Angiotensin II stimulates alpha3(IV) collagen production in mouse podocytes via TGF-beta and VEGF signalling: implications for diabetic glomerulopathy.

BACKGROUND: The podocyte is bathed in an angiotensin II (AngII)-rich ultrafiltrate, but the impact of AngII on podocyte pathobiology is not well known. Because podocytes play a direct role in the glomerular basement membrane (GBM) thickening of diabetes, the alpha3(IV) collagen chain was examined. Podocyte expression of alpha3(IV) collagen may involve the transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF) systems. METHODS: Cultured mouse podocytes were treated with various doses of AngII for selected periods of time, with or without inhibitors of TGF-beta and VEGF signalling, SB-431542 and SU5416, respectively. TGF-beta1 and VEGF were assayed by enzyme-linked immunosorbent assay (ELISA); alpha3(IV) collagen, TGF-beta type II receptor and phospho-Smad2 were assayed by immunoblotting. RESULTS: AngII >or=10(-10) M was found to stimulate the production of alpha3(IV) collagen significantly in as short a time as 3 h. The expression of alpha3(IV) collagen was influenced by the TGF-beta system, but AngII did not increase the podocyte's production of TGF-beta1 ligand; rather, it increased the expression of the TGF-beta type II receptor and activated the TGF-beta signalling system through Smad2. Despite the TGF-beta receptor upregulation, synergy between AngII and TGF-beta1 to boost alpha3(IV) collagen production was not observed. However, blockade of TGF-beta signalling with SB-431542 prevented AngII from stimulating alpha3(IV) collagen production. Podocyte expression of alpha3(IV) collagen was also increased by the autocrine activity of VEGF. Podocytes were stimulated to secrete VEGF by 10(-10) M or higher AngII after 48 h. Blockade of the endogenous VEGF activity by SU5416 prevented AngII-stimulated alpha3(IV) collagen production. CONCLUSIONS: AngII stimulates the podocyte to produce alpha3(IV) collagen protein via mechanisms involving TGF-beta and VEGF signalling. Alterations in alpha3(IV) collagen production may contribute to GBM thickening and perhaps proteinuria in diabetes.     

How valid is the arthroscopic diagnosis of cartilage lesions? Results of an opinion survey among highly experienced arthroscopic surgeons

Aim  In general, arthroscopy is considered the “gold standard” for the evaluation of cartilage lesions. In this multicenter survey, we ascertained the general opinion of surgeons regarding arthroscopic cartilage diagnoses. Method  A total of 301 highly experienced arthroscopists (instructors of the AGA, the German-speaking society of arthroscopy) were contacted in writing with a request to complete the survey. Results  The data from 105 respondents (34.8% of those contacted) were used for the investigation. In the grading of the cartilage lesions, the Outerbridge classification was most frequently used (n = 87), followed by the ICRS protocol (n = 8) and the Insall score (n = 3). The majority (61%) of the arthroscopic surgeons felt that differentiation between healthy cartilage and low-grade cartilage lesions was simple. For differentiation between grade I and grade II lesions, and for differentiation between grade II and grade III lesions, 41.9 and 51.4%, respectively, thought that there was a “need for improvement”. In the case of grade IV lesions, 70.5% of the surgeons thought that the diagnosis was valid. The respondents also judged the utility of incorporating objective measurements (e.g., intraoperative biomechanical tests): 13.3% (n = 14) responded that such measurements would be “very useful” and 61.9% (n = 65) responded that they would be “somewhat useful”. Conclusions  Among surgeons, arthroscopy was not perceived to be as reliable as a “gold standard” for the diagnosis of cartilage lesions. The majority of experienced arthroscopists felt unsure of the results in general, or at least in some cases. A universal and definitive grading system for lesions appears to be needed. For questionable cases, measurement devices are needed for objective cartilage grading.     

Preoperative (neoadjuvant) systemic treatment of breast cancer

Preoperative systemic treatment (PST) is a valid option not only for advanced breast cancer stages but also for operable breast cancer. We know that disease-free and overall survival after PST are equivalent to those after adjuvant therapy. Furthermore, PST is able to improve surgical treatment by increasing the rate of breast conservation surgery, which minimises psychological distress for patients fearing mastectomy. Response to PST is a predictor of long-term outcome and gives prognostic information after a short-term interval in contrast to adjuvant trials, which do not show their results until after a 5- to 10-year follow-up. More often, endocrine non-responsive tumours demonstrate a pathological complete response (pCR). Thus, PST can change the formerly bad prognostic marker into one that indicates a favourable prognosis if pCR is achieved by PST. If PST is performed outside clinical trials, anthracycline/taxane-based regimens should be used, especially in sequential prolonged schedules. The use of aromatase inhibitors in preoperative endocrine therapy in elderly postmenopausal patients with endocrine-responsive breast cancer yields a larger proportion of local response than tamoxifen. The duration of PST is not well established, but at least four cycles of chemotherapy should be administered and endocrine therapy needs a minimal time to show greatest benefit when given for at least 3-4 months . The concurrent use of chemotherapy and endocrine drugs did not show any benefit, even in endocrine-responsive tumours and should therefore be avoided. Sentinel node biopsy is a reasonable approach, but this technique should be reserved for experienced surgeons. PCR is the most important surrogate marker of PST, demonstrating an improved disease-free and overall survival. But even if pCR of the primary tumour is achieved, the detection of lymph node metastases is the most important prognostic factor, indicating a substantial risk of cancer recurrence. PST will lead to individualised (tailored) treatment in patients with primary breast cancer.     

Whole-Organ Arthroscopic Knee Score (WOAKS)

Background  

To describe a semi-quantitative score for multi-feature, whole-organ evaluation of the knee in osteoarthritis based on the results of arthroscopic evaluation.     

Titanium elastic nailing in femoral diaphyseal fractures of children in 6-16 years of age

Background:

Management of femoral diaphyseal fractures in the age group of 6-16 years is controversial. There has been a resurgence worldwide for operative fixation.

Materials and Methods:

Twenty-two children (18 boys, 4 girls) aged 6-16 years with recent (> 3 days) femoral diaphyseal fractures (20 closed, 2 open) were stabilized with Titanium Elastic Nail (TEN). These fractures were in proximal third (n=3), middle third (n=15) and in the distal third (n=4) 17 patients underwent surgery within seven days of their injury. The results were evaluated using Flynn''s scoring criteria. Statistical analysis was done using Fischer''s exact test.

Results:

All 22 patients were available for evaluation after a mean of 26 months (14-36 months) of followup. Radiological union in all cases were achieved in a mean time of 8.7 weeks. Full weight bearing was possible in a mean time of 8.8 weeks. Mean duration of hospital stay was 9.8 days. The results were excellent in 13 patients (59.0%), successful in six (27.2%) and poor in three patients (13.6%). All patients had early return to school.

Conclusion:

Intramedullary fixation titanium elastic nailing is an effective treatment of diaphyseal fractures of the femur in properly selected patients of the 6-16 years age group.     

How reliable is MRI in diagnosing cartilaginous lesions in patients with first and recurrent lateral patellar dislocations?

Background  

Lateral dislocation of the patella (LPD) leads to cartilaginous injuries, which have been reported to be associated with retropatellar complaints and the development of patellofemoral osteoarthritis. Therefore, the purpose of this study was to determine the reliability of MRI for cartilage diagnostics after a first and recurrent LPD.     

Treatment of osteoporosis after liver transplantation with ibandronate

Osteoporosis is a major side‐effect after liver transplantation (LTX). Therefore, the objective of the study was to evaluate the efficacy of ibandronate to reduce fractures after LTX. Seventy‐four patients after LTX were included in the study and measurements of bone mineral density (BMD) of lumbar spine and proximal femur using dual energy X‐ray absorptiometry (DEXA) were performed prior to and 3, 6, 12 and 24 months after surgery. The study group (IBA) consisted of 34 patients who received calcium (1 g/day), vitamin D3 (800–1000 IE/day) and ibandronate 2 mg every 3 months intravenously for 1 year. The control group consisted of 40 patients (CON) who received calcium and vitamin D3 at the same dosages. Prevalence of new fractures was predefined as primary endpoint. Changes of BMD and biochemical markers of bone metabolism were also investigated. In all patients, we found a reduction of BMD in the first few months after LTX. In the lumbar spine and the proximal femur the maximum reduction occurred 3 and 6 months post‐LTX. One and 2 years after transplantation, the group receiving ibandronate demonstrated a better recovery from loss of BMD and a significantly lower prevalence of fractures (IBA 2 vs. CON 10 P < 0.04, χ²). Ibandronate with calcium and vitamin D3 reduces the BMD‐loss after LTX and decreases the rate of bone fractures significantly.     

Compartment-specific expression and function of the chemokine IP-10/CXCL10 in a model of renal endothelial microvascular injury

The recruitment of inflammatory cells into renal tissue, mainly T cells and monocytes, is a typical feature of various renal diseases such as glomerulonephritis, thrombotic angiopathies, allograft rejection, and vasculitis. T cells predominantly infiltrate the tubulointerstitium, whereas monocytes are present in the tubulointerstitial and glomerular compartment. Because chemokines play a pivotal role in leukocyte trafficking under inflammatory conditions, this study investigated whether a differential expression of chemokines contributes to the precise coordination of leukocyte subtype trafficking in a rat model of renal microvascular endothelial injury. Renal microvascular endothelial injury was induced in rats by selective renal artery perfusion with an anti-endothelial antibody. Induction of the disease led to severe glomerular and tubulointerstitial endothelial injury with subsequent upregulation of chemokines followed by inflammatory cell recruitment. Among the analyzed chemokine mRNA, IP-10/CXCL10 (119-fold), acting via CXCR3 on activated T cells, and MCP-1/CCL2 (65-fold), acting via CCR2 on monocytes, were by far the most strongly upregulated chemokines. In situ hybridization revealed that IP-10/CXCL10 mRNA was selectively expressed by endothelial cells in the tubulointerstitial area, co-localizing with infiltrating T cells. Despite extensive damage of glomerular vasculature, no IP-10/CXCL10 expression by glomerular endothelial cells was detected. MCP-1/CCL2 mRNA in contrast was detectable in the glomerulus and the tubulointerstitium. Treatment with a neutralizing anti-IP-10/CXCL10 antibody significantly reduced the number of infiltrating tubulointerstitial T cells without affecting monocyte migration and led to an improved renal function. Our study demonstrates a role of IP-10/CXCL10 on T cell recruitment in a rat model of renal endothelial microvascular injury. Furthermore, a differential chemokine expression profile by endothelial cells in different renal compartments was found. These findings are consistent with the hypothesis that functional heterogeneity of endothelial cells from different vascular sites exists and provide an insight into the molecular mechanisms that may mediate compartment-specific T cell and monocyte recruitment in inflammatory renal disease.     

Management of emergencies in adults with congenital cardiac disease

The aim of the study was to assess the quantity and nature of emergencies affecting adults with congenital cardiac disease (CCD) and evaluate infrastructural requirements for adequate management. There is an increasing number of adults with CCD requiring specialized complex care. This multicenter study evaluated all emergency admissions to 1 of 5 centers for adults with CCD within 1 year. Within 1 year, there were 1,033 admissions of adults with CCD, and 201 (160 patients; age 16 to 71 years) were emergencies. Underlying cardiac anomalies were univentricular heart (22%), complete transposition (14%), tetralogy of Fallot (21%), and others (43%). Seventy percent of patients had undergone previous cardiac surgery. The main reason for acute admission was cardiovascular (arrhythmia, heart failure, syncope, aortic dissection, and endocarditis). Diagnostic procedures most often assigned were echocardiography (n = 223), chest x-ray (n = 95), Holter electrocardiography (n = 85), cardiac catheterization/electrophysiologic study (n = 39), and others (n = 143). Forty-six patients underwent surgery (cardiovascular n = 41, general n = 5) or electrophysiologic treatment (n = 41). One hundred twenty-six of 201 emergencies (63%) required cooperation with another specialized department: surgery (n = 46), internal medicine (n = 42), neurology (n = 12), ophthalmology (n = 6), otorhinolaryngology (n = 5), gynecology (n = 5), psychiatry (n = 4), radiology (n = 3), dermatology (n = 2), and orthopedics (n = 2). In conclusion, physicians and consultants attending adult patients with CCD need a high degree of specialized experience concerning the cardiac anomaly to manage emergencies properly. Furthermore, a wide range of noncardiac diagnostic and therapeutic procedures must be available. Data support the demand for a multidisciplinary approach in specialized centers for adequate care of adults with CCD.