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Background: The COVID-19 pandemic has a great impact on solid organ transplant (SOT) recipients due to their comorbidities and their maintenance immunosuppression. So far, studies about the different aspects of the impact of the pandemic on SOT recipients are limited., Objectives: This systematic review summarizes the risk factors that make SOT patients more vulnerable for severe COVID-19 disease or mortality and the impact of immunosuppressive therapy. Furthermore, their clinical outcomes, mortality risk, immunosuppression, immunity and COVID-19 vaccination efficacy are discussed., Methods: A systematic search on PubMed was performed to select original articles on SOT recipients concerning the following four topics: (1) mortality and clinical course; (2) risk factors for mortality and composite outcomes; (3) maintenance immunosuppression; (4) immunity to COVID-19 infection and (5) vaccine immunogenicity. Relevant data were extracted, analyzed and summarized in tables., Results: This systematic review includes 77 articles. Mortality was associated with advanced age. Post-transplantation time or comorbidities were variably identified as independent risk factors for mortality or severe disease. However, generally, no comorbidity was reported as a major risk factor. SOT recipients have a higher risk of acute kidney injury, but no higher rate of mortality compared to non-transplanted patients was found. Immunosuppression was individually adjusted, without leading to high rates of graft dysfunction. Generally, no association between type of immunosuppression and mortality was found. SOT patients established humoral and cellular immune responses after COVID-19 disease comparable to immunocompetent people. At last, SOT patients experience a diminished immune response after two-dose vaccination with SARS-COV-2-mRNA-vaccines., Conclusion: More research is needed to address the direct effect of COVID-19 disease on the graft in lung transplant recipients, as well as the factors ameliorating the immune response in SOT recipients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Amyloid precursor protein (APP) cleavage by the β-secretase produces the C99 transmembrane (TM) protein, which contains three dimerization-inducing Gly-x-x-x-Gly motifs. We demonstrate that dimeric C99 TM orientations regulate the precise cleavage lines by γ-secretase. Of all possible dimeric orientations imposed by a coiled-coil to the C99 TM domain, the dimer containing the 33 Gly-x-x-x-Gly 37 motif in the interface promoted the Aβ 42 processing line and APP intracellular domain-dependent gene transcription, including the induction of BACE1 mRNA, enhancing amyloidogenic processing and signaling. Another orientation exhibiting the 25 Gly-x-x-x-Gly 29 motif in the interface favored processing to Aβ 43/40 . It induced significantly less gene transcription, while promoting formation of SDS-resistant "Aβ-like" oligomers, reminiscent of Aβ peptide oligomers. These required both Val24 of a pro-β motif and the 25 Gly-x-x-x-Gly 29 interface. Thus, crossing angles imposed by precise dimeric orientations control γ-secretase initial cleavage at Aβ 48 or Aβ 49, linking the former to enhanced signaling and Aβ 42 production., Competing Interests: S.N.C. is co-founder of Alsatech – Boston, MA and close family is owning stock in A.C. Immune Lausanne. The work of this manuscript is not linked to any current project at Alsatech or A.C. Immune, which are companies that work in the field of Alzheimer's disease., (© 2020 The Author(s).)

The amyloid precursor protein (APP) has been extensively studied as the precursor of the β-amyloid (Aβ) peptide, the major component of the senile plaques found in the brain of Alzheimer's disease (AD) patients. However, the function of APP per se in neuronal physiology remains to be fully elucidated. APP is expressed at high levels in the brain. It resembles a cell adhesion molecule or a membrane receptor, suggesting that its function relies on cell-cell interaction and/or activation of intracellular signaling pathways. In this respect, the APP intracellular domain (AICD) was reported to act as a transcriptional regulator. Here, we used a transcriptome-based approach to identify the genes transcriptionally regulated by APP in the rodent embryonic cortex and on maturation of primary cortical neurons. Surprisingly, the overall transcriptional changes were subtle, but a more detailed analysis pointed to genes clustered in neuronal-activity dependent pathways. In particular, we observed a decreased transcription of neuronal PAS domain protein 4 (NPAS4) in APP-/- neurons. NPAS4 is an inducible transcription factor (ITF) regulated by neuronal depolarization. The downregulation of NPAS4 co-occurs with an increased production of the inhibitory neurotransmitter GABA and a reduced expression of the GABA A receptors α1. CRISPR-Cas-mediated silencing of NPAS4 in neurons led to similar observations. Patch-clamp investigation did not reveal any functional decrease of GABA A receptors activity, but long-term potentiation (LTP) measurement supported an increased GABA component in synaptic transmission of APP-/- mice. Together, NPAS4 appears to be a downstream target involved in APP-dependent regulation of inhibitory synaptic transmission., (Copyright © 2020 Opsomer et al.)

Extracellular deposition of β-amyloid (Aβ) peptides in the brain is a hallmark of Alzheimer's disease (AD). Upon β-secretase-mediated cleavage of the β C-terminal fragment (β-CTF) from the Aβ precursor protein, the γ-secretase complex produces the Aβ peptides associated with AD. The familial T43I mutation within the transmembrane domain of the β-CTF (also referred to as C99) increases the ratio between the Aβ42 and Aβ40 peptides largely due to a decrease in Aβ40 formation. Aβ42 is the principal component of amyloid deposits within the brain parenchyma, and an increase in the Aβ42/Aβ40 ratio is correlated with early-onset AD. Using NMR and FTIR spectroscopy, here we addressed how the T43I substitution influences the structure of C55, the minimal sequence containing the entire extracellular and transmembrane (TM) domains of C99 needed for γ-secretase processing. 13 C NMR chemical shifts indicated that the T43I substitution increases helical structure within the TM domain of C55. These structural changes were associated with a shift of the C55 dimer to the monomer and an increase in the tilt of the TM helix relative to the membrane normal in the T43I mutant compared with that of WT C55. The A21G (Flemish) mutation was previously found to increase secreted Aβ40 levels; here, we combined this mutation in the extracellular domain of C99 with T43I and observed that the T43I/A21G double mutant decreases Aβ40 formation. We discuss how the observed structural changes in the T43I mutant may decrease Aβ40 formation and increase the Aβ42/Aβ40 ratio., (© 2019 Tang et al.)

Para-Phenylenediamine (PPD) is an aromatic amine used in hair dyes and in temporary black henna tattoos, which is a frequent cause of allergic contact dermatitis (ACD). ACD is a skin inflammatory reaction characterized by modifications such as spongiosis, exocytosis and acanthosis. The aim of this study is to characterize the expression and the role of IL-20-related cytokines, including IL-19, IL-20, IL-22 and IL-24, in ACD. The expression of IL19, IL20, IL22 and IL24 is increased in affected skin from PPD allergic patients compared with uninvolved skin. In addition, the expression of these cytokines positively correlates with clinical symptoms. To assess their role in ACD, we set up a mouse model of PPD-induced allergic contact dermatitis and we showed that, in contrast to Il22-deficient mice, Il22ra1-, Il20rb- and Il24-deficient mice are partially protected against development of PPD-induced contact hypersensitivity. These mice have decreased ear thickening and less acanthosis compared with WT mice after PPD treatment. In addition, the absence of IL-22R, IL-20R2 or IL-24 affects the recruitment of neutrophils into the skin but not the total IgE production. Taken together, these results demonstrate the implication of IL-24 via the IL-20R type II receptor in the inflammatory process of ACD.

Aβ peptides, the major components of Alzheimer's disease (AD) amyloid deposits, are released following sequential cleavages by secretases of its precursor named the amyloid precursor protein (APP). In addition to secretases, degradation pathways, in particular the endosomal/lysosomal and proteasomal systems have been reported to contribute to APP processing. However, the respective role of each of these pathways toward APP metabolism remains to be established. To address this, we used HEK 293 cells and primary neurons expressing full-length wild type APP or the β-secretase-derived C99 fragment (β-CTF) in which degradation pathways were selectively blocked using pharmacological drugs. APP metabolites, including carboxy-terminal fragments (CTFs), soluble APP (sAPP) and Aβ peptides were studied. In this report, we show that APP-CTFs produced from endogenous or overexpressed full-length APP are mainly processed by γ-secretase and the endosomal/lysosomal pathway, while in sharp contrast, overexpressed C99 is mainly degraded by the proteasome and to a lesser extent by γ-secretase.

Accumulating evidence indicates that motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is a non-cell-autonomous process and that impaired glutamate clearance by astrocytes, leading to excitotoxicity, could participate in progression of the disease. In astrocytes derived from an animal model of ALS (hSOD1 G93A rats), activation of type 5 metabotropic glutamate receptor (mGluR5) fails to increase glutamate uptake, impeding a putative dynamic neuroprotective mechanism involving astrocytes. Using astrocyte cultures from hSOD1 G93A rats, we have demonstrated that the typical Ca 2+ oscillations associated with mGluR5 activation were reduced, and that the majority of cells responded with a sustained elevation of intracellular Ca 2+ concentration. Since the expression of protein kinase C epsilon isoform (PKCɛ) has been found to be considerably reduced in astrocytes from hSOD1 G93A rats, the consequences of manipulating its activity and expression on mGluR5 signaling and on the regulation of glutamate uptake have been examined. Increasing PKCɛ expression was found to restore Ca 2+ oscillations induced by mGluR5 activation in hSOD1 G93A -expressing astrocytes. This was also associated with an increase in glutamate uptake capacity in response to mGluR5 activation. Conversely, reducing PKCɛ expression in astrocytes from wild-type animals with specific PKCɛ-shRNAs was found to alter the mGluR5 associated oscillatory signaling profile, and consistently reduced the regulation of the glutamate uptake-mediated by mGluR5 activation. These results suggest that PKCɛ is required to generate Ca 2+ oscillations following mGluR5 activation, which support the regulation of astrocytic glutamate uptake. Reduced expression of astrocytic PKCɛ could impair this neuroprotective process and participate in the progression of ALS., (© 2017 Wiley Periodicals, Inc.)

Familial mutations in C99 can increase the total level of the soluble Aβ peptides produced by proteolysis, as well as the Aβ42/Aβ40 ratio, both of which are linked to the progression of Alzheimer's disease. We show that the extracellular sequence of C99 forms β-sheet structure upon interaction with membrane bilayers. Mutations that disrupt this structure result in a significant increase in Aβ production and, in specific cases, result in an increase in the amount of Aβ42 relative to Aβ40. Fourier transform infrared and solid-state NMR spectroscopic studies reveal a central β-hairpin within the extracellular sequence comprising Y10-E11-V12 and L17-V18-F19 connected by a loop involving H13-H14-Q15. These results suggest how familial mutations in the extracellular sequence influence C99 processing and provide a structural basis for the development of small molecule modulators that would reduce Aβ production.

Mitochondrial dysfunction plays a pivotal role in the progression of Alzheimer's disease (AD), and yet the mechanisms underlying the impairment of mitochondrial function in AD remain elusive. Recent evidence suggested a role for Presenilins (PS1 or PS2) in mitochondrial function. Mutations of PSs, the catalytic subunits of the γ-secretase complex, are responsible for the majority of inherited AD cases (FAD). PSs were shown to be present in mitochondria and particularly enriched in mitochondria-associated membranes (MAM), where PS2 is involved in the calcium shuttling between mitochondria and the endoplasmic reticulum (ER). We investigated the precise contribution of PS1 and PS2 to the bioenergetics of the cell and to mitochondrial morphology in cell lines derived from wild type (PS+/+), PS1/2 double knock-out (PSdKO), PS2KO and PS1KO embryos. Our results showed a significant impairment in the respiratory capacity of PSdKO and PS2KO cells with reduction of basal oxygen consumption, oxygen utilization dedicated to ATP production and spare respiratory capacity. In line with these functional defects, we found a decrease in the expression of subunits responsible for mitochondrial oxidative phosphorylation (OXPHOS) associated with an altered morphology of the mitochondrial cristae. This OXPHOS disruption was accompanied by a reduction of the NAD + /NADH ratio. Still, neither ADP/ATP ratio nor mitochondrial membrane potential (ΔΨ) were affected, suggesting the existence of a compensatory mechanism for energetic balance. We observed indeed an increase in glycolytic flux in PSdKO and PS2KO cells. All these effects were truly dependent on PS2 since its stable re-expression in a PS2KO background led to a complete restoration of the parameters impaired in the absence of PS2. Our data clearly demonstrate here the crucial role of PS2 in mitochondrial function and cellular bioenergetics, pointing toward its peculiar role in the formation and integrity of the electron transport chain.

A critical role has been assigned to protein kinase C (PKC)ε in the control of intracellular calcium oscillations triggered upon activation of type 5 metabotropic glutamate receptor (mGluR5) in cultured astrocytes. Nevertheless, the physiological significance of this particular signalling profile in the response of astrocytes to glutamate remains largely unknown. Considering that kinases are frequently involved in the regulation of G protein-coupled receptors, we have examined a putative link between the nature of the calcium signals and the response regulation upon repeated exposures of astrocytes to the agonist (S)-3,5-dihydroxyphenylglycine. We show that upon repeated mGluR5 activations, a robust desensitization was observed in astrocytes grown in culture conditions favouring the peak-plateau-type response. At variance, in cell cultures where calcium oscillations were predominating, the response was fully preserved even during repeated challenges with the agonist. Pharmacological inhibition of PKCε or genetic suppression of this isoform using shRNA was found to convert an oscillatory calcium profile to a sustained calcium mobilization and this latter profile was subject to desensitization upon repetitive mGluR5 activation. Our results suggest a yet undocumented scheme in which the activity of PKCε contributes to preserve the receptor sensitivity upon repeated or sustained activations. Cover Image for this issue: doi: 10.1111/jnc.13797., (© 2017 International Society for Neurochemistry.)

The amyloid precursor protein (APP) modulates synaptic activity, resulting from the fine tuning of excitatory and inhibitory neurotransmission. GABAergic inhibitory neurotransmission is affected by modifications in intracellular chloride concentrations regulated by Na + -K + -2Cl - cotransporter 1 (NKCC1) and neuronal K + -Cl - cotransporter 2 (KCC2), allowing entrance and efflux of chloride, respectively. Modifications in NKCC1 and KCC2 expression during maturation of cortical cells induce a shift in GABAergic signaling. Here, we demonstrated that APP affects this GABA shift. Expression of APP in cortical cells decreased the expression of KCC2, without modifying NKCC1, eliciting a less inhibitory GABA response. Downregulation of KCC2 expression by APP was independent of the APP intracellular domain, but correlated with decreased expression of upstream stimulating factor 1 (USF1), a potent regulator of Slc12a5 gene expression (encoding KCC2). KCC2 was also downregulated in vivo following APP expression in neonatal mouse brain. These results argue for a key role of APP in the regulation of GABAergic neurotransmission.

Understanding the molecular mechanisms controlling the physiological and pathological activity of γ-secretase represents a challenging task in Alzheimer disease research. The assembly and proteolytic activity of this enzyme require the correct interaction of the 19 transmembrane domains (TMDs) present in its four subunits, including presenilin (PS1 or PS2), the γ-secretase catalytic core. GXXXG and GXXXG-like motifs are critical for TMDs interactions as well as for protein folding and assembly. The GXXXG motifs on γ-secretase subunits (e.g. APH-1) or on γ-secretase substrates (e.g. APP) are known to be involved in γ-secretase assembly and in Aβ peptide production, respectively. We identified on PS1 and PS2 TMD8 two highly conserved AXXXAXXXG motifs. The presence of a mutation causing an inherited form of Alzheimer disease (familial Alzheimer disease) in the PS1 motif suggested their involvement in the physiopathological configuration of the γ-secretase complex. In this study, we targeted the role of these motifs on TMD8 of PSs, focusing on their role in PS assembly and catalytic activity. Each motif was mutated, and the impact on complex assembly, activity, and substrate docking was monitored. Different amino acid substitutions on the same motif resulted in opposite effects on γ-secretase activity, without affecting the assembly or significantly impairing the maturation of the complex. Our data suggest that AXXXAXXXG motifs in PS TMD8 are key determinants for the conformation of the mature γ-secretase complex, participating in the switch between the physiological and pathological functional conformations of the γ-secretase., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Introduction: The HelpED study assessed men with erectile dysfunction (ED) treated with a phosphodiesterase type 5 (PDE5) inhibitor and their female partner in a community setting., Aim: To examine agreement in Erection Hardness Score (EHS) in patients and partners; to assess impact of EHS changes on other sexual health outcomes and behaviors., Methods: At baseline and follow-up 2 to 4 months later, men in a stable heterosexual relationship who had newly diagnosed or untreated ED (≥6 months) completed the single-item EHS, the International Index of Erectile Function questions 4 and 5 (assessing erection maintenance), the Self-Esteem And Relationship (SEAR) questionnaire, and a modified Quality of Life domain of the Sexual Life Quality Questionnaire (mSLQQ-QOL). Partners completed the EHS, Female Sexual Function Index, and the mSLQQ-QOL., Main Outcome Measures: EHS agreement assessed by Cohen weighted kappa coefficient, associations between change in EHS and change in measures of sexual function and quality of life; outcomes stratified by patient age (≤55 years vs. >55 years)., Results: Questionnaires were completed by 447 men (64% aged 51-70 years) and 253 partners (52% aged 46-60 years) at baseline and by 266 and 152, respectively, at follow-up. At baseline, the consulting physician proposed PDE5 inhibitor treatment for 99% of patients, and EHS mean values were similar in patients and partners. All outcomes improved significantly (P<0.05), including EHS in 75% of men (EHS3 [hardness sufficient for sexual intercourse but not fully hard] improved to EHS4 [fully hard erection] in almost 60%). For most other outcomes, improvement was greater in younger men and in those who improved from EHS3 to EHS4., Conclusions: Strong agreement in EHS between patient and partner and associations between improvement in EHS and improvements in measures of sexual function and quality of life in patients and partners support its clinical use in ED management., (© 2012 International Society for Sexual Medicine.)

Objective: Here, we report the results of a randomized controlled trial (RCT) assessing the efficacy of emergency ESWL (eESWL) on the short-term outcome of symptomatic ureteral stones., Material: The trial enrolled 100 patients admitted in emergency room for renal colic caused by a ureteral radioopaque [corrected] stone. Patients were randomized to medical therapy alone or combined with eESWL. eESWL was performed within 6 hours of the onset of renal colic without specific analgesia on a Lithostar lithotripter (Siemens Medical, Munich, Germany). The primary endpoints were the proportion of patients stone free rate after 48 hours (SF-48) and the cumulative proportion of patients discharged from the hospital after 48 and 72 hours., Results: Ureteral stone's location was proximal and distal in respectively 46% and 54% of the patients; stone's mean size was 5.5 mm (range 2-10 mm). Median hospital stay was 3 days, ranging from 1 to 14 days. SF-48 in the control group varied from 76% for distal stones <5 mm to 28.6% for proximal stones >5 mm, averaging at 61%. On average, eESWL increased SF-48 by 13% (p: 0.126), the gain strictly depending on stone size and location. SF-48 increase ranged from 40% for proximal stones >5 mm to 1.8% for distal stone <5 mm. On average, eESWL increased the median duration of hospital stay by one day. This mean negative impact results from ESWL increasing significantly the duration of hospital stay in case of distal stone, while slightly shortened it for stones located proximally., Conclusion: This study demonstrated for the first time that rapidly performed ESWL is a valuable therapeutic option to improve elimination of ureteral stones and shorten duration of hospital stay, proven that the stone is located proximally to the iliac vessels.

Erectile dysfunction (ED) and depression are highly prevalent and frequently comorbid. Sildenafil effectively treats ED in men with depression and in men taking antidepressants. We evaluated the efficacy of sildenafil in men with depression in remission and ED. Patients with a history of ED when major depressive disorder (MDD) was diagnosed, which persisted after MDD was treated to remission, were randomized to 12 weeks of treatment with sildenafil (50 mg, flexible) or placebo. Efficacy was assessed using intercourse success rates, a global efficacy question (Has treatment improved your erections?), the International Index of Erectile Function (IIEF) and Life Satisfaction Checklist (LSC). By week 12, intercourse success rates were significantly higher among sildenafil- (74%) compared to placebo-treated patients (29%; P=0.0001). About 83% and 34% of sildenafil- and placebo-treated patients, respectively, reported improved erections (odds ratio=9.4, P=0.0001). IIEF scores in the sildenafil group (n=83) were significantly improved compared to those in the placebo group (n=85; P <0.0001). LSC sexual life item improved significantly among sildenafil- versus placebo-treated patients. The most frequently reported adverse events were transient and mild-to-moderate. Sildenafil is an effective and well-tolerated treatment for ED in patients with a history of ED at the time of MDD diagnosis, and which persisted after the MDD was treated to remission.

Objective: To evaluate whether individual labelling and processing of the sextant of origin improves the accuracy of prostate biopsy in predicting the final pathological stage after radical prostatectomy in patients with T1c prostate cancer., Patients and Methods: The charts of 386 patients treated for prostate cancer by radical prostatectomy between January 1996 and June 1999 were reviewed. In all, 124 patients fulfilled the following inclusion criteria: no abnormality on digital rectal examination (DRE) or transrectal ultrasonography, a prostate specific antigen (PSA) level before biopsy of < or = 20 ng/mL, and prostate cancer diagnosed after one set of random sextant biopsies, with the cores being submitted in six separate containers individually labelled for the sextant of origin., Results: Within this series of patients with a low tumour burden, the preoperative PSA, biopsy Gleason score and unilateral vs bilateral involvement were not significant predictors of disease extension. The percentage of positive cores and the number and topography of positive sextants were both statistically significant predictors of organ-confined disease. Although these two variables appeared to be statistically equivalent on a first analysis in the overall series, a subgroup of patients was identified who benefited from the complete topographical information, i.e. those 52 (42%) patients with a Gleason score of < 7, 25-75% positive biopsies and < or =3 positive sextants., Conclusion: These results support the individual labelling of biopsy cores in selected patients with a normal DRE and a moderately elevated PSA, as it helps to better predict the final pathological stage. This substantial benefit outweighs the additional effort by the pathologist.

Objectives: Despite several publications, the ability of the free/total (F/T) prostate-specific antigen (PSA) ratio to predict the pathologic extension of prostate cancer is still a matter of controversy. In addition, its ability to predict biochemical recurrence after radical prostatectomy has not yet been reported., Methods: Since January 6, 1996, the F/T PSA ratio was prospectively measured preoperatively in 343 patients undergoing radical prostatectomy as the first treatment for localized prostate cancer., Results: The ability to predict organ-confined disease was measured by receiver operating characteristic analysis. The areas under the curve were 0.66 for PSA density, 0.61 for total PSA, 0.60 for Gleason score, and 0.587 for the F/T PSA ratio. In multiple logistic regression analyses, the F/T PSA ratio was not a relevant predictor of organ-confined disease (Wald statistic 0.345 for P = 0.55). Similar results were obtained in the subgroup of patients with a PSA level between 2.5 and 10 ng/mL. The biochemical survival for the 270 patients who did not receive adjuvant therapy was 86% at 61 months. Statistically significant univariate predictors (P <0.05) of PSA recurrence were pT stage (log-rank 18.2) and Gleason grade (log-rank 8.8). The F/T PSA ratio was not a significant predictor of recurrence in the univariate analysis (log-rank 3.6 for P = 0.314) and in multivariate analysis (Wald statistic 0.2 for P = 0.97)., Conclusions: These results suggest that the F/T PSA ratio is not helpful for the prediction of organ-confined disease and PSA recurrence after radical prostatectomy.

Objective: To determine the incidence and natural history of stage T1a-T1b prostate cancer in patients undergoing surgery for benign prostatic hypertrophy (BPH), and thus evaluate the effect that recent medical and 'minimally invasive' treatments (which provide no prostate sample for pathological examination) might have on the percentage of patients with unsuspected prostate cancer., Patients and Methods: A series of 1648 patients undergoing surgery for BPH over a 13-year period were reviewed retrospectively; the period overlapped the introduction of serum prostate specific antigen (PSA) as a detection method., Results: Stage T1 prostate cancer was found in 182 patients (11%), comprising 126 (11%) of 1199 transurethral resections and 56 (12%) of 449 open enucleations. The introduction of systematic PSA assays gradually reduced the mean incidence of T1 cancer from 23% to 7%, with a greater effect on T1b (from 15% to 2%), while the incidence of T1a remained nearly constant (+/-5%). The pathological features of surgical specimens from 43 radical prostatectomies undertaken for T1 tumours were reviewed. Locally advanced disease (stage >/=pT3) was apparent in 13% of T1a and 28% of T1b tumours. Amongst the patients electing for surveillance, only 8% of those with T1a progressed within 30-97 months of follow-up (mean progression time 73 months), whereas 29% of those with stage T1b progressed within 36 months of follow-up (mean progression time 17 months)., Conclusion: These results show that the use of the PSA assay has decreased but not suppressed the incidence of pT1 prostate cancer, with a greater effect on those tumours at higher risk of progression (T1b). This suggests that the detection of prostate cancer based on PSA and transrectal ultrasonography is appropriate for screening patients and is sufficiently accurate that treatments for BPH that provide no pathological materials can be applied safely.

Lymph node metastases are rarely detected during radical prostatectomy (55/647 patients in our series or 8.5%) and several authors consider that lymphadenectomy is unnecessary in most cases. Criteria based on clinical stage, PSA and tumor grade have been elaborated in order to avoid pelvic lymph node dissection in a low risk population. It is commonly admitted that patients with clinically localized prostate cancer, a PSA level < 10 ng/ml, and a Gleason score < 7 could be spared a pelvic lymphadenectomy. In our series, these patients account for 12% of positive nodes. The best treatment for prostate cancer patients with a nodal disease is controversial. We compare the evolution of two groups of patients: radical prostatectomy alone or combined with an immediate adjuvant hormonal treatment. We observe a difference between the two groups for biological progression (PSA failure) but not yet for clinical progression nor for survival as our mean follow-up in only 6 years.

Purpose: We analyzed the potential influence of adjuvant radiotherapy on urinary continence after radical prostatectomy., Materials and Methods: A total of 100 patients with N0M0 prostate cancer randomized in a prospective study on postoperative radiotherapy for locally advanced disease (positive surgical margin, capsular perforation and/or seminal vesicle infiltration) were studied. Objective pad weighing tests corroborated by direct personal interviews were used to evaluate urinary continence at regular postoperative intervals., Results: Of the patients 48 received 60 Gy. external radiotherapy with 18 MV photon beams between 12 and 16 weeks postoperatively, and 52 were followed expectantly. Risk factors were similar in both groups. With a mean followup of 24 months, no difference in complete urinary continence was observed. Of the irradiated group 77% and of the surveillance group 83% were totally dry. The fate of the bladder neck had no significant influence on final continence status, although there was a trend for faster recovery when the bladder neck was preserved., Conclusions: In this prospective randomized study 60 Gy. external radiation therapy administered between 3 and 4 months after radical prostatectomy for pathologically locally advanced prostate cancer had no significant influence on urinary continence.

Unexpected severe electrolyte imbalance in the postoperative period. Report two cases. Two cases of inappropriate secretion of antidiuretic hormone are reported. In each patient, the physiopathology is reviewed. Differential diagnosis and treatment of hyponatremia is discussed.

Objectives: Improved discrimination between prostate cancer (PC) and benign prostatic hyperplasia (BPH) is clearly needed. Our aim in this study was to evaluate whether the free to total prostate-specific antigen (PSA) ratio would be useful in the gray zone of 1.8-10 ng/mL total PSA range., Methods: In a consecutive series of 435 clinic patients referred for prostate evaluation, 308 had a total PSA < 10 ng/mL (92 had PC and 216 BPH). Free and total PSA were measured, and the free to total PSA ratio calculated., Results: Total PSA values were significantly different between the two groups. For the 200 patients with a total PSA < 6 ng/mL, no significant difference in total PSA values were seen (P = 0.411), whereas free to total PSA ratios remained statistically different (P < 0.001). Receiver operating characteristic (ROC) curve analysis comparing the performances of total PSA over the ratio of free to total PSA showed a clear advantage for the ratio at all sensitivity levels., Conclusions: These data demonstrate that in a significant number (n = 308) of prostatic patients in the diagnostic gray zone of 1.8-10 ng/mL total PSA, the routine use of free to total PSA might be advantageous in discriminating between cancer and benign hyperplasia. This advantage remained for total PSA < 4 ng/mL. Further study is warranted to confirm these findings in an unselected population.

The authors report a case of acute urinary retention in a young female patient with a large uterine leiomyoma. Urinary symptoms resolved completely after surgery.

We studied the influence of vessels crossing the ureteropelvic junction and of the grade of hydronephrosis in 86 patients who underwent endoureteropyelotomy. With a follow-up ranging from 1 to 12 years, the presence of crossing vessels had a significant negative influence on the outcome and recurrence rate of the procedure. The success rate was 82% when no vessels were present but only 33% when crossing vessels were documented. In 13 of 15 failures (87%), a crossing vessel was found at open pyeloplasty. The degree of hydronephrosis was a less potent detrimental factor, with an 81% success rate in low-grade and 54% in high-grade hydronephrosis. The best results (90% success) were obtained in patients with no crossing vessels and low-grade hydronephrosis and the worst (30% success) in those with high-grade hydronephrosis in the presence of crossing vessels. Selection of patients according to those prognostic factors is recommended. Conventional intravenous urographic imaging techniques proved insufficient, and only angiography provided diagnostic accuracy; less-invasive methods are desirable.

Background: Serum prostate-specific antigen (PSA) exists in different molecular forms, and their respective concentration has been proposed as a useful tool to improve discrimination between benign prostatic hypertrophy (BPH) and prostate cancer (PC)., Methods: The relevance of the free to total PSA ratio was prospectively studied in a selected urology clinic population of 420 patients. Total serum PSA ranged from 2.1 to 30 ng/ml; 154 had PC and 266 had BPH., Results: Receiver operating characteristic (ROC) curves were constructed for the total population (total-PSA range from 2.1 to 30 ng/ml) and for the diagnostic gray zone of 2.1-10 ng/ml. For the two groups, the free to total PSA ratio had a higher specificity than total-PSA for all sensitivity levels. Cut-off values were found to, vary with prostate weight., Conclusions: Although free to total PSA ratio demonstrated better performances than total-PSA, its use in screening appears problematic, due to the low prevalence of prostate cancer.

Laparoscopic nephrolithotomy was used as an alternative to open surgery in a patient who had failed extracorporeal shock-wave lithotripsy and whose anteriorly located stone-bearing calix precluded percutaneous extraction. Endocavitary ultrasonography and color Doppler render the procedure safe and effective; localization of the stone, selection of an optimal nephrotomy site away from large vessels and where cortical thickness is minimal, and control of fragment clearance are greatly facilitated.

Accurate preoperative staging is important for adequate selection of patients for radical prostatectomy. We reviewed the preoperative PSA levels of 214 patients who underwent radical retropubic prostatectomy and analysed the results in relation to pathological stage. 32 (15%) patients had a PSA level below 4 ng/ml; nevertheless 8 of them had already a extracapsular disease and one present with positive lymph nodes. Thus, although a specificity of 90%, the sensitivity is only 18%. 98 (46%) patients had PSA levels beyond 10 ng/ml of which 47 (48%) had extracapsular tumor; this gives a specificity of 62% and a sensitivity of 59%. Finally 35 (16%) patients had a PSA over 20 ng/ml of which 18 (51%) present a extracapsular disease thus the specificity is 87% but the sensibility remains low at 23%. We concluded that although PSA levels are grossly related to the pathological stage, that relation is not reliable to distinguish patients with organ-confined from those who have extracapsular tumor extension and for either definition of a positive PSA level many patients would be denied a curative operation. Therefore, PSA value cannot be used to decide whether to recommend radical prostatectomy for potential cure.