Corticosteroid-resistant nephrotic syndrome with focal and segmental glomerulosclerosis : an update of treatment options for children

Corticosteroid-resistant nephrotic syndrome (CRNS) with focal and segmental glomerulosclerosis (FSGS) is a heterogeneous disorder and the most severe and frequent type of all glomerulopathies in children leading to end-stage renal failure. The podocyte is at the center of development and progress of FSGS; this unique cell type plays a major role in the integrity of glomerular structure and permeability. The rate of complete remission of CRNS after induction therapy using different immunosuppressant agents is reported to range between 30% and 84%, depending on the treatment schedule and on the underlying defects of FSGS. Children with genetic types of FSGS barely respond to immunosuppressant therapies and over-treatment prior to transplantation should be avoided. The response of children with an idiopathic type of FSGS to immunosuppressants is superior to those with genetic FSGS. However, many children with idiopathic FSGS do not enter complete remission if they are under-treated, for example, with short-term immunosuppressant monotherapies. If immunosuppressant treatment fails, these patients will have to undergo renal transplantation. However, as unknown pathogenetic mechanisms may persist, more than one-third of these patients with idiopathic FSGS develop a rapid recurrence of CRNS that responds poorly to further long-term therapeutic attempts. In contrast with previously published data, this review takes into account recently identified genetic etiologies of CRNS, and superior results with long-term combination therapy in idiopathic forms to avoid over- and under-treatment.     

Cost effectiveness of ibandronate for the prevention of fractures in inflammatory bowel disease-related osteoporosis: cost-utility analysis using a Markov model

BACKGROUND: Osteoporosis is a frequent complication in patients with inflammatory bowel disease. Recent studies have shown bisphosphonates to considerably reduce fracture risk in patients with osteoporosis, and preventing fractures with bisphosphonates has been reported to be cost effective in older populations. However, no studies of the cost effectiveness of these agents in preventing fractures in patients with inflammatory bowel disease are available. OBJECTIVE: To investigate the cost effectiveness of the bisphosphonate ibandronate combined with calcium/colecalciferol ('ibandronate') in patients with osteopenia or osteoporosis due to inflammatory bowel disease in Germany. Treatment strategies used for comparison were sodium fluoride combined with calcium/colecalciferol ('fluoride') and calcium/colecalciferol ('calcium') alone. STUDY DESIGN AND METHODS: A cost-utility analysis was conducted using data from a randomized controlled trial (RCT). Changes in bone mineral density (BMD) were adjusted and predicted for a standardized population receiving each respective treatment. A Markov model was developed, with probabilities of transition to fracture states consisting of BMD-dependent and -independent components. The BMD-dependent component was assessed using predicted change in BMD from the RCT. The independent component captured differences in bone quality and micro-architecture resulting from prevalent fractures or treatment with anti-resorptive drugs.The analysis was conducted for a population with a mean age of the RCT patients (women aged 36 years, men aged 38 years) with osteopenia (T-score about -2.0 at baseline), a population of the same age with osteoporosis (T-score of -3.0 at baseline) and for an older population (both sexes aged 65 years) with osteoporosis (T-score of -3.0). Outcomes were measured as costs per QALY gained from a societal perspective. The treatment duration in the RCT was 42 months. A 5-year period was assumed to follow, during which the treatment effects linearly declined to 0. The simulation time was 10 years.Prices for medication and treatment were presented as year 2004 values; costs and effects were discounted at 5%. To test the robustness of the results, univariate and probabilistic sensitivity analyses (Monte Carlo simulation) were conducted. RESULTS: The calcium strategy dominated the fluoride strategy. When the ibandronate strategy was compared with the calcium strategy, the base-case cost-effectiveness ratios (costs per QALY gained) were between euro 407 375 for an older female population with osteoporosis and euro 6 516 345 for a younger female population with osteopenia. Univariate sensitivity analyses resulted in variations between 4% of base-case results and dominance of calcium. In Monte Carlo simulations, conducted for the various populations, the probability of an ICER of ibandronate below euro 50 000 per QALY was never greater than 20.2%. CONCLUSION: The ibandronate strategy is unlikely to be considered cost effective by decision makers in men or women with characteristics of those in the target population of the RCT, or in older populations with osteoporosis.     

Endothelial Lipase: a key player in HDL metabolism modulates inflammation and atherosclerotic risk

Endothelial Lipase (EL) is a newly identified member of the triacylglycerol lipase family. Recent studies suggested that EL may be an important determinant of HDL-metabolism and inflammation acting at the level of the vessel wall. The aim of this review is to summarize important facts derived from experimental approaches and from epidemiologic human studies to provide a comprehensive view on the role of EL in inflammation and atherogenesis as well as target for potential pharmaceutical interventions.     

Synthesis and biological evaluation of NO-donor-tacrine hybrids as hepatoprotective anti-Alzheimer drug candidates

In search of safer anti-Alzheimer drugs, 14 NO-donor-tacrine hybrids (1- 14) were synthesized and evaluated for their ability to inhibit cholinesterases and for vasorelaxation effects. Compounds 1- 13 showed good cholinesterases inhibitory activities in vitro, while 14, particularly, was highly selective, preferring butyrylcholinesterase rather than acetylcholinesterase. Four selected compounds (1, 9, 11, and 14) moderately relaxed the porcine pulmonary arteries in organ bath. In the hepatotoxicity study, significant hepatotoxicity was caused by tacrine but not by 9.     

Dose timing and patient compliance with two antibiotic treatment regimens for lower respiratory tract infections in primary care

The objective of this study was to assess compliance with a 10-day treatment of antibiotics or placebo once-daily (OD) and three-times-daily (TD) for lower respiratory tract infections (LRTIs) using electronic monitoring, and to evaluate whether compliance depends on time since the start of treatment and weekday. Taking compliance, timing compliance, correct dosing compliance and mean interdose intervals were assessed using data from 155 LRTI patients who received either a 10-day treatment of amoxicillin TD and placebo OD or roxithromycin OD and placebo TD using a double-dummy technique. Compliance was assessed by electronic monitoring. Taking compliance was 98.0% for the OD regimen and 91.0% for the TD regimen. Correct dosing was 98.1% for the OD regimen and 91.1% for the TD regimen and timing compliance was 48.2% and 10.9%, respectively. The mean interdose interval before the first daily dose for the TD group was particularly prolonged to >13h. Correct dosing over time showed fewer patients with correct dosing compliance, reaching a low of 79% for the TD group towards the end of the 10-day treatment. Compliance was not influenced by weekday. This study adds important information to the limited evidence on compliance with antibiotics for LRTI, one of the most common reasons for consultation in primary care. Taking compliance was high for both regimens, yet timing compliance was poor. The prolonged mean interdose intervals provide striking new insights into understanding non-compliance with more-than-once-daily regimens. These findings require consideration when exploring ways to improve future compliance in short-term antibiotic treatment for respiratory tract infections.     

Articular surface segmentation using active shape models for intraoperative implant assessment

Purpose

In orthopedic surgeries, it is important to avoid intra-articular implant placements, which increase revision rates and the risk of arthritis. In order to support the intraoperative assessment and correction of surgical implants, we present an automatic detection approach using cone-beam computed tomography (CBCT).

Methods

Multiple active shape models (ASM) with specified articular surface regions are used to isolate the joint spaces. Fast and easy-to-implement methods are integrated in the ASM segmentation to optimize the robustness and accuracy for intraoperative application. A cylinder detection method is applied to determine metal implants. Intersections between articular surfaces and cylinders are detected and used to find intra-articular collisions.

Results

Segmentations of two calcaneal articular surfaces were evaluated on 50 patient images and have shown average surface distance errors of 0.59 and 0.46 mm, respectively. The proposed model-independent segmentation at the specified articular surface regions allowed to significantly decrease the error by 22 and 25 % on average. The method was able to compensate suboptimal initializations for translations of up to 16 mm and rotations of up to 21\(^{\circ }\). In a human cadaver test, articular perforations could be localized with an accuracy of 0.80 mm on average.

Conclusions

A concept for automatic intraoperative detection of intra-articular implants in CBCT images was presented. The results show a reliable segmentation of articular surfaces in retrospective patient data and an accurate localization of misplaced implants in artificially created human cadaver test cases.

     

Mutations in genes encoding PI3K‐AKT and MAPK signaling define anogenital papillary hidradenoma

Papillary hidradenoma (a.k.a. hidradenoma papilliferum) is a benign tumor of the anogenital region that almost exclusively arises in middle‐aged Caucasian women. These tumors may recur and rare cases of malignant development have been reported. The genetic basis of papillary hidradenoma is currently unknown. Hence, we employed targeted high‐coverage next generation sequencing interrogating 50 cancer‐related genes and conventional Sanger sequencing to investigate the mutational landscape in a cohort of 15 cases. Additionally, we analyzed the HPV status of these tumors. Thirteen cases (87%) harbored mutations in cancer‐related genes. Recurrent mutations in PIK3CA and AKT1 were present in 10 of the cases (67%). One PIK3CA mutated case had a concomitant STK11 mutation. Three cases harbored mutually exclusive mutations in BRAF, APC and ERBB4. The remaining two cases showed no mutations. None of the cases harbored DNA of human papilloma virus. Our results also provide evidence that –just as BRAF V600E mutations in hyperplastic polyps and benign nevi‐ a mutated driver gene does not imply malignant behavior per se but may set the basis for malignant transformation. The latter point may explain why rare cases of papillary hidradenoma have been reported to take a malignant course. Lastly, our genetic data may suggest treatment avenues beyond conventional surgery for some of these tumors. © 2015 Wiley Periodicals, Inc.