mTOR and rapamycin in the kidney: signaling and therapeutic implications beyond immunosuppression

The immunosuppressive drug rapamycin has helped to identify a large signaling network around the target of rapamycin (TOR) protein that integrates information on nutrient availability and growth factors to control protein synthesis and cell size. Studies using rapamycin in animal models of kidney disease indicate that mTOR deregulation has a role in glomerular disease, polycystic kidney disease, and renal cancer. The role of mTOR activation in podocytes is context dependent, and indirect evidence suggests that mTOR may have a role in chronic podocyte loss. Several lines of evidence show that cyst formation in polycystic kidney disease (PKD) involves mTOR activation and its upstream regulator TSC. Polycystin 1 regulates mTOR activity through different pathways, and TSC intersects with the primary cilium, a crucial cell organelle in the pathogenesis of PKD. Data from hamartoma syndromes provide clear evidence that mutation of members of the mTOR network results in renal cancers. The detailed analysis of renal cell carcinomas has revealed a positive feedback loop involving VHL and mTOR. Rapamycin and its derivatives have been approved for the treatment of advanced renal cancer and are being investigated for the treatment of PKD. Discrepancies exist between the effects of rapamycin in animal models and the clinical experience with patients, precluding the widespread use of mTOR inhibitors in kidney disease. The details of mTOR signaling in the kidney need to be clarified to hopefully develop targeted treatments for renal disease in the future.     

Combined CT- and fluoroscopy-guided nephrostomy in patients with non-obstructive uropathy due to urine leaks in cases of failed ultrasound-guided procedures

AimTo report our experience of combined CT- and fluoroscopy-guided nephrostomy in patients with non-obstructive uropathy due to urine leaks in cases of failed ultrasound-guided procedures.Patients and methodsEighteen patients (23 kidneys) with non-obstructive uropathy due to urine leaks underwent combined CT- and fluoroscopy-guided nephrostomy. All procedures were indicated as second-line interventions after failed ultrasound-guided nephrostomy. Thirteen males and five females with an age of 62.3 ± 8.7 (40–84) years were treated. Urine leaks developed in majority after open surgery, e.g. postoperative insufficiency of ureteroneocystostomy (5 kidneys). The main reasons for failed ultrasound-guided nephrostomy included anatomic obstacles in the puncture tract (7 kidneys), and inability to identify pelvic structures (7 kidneys). CT-guided guidewire placement into the collecting system was followed by fluoroscopy-guided nephrostomy tube positioning. Procedural success rate, major and minor complication rates, CT-views and needle passes, duration of the procedure and radiation dose were analyzed.ResultsProcedural success was 91%. Major and minor complication rates were 9% (one septic shock and one perirenal abscess) and 9% (one perirenal haematoma and one urinoma), respectively. 30-day mortality rate was 6%. Number of CT-views and needle passes were 9.3 ± 6.1 and 3.6 ± 2.6, respectively. Duration of the complete procedure was 87 ± 32 min. Dose-length product and dose-area product were 1.8 ± 1.4 Gy cm and 3.9 ± 4.3 Gy cm², respectively.ConclusionsCombined CT- and fluoroscopy-guided nephrostomy in patients with non-obstructive uropathy due to urine leaks in cases of failed ultrasound-guided procedures was feasible with high technical success and a tolerable complication rate.     

Atrophy of the residual alveolar ridge following tooth loss in an historical population

Oral Diseases (2010) 17 , 33–44 Objectives: To study the natural aetiopathology of jaw atrophy after tooth loss, unaltered by prosthetic procedures, an historical population without modern dental treatment was examined. Methods: Based on the hypothesis that there are predictable changes in shape during jaw‐atrophy, frequency and degree of atrophy as well as clinical aspects of bone quality and resorption were determined in the skeletal remains of 263 individuals. The potential association between age and frequency/severity of atrophy was analysed. Results: Atrophy in at least one jaw segment was present in 45.2% of the analysed jaw specimens. The residual ridge underwent a series of changes in shape and height following the pattern of resorption described for modern populations. The severity of these alterations was associated with the age of the individual and the region within the jaw. Atrophy was frequently related to structural degradation of the covering cortical layer. Conclusions: These findings prove that atrophy of the jaw evidently does occur, displaying similar patterns of resorption in a population without modern prosthetics, where the negative effect of ill‐fitting dentures is excluded. The basic information about alterations of shape and the cortical layer covering the residual crest might help to provide a deeper insight into aetiopathological mechanisms of this common oral disease.     

Experimental blunt chest trauma impairs fracture healing in rats

In poly‐traumatic patients a blunt chest trauma is an important trigger of the posttraumatic systemic inflammatory response. There is clinical evidence that fracture healing is delayed in such patients, however, experimental data are lacking. Therefore, we investigated the influence of a thoracic trauma on fracture healing in a rat model. Male Wistar rats received either a blunt chest trauma combined with a femur osteotomy or an isolated osteotomy. A more rigid or a more flexible external fixator was used for fracture stabilization to analyze whether the thoracic trauma influences regular healing and mechanically induced delayed bone healing differently. The blunt chest trauma induced a significant increase of IL‐6 serum levels after 6 and 24 h, suggesting the induction of a systemic inflammation, whereas the isolated fracture had no effect. Under a more rigid fixation the thoracic trauma considerably impaired fracture healing after 35 days, reflected by a significantly reduced flexural rigidity (three‐point‐bending test), as well as a significantly diminished callus volume, moment of inertia, and relative bone surface (µCT analysis). In confirming the clinical evidence, this study reports for the first time that a blunt chest trauma considerably impaired bone healing, possibly via the interaction of the induced systemic inflammation with local inflammatory processes. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:734–739, 2011     

Decision-making in localized prostate cancer: lessons learned from an online support group

Study Type – Patient (preference/ecological)
Level of Evidence 2c What's known on the subject? and What does the study add? Social support plays a major role for decision‐making in localized prostate cancer and the importance of online resources has become increasingly recognized. However, so far most of the knowledge has been generated on formal and stylistic aspects. The study adds to understanding the content and the dynamics of peer‐to‐peer counselling in an online support group.

OBJECTIVE

? To investigate patient‐to‐patient communication with regard to decision‐making in localized prostate cancer; as most of it is done in private, online support groups are a unique means for this task.

PATIENTS AND METHODS

? Over a 32‐month period, we screened 501 threads in the largest German online support group for prostate cancer. ? Threads started by questioners newly diagnosed with localized prostate cancer and stating decision‐making as the key topic were included; in all, 82 (16.4%) threads met these criteria. ? Two independent investigators characterized every thread following a standardized protocol. ? Fisher’s exact test and Mann–Whitney U‐test were applied for group analyses. A complementary qualitative linguistic approach was chosen.

RESULTS

? Threads were most commonly started to ask for therapy recommendations (66%), information on the course of treatment (46%) and emotional support (46%). ? Answers consisted of treatment recommendations (40%), emotional support (37%) and personal experiences (28%). ? A second opinion on the biopsy cores (51%) and additional imaging (40%) were common suggestions. ? The rate of advice for radical prostatectomy (RP) vs radiotherapy was 67 vs 82%. Thus, surgery was less recommended in our sample (P= 0.01); 75% of the men with an initial therapeutic preference were finally confirmed herein. ? Linguistic analysis showed that posters frequently use a tentative language style and that common language is avoided.

CONCLUSIONS

? Patients readily receive information, advice and emotional support as part of an online support group. ? The scientific evaluation of an online support group is a complementary way of getting to know our patients’ needs and worries. ? Patient–physician contact can benefit from this knowledge.     

Adjustable bulbourethral male sling: experience after 101 cases of moderate-to-severe male stress urinary incontinence

Study Type – Therapy (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? First data on the ARGUS® sling was published in 2006 by Romano SV et al. as a multicentre study, evaluating the data of 48 patients with a mean follow up (FU) of 7.5 months, with the conclusion that this new adjustable sling was effective in treatment of SUI and the complication rate was acceptable. In 2009, Romano SV et al. published a long‐term FU (mean: 45 months) of the same patient group, demonstrating the long‐term efficacy of the sling. Our study evaluated the data of 101 cases of moderate to severe male stress urinary incontinence (SUI) after implantation of the ARGUS® sling at mean follow‐up of 2.1 (0.1–4.5) years. In addition we made a subgroup analysis of representative “index patients”, patients after external beam radiation therapy (EBRT) and of a subgroup after differentiation of the retrograde leak point pressure (RLPP).

OBJECTIVES

• ? To report our experience using an adjustable bulbourethral sling since April 2005 for male stress urinary incontinence (SUI) after prostatic surgery.
• ? To evaluate the safety, efficacy and health‐related quality of life in recipients of the Argus® (Promedon SA; Cordoba, Argentina) adjustable bulbourethral sling.

PATIENTS AND METHODS

• ? Between April 2005 and April 2009, 101 men with moderate‐to‐severe SUI after prostatic surgery were implanted with the Argus sling.
• ? The radio‐opaque Argus system comprises a thick silicone‐foam pad for soft bulbar urethral support. The pad is attached to silicone columns that, after being passed with needles from the perineum to the abdominal wall, are adjusted with silicone washers to maintain the desired position.
• ? Between prostatic surgery and Argus sling placement, most patients (74.3%) had undergone various procedures for SUI or bladder neck pathologies: 22 had undergone secondary irradiation therapy after surgery (19 after retropubic radical prostatectomy [RP], one after perineal RP and two after transurethral resection of the prostate).
• ? All patients were evaluated before and after sling placement with 20‐min pad tests, the Urinary Incontinence Quality of Life Scale (I‐QoL), cystoscopy and uroflowmetry. The study was designed in a retrospective longitudinal fashion.

RESULTS

• ? The mean (range) follow‐up was 2.1 (0.1–4.5) years. The mean (range) sling surgery duration was 49 (28–105) min.
• ? Adjustment was necessary in 39 cases (38.6%), either loosening (10/101; 9.9%) or tightening (29/101; 28.7%) at a mean of 104.3 (14–910) days after the initial implantation.
• ? The sling had to be removed in 16/101 patients (15.8%) at a mean of 371.1 (20–1260) days after implantation due to urethral erosion or infection. However, six of the 16 patients were within the first 22 placements and probably represent the ‘learning curve’. In all, 13 of these patients received later successful treatment (seven with an artificial urinary sphincter, five with re‐implantation of the sling). Four of these patients were lost for follow‐up.
• ? After a median (mean) follow‐up of 2.2 (2.1) years, 80/101 (79.2%) patients were considered as dry, with a pad test of 0–1 g (70 patients, 0 g; 10 patients, 1 g). The I‐QoL score improved from a mean of 28.8 (14.5–61.8) to 63.2 (16.4–115) points after sling placement.
• ? Both the 20‐min pad‐weight tests and I‐QoL responses improved significantly compared with baseline (P < 0.001).

CONCLUSION

• ? We think that the Argus male bulbourethral sling system is an excellent first‐ or second‐line treatment for moderate‐to‐severe male SUI, even after external beam radiation treatment.

     

Scientific and ethical concerns regarding engineering human longevity

The goal of biogerontological research is to elucidate the biological factors underlying adverse age-related changes in structure and function of molecules, cells, tissues, and organisms. In spite of the considerable progress achieved so far, it is still too early to predict what strategies will be both safe and effective at preventing, delaying, or reversing these changes in humans, and whether such strategies will also increase longevity.