Trans-peritoneal vs. retroperitoneal robotic assisted partial nephrectomy in posterior renal tumours: need for a risk-stratified patient individualised approach. A systematic review and meta-analysis

Journal of Robotic Surgery - To systematically review world literature and compare peri-operative outcome including operating time (OT), estimated blood loss (EBL), warm ischemia time (WIT), length...     

Aberrant Glycosylation and Localization of Polycystin-1 Cause Polycystic Kidney in an AQP11 Knockout Model

We previously reported that disruption of the aquaporin-11 (AQP11) gene in mice resulted in cystogenesis in the kidney. In this study, we aimed to clarify the mechanism of cystogenesis in AQP11(−/−) mice. To enable the analyses of AQP11 at the protein level in vivo, AQP11 BAC transgenic mice (Tg^AQP11) that express 3×HA-tagged AQP11 protein were generated. This AQP11 localized to the endoplasmic reticulum (ER) of proximal tubule cells in Tg^AQP11 mice and rescued renal cystogenesis in AQP11(−/−) mice. Therefore, we hypothesized that the absence of AQP11 in the ER could result in impaired quality control and aberrant trafficking of polycystin-1 (PC-1) and polycystin-2 (PC-2). Compared with kidneys of wild-type mice, AQP11(−/−) kidneys exhibited increased protein expression levels of PC-1 and decreased protein expression levels of PC-2. Moreover, PC-1 isolated from AQP11(−/−) mice displayed an altered electrophoretic mobility caused by impaired N-glycosylation processing, and density gradient centrifugation of kidney homogenate and in vivo protein biotinylation revealed impaired membrane trafficking of PC-1 in these mice. Finally, we showed that the Pkd1(+/−) background increased the severity of cystogenesis in AQP11(−/−) mouse kidneys, indicating that PC-1 is involved in the mechanism of cystogenesis in AQP11(−/−) mice. Additionally, the primary cilia of proximal tubules were elongated in AQP11(−/−) mice. Taken together, these data show that impaired glycosylation processing and aberrant membrane trafficking of PC-1 in AQP11(−/−) mice could be a key mechanism of cystogenesis in AQP11(−/−) mice.Aquaporin-11 (AQP11) is a membrane-channel protein. Although AQP11 is reported to be permeable to the water molecule,^1–3 the permeability of AQP11 to other solutes remains unclear. AQP11(−/−) mice die in the neonatal period because of renal failure and retarded growth.^4,5 Moreover, AQP11(−/−) mice develop renal cysts, suggesting that AQP11 can play a role in cystogenesis.^4,5 However, the mechanisms of cystogenesis in AQP11(−/−) mice have yet to be clarified. One of the reasons for the difficulties in investigating AQP11 has been the lack of a good antibody for detecting endogenous AQP11 in mouse tissues.Autosomal dominant polycystic kidney disease (PKD) is the most common inherited renal disorder, occurring in 1:400 to 1:1000 live births. It is characterized by gradual renal cyst development and expansion, ultimately resulting in massive kidney enlargement and ESRD. Among autosomal dominant PKD patients, 85%–90% of cases result from mutations in the PKD1 gene, whereas another 10%–15% of cases are accounted for by mutations in the PKD2 gene. PKD1 encodes polycystin-1 (PC-1), a 462-kD, 4303–amino acid integral membrane protein with 11 transmembrane domains, a long extracellular N terminus with multiple binding domains, and a short cytoplasmic C terminus that interacts with multiple proteins, including the protein product of PKD2, polycystin-2 (PC-2).⁶ PC-2 is a significantly smaller 110-kD protein with six transmembrane domains. PC-1 and PC-2 are located in the plasma membrane and cilia of renal epithelia.^6–8To enable the analyses of AQP11 in mice at the protein level in vivo, we generated AQP11 BAC transgenic mice (Tg^AQP11) that express AQP11 tagged with 3×hemagglutinin (HA) sequence at its N terminus and showed that AQP11 localizes to the endoplasmic reticulum (ER) of proximal tubule cells in vivo. Moreover, to investigate the mechanisms of cystogenesis in AQP11(−/−) mouse kidneys, we focused on PC-1 and PC-2. Impaired glycosylation processing and membrane trafficking of PC-1 in AQP11(−/−) mouse kidneys were found, which could represent a key mechanism of cyst formation in AQP11(−/−) mice.     

Individualized Anemia Management Reduces Hemoglobin Variability in Hemodialysis Patients

One-size-fits-all protocol-based approaches to anemia management with erythropoiesis-stimulating agents (ESAs) may result in undesired patterns of hemoglobin variability. In this single-center, double-blind, randomized controlled trial, we tested the hypothesis that individualized dosing of ESA improves hemoglobin variability over a standard population-based approach. We enrolled 62 hemodialysis patients and followed them over a 12-month period. Patients were randomly assigned to receive ESA doses guided by the Smart Anemia Manager algorithm (treatment) or by a standard protocol (control). Dose recommendations, performed on a monthly basis, were validated by an expert physician anemia manager. The primary outcome was the percentage of hemoglobin concentrations between 10 and 12 g/dl over the follow-up period. A total of 258 of 356 (72.5%) hemoglobin concentrations were between 10 and 12 g/dl in the treatment group, compared with 208 of 336 (61.9%) in the control group; 42 (11.8%) hemoglobin concentrations were <10 g/dl in the treatment group compared with 88 (24.7%) in the control group; and 56 (15.7%) hemoglobin concentrations were >12 g/dl in the treatment group compared with 46 (13.4%) in the control group. The median ESA dosage per patient was 2000 IU/wk in both groups. Five participants received 6 transfusions (21 U) in the treatment group, compared with 8 participants and 13 transfusions (31 U) in the control group. These results suggest that individualized ESA dosing decreases total hemoglobin variability compared with a population protocol-based approach. As hemoglobin levels are declining in hemodialysis patients, decreasing hemoglobin variability may help reduce the risk of transfusions in this population.Anemia is a common complication of ESRD and is treated with erythropoiesis-stimulating agents (ESAs), iron, and/or blood transfusions. Effective anemia management with an ESA is challenging because of significant interindividual variability in erythropoietic response. A large ESA dose associated with an inability to achieve target hemoglobin (ESA resistance) may be a marker for increased risk of cardiovascular adverse events.^1–4 Until recently, the national guidelines for anemia management in ESRD patients recommended a hemoglobin target of 10–12 g/dl. The current ESA product label approved by the US Food and Drug Administration (FDA) stipulates treatment individualization to decrease the risk of transfusions. Furthermore, changes in reimbursement rules by Medicare, which provides coverage for a large majority of ESRD patients, have led to an evolution of ESA dosing patterns that results in lower average hemoglobin levels and more transfusions.⁵Ever since the introduction of ESAs, dialysis facilities have been providing standardized care using protocols derived from the national guidelines. The new FDA ruling emphasizes the need for individualized ESA dosing.^6,7 The goal of such individualization should be to maintain stable hemoglobin concentrations and prevent hemoglobin excursions below levels that typically trigger blood transfusions. However, as of now, no such level has been uniquely defined, and it is typically left to the clinician’s judgment to decide what hemoglobin level and/or presence of other symptoms should trigger transfusions.We and others have demonstrated the application of automatic control methods to ESA dosing.^8–10 We have shown that a population approach to ESA dosing, based on the principles of model predictive control (MPC), is comparable with a standard protocol.^8,9 We now present the results of a randomized clinical trial of an MPC-based individualized approach to ESA dosing. We tested the hypothesis that individualized ESA dosing improves the total hemoglobin variability defined as the proportion of hemoglobin measurements within a user-specified target (10–12 g/dl) compared with a standard protocol-based population approach. This study was registered at ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT00572533","term_id":"NCT00572533"}}NCT00572533).     

Asymptomatic prostatic inflammation in men with clinical BPH and erectile dysfunction affects the positive predictive value of prostate-specific antigen

ObjectiveTo test the hypothesis that sexual dysfunction in elderly men with benign prostatic hyperplasia leads to prostatic inflammation, diagnosed by prostatic fluid interleukin-8 (IL-8), which lowers the positive predictive value of prostate-specific antigen (PSA).MethodsOverall, 160 men with lower urinary tract symptoms between 50 and 75 years of age with an elevated PSA level of more than 4 ng/ml with normal digital rectal examination and 50 age-matched controls with normal PSA level were prospectively evaluated for prostatic fluid IL-8 levels. Erectile dysfunction was measured by self-administered questionnaire of the Sexual Health Inventory for Men. Total and free serum PSA levels and IL-8 in prostatic fluid were measured 6 to 8 weeks after a course of 400 mg of ofloxacin and 20 mg of piroxicam given daily for 2 weeks. Transrectal ultrasonography–guided biopsy was done only when PSA level did not decrease less than 4 ng/ml.ResultsMean ages of patients and controls were 63.18 (standard deviation [SD]±7.10) and 60.18 (SD+6.02) years, respectively. Mean concentration of IL-8 in prostatic fluid of the patients was significantly higher, i.e., 6678 pg/ml (SD±1985.7) than in control, i.e., 1543 pg/ml (SD±375.7) (P<0.001). Following anti-inflammatory treatment, there was a significant decrease in the mean level of IL-8 from baseline to 5622 pg/ml (SD±1870.66) (P<0.001). Corresponding to this, a significant decrease was noted in total PSA levels to less than 4 ng/ml in 105 (65.62%) patients. Men with the highest levels of IL-8 had a greater degree of erectile dysfunction.ConclusionMen with symptomatic benign prostatic hyperplasia and erectile dysfunction had significant inflammation of the prostate to cause spurious rise in PSA level resulting in an unnecessary biopsy.     

Effect of Tribulus terrestris on Haloperidol-induced Catalepsy in Mice

Haloperidol, an antipsychotic drug, leads to the development of a behavioural state called catalepsy, in which the animal is not able to correct an externally imposed posture. In the present study we have attempted to evaluate the anticataleptic effect of Tribulus terrestris on haloperidol-induced catalepsy in albino mice. Mice were allocated to four groups, each group containing six animals. Both, the test drug, Tribulus terrestris and the standard drug trihexyphenidyl were uniformly suspended in 1% gum acacia solution. Catalepsy was induced in mice with haloperidol (1.0 mg/kg, intraperitoneally). The first group received the vehicle (10 ml/kg, orally), the second group received trihexyphenidyl (10 mg/kg, orally) and the remaining two groups received Tribulus terrestris (100, 200 mg/kg, orally). The animals were assessed after single and repeated dose administration for ten days, 30 min prior to haloperidol, using standard bar test. The result of the present study demonstrates Tribulus terrestris has a protective effect against haloperidol-induced catalepsy, which is comparable to the standard drug used for the same purpose. Our study indicates Tribulus terrestris can be used to prevent haloperidol-induced extrapyramidal side effects.     

Noble Metal Organometallic Complexes Display Antiviral Activity against SARS-CoV-2

SARS-CoV-2 emerged in 2019 as a devastating viral pathogen with no available preventative or treatment to control what led to the current global pandemic. The continued spread of the virus and increasing death toll necessitate the development of effective antiviral treatments to combat this virus. To this end, we evaluated a new class of organometallic complexes as potential antivirals. Our findings demonstrate that two pentamethylcyclopentadienyl (Cp*) rhodium piano stool complexes, Cp*Rh(1,3-dicyclohexylimidazol-2-ylidene)Cl₂ (complex 2) and Cp*Rh(dipivaloylmethanato)Cl (complex 4), have direct virucidal activity against SARS-CoV-2. Subsequent in vitro testing suggests that complex 4 is the more stable and effective complex and demonstrates that both 2 and 4 have low toxicity in Vero E6 and Calu-3 cells. The results presented here highlight the potential application of organometallic complexes as antivirals and support further investigation into their activity.