Management of Pain in Autosomal Dominant Polycystic Kidney Disease and Anatomy of Renal Innervation

Purpose Chronic pain is a prominent feature of autosomal dominant polycystic kidney disease that is difficult to treat and manage, often resulting in a decrease in quality of life. Understanding the underlying anatomy of renal innervation and the various etiologies of pain that occur in autosomal dominant polycystic kidney disease can help guide proper treatments to manage pain. Reviewing previously studied treatments for pain in autosomal dominant polycystic kidney disease can help characterize treatment in a stepwise fashion. Materials and Methods We performed a literature search of the etiology and management of pain in autosomal dominant polycystic kidney disease and the anatomy of renal innervation using PubMed® and Embase® from January 1985 to April 2014 with limitations to human studies and English language. Results Pain occurs in the majority of patients with autosomal dominant polycystic kidney disease due to renal, hepatic and mechanical origins. Patients may experience different types of pain which can make it difficult to clinically confirm its etiology. An anatomical and histological evaluation of the complex renal innervation helps in understanding the mechanisms that can lead to renal pain. Understanding the complex nature of renal innervation is essential for surgeons to perform renal denervation. The management of pain in autosomal dominant polycystic kidney disease should be approached in a stepwise fashion. Acute causes of renal pain must first be ruled out due to the high incidence in autosomal dominant polycystic kidney disease. For chronic pain, nonopioid analgesics and conservative interventions can be used first, before opioid analgesics are considered. If pain continues there are surgical interventions such as renal cyst decortication, renal denervation and nephrectomy that can target pain produced by renal or hepatic cysts. Conclusions Chronic pain in patients with autosomal dominant polycystic kidney disease is often refractory to conservative, medical and other noninvasive treatments. There are effective surgical procedures that can be performed when more conservative treatments fail. Laparoscopic cyst decortication has been well studied and results in the relief of chronic renal pain in the majority of patients. In addition, renal denervation has been used successfully and could be performed concurrently with cyst decortication. Nephrectomy should be reserved for patients with intractable pain and renal failure when other modalities have failed

Systematic screen for mutants resistant to TORC1 inhibition in fission yeast reveals genes involved in cellular ageing and growth

Target of rapamycin complex 1 (TORC1), which controls growth in response to nutrients, promotes ageing in multiple organisms. The fission yeast Schizosaccharomyces pombe emerges as a valuable genetic model system to study TORC1 function and cellular ageing. Here we exploited the combinatorial action of rapamycin and caffeine, which inhibit fission yeast growth in a TORC1-dependent manner. We screened a deletion library, comprising ∼84% of all non-essential fission yeast genes, for drug-resistant mutants. This screen identified 33 genes encoding functions such as transcription, kinases, mitochondrial respiration, biosynthesis, intra-cellular trafficking, and stress response. Among the corresponding mutants, 5 showed shortened and 21 showed increased maximal chronological lifespans; 15 of the latter mutants showed no further lifespan increase with rapamycin and might thus represent key targets downstream of TORC1. We pursued the long-lived sck2 mutant with additional functional analyses, revealing that the Sck2p kinase functions within the TORC1 network and is required for normal cell growth, global protein translation, and ribosomal S6 protein phosphorylation in a nutrient-dependent manner. Notably, slow cell growth was associated with all long-lived mutants while oxidative-stress resistance was not

Delaying Cancer Cases in Urology during COVID-19: Review of the Literature

Purpose: Coronavirus Disease 2019 (COVID-19) is a global pandemic affecting hospital systems and the availability of resources for surgical procedures. Our aim is to provide guidance for urologists to help prioritize urologic cancer surgeries. Material and Methods: We reviewed published literature on bladder cancer, upper tract urothelial carcinoma (UTUC), penile cancer, testis cancer, prostate cancer, renal cancer, and adrenal cancer. Results: For muscle invasive bladder cancer (MIBC), delays should be less than roughly 10 weeks and neoadjuvant chemotherapy should be considered. For non-MIBC, patients should be counseled appropriately based on risk and intravesical therapies can continue. UTUC should also be treated with minimal delays for high risk patients, especially with ureteral tumors. Surgery for T1 renal cancers when indicated can be delayed until adequate resources are available. Patients with T2 renal cancer should be considered for early surgery if there are unfavorable pre-operative characteristics. Higher stage renal tumors should be considered for early surgery. Early multi-disciplinary approach is recommended for metastatic renal cancers. High risk prostate cancer may need preferential treatment and consideration of neoadjuvant hormonal therapy. Penile cancer can have worse sexual or oncologic outcome with prolonged surgical delay. Likewise, adrenal cancer is aggressive and needs early surgical treatment. Testicular cancer should be treated in a timely manner with surgery or chemotherapy, as indicated. Conclusions: This review should further assist urologists in recognizing patients with potentially aggressive tumor biology that warrant early treatment

Novel Use of Folate-Targeted Intraoperative Fluorescence, OTL38, in Robot-Assisted Laparoscopic Partial Nephrectomy: Report of the First Three Cases

Partial nephrectomy is now the preferred surgical option for small renal tumors because it allows nephron preservation without compromising oncologic clearance. Its outcomes depend on the surgeon's ability to continuously identify the edges of the tumor during resection, thus leaving an adequate margin around the tumor without excessive removal of normal parenchyma, as well as keeping a short ischemic time. Folate receptors are highly abundant in the normal kidney, and there is a difference in folate receptor expression between malignant and normal renal tissues. Thus, the use of fluorescent agents that target folate receptors should result in differential fluorescence between the tumor and surrounding parenchyma during partial nephrectomy, which, in turn, helps tumor demarcation for identification and resection. A phase 2 study on the novel use of OTL38 in robot-assisted laparoscopic partial nephrectomy is currently in progress in our institution. The outcomes of the first three cases have shown the possible advantages of OTL38 in intraoperative tumor identification before resection and recognition of residual disease in the surrounding parenchyma after resection. The tumors typically appeared dark while the surrounding parenchyma showed brighter fluorescence. Immediately after tumor resection, the margins of all the specimens appeared to have a uniformly bright fluorescence, suggestive of an intact margin of normal renal parenchyma along the plane of excision. The pattern of intraoperative fluorescence correlates well with immunohistochemistry. No OTL38-related adverse effects have been seen among these three patients. We present the outcomes of these three cases, illustrated with intraoperative and immunohistochemistry images

Recovery for all in the community:Position paper on principles and key elements of community-based mental health care

Backgroud:Service providers throughout Europe have identified the need to define how high-quality community-based mental health care looks to organize their own services and to inform governments, commissioners and funders. In 2016, representatives of mental health care service providers, networks, umbrella organizations and knowledge institutes in Europe came together to establish the European Community Mental Health Services Provider (EUCOMS) Network. This network developed a shared vision on the principles and key elements of community mental health care in different contexts. The result is a comprehensive consensus paper, of which this position paper is an outline. With this paper the network wants to contribute to the discussion on how to improve structures in mental healthcare, and to narrow the gap between evidence, policy and practice in Europe.Main text:The development of the consensus paper started with an expert workshop in April 2016. An assigned writing group representing the workshop participants built upon the outcomes of this meeting and developed the consensus paper with the input from 100 European counterparts through two additional work groups, and two structured feedback rounds via email. High quality community-based mental health care: 1) protects human rights; 2) has a public health focus; 3) supports service users in their recovery journey; 4) makes use of effective interventions based on evidence and client goals; 5) promotes a wide network of support in the community and; 6) makes use of peer expertise in service design and delivery. Each principle is illustrated with good practices from European service providers that are members of the EUCOMS Network.Conclusions:Discussion among EUCOMS network members resulted in a blueprint for a regional model of integrated mental health care based upon six principles.</p

Developing cardiac and skeletal muscle share fast-skeletal myosin heavy chain and cardiac troponin-I expression

Skeletal muscle derived stem cells (MDSCs) transplanted into injured myocardium can differentiate into fast skeletal muscle specific myosin heavy chain (sk-fMHC) and cardiac specific troponin-I (cTn-I) positive cells sustaining recipient myocardial function. We have recently found that MDSCs differentiate into a cardiomyocyte phenotype within a three-dimensional gel bioreactor. It is generally accepted that terminally differentiated myocardium or skeletal muscle only express cTn-I or sk-fMHC, respectively. Studies have shown the presence of non-cardiac muscle proteins in the developing myocardium or cardiac proteins in pathological skeletal muscle. In the current study, we tested the hypothesis that normal developing myocardium and skeletal muscle transiently share both sk-fMHC and cTn-I proteins. Immunohistochemistry, western blot, and RT-PCR analyses were carried out in embryonic day 13 (ED13) and 20 (ED20), neonatal day 0 (ND0) and 4 (ND4), postnatal day 10 (PND10), and 8 week-old adult female Lewis rat ventricular myocardium and gastrocnemius muscle. Confocal laser microscopy revealed that sk-fMHC was expressed as a typical striated muscle pattern within ED13 ventricular myocardium, and the striated sk-fMHC expression was lost by ND4 and became negative in adult myocardium. cTn-I was not expressed as a typical striated muscle pattern throughout the myocardium until PND10. Western blot and RT-PCR analyses revealed that gene and protein expression patterns of cardiac and skeletal muscle transcription factors and sk-fMHC within ventricular myocardium and skeletal muscle were similar at ED20, and the expression patterns became cardiac or skeletal muscle specific during postnatal development. These findings provide new insight into cardiac muscle development and highlight previously unknown common developmental features of cardiac and skeletal muscle. © 2012 Clause et al