Carsten P. Bramlage

Bone morphogenetic proteins promote cartilage differentiation and protect engineered artificial cartilage from fibroblast invasion and destruction.

OBJECTIVEnAn important role in joint and cartilage homeostasis in adults has been demonstrated recently for morphogenetic factors of the transforming growth factor beta family. Therefore, this study was undertaken to investigate the potential of bone morphogenetic proteins (BMPs) in chondrocyte differentiation using current technologies of tissue engineering.nnnMETHODSnComplementary DNAs of recombinant human BMPs 2, 4, 5, 6, and 7 were transfected into primary bovine articular chondrocytes. Transgenic chondrocytes were assembled 3-dimensionally in alginate or in bioresorbable co-polymer fleeces of vicryl and polydioxanon embedded in low-melting-point agarose. Redifferentiation and formation of cartilage tissue in vitro or after subcutaneous transplantation into nude mice were assayed by semiquantitative reverse transcriptase-polymerase chain reaction, histology, and in situ hybridization, and findings were compared with those in unmodified or control-transfected primary chondrocytes.nnnRESULTSnCompared with other BMPs and control vector, BMP-7 induced a decrease in type I collagen expression in artificial cartilage, while transcription of the cartilage-specific type II collagen remained stable. In transplantation experiments, BMP-7 transgenic cartilage revealed the greatest amount of matrix synthesis, and BMP-7 was the only morphogen to suppress the infiltrative response of mouse fibroblastic cells into engineered cartilage, thereby preventing transplant destruction.nnnCONCLUSIONnCartilage differentiation and matrix maturation are promoted by BMPs in cartilage engineering. The inhibitory effect of BMP-7 on a nonspecific infiltrative response in immunocompromised nude mice further suggests that individual morphogens not only may contribute to cartilage maturation, but also may protect it from nonspecific inflammation and invasive destruction. These properties advance BMPs as promising tools for engineering of cartilaginous joint bioprostheses and as candidate biologic agents or genes for cartilage stabilization in arthritis.

Retrospective Analysis of Long‐term Lipid Apheresis at a Single Center

We retrospectively analyzed 10u2003906 lipid apheresis sessions (heparin‐induced lipoprotein precipitation, direct adsorption of lipoproteins, double filtration plasmapheresis, dextran sulfate adsorption, and immunoadsorption) in 38 patients who were consecutively treated in our department during the last 20u2003years. The incidences of major cardiovascular events (MACE) (death, cerebrovascular accident, myocardial infarction, limb amputation, and renal vascular involvement) were taken separately as primary end‐points or as a combined end‐point. The time‐course of secondary end‐points (coronary and extracranial status of arteries, left ventricular function, occlusive artery disease, and calculated glomerular filtration rate [cGFR]) were also evaluated, as well as the extent of the reduction in plasma lipids and lipoproteins and the incidence of therapy associated side‐effects. MACE decreased from 7.02% events per patient per year at the start of lipid apheresis to 1.17% during lipid apheresis and the rate of myocardial revascularization decreased from 22.8% to 3.8% per patient per year. Classical (diabetes mellitus, arterial hypertension, and smoking history), as well as novel risk factors (cGFRu2003<u200360u2003mL/min, statin withdrawal, mixed hyperlipoproteinemia, and elevated lipoprotein (a)) were associated with an elevated risk for MACE. All applied methods had comparable effects. All lipid apheresis methods proved to be safe and suitable for long‐term treatment. The present data demonstrate that treatment with lipid apheresis is very effective and leads to long‐term reduction in cardiovascular mortality and morbidity.u2003

Targeted therapies for treatment of renal cell carcinoma: recent advances and future perspectives

PurposeA wide variety of targeted therapies are available for the treatment of renal cancer that has progressed beyond the point at which surgery is a viable option. In addition, there are many more that are in the different stages of clinical trials. Here, we provide a methodical discussion of the efficacy and safety of targeted therapies for the treatment of advanced renal cell carcinoma.MethodsWe conducted a systematic literature employing the search terms: renal cell carcinoma targets, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and each of the drugs discussed within these papers.ResultsThe identified targeted therapies work by disrupting specific signalling pathways involved in tumour progression, such as those responsible for angiogenesis and cell proliferation. Tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors are now established classes of drugs used in the treatment of renal cancer, with a total of six having received regulatory approval to date (sorafenib, sunitinib, pazopanib, axitinib, temsirolimus, and everolimus). Ongoing trials are likely to result in addition to these in the near future, for example, tivozanib, dovitinib, and cediranib. Furthermore, in addition to these small molecule drugs, immunotherapies involving monoclonal antibodies against signalling molecules such as vascular endothelial growth factor (bevacizumab) or programmed death-1 (nivolumab) are receiving increasing attention.ConclusionsTargeted therapies have great potential for disrupting tumour progression by inhibiting certain signalling pathways. As our understanding of the biochemical pathways involved in cancer progresses, additional targets are certain to become apparent, expanding treatment options even further.

Low-density lipoprotein apheresis decreases ferritin, transferrin and vitamin B12, which may cause anemia in serially treated patients.

Clinical observations revealed an increased prevalence of iron deficiency anemia without chronic bleeding in patients treated with serial low‐density lipoprotein (LDL) apheresis. Since several different proteins are adsorbed by LDL apheresis beside pro‐atherogenic lipoproteins, we examined the modification of the full blood count, plasma iron, vitamin B12, folic acid, and hemolysis by LDL apheresis. Nineteen patients (55 (50–59)u2003years, 4 female, 15 male) undergoing chronic LDL apheresis due to mixed dyslipidemia (Nu2003=u200317), homozygous familiar hypercholesterolemia (Nu2003=u20031) or isolated elevated lipoprotein(a) (Nu2003=u20031) were included in this study. They were treated with direct adsorption of lipoproteins (DALI; Nu2003=u20036), heparin‐induced LDL‐precipitation (HELP; Nu2003=u20037) or double filtration plasmapheresis (DFPP; Nu2003=u20036). The patients full blood count, iron metabolism (plasma iron, ferritin, transferrin, transferrin saturation), vitamins involved in erythropoiesis (vitamin B12 and folic acid), and markers of hemolysis (haptoglobin and free hemoglobin) were analyzed directly before and after LDL apheresis. A single LDL apheresis session significantly decreased the levels (reduction in the median [25th–75th percentiles] of: ferritin 9.8 [1.3–18] %; Pu2003=u20030.004), transferrin (12.1 [10.0–15.96] %; Pu2003=u20030.0005), and vitamin B12 (17.8 [16.2–20.8] %; Pu2003=u20030.0005). Thereby, transferrin and vitamin B12 were decreased in all (Nu2003=u200319) and ferritin in 74% (Nu2003=u200314) of the patients. Twelve out of 19 patients (63.2%) had mild anemia despite iron administration in 14 out of 19 patients (73.7%). LDL apheresis had no significant influence on full blood count, plasma iron, transferrin saturation, folic acid, or hemolysis. Similar changes were observed in all LDL apheresis methods used. LDL apheresis significantly decreases ferritin, transferrin, and vitamin B12, suggesting an influence of serial LDL apheresis on erythropoiesis.

Prenatal Dexamethasone Exposure Does Not Alter Blood Pressure and Nephron Number in the Young Adult Marmoset Monkey

The influence of prenatal factors on the development of arterial hypertension has gained considerable interest in recent years. Prenatal dexamethasone exposure was found to induce hypertension and to alter nephron number and size in rodents and sheep. However, it is not clear whether these findings are applicable to nonhuman primates. Thus, we examined the effects of prenatal dexamethasone treatment on blood pressure (BP) and nephron number in marmoset monkeys. Fifty-two marmosets were allotted to 3 groups according to the gestational stage during which their mothers were exposed to oral 5-mg/kg dexamethasone for 7 days (gestation period: 20 weeks): (1) the early dexamethasone group at week 7; (2) the late dexamethasone group at week 13; and (3) the control group. BP was determined by telemetric (n=12) or cuff measurements (n=30), along with cystatin C, proteinuria, and body weight. All of the animals were euthanized at the age of 24 months, and glomerular number and volume were determined. Prenatal exposure to dexamethasone did not lead to a significant difference between the groups with regard to BP, kidney morphology and function, or body weight. BP correlated significantly with body weight, relative kidney weight, and mean glomerular volume and the body weight with the glomerular volume regardless of dexamethasone treatment. In conclusion, prenatal exposure to dexamethasone in marmosets does not, in contrast to other mammals studied, result in hypertension or changes in kidney morphology. Our data support the role of body weight as a predictor of elevated glomerular volume and BP development rather than prenatal dexamethasone exposure.

Difference between renal and splenic resistive index as a novel criterion in Doppler evaluation of renal artery stenosis

Detection of renal artery stenosis (RAS) using Doppler is difficult to evaluate, particularly under conditions such as bilateral RAS or difficultly accessible renal arteries (RA). The objective of the present study was to assess the utility of splenic arterial compared to renal flow as an additional parameter in the Doppler evaluation of RAS. The difference between the resistive indices (RI) determined in renal and splenic parenchymal arteries (ΔRIK−S) was evaluated in 181 hypertensive subjects without any evidence of RAS. Subsequently 47 RA in 24 patients with suspected RAS were angiographically assessed. A ΔRIK−S of 0.055 (median) was determined in the population without any evidence of RAS similar to RA with angiographically excluded stenosis (ΔRIK−S 0.068). In contrast, in angiographic proven RAS, ΔRIK−S was significantly lower (−0.050; P < .005). The assessment of the ΔRIK−S, proved to be an easily feasible parameter, which improves the diagnostic accuracy in the detection of RAS.

Progrediente Niereninsuffizienz bei spontan auftretenden Cholesterinkristallembolien@@@Progressive Renal Failure in Spontaneous-Onset Cholesterol Crystal Embolism

ZusammenfassungFallbeschreibung:Ein 69-jähriger Patient wurde mit einem Kreatininanstieg von 1,4 auf 4,9 mg/dl innerhalb von 4 Monaten, lividen, schmerzhaften Effloreszenzen an den Füßen, rezidivierender Epistaxis und Gleichgewichtsstörungen aufgenommen. In der Vorgeschichte waren drei kürzlich aufgetretene transitorische ischämische Attacken sowie ein metabolisches Syndrom bekannt. Im kranialen Magnetresonanztomogramm zeigten sich fleckförmige vaskulitisähnliche zerebrale Signalanhebungen. Laborchemisch bestanden eine Eosinophilie sowie eine geringgradige Proteinurie vom tubulären Typ. Haut- und Nierenbiopsien erbrachten die Diagnose einer Cholesterinembolie als Ursache der Nierenfunktionsverschlechterung. Als mutmaßliche Quelle der rezidivierenden Cholesterinkristallembolien ließ sich eine massive Sklerose der Aorta sichern.Schlussfolgerung:Auch ohne vorausgehende angiographische Intervention muss bei rasch progredienter Niereninsuffizienz eines Atherosklerosepatienten insbesondere in höherem Alter die Differentialdiagnose Cholesterinkristallembolie in Betracht gezogen werden.AbstractCase Report:A 69-year-old man was admitted to the authors hospital with an increase of plasma creatinine from 1.4 up to 4.9 mg/dl within 4 months and the clinical complaints of painful purple toes, recurrent epistaxis and disturbances of equilibrium. His past medical history was remarkable for three transient ischemic attacks and the diagnosis of a metabolic syndrome. Magnetic resonance imaging showed vasculitis-like lesions in the brain. Eosinophilia and tubular proteinuria were detected. Renal insufficiency was caused by cholesterol crystal embolism, as shown both by skin and renal biopsy. Aortic plaques were identified as the putative source of cholesterol embolization.Conclusion:In case of rapidly progressive renal failure, cholesterol crystal embolism must be considered even without preceding angiography.CASE REPORTnA 69-year-old man was admitted to the authors hospital with an increase of plasma creatinine from 1.4 up to 4.9 mg/dl within 4 months and the clinical complaints of painful purple toes, recurrent epistaxis and disturbances of equilibrium. His past medical history was remarkable for three transient ischemic attacks and the diagnosis of a metabolic syndrome. Magnetic resonance imaging showed vasculitis-like lesions in the brain. Eosinophilia and tubular proteinuria were detected. Renal insufficiency was caused by cholesterol crystal embolism, as shown both by skin and renal biopsy. Aortic plaques were identified as the putative source of cholesterol embolization.nnnCONCLUSIONnIn case of rapidly progressive renal failure, cholesterol crystal embolism must be considered even without preceding angiography.

Prävention kardiovaskulärer Erkrankungen durch Blockade des Endocannabinoidsystems@@@Prevention of Cardiovascular Disease by Blocking the Endocannabinoid System

ZusammenfassungRisikofaktoren für die Entwicklung kardiovaskulärer Erkrankungen, insbesondere des akuten Myokardinfarkts, sind Nikotinabusus, Übergewicht, wenig Bewegung, ungünstige Ernährung, erhöhter Blutdruck, erhöhte Blutglucose bzw. Diabetes mellitus und eine Dyslipidämie. Wird ein Risiko für kardiovaskuläre Morbidität in den nächsten 10 Jahren von 5% (nach dem SCORE-Score) oder für nichttödliche kardiovaskuläre Ereignisse von 20% (PROCAM-Score) überschritten oder liegt eine Gefäßatherosklerose oder ein Diabetes mellitus Typ 2 vor, ist zur Prävention kardiovaskulärer Erkrankungen der Einsatz einer (Poly-)Pharmakotherapie angezeigt, eine Lebensstiländerung (Diät, körperliche Bewegung) allein reicht zu diesem Zeitpunkt in der Regel nicht mehr aus. Eine neue Therapieoption, die eine Reihe kardiovaskulärer Risikofaktoren gleichzeitig günstig beeinflusst, besteht in der Blockade des Endocannabinoidsystems. Für die Substanz Rimonabant wurde in klinischen Studien nicht nur eine Reduktion des Körpergewichts bzw. des Taillenumfangs, sondern auch ein Anstieg des HDL-Cholesterins sowie eine Absenkung der Triglyzeride nachgewiesen. Darüber hinaus wurde auch eine Verminderung des HbA1c bzw. der Nüchternglucose beobachtet. Einschließlich seiner nachgewiesenen Wirksamkeit in der Raucherentwöhnung beeinflusst Rimonabant damit vier der acht vom American College of Cardiology und von der American Heart Association genannten relevanten Risikofaktoren zur Prävention des akuten Myokardinfarkts. Ein umfangreiches klinisches Studienprogramm zur Erforschung von Rimonabant im Rahmen des kardiovaskulären Risikomanagements wird gegenwärtig durchgeführt. Die Substanz wird im Allgemeinen gut vertragen (häufigste Nebenwirkung: Übelkeit). Die bislang veröffentlichten Studienergebnisse zeigen ein gutes Verträglichkeitsprofil und sind vielversprechend im Hinblick auf den zukünftigen Stellenwert von Rimonabant im Rahmen des kardiovaskulären Risikomanagements.AbstractRisk factors for the development of cardiovascular disease, in particular myocardial infarction, are smoking, high body weight, sedentary lifestyle, unfavorable diet, high blood pressure, elevated fasting glucose or diabetes, and dyslipidemia (Tables 1 and 2). If the risk for cardiovascular mortality of 5% (using the SCORE Score) or for nonfatal cardiovascular events of 20% (PROCAM Score) within the next 10 years is exceeded or overt atherosclerosis or type 2 diabetes mellitus is present, the use of (poly)pharmacotherapy is indicated and lifestyle intervention (diet, physical activity) alone is not sufficient at that point (Figure 1). A new therapeutic option, able to modify a number of cardiovascular risk factors at a time, is the blockade of the so-called endocannabinoid system (Figure 2). For rimonabant not only a reduction of body weight and waist circumference was shown in clinical trials, its use was also accompanied by an increase of HDL cholesterol, a decrease in triglycerides, and a reduction in HbA1c and fasting blood glucose (Table 4). Together with preliminary data on the efficacy in smoking cessation, rimonabant has a therapeutic impact on four out of eight relevant risk factors in order to prevent myocardial infarction as promoted by the American College of Cardiology/American Heart Association. Currently, a large clinical study program is ongoing to further investigate the role of rimonabant in managing cardiovascular risk (Table 3). Published clinical trial results have revealed, that rimonabant is generally well tolerated (most frequent side effect: nausea) and the data are promising with regard to the potential future role of rimonabant in managing cardiovascular risk.

Pharmakoepidemiologie antihypertensiver Medikamente bei adipösen Patienten@@@Antihypertensive Drug Utilization in Obese Patients

ZusammenfassungHintergrund und Ziel:Adipositas und arterielle Hypertonie sind epidemisch und treten oft in Kombination auf. Trotz der Häufigkeit und der Schwierigkeiten bei der Einstellung dieser Patienten gibt es keine aktuellen Daten zur Verschreibung von Antihypertensiva in der primärärztlichen Versorgung bei dieser Patientenpopulation.Material und Methodik:Dazu wurden die Daten einer bundesweiten Beobachtungsstudie aus dem Jahre 2004 ausgewertet, die über 70 000 Patienten mit arterieller Hypertonie untersuchte. Es wurde dokumentiert, welchen antihypertensiven Substanzklassen bei adipösen Patienten der Vorzug gegeben wird, welches die am häufigsten verwendeten Substanzen sind und wie diese dosiert werden.Ergebnisse:1. Die antihypertensive Pharmakotherapie adipöser Patienten ist im Hinblick auf Substanzauswahl differenziert, aber nicht in der Dosierung. 2. Es werden häufiger als bei normalgewichtigen Vergleichspersonen Medikamentenkombinationen eingesetzt, um den Blutdruck dieser Patienten einzustellen. ACE-Hemmern und Diuretika wird hier der Vorzug gegeben.Schlussfolgerung:Diese Ergebnisse zeigen, dass die Verfügbarkeit einer großen Zahl von antihypertensiven Medikamenten nicht ausreicht, um eine adäquate Einstellung des Blutdrucks zu gewährleisten. Die frühzeitige Kombination von antihypertensiven Medikamenten in reduzierter Dosierung (α-Blocker, β-Blocker, Diuretika und Calciumantagonisten) in Kombination mit hohen Dosen von Hemmern des Renin-Angiotensin-Systems (RAS) könnte zur Steigerung der Effektivität bei gleichzeitiger Reduktion von Nebenwirkungen beitragen.AbstractBackground and Purpose:Obesity and arterial hypertension are epidemic and often seen in combination. In spite of the frequency and the difficulties in treating these patients to goal, there are no recent data on the prescription of antihypertensive drugs in primary care in this patient population.Material and Methods:Therefore, the data of a nationwide observational study from 2004 were evaluated in which more than 70,000 patients with Anaarterial hypertension were investigated. It was documented, which antihypertensive classes are preferred in obese patients, which are the most often used substances and how these are dosed.Results:(1) Antihypertensive pharmacotherapy of obese patients is differentiated in terms of substances used, but less in terms of dosage. (2) Combinations of drugs are more often used to control the blood pressure of these patients and ACE inhibitors and diuretics are most often preferred.Conclusion:These results show that the availability of a number of effective antihypertensive drugs is not sufficient to secure an adequate control of blood pressure. The timely combination of antihypertensive drugs in reduced dose (α-blockers, β-blockers, diuretics, and calcium antagonists) in combination with high doses of agents blocking the renin-angiotensin system (RAS) could improve the efficacy while reducing side effects.

[Polycythemia vera and D-dimer-negative thromboembolism].

ZusammenfassungFallbeschreibung:Eine 65-jährige Patientin stellte sich mit einem seit 1 Tag bestehenden schmerzhaften Ödem des rechten Arms vor. Seit 1988 ist bei der Patientin eine Polycythaemia vera (PV) bekannt. Die Gerinnungsparameter einschließlich der D-Dimere lagen im Normbereich. Phlebographisch wurde eine Thrombose der proximalen rechten V. subclavia diagnostiziert. 1 Woche nach stationärer Aufnahme entwickelte die Patientin eine D-Dimernegative symptomatische Lungenembolie.Schlussfolgerung:Bei klinischem Verdacht auf ein thromboembolisches Ereignis reicht die negative Prädiktion der D-Dimer-Bestimmung als Ausschlusskriterium allein nicht aus. In diesem Fall sollte der Patient einer bildgebenden Diagnostik zugeführt werden. Aufgrund der erhöhten Inzidenz thromboembolischer Ereignisse bei PV sollten die Patienten eine prophylaktische Thrombozytenaggregationshemmung, z. B. mit Acetylsalicylsäure 100 mg/d, erhalten.AbstractCase Report:A 65-year-old patient with polycythemia vera (PV) was admitted with a painful edema of the right arm lasting for 24 h. The D-dimer assay was negative. By phlebography the patient was diagnosed with a fresh thrombosis of the right subclavian vein. 1 week later she developed a D-dimer-negative symptomatic pulmonary embolism.Conclusion:If clinical signs of a thromboembolic event are present, the negative predictive value of the D-dimer assay is not sufficient to abandon further definitive diagnosis. Since thromboembolic events are frequent in PV patients, a prophylactic treatment with low-dose acetylsalicylic acid is recommended.