A Novel Model of Urinary Tract Differentiation,Tissue Regeneration,and Disease: Reprogramming Human Prostate and Bladder Cells into Induced Pluripotent Stem Cells

Background

Primary culture and animal and cell-line models of prostate and bladder development have limitations in describing human biology, and novel strategies that describe the full spectrum of differentiation from foetal through to ageing tissue are required. Recent advances in biology demonstrate that direct reprogramming of somatic cells into pluripotent embryonic stem cell (ESC)-like cells is possible. These cells, termed induced pluripotent stem cells (iPSCs), could theoretically generate adult prostate and bladder tissue, providing an alternative strategy to study differentiation.

Objective

To generate human iPSCs derived from normal, ageing, human prostate (Pro-iPSC), and urinary tract (UT-iPSC) tissue and to assess their capacity for lineage-directed differentiation.

Design, setting, and participants

Prostate and urinary tract stroma were transduced with POU class 5 homeobox 1 (POU5F1; formerly OCT4), SRY (sex determining region Y)-box 2 (SOX2), Kruppel-like factor 4 (gut) (KLF4), and v-myc myelocytomatosis viral oncogene homolog (avian) (MYC, formerly C-MYC) genes to generate iPSCs.

Outcome measurements and statistical analysis

The potential for differentiation into prostate and bladder lineages was compared with classical skin-derived iPSCs. The student t test was used.

Results and limitations

Successful reprogramming of prostate tissue into Pro-iPSCs and bladder and ureter into UT-iPSCs was demonstrated by characteristic ESC morphology, marker expression, and functional pluripotency in generating all three germ-layer lineages. In contrast to conventional skin-derived iPSCs, Pro-iPSCs showed a vastly increased ability to generate prostate epithelial-specific differentiation, as characterised by androgen receptor and prostate-specific antigen induction. Similarly, UT-iPSCs were shown to be more efficient than skin-derived iPSCs in undergoing bladder differentiation as demonstrated by expression of urothelial-specific markers: uroplakins, claudins, and cytokeratin; and stromal smooth muscle markers: α-smooth-muscle actin, calponin, and desmin. These disparities are likely to represent epigenetic differences between individual iPSC lines and highlight the importance of organ-specific iPSCs for tissue-specific studies.

Conclusions

IPSCs provide an exciting new model to characterise mechanisms regulating prostate and bladder differentiation and to develop novel approaches to disease modelling. Regeneration of bladder cells also provides an exceptional opportunity for translational tissue engineering.     

Laparoscopic adrenalectomy in patients with subclinical Cushing syndrome

Background

Subclinical Cushing syndrome in patients with adrenal incidentalomas has been associated with an increased prevalence of the metabolic syndrome and cardiovascular risk. The management of these patients, be it conservative or surgical, is still debated, but there is accumulating evidence that surgery is best and that laparoscopic adrenalectomy, when possible, is the most preferred procedure. Here we present the short- and long-term results of laparoscopic adrenalectomy for subclinical Cushing syndrome and determine the effect of this procedure on components of the metabolic syndrome.

Methods

Twenty-nine patients, 8 men and 21 women with adrenal incidentalomas and subclinical Cushing syndrome who underwent laparoscopic adrenalectomy, were studied retrospectively. They had undergone postoperative follow-up for improvement or worsening of their arterial blood pressure, body weight, and fasting glucose level for a mean period of 77 months.

Results

Preoperatively, 17 patients (58.6 %) had arterial hypertension, 14 (48.3 %) had a body mass index exceeding 27 kg/m², and 12 (41.4 %) had diabetes mellitus. Postoperatively, a decrease in mean arterial pressure was found in 12 patients (70.6 %), a decrease in body mass index in 6 patients (42.9 %), and an improvement in glycemic control in 5 patients (41.7 %).

Conclusions

Laparoscopic adrenalectomy is beneficial in many patients with subclinical Cushing syndrome because it reduces arterial blood pressure, body weight, and fasting glucose levels. Prospective randomized studies are needed to compare laparoscopic adrenalectomy with a conservative approach and to confirm these results.     

Intravenous morphine attenuates pain induced changes in skin blood flow in newborn infants

Abstract

In a previous study we found that pain and discomfort caused a marked increase in skin blood flow, in newborn infants, and that skin blood flow decreased after morphine. In this study we tested morphine effect on the skin blood flow response to pain more systematically. Skin blood flow was measured using a laser Doppler technique during 19 percutaneous central venous catheter placements in 18 infants, 10 of whom received intravenous morphine premedication. The mean ± SD baseline skin blood flow was similar between the two groups: 22.5±9.5 ml 100 g-7 m/n-7 in the morphine group, and 23.7± 8.0 ml TOO g~1 min~1 in the no-morphine group, respectively (p = n.s.). During PCVC placement in the morphine treated group, skin blood flow remained low with minimal variability. The mean value was 22.6 ±7.7 ml 100 g~1 min(p = n.s. compared to baseline). In 7/9 infants not treated with morphine skin blood flow increased dramatically during PCVC placement; while in two it did not. But the mean skin blood flow in this group of 9 infants during PCVC placement was 45.3 ±34 ml 100 g~1 min~ \ an overall change of 97% increase from the baseline. This was statistically significant compared with the baseline and the morphine group value during PCVC insertion (p< 0.04). During the 45 min time period after PCVC placement, skin blood flow values between groups again were similar. We conclude that morphine pretreatment for PCVC placement minimizes pain-associated increases in skin blood flow. The issue of whether skin blood flow changes could serve as measures of adequate analgesia needs to be evaluated with further studies. [Neurol Res 1996; 18: 440-444]     

Recurrent episodes of rhabdomyolysis in pontocerebellar hypoplasia type 2

Pontocerebellar hypoplasia type 2 is an autosomal recessive disorder characterized by hypoplasia and atrophy of the cerebellum and pons, leading to microcephaly, dystonia/dyskinesia, seizures, and severe cognitive impairment. Until lately it was considered a CNS-refined disease, but recent reports have associated it with muscular defects, as well. A 5-year-old boy with genetically confirmed pontocerebellar hypoplasia type 2 is described. The patient had all the clinical and radiological features of the disease, but he, additionally, exhibited two episodes of rhabdomyolysis precipitated by respiratory infections. The possible mechanisms associating encephalopathy and myopathy in pontocerebellar hypoplasia type 2 are discussed.     

Impact of COVID-19 lockdown on progressive multiple sclerosis patients

Neurological Sciences - The COVID-19 pandemic caused major changes in the lifestyle and in the access to health services worldwide. Progressive multiple sclerosis (pMS) patients are a vulnerable...     

Endoscopic third ventriculostomy in the treatment of idiopathic normal pressure hydrocephalus: a review study

Idiopathic normal pressure hydrocephalus is a hydrodynamic disorder whose etiology remains unclear. The diagnosis is mainly clinical and the traditional treatment is cerebrospinal fluid shunt diversion. With the introduction of modern management strategies, endoscopic third ventriculostomy has become a viable alternative to shunting and constitutes a well-established method of treatment for obstructive hydrocephalus. The new hydrodynamic concept of hydrocephalus suggests that endoscopic third ventriculostomy (ETV) may be an effective treatment for communicative hydrocephalus. In our current review, the authors focus on the up-to-date knowledge regarding the consideration of endoscopic third ventriculostomy as a safe surgical option in the management of idiopathic normal pressure hydrocephalus.     

Nuclear cardiology practice and associated radiation doses in Europe: results of the IAEA Nuclear Cardiology Protocols Study (INCAPS) for the 27 European countries

Purpose

Nuclear cardiology is widely used to diagnose coronary artery disease and to guide patient management, but data on current practices, radiation dose-related best practices, and radiation doses are scarce. To address these issues, the IAEA conducted a worldwide study of nuclear cardiology practice. We present the European subanalysis.

Methods

In March 2013, the IAEA invited laboratories across the world to document all SPECT and PET studies performed in one week. The data included age, gender, weight, radiopharmaceuticals, injected activities, camera type, positioning, hardware and software. Radiation effective dose was calculated for each patient. A quality score was defined for each laboratory as the number followed of eight predefined best practices with a bearing on radiation exposure (range of quality score 0 – 8). The participating European countries were assigned to regions (North, East, South, and West). Comparisons were performed between the four European regions and between Europe and the rest-of-the-world (RoW).

Results

Data on 2,381 European patients undergoing nuclear cardiology procedures in 102 laboratories in 27 countries were collected. A cardiac SPECT study was performed in 97.9 % of the patients, and a PET study in 2.1 %. The average effective dose of SPECT was 8.0?±?3.4 mSv (RoW 11.4?±?4.3 mSv; P?<?0.001) and of PET was 2.6?±?1.5 mSv (RoW 3.8?±?2.5 mSv; P?<?0.001). The mean effective doses of SPECT and PET differed between European regions (P?<?0.001 and P?=?0.002, respectively). The mean quality score was 6.2?±?1.2, which was higher than the RoW score (5.0?±?1.1; P?<?0.001). Adherence to best practices did not differ significantly among the European regions (range 6 to 6.4; P?=?0.73). Of the best practices, stress-only imaging and weight-adjusted dosing were the least commonly used.

Conclusion

In Europe, the mean effective dose from nuclear cardiology is lower and the average quality score is higher than in the RoW. There is regional variation in effective dose in relation to the best practice quality score. A possible reason for the differences between Europe and the RoW could be the safety culture fostered by actions under the Euratom directives and the implementation of diagnostic reference levels. Stress-only imaging and weight-adjusted activity might be targets for optimization of European nuclear cardiology practice.