 3T

MR colonography is a powerful noninvasive method to image colorectal masses and inflammatory bowel disease. This article describes current techniques of MR colonography and compares its implementation at 1.5T and 3T.

[Unilateral vs. bilateral lung transplantation in obstructive pulmonary disease]

BACKGROUND: The question whether patients suffering from end-stage emphysema who are candidates for lung transplantation should be treated with a single lung or with a double lung transplantation is still unanswered. METHODS: We reviewed 24 consecutive lung transplant procedures, comparing the results of 6 patients with an unilateral and 17 with a bilateral transplantation. PATIENTS AND RESULTS: After bilateral transplantation the patients showed a trend towards better blood gas exchange with shorter time on ventilator and intensive care compared patients after unilateral procedure. Three-year-actuarial survival was higher in the group after bilateral transplantation (83% versus 67%). There was a continuous improvement in pulmonary function in both groups during the first months after transplantation. Vital capacity and forced exspiratory ventilation therapies during the first second were significantly higher in the bilateral transplant group. CONCLUSION: Both unilateral and bilateral transplantation are feasible for patients with end-stage emphysema. Bilateral transplantation results in better pulmonary reserve capacity and faster rehabilitation.

Revascularisation of coronary artery disease in patients with diabetes mellitus

Diabetes mellitus is becoming increasingly prevalent and magnifies the risk of cardiovascular complications. Endothelial dysfunction caused by oxidative stress is a hallmark of diabetes and is responsible for the ubiquitous manifestations of vascular disease in diabetics. Compared with non-diabetic patients, coronary artery disease is more severe and the clinical outcome impaired in diabetic patients undergoing revascularisation. Despite these limitations the benefit of revascularisation therapy is particularly pronounced in diabetics. The optimal revascularisation strategy (coronary artery bypass graft surgery versus percutaneous coronary intervention) in diabetic patients with coronary artery disease depends on clinical and anatomical considerations.

Comparison of long versus short ("spot") drug-eluting stenting for long coronary stenoses

We compared spot drug-eluting stenting (DES) to full stent coverage for treatment of long coronary stenoses. Consecutive, consenting patients with a long (>20 mm) coronary lesion of nonuniform severity and indication for percutaneous coronary intervention were randomized to full stent coverage of the atherosclerotic lesion with multiple, overlapping stenting (full DES group, n = 90) or spot stenting of hemodynamically significant parts of the lesion only (defined as diameter stenosis >50%; spot DES group, n = 89). At 1-year follow-up, 14 patients with full DES (15.6%) and 5 patients (5.6%) with spot DES had a major adverse cardiac event (MACE; p = 0.031). At 3 years, MACEs occurred in 18 patients with full DES (20%) and 7 patients (7.8%) with spot DES (p = 0.019). Cox proportional hazard model showed that the risk for MACEs was almost 60% lower in patients with spot DES compared to those with full DES (hazard ratio 0.41, 95% confidence interval 0.17 to 0.98, p = 0.044). This association remained even after controlling for age, gender, lesion length, and type of stent used (hazard ratio 0.42, 95% confidence interval 0.17 to 1.00, p = 0.05). In conclusion, total lesion coverage with DES is not necessary in the presence of diffuse disease of nonuniform severity. Selective stenting of only the significantly stenosed parts of the lesion is an appropriate therapeutic alternative in this setting, offering a favorable clinical outcome.

M-ficolin in the neonatal period: Associations with need for mechanical ventilation and mortality in premature infants with necrotising enterocolitis

OBJECTIVE: Necrotising enterocolitis (NEC) causes significant mortality in premature infants. The involvement of the innate immune system in the pathogenesis of NEC remains unclear. M-, L- and H-ficolins recognize microorganisms and activate the complement system, but their role in host defense is largely unknown. This study investigated whether ficolin concentrations are associated with NEC. STUDY DESIGN: Case-control study including 30 premature infants with NEC and 60 controls. M-, L- and H-ficolins were measured in cord blood using time-resolved immunofluorometric assays. Multivariate logistic regression was performed. RESULTS: Of the 30 NEC cases (median gestational age, 29.5 weeks), 12 (40%) were operated and 4 (13%) died. No difference regarding ficolin concentration was found when comparing NEC cases versus controls (p>0.05). However, infants who died of NEC had significantly lower M-ficolin cord blood concentrations than NEC survivors (for M-ficolin <300ng/ml; multivariate OR 12.35, CI 1.03-148.59, p=0.048). In the entire study population, M-, L- and H-ficolins were positively correlated with gestational age (p<0.001) and birth weight (p<0.001). Infants with low M-ficolin required significantly more often mechanical ventilation after birth multivariate (OR 10.55, CI 2.01-55.34, p=0.005). CONCLUSIONS: M-, L- and H-ficolins are already present in cord blood and increase with gestational age. Low cord blood concentration of M-ficolin was associated with higher NEC-associated fatality and with increased need for mechanical ventilation. Future studies need to assess whether M-ficolin is involved in multiorgan failure and pulmonary disease.

Effects of GDNF pretreatment on function and survival of transplanted fetal ventral mesencephalic cells in the 6-OHDA rat model of Parkinson's disease

Transplantation of fetal dopaminergic (DA) neurons offers an experimental therapy for Parkinson's disease (PD). The low availability and the poor survival and integration of transplanted cells in the host brain are major obstacles in this approach. Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor with growth- and survival-promoting capabilities for developing DA neurons. In the present study, we examined whether pretreatment of ventral mesencephalic (VM) free-floating roller tube (FFRT) cultures with GDNF would improve graft survival and function. For that purpose organotypic cultures of E14 rat VM were grown for 2, 4 or 8 days in the absence (control) or presence of GDNF [10 ng/ml] and transplanted into the striatum of 6-hydroxydopamine-lesioned rats. While all groups of rats showed a significant reduction in d-amphetamine-induced rotations at 6 weeks posttransplantation a significantly improved graft function was observed only in the days in vitro (DIV) 4 GDNF pretreated group compared to the control group. In addition, no statistical significant differences between groups were found in the number of surviving tyrosine hydroxylase-immunoreactive (TH-ir) neurons assessed at 9 weeks posttransplantation. However, a tendency for higher TH-ir fiber outgrowth from the transplants in the GDNF pretreated groups as compared to corresponding controls was observed. Furthermore, GDNF pretreatment showed a tendency for a higher number of GIRK2 positive neurons in the grafts. In sum, our findings demonstrate that GDNF pretreatment was not disadvantageous for transplants of embryonic rat VM with the FFRT culture technique but only marginally improved graft survival and function.

Biliary diseases in heart transplanted patients: a comparison between cyclosporine A versus tacrolimus-based immunosuppression

A cyclosporine (CsA)-based immunosuppression is associated with an increased incidence of cholelithiasis after heart transplantation. It is not known if tacrolimus (Tac) has comparable biliary side effects in humans. We evaluated the incidence of gallbladder sludge and cholelithiasis under Tac-based immunosuppression by ultrasound examinations in 31 cardiac transplants (25 male, 6 female, mean age: 59 ' 11 years). Data were compared to 57 patients (47 male, 10 female, mean age: 58 ' 11 years) who received CsA-based immunosuppression. 6 patients receiving Tac and 6 patients receiving CsA had already gallstones prior to transplantation so that finally 25 patients of the Tac group and 51 patients of the CsA group could be evaluated. In the Tac group the incidence of biliary sludge was 4% (1 of 25), of gallstones 28% (7 of 25). In comparison, patients receiving CsA developed biliary sludge in also 4% (2 of 51) and gallstones in 25% (13 of 51). Nine of 42 males in the CsA group (21%) and eight of 20 males in the Tac group (40%) developed either gallstones or sludge (n.s). Six of nine females in the CsA group (67%), but none of five females in the Tac group (0%) developed either gallstones or sludge (p = 0.01). In summary, the incidence of biliary disease in patients with Tac is comparable with CsA-based immunosuppression. We recommend regular sonographical examinations to detect biliary diseases as early as possible. In cases of clinically, laboratory and sonographical signs of cholecystitis cholecystectomy is indicated. It seems that towards lithogenicity female patients benefit more from a Tac-based treatment because the occurrence of gallstones is rare.

Persistent versus transient depressive symptoms in relation to platelet hyperactivation: a longitudinal analysis of dementia caregivers

BACKGROUND: Depressive symptoms and caregiving stress may contribute to cardiovascular disease (CVD) via chronic platelet activation; however, it remains unclear whether this elevated activation constitutes a trait or state marker. The primary objective was to investigate whether persistent depressive symptoms would relate to elevated platelet activation in response to acute psychological stress over a three-year period. METHODS: Depressive symptoms (Brief Symptom Inventory) were assessed among 99 spousal dementia caregivers (52-88 years). Platelet P-selectin expression was assessed in vivo using flow cytometry at three time-points over the course of an acute stress test: baseline, post-stress, and after 14 min of recovery. Two competing structural analytic models of depressive symptoms and platelet hyperactivity with three yearly assessments were compared. RESULTS: Although depressive symptoms were generally in the subclinical range, their persistent elevation was associated with heightened platelet reactivity and recovery at all three-years while the change in depressive symptoms from the previous year did not predict platelet activity. LIMITATIONS: These results focus on caregivers providing consistent home care, while future studies may extend these results by modeling major caregiving stressors. CONCLUSIONS: Enduring aspects of negative affect, even among those not suffering from clinical depression are related to hemostatic changes, in this case platelet reactivity, which might be one mechanism for previously reported increase in CVD risk among elderly Alzheimer caregivers.