[Subacute kidney injury in a 40-year-old female Northern African patient]. / Subakutes Nierenversagen bei einer 40-jährigen nordafrikanischen Patientin.

A 40-year old woman from Eritrea was admitted due to worsening renal function of unknown origin. The basic nephrologic workup provided no further information. Renal biopsy was performed and revealed acute interstitial nephritis (AIN) while no offending medication could be identified. Further investigations showed a recurrence of the urogenitary tuberculosis that had already been in 2015. The finding of AIN in the absence of a typical medical history should raise suspicion of infection-related forms or AIN associated with systemic diseases.

[Metabolic acidosis of surprising origin in a 61-year-old female patient]. / Metabolische Azidose mit überraschender Ursache bei einer 61-jährigen Patientin.

A 61-year-old female patient presented to the emergency room with nausea. Laboratory findings revealed metabolic acidosis, which had to be associated with a sodium-glucose co-transporter­2 (SGLT2) inhibitor. Due to increasing prescription rates of SGLT2 inhibitors for diabetes mellitus, congestive heart failure or chronic renal insufficiency, a growing numbers of cases of SGLT2 inhibitor-associated ketoacidosis should be expected. Calculating the anion gap can provide orientation in the case of acidosis of unknown origin. Presumably, a relevant proportion of such cases of ketoacidosis is currently being overlooked or its diagnosis delayed.

[Fulminant acute kidney injury after cholecystectomy in a 45-year-old female patient]. / Fulminantes akutes Nierenversagen nach Cholezystektomie bei einer 45­jährigen Patientin.

A cholecystectomy was carried out on a 45-year-old female patient with fever, myalgia and right upper abdominal pain because of a suspected cholecystitis. Postoperatively acute kidney injury occurred. A comprehensive medical history taken later revealed a presumed occupational contact to rodents. Serological testing detected a recent infection with Dobrava-Belgrade hantavirus. The kidney function normalized with supportive therapeutic measures. Hantavirus infection should be considered in the differential diagnosis of acute kidney injury combined with fever, myalgia and abdominal pain.

How can we improve teaching of ECG interpretation skills? Findings from a prospective randomised trial.

BACKGROUND: There is an ongoing debate on how ECG interpretation should be taught during undergraduate medical training. This study addressed the impact of teaching format, examination consequences and student motivation on skills retention. METHODS: A total of 493 fourth-year medical students participated in a six-group, partially randomised trial. Students received three levels of teaching intensity: self-directed learning (2 groups), lectures (2 groups) or small-group peer-teaching (2 groups). On each level of teaching intensity, end-of-course written examinations (ECG exit exam) were summative in one group and formative in the other. Learning outcome was assessed in a retention test two months later. RESULTS: Retention test scores were predicted by summative assessments (adjusted beta 4.08; 95% CI 1.39-6.78) but not by the type of teaching. Overall performance levels and motivation did not predict performance decrease or skills retention. CONCLUSIONS: Summative assessments increase medium-term retention of ECG interpretation skills, irrespective of instructional format.

Topics of internal medicine for undergraduate dental education: a qualitative study.

INTRODUCTION: Due to the ageing population, internal medicine has become increasingly important for dental education. Although several studies have reported dentists' dissatisfaction with their internal medicine training, no guidelines exist for internal medicine learning objectives in dental education. The aim of this study was to identify topics of internal medicine considered to be relevant for dental education by dentists and internists. METHODS: Eight dentists from private dental practices in Hamburg and eight experienced internal medicine consultants from Hamburg University Hospital were recruited for semi-structured interviews about internal medicine topics relevant for dentists. Internal diseases were clustered into representative subspecialties. Dentists and internists were also asked to rate medical diseases or emergencies compiled from the literature by their relevance to dental education. RESULTS: Coagulopathy and endocarditis were rated highest by dentists, whilst anaphylaxis was rated highest by internists. Dentists rated hepatitis, HIV, organ transplantation and head/neck neoplasm significantly higher than internists. The largest number of different internal diseases mentioned by dentists or internists could be clustered under cardiovascular diseases. The number of specific diseases dentists considered to be relevant for dental education was higher in the subspecialties cardiovascular diseases, haematology/oncology and infectiology. CONCLUSION: We identified the internal medicine topics most relevant for dental education by surveying practising dentists and internists. The relevance of these topics should be confirmed by larger quantitative studies to develop guidelines how to design specific learning objectives for internal medicine in the dental curriculum.

An argument-based approach to the validation of UHTRUST: can we measure how recent graduates can be trusted with unfamiliar tasks?

There is a need for valid methods to assess the readiness for clinical practice of medical graduates. This study evaluates the validity of Utrecht Hamburg Trainee Responsibility for Unfamiliar Situations Test (UHTRUST), an authentic simulation procedure to assess whether medical trainees are ready to be entrusted with unfamiliar clinical tasks near the highest level of Miller's pyramid. This assessment, in which candidates were judged by clinicians, nurses and standardized patients, addresses the question: can this trainee be trusted with unfamiliar clinical tasks? The aim of this paper is to provide a validity argument for this assessment procedure. We collected data from various sources during preparation and administration of a UHTRUST-assessment. In total, 60 candidates (30 from the Netherlands and 30 from Germany) participated. To provide a validity argument for the UHTRUST-assessment, we followed Kane's argument-based approach for validation. All available data were used to design a coherent and plausible argument. Considerable data was collected during the development of the assessment procedure. In addition, a generalizability study was conducted to evaluate the reliability of the scores given by assessors and to determine the proportion of variance accounted by candidates and assessors. It was found that most of Kane's validity assumptions were defendable with accurate and often parallel lines of backing. UHTRUST can be used to compare the readiness for clinical practice of medical graduates. Further exploration of the procedures for entrustment decisions is recommended.

Rituximab in adult patients with immunosuppressive-dependent minimal change disease.

BACKGROUND: Minimal change disease (MCD) is one of the leading causes of nephrotic syndrome. Steroid therapy is effective in achieving remission, but relapses, steroid dependence, and steroid resistance are therapeutic challenges. The use of second-line agents such as cyclophosphamide is associated with toxicity and adverse effects. Therefore, we studied the effect of rituximab (RTX) on proteinuria in adult patients with immunosuppressive (IS)-dependent MCD. METHODS: In this single-center, prospective, open series study, 6 consecutive patients with IS-dependent MCD and frequent relapses on different IS regimens - one of them after previous RTX treatment - were included. Patients were treated with a single dose of RTX (375 mg/m²). An additional dose of RTX was administered depending on B-cell count and proteinuria. RESULTS: 5 out of 6 patients achieved complete remission at the end of the follow-up; the other patient had a partial remission. All patients are free of additional IS agents and other medications were remarkably reduced. Three patients had a relapse, which was successfully treated with a further RTX treatment. CONCLUSIONS: RTX could be an alternative in the therapy of patients with IS-dependent MCD, leading to successful cessation of other IS treatment.

Significant increase in factual knowledge with web-assisted problem-based learning as part of an undergraduate cardio-respiratory curriculum.

In recent years, increasing attention has been paid to web-based learning although the advantages of computer-aided instruction over traditional teaching formats still need to be confirmed. This study examined whether participation in an online module on the differential diagnosis of dyspnoea impacts on student performance in a multiple choice examination of factual knowledge in cardiology and pneumology. A virtual problem-based learning environment for medical students supervised by postgraduate teachers was created. Seventy-four out of 183 fourth-year medical students volunteered to use the online module while attending a 6-week cardio-respiratory curriculum in summer 2007. Of these, 40 were randomly selected to be included (intervention group); the remaining 34 served as an internal control group. Analysis of all written exams taken during the preceding term showed that both groups were comparable (86.4 ± 1.1 vs. 85.9 ± 1.1%; p = 0.751). Students in the intervention group scored significantly higher in the final course assessment than students allocated to the control group (84.8 ± 1.3 vs. 79.5 ± 1.4%; p = 0.006; effect size 0.67). Thus, additional problem-based learning with an online module as part of an undergraduate cardio-respiratory curriculum lead to higher students' scores in an exam testing factual knowledge. Whether using this teaching format increases overall student motivation to engage in the learning process needs to be further investigated.

Influence of educational programs on attitudes of medical students towards psychiatry: Effects of psychiatric experience, gender, and personality dimensions.

BACKGROUND: Attitudes of medical students form the basis for medical actions. Because of the specific characteristics of psychiatric patients, positive attitudes of medical students towards psychiatry should be a higher goal in medical education. AIM: We hypothesize that medical students in different educational programs develop different attitudes towards psychiatry. METHODS: In a cross-sectional study, students enrolled in different educational programs completed the 'attitudes towards psychiatry' questionnaire (ATP-30). Data concerning experiences in psychiatry, personality traits and socio-demographic variables including gender were also analyzed. RESULTS: The response rate of students in the PBL-curriculum (n = 61) was >90%, in the traditional curriculum (n = 280) >75%. Attitudes towards psychiatry of male students in the Problem-Based Learning program were equal to the female students' attitudes in both programs. Female students' attitudes in the traditional curriculum reached comparably good results while male students' displayed the worst attitudes. The personality factors 'openness to experience' and 'agreeableness' correlated significantly with positive attitudes towards psychiatry. PBL-students showed significantly more 'openness to experience'. CONCLUSION: Educational programs might play a role for the development of attitudes towards psychiatry, especially in male students. Factors influencing enrollment into special educational programs should also have been taken into account. An independent study with a larger number of participants will be required to support these findings.

[Medical education in a bachelors and masters system]. / Das Medizinstudium als Bachelor- und Master-Studiengang.

Gain of basic and applied medical knowledge and the changing demands of society with regard to medical professions are the main factors for continuous reforms in medical curricula. The Bologna Declaration of 1999 initiated the development of a unified European higher education area. A key tool for unification is the introduction of the Bachelors/Masters system. Although some European countries have adapted their medical curricula to the Bachelors/Masters system there is still debate on this issue in Germany. Some societies, e.g., the Society for Medical Education, demonstrated how the Bachelors/Masters system might be transferred to Germany. Moreover, the German Association of Medical Students already published a core curriculum compatible with the Bologna criteria. Some central elements of the Bologna Declaration have already been or could easily be integrated into the current structure of medical studies, e.g., quality assurance or a credit point transfer system. Furthermore, in the framework of the German medical licensure law, it is possible to introduce a curriculum fully compatible with the Bologna Declaration. A meaningful prerequisite would be a unified national (or European) qualification frame and catalog of learning objectives, designed according to the Bologna criteria. This should guarantee good mobility for medical students within Europe.

[Dysfunction of a kidney allograft with life-threatening results]. / Dysfunktion einer Transplantatniere mit bedrohlichem Befund.

Post-transplant lymphoproliferative disease (PTLD) is a serious complication after organ transplantation. We describe the case of a 45-year old patient who developed an EBV associated B-cell lymphoma in a cadaveric renal allograft. This case underscores the importance of considering PTLD as possible differential diagnosis for allograft dysfunction. Careful diagnostic evaluation should be undertaken in patients who present with risk factors for development of PTLD such as high doses of immunosuppression for rejection therapy, suspicious EBV serologies or negative EBV serologies before transplantation. PTLD can be of donor or recipient origin. Independent of its origin PTLD needs an immediate therapy which depends on the histology of the lymphoma and on the clinical conditions of the patient. Therapeutic options are reduction of the immunosuppression, chemotherapy or radiation, administration of lymphocyte-specific antibodies or removal of the kidney allograft.

The hematopoietic transcription factor PU.1 represses gelatinase A transcription in glomerular mesangial cells.

The matrix metalloproteinase gelatinase A plays a key role in the evolution of glomerular injury and is a major contributing factor to the development of glomerulosclerosis. Prior studies have focused on a potent cis-acting enhancer element located in the near 5'-flanking region of the rat and human gelatinase A genes (Harendza, S., Pollock, A. S., Mertens, P. R., and Lovett, D. H. (1995) J. Biol. Chem. 270, 18286-18796; Mertens, P. R., Alfonso-Jaume, M. A., Steinmann, K., and Lovett, D. H. (1999) J. Am. Soc. Nephrol. 10, 2480-2487). Given the combinatorial nature of transcriptional regulation, we examined additional regions of the 5'-flanking region of the rat gelatinase A gene to identify further regulatory elements. In this study the identification of a silencing element located between -1903 and -1847 base pairs of the 5'-flanking region of the rat gelatinase A gene is reported. Sequence analysis, electrophoretic mobility studies, and transfection experiments demonstrate that a specific binding sequence for the hematopoietic transcription factor PU.1 is present within the silencing sequence. PU.1 activity is absolutely required for the expression of silencing activity within the context of transfected glomerular mesangial cells. Western blots identify the PU.1 protein within nuclear extracts of mesangial cells, and cotransfection with a PU.1 expression vector directly augments silencing activity. These studies underscore the complex patterns of gelatinase A transcriptional regulation and also strongly suggest that glomerular mesangial cells are ultimately derived from bone marrow cells.

Extracellular matrix deposition and cell proliferation in a model of chronic glomerulonephritis in the rat.

BACKGROUND: Resident glomerular cell proliferation, matrix deposition and secretion of matrix metalloproteinases play a major role in the progression of chronic glomerular disease. These features were studied in a novel approach in a rat model of chronic glomerulonephritis induced by four injections of an anti-Thy 1.1 antiserum at weekly intervals. METHODS: Chronic immune mediated mesangial injury was induced in male Sprague-Dawley rats by repeated intravenous injection of an anti-Thy 1.1 antiserum. One week after the first and fourth injection of the antiserum proteinuria was evaluated and the kidneys were removed. Immunohistology was performed for proliferating cells, monocytes and collagen type IV. Furthermore, mRNA expression of collagen type IV, TGF-beta and the matrix degrading enzyme MMP-2 as well as MMP-2 protein expression were studied. RESULTS: Urinary protein excretion was dramatically increased after one antiserum injection and stayed elevated at a lower level after the fourth antiserum injection. After the initial induction of nephritis, 7 days following antiserum, resident glomerular cell proliferation was increased whereas with repeated injections of the antiserum cell numbers were not different from controls, as measured 1 week after the fourth injection. In contrast, extracellular matrix accumulation (collagen type IV) increased after the first antiserum injection and further increased after the fourth antiserum injection. The mRNA expression for collagen type IV increased after the first antiserum injection and showed further increase after the fourth antiserum injection. Induction of nephritis also stimulated glomerular mRNA expression of MMP-2 and TGF-beta, both of which remained at a high level after the fourth antiserum injection. Glomerular protein levels of MMP-2 also increased after the first antiserum injection and showed a further slight increase after the fourth injection. CONCLUSION: Increased cellular proliferation is involved in an early stage of this disease, while enhanced expression of glomerular matrix and augmented mRNA and protein expression of the matrix degrading enzyme MMP-2 continue into the chronic phase, and contribute to the extensive structural remodeling process that accompanies this form of glomerular injury.

Cyclooxygenase metabolites mediate glomerular monocyte chemoattractant protein-1 formation and monocyte recruitment in experimental glomerulonephritis.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) has been shown to play a significant role in the recruitment of monocytes/macrophages in experimental glomerulonephritis. Whereas a number of inflammatory mediators have been characterized that are involved in the expression of MCP-1 in renal disease, little is known about repressors of chemokine formation in vivo. We hypothesized that cyclooxygenase (COX) products influence the formation of MCP-1 and affect inflammatory cell recruitment in glomerulonephritis. METHODS: The effect of COX inhibitors was evaluated in the antithymocyte antibody model and an anti-glomerular basement membrane model of glomerulonephritis. Rats were treated with the COX-1/COX-2 inhibitor indomethacin and the selective COX-2 inhibitors meloxicam and SC 58125. Animals were studied at 1 hour, 24 hours, and 5 days after induction of the disease. RESULTS: Indomethacin, to a lesser degree the selective COX-2 inhibitors, enhanced glomerular MCP-1 and RANTES mRNA levels. Indomethacin enhanced glomerular monocyte chemoattractant activity an the infiltration of monocytes/macrophages at 24 hours and 5 days. CONCLUSIONS: Our studies demonstrate that COX products may serve as endogenous repressors of MCP-1 formation in experimental glomerulonephritis. The data suggest that COX-1 and COX-2 products mediate these effects differently because the selective COX-2 inhibitors had less influence on chemokine expression.

Glomerular mesangial cell-specific transactivation of matrix metalloproteinase 2 transcription is mediated by YB-1.

Mesangial cell (MC) activation plays a pivotal role in the development of the end stage sclerotic lesion characteristic of most forms of chronic glomerular disease. We have previously demonstrated that MC activation is directly linked to high level expression of the matrix metalloproteinase-2 (MMP-2) enzyme (Turck, J., Pollock, A. S., Lee, L., Marti, H.-P., and Lovett, D. H. (1996) J. Biol. Chem. 25, 15074-15083), the transcription of which is regulated in a tissue-specific fashion. Recent studies (Harendza, S., Pollock, A., Mertens, P. R., and Lovett, D. H. (1995) J. Biol. Chem. 270, 18786-18796) delineated a strong cis-acting enhancer element, designated MMP-2 RE1, within the 5'-flanking region of the rat MMP-2 gene. Gel shift, DNA footprint, and transcriptional analyses mapped the enhancer element to a unique 40-base pair (bp) sequence located at -1322 to -1282 bp relative to the translational start site. Bromodeoxyuridine-substituted UV cross-linking of the 40-bp enhancer element with MC nuclear extracts yielded a single protein of 52 kDa, while Southwestern blot analysis with MMP-2 RE1 demonstrated three hybridizing nuclear proteins of 52, 62, and 86 kDa size. Screening of a human MC cDNA expression library with MMP-2 RE1 exclusively yielded clones with the identical sequence of the transcription factor YB-1. Western blot and supershift gel analysis of MC nuclear extracts with an anti-YB-1 antibody confirmed the presence of YB-1 within the shifted complex. Examination of the MMP-2 RE1 sequence revealed an incomplete Y-box sequence (CTGCTGGGCAAG), which specifically interacted with recombinant YB-1 on DMS protection footprinting analysis. YB-1 protein preferentially bound the single-stranded components of the 40-bp MMP-2 RE1 and, with increasing concentrations, formed multimeric complexes. Co-transfection of YB-1 in MC increased the enhancer activity within the context of the native MMP-2 promoter, while transfection of non-MMP-2-synthesizing glomerular epithelial cells with YB-1 led to transcriptional suppression. This study indicates that YB-1 is a major, cell type-specific transactivator of MMP-2 transcription by glomerular mesangial cells.

Prostaglandin E2 stimulates expression of matrix metalloproteinase 2 in cultured rat mesangial cells.

Prostaglandins of the E-series have been demonstrated to reduce extracellular accumulation of collagens in some models of glomerulonephritis. This effect is partially due to reduction of collagen formation by mesangial cells. The potential effects of prostaglandins on the expression of collagen degrading enzymes in mesangial cells are largely unknown. Since rat mesangial cells generate a matrix metalloproteinase 2 (MMP-2) that specifically degrades collagen type IV, the effects of prostaglandin E2 (PGE2) on transcription, steady-state mRNA levels, extracellular enzyme activity and protein concentration of this proteinase were evaluated. Mesangial cells (MC) were incubated with PGE2 (2 microM) for different time-periods (1 to 48 hr), and steady-state mRNA levels of MMP-2 were determined by Northern blotting. PGE2 increased MMP-2 mRNA levels beginning at one hour of incubation and remained elevated up to 24 hours. Nuclear run off experiments revealed that the PGE2-induced increase in mRNA expression for MMP-2 is due to stimulated gene transcription. Western blot analysis and zymography revealed that MMP-2 protein production and enzyme activity was also enhanced by PGE2. The cAMP analogue 8-bromo-cAMP increased MMP-2 mRNA levels, suggesting that PGE2-induced generation of intracellular cAMP plays a role in MMP-2 induction in MC. These studies demonstrate that PGE2 stimulates the transcription, protein formation and enzyme activity of MMP-2 in cultured rat MC. This effect may contribute to the prostaglandin mediated reduction of extracellular collagen deposition in glomerulonephritis.

In vitro characterization of the mesangial phenotype in a proliferative glomerulonephritis of the rat.

BACKGROUND: Mesangial cell proliferation is a predominant feature of many glomerular diseases. We have demonstrated in previous studies that an experimental model of mesangial-proliferative glomerulonephritis in the rat could be transferred to in vitro conditions. Using this model we now have been able to study the mesangial phenotype in several subcultures of mesangial cells from nephritic animals regarding proliferation, and the synthesis of prostaglandins and the matrix degrading enzyme MMP-2. METHODS: Mesangial-proliferative glomerulonephritis was induced in male Sprague-Dawley rats by a single injection of an anti-Thy 1.1 antiserum. Four days after injection of the antiserum glomeruli were isolated and transferred to tissue culture conditions. Immunohistological characterization of cells, cell growth, synthesis of prostaglandins and expression of MMP-2 were studied in the first and second subculture. RESULTS: Cells from controls and from nephritic animals showed the characteristics of glomerular mesangial cells. Proliferation was decreased in the first and second subculture of cells from nephritic rats compared with controls while there were no immunohistological differences between the cells. Biosynthesis of prostaglandin E2 was significantly increased in subcultures of mesangial cells from nephritic rats. There was also a significant increase in mRNA expression of MMP-2 in the first subculture of mesangial cells from nephritic rats when compared with controls. CONCLUSIONS: Our data suggest that mesangial cells from nephritic animals show a different phenotype in vitro in several subcultures compared with cells from control animals. This difference can be demonstrated in the patterns of proliferation and biosynthesis of prostaglandins and MMP-2, while immunohistological characteristics of mesangial cells were unchanged between nephritic animals and controls. This experimental in vivo-in vitro approach may serve as a model to study the mesangial phenotype in glomerular diseases.

Tissue-specific enhancer-promoter interactions regulate high level constitutive expression of matrix metalloproteinase 2 by glomerular mesangial cells.

The 72-kDa gelatinase A (MMP-2) is a central mediator of the response of the intrinsic glomerular mesangial cell to inflammatory stimuli and is regulated in a unique, cell-specific manner. We isolated a 6-kilobase pair genomic fragment of the rat MMP-2 gene and sequenced and characterized 1686-base pair of the 5'-flanking region. Using a series of 5' deletion constructs of the proximal 5'-flanking region, a strong MMP-2 enhancer element was identified. Gel shift and mutational analyses suggest tha the enhancer region represents the binding site for complex transcription factor demonstrating separable DNA-binding and transcriptional activating domains. The presence and activity of the enhancer element was evaluated in several cell types with varying capabilities to synthesize MMP-2 including mesangial cells, glomerular epithelial cells, and the monocytic U937 cell. Although binding activity was present in all cell types studied, enhancer activity was demonstrated only in mesangial and glomerular epithelial cells. Additional transcriptional control resided in a tissue-specific promoter, which supported transcription only in mesangial cells. These results indicate that the final control of mesangial cell-specific synthesis of MMP-2 derives from an interaction between the strong enhancer element and the tissue-specific MMP-2 promoter.