The role of interstitial macrophages in nephropathy of type 2 diabetic db/db mice

Diabetic nephropathy is associated with interstitial macrophage infiltrates, but their contribution to disease progression is unclear. We addressed this question by blockade of chemokine receptor (CCR)1 because CCR1 mediates the macrophage recruitment to the renal interstitium. In fact, when CCR1 was blocked with BL5923, a novel orally available CCR1 antagonist, the interstitial recruitment of ex vivo labeled macrophages was markedly decreased in uninephrectomized male db/db mice with advanced diabetic nephropathy. Likewise, BL5923 (60 mg/kg, twice a day) orally administered from months 5 to 6 of life reduced the numbers of interstitial macrophages in uninephrectomized db/db mice. This was associated with reduced numbers of Ki-67 proliferating tubular epithelial and interstitial cells, tubular atrophy, and interstitial fibrosis in uninephrectomized db/db mice. Glomerular pathology and proteinuria were not affected by the CCR1 antagonist. BL5923 reduced renal mRNA expression of Ccl2, Ccr1, Ccr2, Ccr5, transforming growth factor-beta1, and collagen I-alpha1 when compared with untreated uninephrectomized male db/db mice of the same age. Thus, we identified a previously unrecognized role for interstitial macrophages for tubulointerstitial injury, loss of peritubular microvasculature, interstitial inflammation, and fibrosis in type 2 diabetic db/db mice. These data identify oral treatment with the CCR1 antagonist BL5923 as a potential therapy for late-stage diabetic nephropathy.     

Abnorme Verkürzung der linksventrikul?ren Diastolendauer unter k?rperlicher Belastung bei Patienten mit dilatativer Kardiomyopathie

BACKGROUND AND PURPOSE: Cardiac performance can be characterized in terms of the relative duration of systole and diastole. In pediatric patients with dilated cardiomyopathy (DCM), a disproportionate shortening of left ventricular diastole was observed. The present study was intended to reproduce these findings in an adult patient group and to evaluate exercise-related changes of both time intervals. PATIENTS AND METHODS: Exercise radionuclide angiography was used in 61 patients with DCM NYHA (New York Heart Association) stage II-III. The phases of the cardiac cycle were derived from a radionuclide time-activity curve with high temporal resolution. The control group consisted of 26 patients referred for ventricular function assessment with radionuclide angiography before cardiotoxic cancer treatment. RESULTS: When the duration of systole was expressed as the product of systolic time and heart rate, DCM patients exhibited a significant increase in left ventricular systolic time at rest (23.9 vs. 21.5 s/min; p = 0.006) and during peak exercise (29.2 vs. 26.7 s/min; p = 0.01). The prolongation of left ventricular systole at peak exercise was evident, although the peak heart rate was significantly lower in the patient group than in the control group (118 vs. 127/min; p = 0.04). In DCM patients the diastolic time loss per beat was further quantified using a regression equation obtained from the healthy control group. A significant shortening of left ventricular diastolic time was confirmed during peak exercise. Furthermore, a progressive loss in diastolic time per beat from rest to peak exercise was noted. CONCLUSION: Cardiac cycle abnormalities of patients with DCM are characterized by a prolongation of left ventricular systole and an abnormal shortening of left ventricular diastole. The systolic-diastolic mismatch is accentuated during exercise and has the potential to impair the cardiac reserve in these patients by restricting ventricular filling and perfusion.     

Pharmacological profile of astemizole-derived compounds at the histamine H1 and H4 receptor—H1/H4 receptor selectivity

Astemizole, a H₁R antagonist shows high affinity to the histamine H₁ receptor but only a moderate affinity to the histamine H₄ receptor. This study aims to modify the astemizole to keep high affinity to the histamine H₁ receptor and to increase affinity to the histamine H₄ receptor. Therefore, 13 astemizole-derived compounds and astemizole-JNJ7777120-derived hybrid compounds were synthesized and pharmacologically characterized at the histamine H₁ and H₄ receptors. The new compounds show affinity to the histamine H₁ receptor in the pK _i range from 5.3 to 8.8, whereas the affinity of these compounds to the histamine H₄ receptor was surprisingly rather low (pK _i from 4.4 to 5.6). Three representative compounds were docked into the histamine H₁ receptor and molecular dynamic studies were performed to explain the binding mode and the experimental results on a molecular level. Furthermore, taking into account the binding mode of compounds with high affinity to the histamine H₄ receptor, a H₁/H₄-pharmacophore hypothesis was developed.     

Factors influencing heart rate variability in patients with severe aortic valve disease

Background and hypothesis: Heart rate variability (HRV) is an accepted tool for the assessment of cardiovascular autonomic tone. There are no sufficient data concerning its application to patients with severe aortic valve disease (AVD) requiring cardiac surgery. Methods: It was the aim of this study to examine HRV and its physiologic correlates in patients with severe aortic valve disease requiring cardiac surgery. The correlates of time domain indices of HRV obtained from 24-h Holter electrocardiographic recordings were analyzed in 36 consecutive patients (23 men and 13 women, mean age 62 ± 11 years) with AVD prior to cardiac surgery (aortic stenosis: 17 patients, aortic valve regurgitation: 3 patients, combined aortic valve disease: 16 patients). Results: Low values of HRV were found in the entire study group: SDNN 96.8 ± 30.9 ms, SDNNI 39.3 ± 14.4 ms, SDANN 86 ± 28.9 ms, and RMSSD 30 ± 18.1 ms. In a univariate analysis, there was no significant correlation between the time domain measures of HRV and age, gender, medication, left ventricular ejection fraction, peak aortic pressure gradient, fraction of aortic valve regurgitation, and left ventricular mass assessed by echocardiography. Patients in advanced functional classes of heart failure [New York Heart Association (NYHA) III or IV] had significantly lower values for SDNN (83.8 ± 33.6 vs. 107.3 ± 24.7 ms; p<0.05) and SDANN (72.7 ± 29.4 vs. 96.6 ± 24.3 ms; p<0.05) than patients in NYHA class I or II. Reassessment of HRV 1 week after aortic valve replacement was performed in 17 patients and showed a significant further decrease of SDNN (102.4 ± 29.7 vs. 61.5 ± 23.5 ms; p<0.001), SDNNI (40.7 ± 13.6 vs. 23.4 ± 12.4 ms; p<0.001) and SDANN (91.8 ±29.2 vs. 54.2 ± 22.8 ms;p<0.001). Conclusion: Patients with AVD requiring cardiac surgery reveal reduced time domain indices of HRV. This observation is pronounced in patients with a progressed clinical class of heart failure, whereas hemodynamic and echocardiographic parameters seem to have no significant influence on HRV parameters in this population. In addition, there is evidence of a further reduction of HRV time domain indices 1 week after uncomplicated aortic valve replacement.     

The Combination of Exercise and Respiratory Training Improves Respiratory Muscle Function in Pulmonary Hypertension

Purpose

Increased dyspnea and reduced exercise capacity in pulmonary arterial hypertension (PAH) can be partly attributed to impaired respiratory muscle function. This prospective study was designed to assess the impact of exercise and respiratory training on respiratory muscle strength and 6-min walking distance (6MWD) in PAH patients.

Methods

Patients with invasively confirmed PAH underwent 3 weeks of in-hospital exercise and respiratory training, which was continued at home for another 12 weeks. Medication remained constant during the study period. Blinded observers assessed efficacy parameters at baseline (I) and after 3 (II) and 15 weeks (III). Respiratory muscle function was assessed by twitch mouth pressure (TwPmo) during nonvolitional supramaximal magnetic phrenic nerve stimulation.

Results

Seven PAH patients (4 women; mean pulmonary artery pressure 45 ± 11 mmHg, median WHO functional class 3.1 ± 0.4, idiopathic/associated PAH n = 5/2) were included. The training program was feasible and well tolerated by all patients with excellent compliance. TwPmo was I: 0.86 ± 0.37 kPa, II: 1.04 ± 0.29 kPa, and III: 1.27 ± 0.44 kPa, respectively. 6MWD was I: 417 ± 51 m, II: 509 ± 39 m, and III: 498 ± 39 m, respectively. Both TwPmo (+0.41 ± 0.34 kPa, +56 ± 39 %) and 6MWD (+81 ± 30 m, +20 ± 9 %) increased significantly in the period between baseline and the final assessment (pairwise comparison: p = 0.012/<0.001; RM-ANOVA considering I, II, III: p = 0.037/<0.001).

Conclusions

Exercise and respiratory training as an adjunct to medical therapy may be effective in patients with PAH to improve respiratory muscle strength and exercise capacity. Future, randomized, controlled trials should be carried out to further investigate these findings.     

3D-based full-guided ridge expansion osteotomy – A case report about a new method with successive use of different surgical guides,transfer of splitting vector and simultaneous implant insertion

For horizontal bone deficiency alveolar ridge osteotomy is considered an option for augmentation. Major advantages are the option for a one-stage approach and the absence of donor site morbidity. However, the conventional technique is associated with complications such as perforations and fractures of the cortical bone.A case using a 3D based modified, full-guided alveolar ridge expansion is described to explain the technique step by step. Main features of modified technique: successive application of surgical guides for ridge osteotomy and expansion – implementation of virtually determined splitting vector, which allows guided bone splitting along a guide surface of template in an ideal direction - osteotomy as deep as implant length. The example shows that the 3D based modified alveolar ridge osteotomy is a suitable alternative to the conventional technique as it has several advantages such as fewer fractures and perforations of the cortical vestibular bone.The individualized preoperative planning helps to minimize complications. However, long-term outcomes and a study, conducted on a study group, is needed to evaluate the benefits of our presented treatment protocol.     

Kosteneffektivität eines krankenkassengestützten Case-Management-Programms für Patienten mit affektiven Störungen

Objective

Health economic evaluation of a health insurance based case management intervention for persons with mood to severe depressive disorders from payers’ perspective. Intervention intended to raise utilization rates of outpatient health services.

Methods

Comparison of patients of one German health insurance company in two different regions/states. Cohort study consists of a control region offering treatment as usual. Patients in the experimental region were exposed to a case management programme guided by health insurance account manager who received trainings, quality circles and supervisions prior to intervention. Utilization rates of ambulatory psychiatrist and/or psychotherapist should be increased. Estimation of incremental cost effectiveness ratio (ICER) was intended.

Results

Intervention yielded benefits for patients at comparable costs. A conservative estimation of the ICER was 44,16 €. Maximum willingness to pay was 378,82 € per year. Sensitivity analyses showed that this amount of maximum willingness to pay can be reduced to 34,34 € per year or 2,86 € per month due to cost degression effects.

Conclusions

The intervention gains increasing cost effectiveness by the number of included patients and case managers. Cooperation between health insurances is suggested in order to minimize intervention cost and to maximize patient benefits. Results should be confirmed by individual longitudinal data (bottom-up approach) first.