Gunter Wolf - Academia.edu (original) (raw)

Papers by Gunter Wolf

Medizinische Klinik, 2008

Eosinophilia is not uncommon in clinical practice. The main causes are allergies and parasitic in... more Eosinophilia is not uncommon in clinical practice. The main causes are allergies and parasitic infections. Rarely, eosinophilia is associated with pulmonary affections, malignant tumors, gastroenteritis, and autoimmune diseases. A new classification based on pathophysiological data for the hypereosinophilic syndrome in order to simplify diagnosis and therapy was introduced in 2006. A 22-year-old man was admitted to another hospital because of acute abdominal pain. An unspecific colitis was diagnosed. Blood counts showed a mild neutrophilic leukocytosis (12.6 Gpt/l) with a severe relative eosinophilia (30%), thrombocytopenia (67 Gpt/l), and an increased C-reactive protein (CRP 122 mg/l). The patient also had a deep venous thrombosis of the left leg. An explorative laparotomy was performed because of a strong suspicion of a presacral abscess. Pulmonary embolism and embolic pneumonia developed after surgery. A macular-cockade exanthema on the trunk and extremities was found. Histological examination revealed perivascular eosinophilic infiltrates. Histological and cytological analysis of bone marrow showed many eosinophilic granulocytes and a hypercellular medulla without increased numbers of blasts. No parasites in the blood and stools were found, and there was no evidence of neoplasm or cardiac involvement. p- and c-ANCAs (antineutrophil cytoplasmic antibodies), ANAs (antinuclear antibodies), and antibody against dsDNA were negative. Further genetic, FISH (fluorescence in situ hybridization), and PCR (polymerase chain reaction) analyses showed no evidence for chromosomal aberrations. An undefined hypereosinophilic syndrome with multiple organ involvement was diagnosed. Shortly after starting an oral prednisolone therapy (1 mg/kg body weight), the eosinophilia normalized. This therapy was stopped after 2 months and the patient is now, 6 months after diagnosis, in normal health. As demonstrated in this case, eosinophilia requires a broad differential diagnosis. A hypereosinophilic syndrome can involve many organs and mimic other diseases. The new classification of the hypereosinophilic syndrome from 2006, based on pathophysiological insights, may foster better diagnosis and therapy for this rare disease.

Rheumatology International, 2006

To investigate the relationship between ionized calcium and disease activity, parameters of bone ... more To investigate the relationship between ionized calcium and disease activity, parameters of bone metabolism and bone mineral density (BMD) at the lumbar spine (BMD-LS) and the femoral neck (BMD-FN) measured by dual X-ray absorptiometry in rheumatoid arthritis (RA). In 146 patients with RA, the following parameters were investigated: serum levels of ionized calcium, total calcium, vitamin D metabolites 25-hydroxyvitamin D3 (25D3) and 1,25-dihydroxyvitamin D3 (1,25D3), intact parathyroid hormone (iPTH), interleukin-6, osteocalcin, erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP); renal excretion of pyridinolin (PYD)- and desoxypyridinolin (DPD)-crosslinks. A total of 30.1% of the patients were hypercalcemic (ionized calcium >1.30 mmol/l). In comparison with normocalcemic patients, those with hypercalcemia had significantly higher ESR (P<0.01) and CRP values (P<0.05) and significantly lower serum levels of both iPTH (P<0.01) and 1,25D3 (P<0.05) and a significantly lower BMD-LS (P<0.05). The results indicate that a substantial part of RA patients is hypercalcemic. Hypercalcemia is associated with high disease activity and may contribute to suppression of PTH secretion and vitamin D hormone synthesis. High levels of ionized calcium may be a reflection of disease-activity-related systemic bone loss, and could be a predictor of BMD at the lumbar spine in RA.

Rheumatology International, 2010

The objective of this study is to investigate the relationship between soluble components of the ... more The objective of this study is to investigate the relationship between soluble components of the interleukin 6 (IL-6) system mediating and modifying IL-6 trans-signaling and the RANKL-RANK-osteoprotegerin system in postmenopausal women with rheumatoid arthritis (RA). The following parameters were investigated in 126 postmenopausal women with RA: IL-6, soluble IL-6-receptor (sIL-6R), soluble glycoprotein 130 (sgp130), sRANKL, osteoprotegerin (OPG), osteocalcin, erythrocyte sedimentation rate and C-reactive protein in sera, pyridinolin and desoxypyridinolin crosslinks in the morning urine. Bone mineral density (BMD) was measured by dual X-ray absorptiometry at the lumbar spine (BMD-LS) and at the femoral neck (BMD-FN). Predictors of RANKL/OPG ratio and BMD were evaluated by multiple linear regression analysis. The following determinants of the RANKL/OPG ratio were identified: sIL-6R/sgp130 ratio and daily glucocorticoid (GC) dose as positive determinants in the whole group (R (2) = 0.56; P = 0.001), sIL-6R/sgp130 ratio as the exclusive positive determinant in patients with GC therapy (R (2) = 0.48; P = 0.001) and sgp130 as negative determinant in patients without GC (R (2) = 0.42; P = 0.031). Sgp130 was highly significantly positively correlated with OPG in the whole group (P < 0.001) as well as in patients with (n = 70; P < 0.05) and without GC therapy (n = 56; P < 0.01). sIL-6R was the main negative predictor of BMD-LS (R (2) = 0.41; P = 0.019). High sIL-6R/sgp130 ratio and/or low sgp130 are associated with a high sRANKL/OPG ratio in sera of postmenopausal women with RA indicating the critical significance of IL-6 trans-signaling for an increase in the RANKL/OPG ratio and of bone resorption. Inhibition of IL-6 trans-signaling may be an effective bone-protecting principle in postmenopausal women with RA.

Rheumatology International, 2008

The aim of the present study was to evaluate the effect of long-term leflunomide and methotrexate... more The aim of the present study was to evaluate the effect of long-term leflunomide and methotrexate (MTX) therapy during the course of rheumatoid arthritis (RA) estimated by digital X-ray radiogrammetry (DXR) and computer-aided joint space analysis (CAJSA) as diagnostic tools for the quantification of disease-related periarticular osteoporosis and joint space narrowing. Fourty matchable patients with verified RA were treated with leflunomide or MTX during an observation period of 2.5 years. All patients underwent complete computerized calculations of bone mineral density (BMD) and metacarpal index (MCI) by DXR as well as semi-automated measurements of joint space widths (JSW) at the metacarpophalangeal articulations (MCP, thumb to small finger) and proximal interphalangeal joints (PIP, index finger to small finger) using digitized hand radiographs. DXR-BMD revealed an increase of 0.4% (leflunomide-group) versus a reduction of -9.1% (MTX-group). Regarding DXR-MCI, a reduction of -1.1% (leflunomide-group) and -5.3% (MTX-group) was observed. The CAJSA parameters showed a decline of -2.7% (JSW-MCP) versus -2.1% (JSW-PIP) in patients treated with leflunomide. An accentuated joint space narrowing was revealed (JSW-MCP: -5.7%; JSW-PIP: -6.2%) in the MTX group. Digital X-ray radiogrammetry and CAJSA could discriminate the influence of different therapeutic regimes on periarticular osteoporosis and joint space narrowing showing a less accentuated radiographic progression in patients treated with leflunomide.

Rheumatology International, 2008

To evaluate the associations between sex, age, body mass index (BMI) and handedness regarding the... more To evaluate the associations between sex, age, body mass index (BMI) and handedness regarding the radiogeometric detectable joint space distances of the finger articulations in patients suffering from a prolonged course of rheumatoid arthritis (RA). The joint space widths were measured by a new available Computer-aided joint space analysis (CAJSA); 128 patients with RA underwent computerized semi-automated joint space analysis of joint space distances at the metacarpal-phalangeal articulation (JSD-MCP II-V), proximal-interphalangeal joint (JSD-PIP II-V) and distal-interphalangeal joint (JSD-DIP II-V) based on digitally performed radiographs of the hand (Radiogrammetry Kit, Version 1.3.6; Sectra; Sweden). The joint space distance (JSD) of each articulation was expressed as JSD total in millimeter. The patient cohort was differentiated for gender, age, handedness and BMI (BMI < 20; BMI 20-25, BMI > 25). JSD revealed a significant age-related narrowing of 24.8% (JSD-MCP), 22.6% (JSD-PIP) and 28.7% (JSD-DIP) between the ages of 20 and 79. Additionally, males showed a significantly wider JSD compared to the female cohort for all age groups. All JSD-distances were varied between the right and left hand. The JSD-MCP demonstrated significant differences regarding the BMI groups. In contrast to JSD-MCP an effect of the BMI on measurements of JSD-PIP and JSD-DIP could not be observed. These influences must be differentiated from disease-related alterations caused by RA.

Neuroscience Letters, 2009

The Lancet, 2003

Proteinuria is a major cause of progression in renal disease. The glomerular ultrafiltration barr... more Proteinuria is a major cause of progression in renal disease. The glomerular ultrafiltration barrier, containing highly differentiated podocytes, normally restricts protein access to the urine. Patients with urinary protein in the nephrotic range (>3.5 g daily) often have effaced podocyte foot-processes. Slit diaphragms span the gaps between foot processes as a barrier to macromolecules. Nephrin and podocin are slit-diaphragm proteins identified in families with congenital nephrotic syndromes. CD2-associated protein (CD2AP) is an adapter protein originally identified as a novel ligand interacting with the T-cell-adhesion protein CD2. CD2AP knockout (-/-) mice develop a congenital nephrotic syndrome with podocyte foot-process effacements and die at 6 weeks of age from renal failure. CD2AP localises to the slit diaphragm and links nephrin and podocin to phosphoinositide 3-OH kinase; this complex has cell-signalling properties. The CD2AP +/- heterozygous mice developed by Jeong Kim and colleagues (Science 2003; 300: 1298-300) are haploinsufficient and develop glomerular changes at 9 months of age with a histological pattern similar to that in human focal segmental glomerulosclerosis. These researchers found that 2 of 30 African-American patients with idiopathic focal segmental glomerulosclerosis had a CD2AP mutation that ablated expression of one allele. WHERE NEXT? Further studies should address the normal distribution of the CD2AP heterozygous mutation in different ethnic populations, because the association with human idiopathic focal segmental glomerulosclerosis could be accidental. Decreased expression of CD2AP in podocytes of individuals with the CD2AP heterozygous mutation would help to understand how the haploinsufficiency translates into increased susceptibility to renal disease. Transfection of podocytes with mutated CD2AP or study of cultured podocytes from CD2AP +/- mice would provide further insight into whether the nephrin-podocin-CD2AP signal-transduction pathway is altered and leads to increased apoptosis of podocytes. Assuming that a decrease in CD2AP attenuates clearance of glomerular immune complexes, patients with other types of idiopathic glomerulonephritis should also have a CD2AP mutation. However, first studies looking at the most common form of glomerulonephritis, IgA nephropathy, have failed to show decreased renal CD2AP expression.

Kidney International, 1990

Clinical Imaging, 2013

Image quality of gadofosveset trisodium-enhanced magnetic resonance venography (MRV) of the upper... more Image quality of gadofosveset trisodium-enhanced magnetic resonance venography (MRV) of the upper extremities was evaluated. Imaging was performed using a 3D Fast Low Angle Shot gradient recalled echo sequence (3D FLASH) and 3D gradient echo Volumetric Interpolated Breath-hold Examination with fat suppression (3D VIBE FS). Image quality was evaluated by two raters. 3D FLASH sequences demonstrated good image quality for depiction of the central venous system; 3D VIBE FS sequences showed good image quality for peripheral veins. MRV using Gadofosveset trisodium enables good quality depiction of the venous system of the upper extremities.

CardioVascular and Interventional Radiology, 2009

This case report describes cardiac manifestations in a female patient with Churg-Strauss syndrome... more This case report describes cardiac manifestations in a female patient with Churg-Strauss syndrome (CSS). Cardiac magnetic resonance imaging (CMRI) is the only imaging modality able to depict cardiac involvement with endomyocardial fibrosis, myocardial edema, pericarditis associated with pericardial effusions, and apical thrombi in the left or right ventricle. The encasement of the tricuspid valve caused by an obliterating thrombus of the right ventricular cavity, as observed in our patient, is very rare. CMRI is a potentially important diagnostic tool for the early detection of dangerous cardiac complications of CSS, allowing optimal and timely therapy and reducing the comorbidity of the disease.

American Journal of Nephrology, 2002

Background: Richard Bright (1789–1858) discovered that edema and proteinuria are linked with rena... more Background: Richard Bright (1789–1858) discovered that edema and proteinuria are linked with renal disease. Friedrich Theodor von Frerichs (1819–1885) performed microscopic studies on Bright’s disease and wrote the first German textbook of nephrology. The present contribution analyzes Frerichs’ work. Methods: Frerichs’ career and his book Die Bright`sche Nierenkrankheit und deren Behandlung are examined in terms of contemporary medical knowledge. Results: Frerichs conducted clinical and microscopic studies that led him to conclude that Bright’s disease is a single pathological entity with many possible causes. Frerichs identified three stages through which the condition progresses. Although an oversimplification, Frerichs’ various stages are reflected in the current notion that chronic renal disease, irrespectively of its etiology, relentlessly progresses to end-stage renal failure with common features of tubulointerstitial fibrosis and tubular atrophy. After writing his monograph, ...

American Journal of Nephrology, 2011

Background/Aims: The interaction of ‘advanced glycation end products’ (AGEs) and their receptor ‘... more Background/Aims: The interaction of ‘advanced glycation end products’ (AGEs) and their receptor ‘RAGE’ plays an important role in diabetic nephropathy. We have previously found that in cultured differentiated podocytes, angiotensin II (ANG II) induces RAGE expression via an AT2 receptor-mediated pathway. Methods: To further confirm our results in an in vivo study, AT2 receptor knockout mice (AT2–/–) and wild-type mice were infused with ANG II by osmotic minipumps for 14 days. Results: As shown by immunohistochemistry, ANG II treatment of wild-type animals (C57BL6) allowed a significantly increased RAGE expression in renal podocytes in comparison to sham-operated C57BL6 mice. In contrast, RAGE expression in podocytes of ANG II-treated knockout mice (AT2–/–) was only moderately higher than in control animals, but significantly lower than in ANG II-treated wild-type mice. For the AGE species NΕ-carboxymethyllysine, a similar immunohistochemical staining pattern was found. There was no ...

Kidney International, 2002

Angiotensin II (ANG II) can have multiple effects on the kidney, including influences on the regu... more Angiotensin II (ANG II) can have multiple effects on the kidney, including influences on the regulation of glomerular hemodynamics and tubular transport as well as consequences for the glomerular processing of macromolecules. The recognized suppressive ef- fects of angiotensin-converting enzyme inhibitors on compensatory renal growth, even in the absence of hemodynamic effects, and the well-documented proliferative effect of ANG II

BMC Musculoskeletal Disorders, 2015

Introduction: The established scoring techniques based on radiographs present limitations in the ... more Introduction: The established scoring techniques based on radiographs present limitations in the evaluation of structural integrity due to high effectiveness of innovative therapeutic strategies. The aim of this study was to evaluate the periarticular mineralisation as detected by Digital X-ray Radiogrammetry (DXR) as surrogate marker for structural integrity during the course of rheumatoid arthritis (RA). Methods: 11 centers throughout Germany contributed data of 94 patients with verified RA. The patients were treated with leflunomide or methotrexate during a mean observation period of 22 months. All patients underwent complete computerized calculations of bone mineral density (BMD) and metacarpal index (MCI) by DXR using digitized hand radiographs. The radiological assessment of disease progression was estimated by the Sharp Score. Results: The Sharp Score revealed no significant change during the study period. DXR-BMD revealed minimal decrease of −1.4 % (leflunomide group) versus a higher reduction of −4.3 % (methotrexate group). Regarding DXR-MCI, a reduction of −2.2 % (leflunomide group) and −4.9 % (methotrexate group) was observed. Conclusion: Quantitative data of hand bone mass estimated by the presented DXR-technique may be a complementary precise tool in the identification of RA-related radiographic changes and in the assessment of structural integrity.

Der Gynäkologe, 2014

ABSTRACT Je fortgeschrittener die Funktionseinschränkung der Niere ist, desto größer ist die Wahr... more ABSTRACT Je fortgeschrittener die Funktionseinschränkung der Niere ist, desto größer ist die Wahrscheinlichkeit einer Infertilität oder des Auftretens von (Prä-)Eklampsie, Frühgeburt, fetalen Wachstumsstörungen und langfristiger nephrologischer Probleme bei einer eingetretenen Schwangerschaft. Die Betreuung und Beratung nierenkranker Patientinnen sollte schon präkonzeptionell erfolgen. Eine frühzeitige Bestimmung der Kreatinin-Clearance, der Proteinurie (optimal im Sammelurin) und des Blutdrucks helfen, bei geplanter oder eingetretener Schwangerschaft niereninsuffizienter Patientinnen den Verlauf besser zu beurteilen. Viele der aus nephrologischer Indikation eingesetzten Medikamente können wegen fetaler Nebenwirkungen nicht gegeben werden, bei eingeschränkter glomerulärer Filtrationsrate muss zudem oft eine Dosisanpassung erfolgen. Eine interdisziplinäre Betreuung nierenkranker Schwangerer sollte obligat erfolgen. Abstract The risk of infertility, the incidence of (pre)eclampsia, preterm delivery, fetal growth restriction and long-term renal complications increase with the stage of renal insufficiency in pregnant women. Medical care of such patients should be initiated before conception. Early determination of creatinine clearance, proteinuria (optimal in 24 h urine) and blood pressure before or during the early stages of pregnancy help physicians to assess the time course of renal function and to detect any complications. Physicians should be aware of the risk of fetal side effects of several drugs as well as dose adjustment according to renal excretory function. Supervision of pregnant women with renal diseases by an interdisciplinary team should be obligatory.

Thrombosis and Haemostasis, 2009

SummaryThrombocytopenia during pregnancy is a common diagnostic and management problem. Several d... more SummaryThrombocytopenia during pregnancy is a common diagnostic and management problem. Several differential diagnosis must be considered including manifestations of thrombotic thrombocytopenic purpura (TTP). We report here on a case of a 21-year-old pregnant woman who presented initially severe thrombocytopenia (8 Gpt/l) in the 20th+1 week of gestation. The patient had an antibody against ADAMTS13, and enzyme activity was <5%. Immediate plasmapheresis treatment was initiated, followed by plasma infusions, and again plasmapheresis. A male neonate was delivered by caesarean section in the 32nd week of gestation. The child had an uncomplicated postnatal development. After delivery, the mother’s platelet count and ADAMTS13 activity increased to normal values. This case shows interesting aspects of TTP in pregnancy and a close cooperation between obstetricians, nephrologists and pediatricians is necessary for a successful outcome of the pregnancy.

Nephrology Dialysis Transplantation, 2008

In the poor Whitechapel district of the East End of London in the fall of 1888, at least five pro... more In the poor Whitechapel district of the East End of London in the fall of 1888, at least five prostitutes were brutally murdered, and in all but one case, also mutilated. The murderer was never caught and became known by his nickname 'Jack the Ripper'. The left kidney and the uterus were cut out and taken away from one of the victims named Catherine Eddowes. A kidney was also cut out of the body from another victim, but not taken away. Two weeks later, George Lusk, president of the Whitechapel Vigilance Committee, received a small cardboard box with half of a longitudinally divided kidney and a letter entitled 'From hell' claiming that the kidney inside the box was taken from the victim. The kidney was brought to Dr Thomas Horrocks Openshaw, the Curator of the London Pathological Museum, where the kidney could be microscopically examined. The press jumped on the topic and made a circumstantial case that this kidney had been indeed torn from the body of Catherine Eddowes. According to the later memoirs of Major Henry Smith of the City Police published more than 20 years after the incident, the kidney left in the corpse of Catherine Eddowes was in an advanced stage of Bright's disease and the kidney sent to George Lusk was in exactly a similar stage. Today, the majority of criminologists believe that the kidney sent to Mr Lusk was a hoax as were other letters signed with Jack the Ripper. However, the murderer took organs from his victims, and in the case of Catherine Eddowes, the kidney. Serial killers often mutilate their victims and abscond with the removed body parts as trophies. By removing the kidney from Catherine Eddowes, Jack the Ripper may have tried to take possession of the conscience, emotions and desires of one of his victims, attributes residing in the kidney as described in the Bible. Jack the Ripper was never caught; many suspects have been suggested, and the murder series ended as suddenly as it had begun. We will never know who this mentally disturbed 'nephrophilic' was. Today, the story of Jack the Ripper is part of contemporary culture.

Journal of Medicinal Chemistry, 2005

Diabetes Care, 2013

OBJECTIVE Patients with diabetes and insulin therapy with human insulin were usually instructed t... more OBJECTIVE Patients with diabetes and insulin therapy with human insulin were usually instructed to use an interval of 20–30 min between the injection and meal. We examined the necessity of the injection-to-meal interval (IMI) in patients with type 2 diabetes mellitus (T2DM) and flexible insulin therapy with human insulin. RESEARCH DESIGN AND METHODS In this randomized, open crossover trial, 100 patients with T2DM (47% men, mean age = 66.7 years) were randomized to the IMI first group (phase 1, IMI 20 min; phase 2, no IMI) or IMI last group (phase 1, no IMI; phase 2, IMI 20 min). The main outcome measures were HbA1c, blood glucose profile, incidence of hypoglycemia, quality of life, treatment satisfaction, and patient preference. RESULTS Forty-nine patients were randomized to the IMI first group and 51 patients to the IMI last group. Omitting the IMI only slightly increases HbA1c (average intraindividual difference = 0.08% [95% CI 0.01–0.15]). Since the difference is not clinically r...

Medizinische Klinik, 2008

Eosinophilia is not uncommon in clinical practice. The main causes are allergies and parasitic in... more Eosinophilia is not uncommon in clinical practice. The main causes are allergies and parasitic infections. Rarely, eosinophilia is associated with pulmonary affections, malignant tumors, gastroenteritis, and autoimmune diseases. A new classification based on pathophysiological data for the hypereosinophilic syndrome in order to simplify diagnosis and therapy was introduced in 2006. A 22-year-old man was admitted to another hospital because of acute abdominal pain. An unspecific colitis was diagnosed. Blood counts showed a mild neutrophilic leukocytosis (12.6 Gpt/l) with a severe relative eosinophilia (30%), thrombocytopenia (67 Gpt/l), and an increased C-reactive protein (CRP 122 mg/l). The patient also had a deep venous thrombosis of the left leg. An explorative laparotomy was performed because of a strong suspicion of a presacral abscess. Pulmonary embolism and embolic pneumonia developed after surgery. A macular-cockade exanthema on the trunk and extremities was found. Histological examination revealed perivascular eosinophilic infiltrates. Histological and cytological analysis of bone marrow showed many eosinophilic granulocytes and a hypercellular medulla without increased numbers of blasts. No parasites in the blood and stools were found, and there was no evidence of neoplasm or cardiac involvement. p- and c-ANCAs (antineutrophil cytoplasmic antibodies), ANAs (antinuclear antibodies), and antibody against dsDNA were negative. Further genetic, FISH (fluorescence in situ hybridization), and PCR (polymerase chain reaction) analyses showed no evidence for chromosomal aberrations. An undefined hypereosinophilic syndrome with multiple organ involvement was diagnosed. Shortly after starting an oral prednisolone therapy (1 mg/kg body weight), the eosinophilia normalized. This therapy was stopped after 2 months and the patient is now, 6 months after diagnosis, in normal health. As demonstrated in this case, eosinophilia requires a broad differential diagnosis. A hypereosinophilic syndrome can involve many organs and mimic other diseases. The new classification of the hypereosinophilic syndrome from 2006, based on pathophysiological insights, may foster better diagnosis and therapy for this rare disease.

Rheumatology International, 2006

To investigate the relationship between ionized calcium and disease activity, parameters of bone ... more To investigate the relationship between ionized calcium and disease activity, parameters of bone metabolism and bone mineral density (BMD) at the lumbar spine (BMD-LS) and the femoral neck (BMD-FN) measured by dual X-ray absorptiometry in rheumatoid arthritis (RA). In 146 patients with RA, the following parameters were investigated: serum levels of ionized calcium, total calcium, vitamin D metabolites 25-hydroxyvitamin D3 (25D3) and 1,25-dihydroxyvitamin D3 (1,25D3), intact parathyroid hormone (iPTH), interleukin-6, osteocalcin, erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP); renal excretion of pyridinolin (PYD)- and desoxypyridinolin (DPD)-crosslinks. A total of 30.1% of the patients were hypercalcemic (ionized calcium &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;1.30 mmol/l). In comparison with normocalcemic patients, those with hypercalcemia had significantly higher ESR (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01) and CRP values (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) and significantly lower serum levels of both iPTH (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01) and 1,25D3 (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) and a significantly lower BMD-LS (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). The results indicate that a substantial part of RA patients is hypercalcemic. Hypercalcemia is associated with high disease activity and may contribute to suppression of PTH secretion and vitamin D hormone synthesis. High levels of ionized calcium may be a reflection of disease-activity-related systemic bone loss, and could be a predictor of BMD at the lumbar spine in RA.

Rheumatology International, 2010

The objective of this study is to investigate the relationship between soluble components of the ... more The objective of this study is to investigate the relationship between soluble components of the interleukin 6 (IL-6) system mediating and modifying IL-6 trans-signaling and the RANKL-RANK-osteoprotegerin system in postmenopausal women with rheumatoid arthritis (RA). The following parameters were investigated in 126 postmenopausal women with RA: IL-6, soluble IL-6-receptor (sIL-6R), soluble glycoprotein 130 (sgp130), sRANKL, osteoprotegerin (OPG), osteocalcin, erythrocyte sedimentation rate and C-reactive protein in sera, pyridinolin and desoxypyridinolin crosslinks in the morning urine. Bone mineral density (BMD) was measured by dual X-ray absorptiometry at the lumbar spine (BMD-LS) and at the femoral neck (BMD-FN). Predictors of RANKL/OPG ratio and BMD were evaluated by multiple linear regression analysis. The following determinants of the RANKL/OPG ratio were identified: sIL-6R/sgp130 ratio and daily glucocorticoid (GC) dose as positive determinants in the whole group (R (2) = 0.56; P = 0.001), sIL-6R/sgp130 ratio as the exclusive positive determinant in patients with GC therapy (R (2) = 0.48; P = 0.001) and sgp130 as negative determinant in patients without GC (R (2) = 0.42; P = 0.031). Sgp130 was highly significantly positively correlated with OPG in the whole group (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) as well as in patients with (n = 70; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) and without GC therapy (n = 56; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). sIL-6R was the main negative predictor of BMD-LS (R (2) = 0.41; P = 0.019). High sIL-6R/sgp130 ratio and/or low sgp130 are associated with a high sRANKL/OPG ratio in sera of postmenopausal women with RA indicating the critical significance of IL-6 trans-signaling for an increase in the RANKL/OPG ratio and of bone resorption. Inhibition of IL-6 trans-signaling may be an effective bone-protecting principle in postmenopausal women with RA.

Rheumatology International, 2008

The aim of the present study was to evaluate the effect of long-term leflunomide and methotrexate... more The aim of the present study was to evaluate the effect of long-term leflunomide and methotrexate (MTX) therapy during the course of rheumatoid arthritis (RA) estimated by digital X-ray radiogrammetry (DXR) and computer-aided joint space analysis (CAJSA) as diagnostic tools for the quantification of disease-related periarticular osteoporosis and joint space narrowing. Fourty matchable patients with verified RA were treated with leflunomide or MTX during an observation period of 2.5 years. All patients underwent complete computerized calculations of bone mineral density (BMD) and metacarpal index (MCI) by DXR as well as semi-automated measurements of joint space widths (JSW) at the metacarpophalangeal articulations (MCP, thumb to small finger) and proximal interphalangeal joints (PIP, index finger to small finger) using digitized hand radiographs. DXR-BMD revealed an increase of 0.4% (leflunomide-group) versus a reduction of -9.1% (MTX-group). Regarding DXR-MCI, a reduction of -1.1% (leflunomide-group) and -5.3% (MTX-group) was observed. The CAJSA parameters showed a decline of -2.7% (JSW-MCP) versus -2.1% (JSW-PIP) in patients treated with leflunomide. An accentuated joint space narrowing was revealed (JSW-MCP: -5.7%; JSW-PIP: -6.2%) in the MTX group. Digital X-ray radiogrammetry and CAJSA could discriminate the influence of different therapeutic regimes on periarticular osteoporosis and joint space narrowing showing a less accentuated radiographic progression in patients treated with leflunomide.

Rheumatology International, 2008

To evaluate the associations between sex, age, body mass index (BMI) and handedness regarding the... more To evaluate the associations between sex, age, body mass index (BMI) and handedness regarding the radiogeometric detectable joint space distances of the finger articulations in patients suffering from a prolonged course of rheumatoid arthritis (RA). The joint space widths were measured by a new available Computer-aided joint space analysis (CAJSA); 128 patients with RA underwent computerized semi-automated joint space analysis of joint space distances at the metacarpal-phalangeal articulation (JSD-MCP II-V), proximal-interphalangeal joint (JSD-PIP II-V) and distal-interphalangeal joint (JSD-DIP II-V) based on digitally performed radiographs of the hand (Radiogrammetry Kit, Version 1.3.6; Sectra; Sweden). The joint space distance (JSD) of each articulation was expressed as JSD total in millimeter. The patient cohort was differentiated for gender, age, handedness and BMI (BMI &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 20; BMI 20-25, BMI &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 25). JSD revealed a significant age-related narrowing of 24.8% (JSD-MCP), 22.6% (JSD-PIP) and 28.7% (JSD-DIP) between the ages of 20 and 79. Additionally, males showed a significantly wider JSD compared to the female cohort for all age groups. All JSD-distances were varied between the right and left hand. The JSD-MCP demonstrated significant differences regarding the BMI groups. In contrast to JSD-MCP an effect of the BMI on measurements of JSD-PIP and JSD-DIP could not be observed. These influences must be differentiated from disease-related alterations caused by RA.

Neuroscience Letters, 2009

The Lancet, 2003

Proteinuria is a major cause of progression in renal disease. The glomerular ultrafiltration barr... more Proteinuria is a major cause of progression in renal disease. The glomerular ultrafiltration barrier, containing highly differentiated podocytes, normally restricts protein access to the urine. Patients with urinary protein in the nephrotic range (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;3.5 g daily) often have effaced podocyte foot-processes. Slit diaphragms span the gaps between foot processes as a barrier to macromolecules. Nephrin and podocin are slit-diaphragm proteins identified in families with congenital nephrotic syndromes. CD2-associated protein (CD2AP) is an adapter protein originally identified as a novel ligand interacting with the T-cell-adhesion protein CD2. CD2AP knockout (-/-) mice develop a congenital nephrotic syndrome with podocyte foot-process effacements and die at 6 weeks of age from renal failure. CD2AP localises to the slit diaphragm and links nephrin and podocin to phosphoinositide 3-OH kinase; this complex has cell-signalling properties. The CD2AP +/- heterozygous mice developed by Jeong Kim and colleagues (Science 2003; 300: 1298-300) are haploinsufficient and develop glomerular changes at 9 months of age with a histological pattern similar to that in human focal segmental glomerulosclerosis. These researchers found that 2 of 30 African-American patients with idiopathic focal segmental glomerulosclerosis had a CD2AP mutation that ablated expression of one allele. WHERE NEXT? Further studies should address the normal distribution of the CD2AP heterozygous mutation in different ethnic populations, because the association with human idiopathic focal segmental glomerulosclerosis could be accidental. Decreased expression of CD2AP in podocytes of individuals with the CD2AP heterozygous mutation would help to understand how the haploinsufficiency translates into increased susceptibility to renal disease. Transfection of podocytes with mutated CD2AP or study of cultured podocytes from CD2AP +/- mice would provide further insight into whether the nephrin-podocin-CD2AP signal-transduction pathway is altered and leads to increased apoptosis of podocytes. Assuming that a decrease in CD2AP attenuates clearance of glomerular immune complexes, patients with other types of idiopathic glomerulonephritis should also have a CD2AP mutation. However, first studies looking at the most common form of glomerulonephritis, IgA nephropathy, have failed to show decreased renal CD2AP expression.

Kidney International, 1990

Clinical Imaging, 2013

Image quality of gadofosveset trisodium-enhanced magnetic resonance venography (MRV) of the upper... more Image quality of gadofosveset trisodium-enhanced magnetic resonance venography (MRV) of the upper extremities was evaluated. Imaging was performed using a 3D Fast Low Angle Shot gradient recalled echo sequence (3D FLASH) and 3D gradient echo Volumetric Interpolated Breath-hold Examination with fat suppression (3D VIBE FS). Image quality was evaluated by two raters. 3D FLASH sequences demonstrated good image quality for depiction of the central venous system; 3D VIBE FS sequences showed good image quality for peripheral veins. MRV using Gadofosveset trisodium enables good quality depiction of the venous system of the upper extremities.

CardioVascular and Interventional Radiology, 2009

This case report describes cardiac manifestations in a female patient with Churg-Strauss syndrome... more This case report describes cardiac manifestations in a female patient with Churg-Strauss syndrome (CSS). Cardiac magnetic resonance imaging (CMRI) is the only imaging modality able to depict cardiac involvement with endomyocardial fibrosis, myocardial edema, pericarditis associated with pericardial effusions, and apical thrombi in the left or right ventricle. The encasement of the tricuspid valve caused by an obliterating thrombus of the right ventricular cavity, as observed in our patient, is very rare. CMRI is a potentially important diagnostic tool for the early detection of dangerous cardiac complications of CSS, allowing optimal and timely therapy and reducing the comorbidity of the disease.

American Journal of Nephrology, 2002

Background: Richard Bright (1789–1858) discovered that edema and proteinuria are linked with rena... more Background: Richard Bright (1789–1858) discovered that edema and proteinuria are linked with renal disease. Friedrich Theodor von Frerichs (1819–1885) performed microscopic studies on Bright’s disease and wrote the first German textbook of nephrology. The present contribution analyzes Frerichs’ work. Methods: Frerichs’ career and his book Die Bright`sche Nierenkrankheit und deren Behandlung are examined in terms of contemporary medical knowledge. Results: Frerichs conducted clinical and microscopic studies that led him to conclude that Bright’s disease is a single pathological entity with many possible causes. Frerichs identified three stages through which the condition progresses. Although an oversimplification, Frerichs’ various stages are reflected in the current notion that chronic renal disease, irrespectively of its etiology, relentlessly progresses to end-stage renal failure with common features of tubulointerstitial fibrosis and tubular atrophy. After writing his monograph, ...

American Journal of Nephrology, 2011

Background/Aims: The interaction of ‘advanced glycation end products’ (AGEs) and their receptor ‘... more Background/Aims: The interaction of ‘advanced glycation end products’ (AGEs) and their receptor ‘RAGE’ plays an important role in diabetic nephropathy. We have previously found that in cultured differentiated podocytes, angiotensin II (ANG II) induces RAGE expression via an AT2 receptor-mediated pathway. Methods: To further confirm our results in an in vivo study, AT2 receptor knockout mice (AT2–/–) and wild-type mice were infused with ANG II by osmotic minipumps for 14 days. Results: As shown by immunohistochemistry, ANG II treatment of wild-type animals (C57BL6) allowed a significantly increased RAGE expression in renal podocytes in comparison to sham-operated C57BL6 mice. In contrast, RAGE expression in podocytes of ANG II-treated knockout mice (AT2–/–) was only moderately higher than in control animals, but significantly lower than in ANG II-treated wild-type mice. For the AGE species NΕ-carboxymethyllysine, a similar immunohistochemical staining pattern was found. There was no ...

Kidney International, 2002

Angiotensin II (ANG II) can have multiple effects on the kidney, including influences on the regu... more Angiotensin II (ANG II) can have multiple effects on the kidney, including influences on the regulation of glomerular hemodynamics and tubular transport as well as consequences for the glomerular processing of macromolecules. The recognized suppressive ef- fects of angiotensin-converting enzyme inhibitors on compensatory renal growth, even in the absence of hemodynamic effects, and the well-documented proliferative effect of ANG II

BMC Musculoskeletal Disorders, 2015

Introduction: The established scoring techniques based on radiographs present limitations in the ... more Introduction: The established scoring techniques based on radiographs present limitations in the evaluation of structural integrity due to high effectiveness of innovative therapeutic strategies. The aim of this study was to evaluate the periarticular mineralisation as detected by Digital X-ray Radiogrammetry (DXR) as surrogate marker for structural integrity during the course of rheumatoid arthritis (RA). Methods: 11 centers throughout Germany contributed data of 94 patients with verified RA. The patients were treated with leflunomide or methotrexate during a mean observation period of 22 months. All patients underwent complete computerized calculations of bone mineral density (BMD) and metacarpal index (MCI) by DXR using digitized hand radiographs. The radiological assessment of disease progression was estimated by the Sharp Score. Results: The Sharp Score revealed no significant change during the study period. DXR-BMD revealed minimal decrease of −1.4 % (leflunomide group) versus a higher reduction of −4.3 % (methotrexate group). Regarding DXR-MCI, a reduction of −2.2 % (leflunomide group) and −4.9 % (methotrexate group) was observed. Conclusion: Quantitative data of hand bone mass estimated by the presented DXR-technique may be a complementary precise tool in the identification of RA-related radiographic changes and in the assessment of structural integrity.

Der Gynäkologe, 2014

ABSTRACT Je fortgeschrittener die Funktionseinschränkung der Niere ist, desto größer ist die Wahr... more ABSTRACT Je fortgeschrittener die Funktionseinschränkung der Niere ist, desto größer ist die Wahrscheinlichkeit einer Infertilität oder des Auftretens von (Prä-)Eklampsie, Frühgeburt, fetalen Wachstumsstörungen und langfristiger nephrologischer Probleme bei einer eingetretenen Schwangerschaft. Die Betreuung und Beratung nierenkranker Patientinnen sollte schon präkonzeptionell erfolgen. Eine frühzeitige Bestimmung der Kreatinin-Clearance, der Proteinurie (optimal im Sammelurin) und des Blutdrucks helfen, bei geplanter oder eingetretener Schwangerschaft niereninsuffizienter Patientinnen den Verlauf besser zu beurteilen. Viele der aus nephrologischer Indikation eingesetzten Medikamente können wegen fetaler Nebenwirkungen nicht gegeben werden, bei eingeschränkter glomerulärer Filtrationsrate muss zudem oft eine Dosisanpassung erfolgen. Eine interdisziplinäre Betreuung nierenkranker Schwangerer sollte obligat erfolgen. Abstract The risk of infertility, the incidence of (pre)eclampsia, preterm delivery, fetal growth restriction and long-term renal complications increase with the stage of renal insufficiency in pregnant women. Medical care of such patients should be initiated before conception. Early determination of creatinine clearance, proteinuria (optimal in 24 h urine) and blood pressure before or during the early stages of pregnancy help physicians to assess the time course of renal function and to detect any complications. Physicians should be aware of the risk of fetal side effects of several drugs as well as dose adjustment according to renal excretory function. Supervision of pregnant women with renal diseases by an interdisciplinary team should be obligatory.

Thrombosis and Haemostasis, 2009

SummaryThrombocytopenia during pregnancy is a common diagnostic and management problem. Several d... more SummaryThrombocytopenia during pregnancy is a common diagnostic and management problem. Several differential diagnosis must be considered including manifestations of thrombotic thrombocytopenic purpura (TTP). We report here on a case of a 21-year-old pregnant woman who presented initially severe thrombocytopenia (8 Gpt/l) in the 20th+1 week of gestation. The patient had an antibody against ADAMTS13, and enzyme activity was <5%. Immediate plasmapheresis treatment was initiated, followed by plasma infusions, and again plasmapheresis. A male neonate was delivered by caesarean section in the 32nd week of gestation. The child had an uncomplicated postnatal development. After delivery, the mother’s platelet count and ADAMTS13 activity increased to normal values. This case shows interesting aspects of TTP in pregnancy and a close cooperation between obstetricians, nephrologists and pediatricians is necessary for a successful outcome of the pregnancy.

Nephrology Dialysis Transplantation, 2008

In the poor Whitechapel district of the East End of London in the fall of 1888, at least five pro... more In the poor Whitechapel district of the East End of London in the fall of 1888, at least five prostitutes were brutally murdered, and in all but one case, also mutilated. The murderer was never caught and became known by his nickname 'Jack the Ripper'. The left kidney and the uterus were cut out and taken away from one of the victims named Catherine Eddowes. A kidney was also cut out of the body from another victim, but not taken away. Two weeks later, George Lusk, president of the Whitechapel Vigilance Committee, received a small cardboard box with half of a longitudinally divided kidney and a letter entitled 'From hell' claiming that the kidney inside the box was taken from the victim. The kidney was brought to Dr Thomas Horrocks Openshaw, the Curator of the London Pathological Museum, where the kidney could be microscopically examined. The press jumped on the topic and made a circumstantial case that this kidney had been indeed torn from the body of Catherine Eddowes. According to the later memoirs of Major Henry Smith of the City Police published more than 20 years after the incident, the kidney left in the corpse of Catherine Eddowes was in an advanced stage of Bright's disease and the kidney sent to George Lusk was in exactly a similar stage. Today, the majority of criminologists believe that the kidney sent to Mr Lusk was a hoax as were other letters signed with Jack the Ripper. However, the murderer took organs from his victims, and in the case of Catherine Eddowes, the kidney. Serial killers often mutilate their victims and abscond with the removed body parts as trophies. By removing the kidney from Catherine Eddowes, Jack the Ripper may have tried to take possession of the conscience, emotions and desires of one of his victims, attributes residing in the kidney as described in the Bible. Jack the Ripper was never caught; many suspects have been suggested, and the murder series ended as suddenly as it had begun. We will never know who this mentally disturbed 'nephrophilic' was. Today, the story of Jack the Ripper is part of contemporary culture.

Journal of Medicinal Chemistry, 2005

Diabetes Care, 2013

OBJECTIVE Patients with diabetes and insulin therapy with human insulin were usually instructed t... more OBJECTIVE Patients with diabetes and insulin therapy with human insulin were usually instructed to use an interval of 20–30 min between the injection and meal. We examined the necessity of the injection-to-meal interval (IMI) in patients with type 2 diabetes mellitus (T2DM) and flexible insulin therapy with human insulin. RESEARCH DESIGN AND METHODS In this randomized, open crossover trial, 100 patients with T2DM (47% men, mean age = 66.7 years) were randomized to the IMI first group (phase 1, IMI 20 min; phase 2, no IMI) or IMI last group (phase 1, no IMI; phase 2, IMI 20 min). The main outcome measures were HbA1c, blood glucose profile, incidence of hypoglycemia, quality of life, treatment satisfaction, and patient preference. RESULTS Forty-nine patients were randomized to the IMI first group and 51 patients to the IMI last group. Omitting the IMI only slightly increases HbA1c (average intraindividual difference = 0.08% [95% CI 0.01–0.15]). Since the difference is not clinically r...