Systemic inflammation following traumatic injury and its impact on neuroinflammatory gene expression in the rodent brain.

BACKGROUND: Trauma can result in systemic inflammation that leads to organ dysfunction, but the impact on the brain, particularly following extracranial insults, has been largely overlooked. METHODS: Building upon our prior findings, we aimed to understand the impact of systemic inflammation on neuroinflammatory gene transcripts in eight brain regions in rats exposed to (1) blast overpressure exposure [BOP], (2) cutaneous thermal injury [BU], (3) complex extremity injury, 3 hours (h) of tourniquet-induced ischemia, and hind limb amputation [CEI+tI+HLA], (4) BOP+BU or (5) BOP+CEI and delayed HLA [BOP+CEI+dHLA] at 6, 24, and 168 h post-injury (hpi). RESULTS: Globally, the number and magnitude of differentially expressed genes (DEGs) correlated with injury severity, systemic inflammation markers, and end-organ damage, driven by several chemokines/cytokines (Csf3, Cxcr2, Il16, and Tgfb2), neurosteroids/prostaglandins (Cyp19a1, Ptger2, and Ptger3), and markers of neurodegeneration (Gfap, Grin2b, and Homer1). Regional neuroinflammatory activity was least impacted following BOP. Non-blast trauma (in the BU and CEI+tI+HLA groups) contributed to an earlier, robust and diverse neuroinflammatory response across brain regions (up to 2-50-fold greater than that in the BOP group), while combined trauma (in the BOP+CEI+dHLA group) significantly advanced neuroinflammation in all regions except for the cerebellum. In contrast, BOP+BU resulted in differential activity of several critical neuroinflammatory-neurodegenerative markers compared to BU. t-SNE plots of DEGs demonstrated that the onset, extent, and duration of the inflammatory response are brain region dependent. Regardless of injury type, the thalamus and hypothalamus, which are critical for maintaining homeostasis, had the most DEGs. Our results indicate that neuroinflammation in all groups progressively increased or remained at peak levels over the study duration, while markers of end-organ dysfunction decreased or otherwise resolved. CONCLUSIONS: Collectively, these findings emphasize the brain's sensitivity to mediators of systemic inflammation and provide an example of immune-brain crosstalk. Follow-on molecular and behavioral investigations are warranted to understand the short- to long-term pathophysiological consequences on the brain, particularly the mechanism of blood-brain barrier breakdown, immune cell penetration-activation, and microglial activation.

Retrospective analysis of the perioperative outcome in living donor kidney transplantation with multiple renal arteries: does accessory vessel ligation affect the outcome?

PURPOSE: Accurate surgical reconstruction of arterial vascular supply is a crucial part of living kidney transplantation (LDKT). The presence of multiple renal arteries (MRA) in grafts can be challenging. In the present study, we investigated the impact of ligation versus anastomosis of small accessory graft arteries on the perioperative outcome. METHODS: Clinical and radiological outcomes of 51 patients with MRA out of a total of 308 patients who underwent LDKT with MRA between 2011 and 2020 were stratified in two groups and analyzed. In group 1 (20 patients), ligation of accessory arteries (ARAs) and group 2 (31 patients) anastomosis of ARAs was performed. RESULTS: Significant differences were observed in the anastomosis-, surgery-, and warm ischemia time (WIT) in favor of group 1. Students t-test showed comparable serum creatinine levels of 2.33 (± 1.75) to 1.68 (± 0.83) mg/dL in group 1 and 2.63 (± 2.47) to 1.50 (± 0.41) mg/dL in group 2, were seen from 1 week to 1 year after transplant. No increased rates of Delayed graft function (DGF), primary transplant dysfunction and transplant rejection were seen, but graft loss and revision rates were slightly higher when the ARAs were ligated. Analysis of Doppler sonography revealed that segmental perfusion deficits tend to regenerate during the clinical course. CONCLUSION: Ligation of smaller accessory renal arteries may not affect the outcome of living kidney transplantation, except for a minor increase in the reoperation rate. Segmental perfusion deficits of the graft seem to regenerate in most cases as seen in Doppler sonography.

Transplant nephrectomy: indication, surgical approach and complications-experiences from a single transplantation center.

PURPOSE: Management of a failed kidney allograft, and the question whether it should be removed is a challenging task for clinicians. The reported risks for transplant nephrectomy (TN) vary, and there is no clear recommendation on indications or surgical approach that should be used. This study gives an overview of indications, compares surgical techniques, and identifies risk factors for higher morbidity. METHODS: Retrospective analysis was conducted on all transplant nephrectomies performed between 2005 and 2020 at Charité Hospital Berlin, Department of Urology. Patient demographics, laboratory parameters, graft survival data, indication for TN, and surgical complications were extracted from medical reports. RESULTS: A total of 195 TN were performed, with graft intolerance syndrome being the most common indication in 52 patients (26.7%), acute rejection in 36 (18.5%), acute infection in 30 (15.4%), and other reasons to stop immunosuppression in 26 patients (13.3%). Rare indications were vascular complications in 16 (8.2%) and malignancies in the allograft in six (3.1%) cases. Extracapsular surgical approach was significantly more often used in cases of vascular complications and earlier allograft removal, but there was no difference in complication rates between extra- and intracapsular approach. Acute infection was identified as an independent risk factor for a complication grade IIIb or higher according to Clavien-Dindo classification, with a HR of 12.3 (CI 2.2-67.7; p = 0.004). CONCLUSION: Transplant nephrectomy should only be performed when there is a good indication, and non-elective surgery should be avoided, when possible, as it increases morbidity.

Exploring sleep duration and clinical reasoning process in resident physicians: a thematic analysis.

STUDY OBJECTIVES: Connecting resident physician work hours and sleep deprivation to adverse outcomes has been difficult. Our study explores clinical reasoning rather than outcomes. Diagnostic errors are a leading cause of medical error and may result from deficits in clinical reasoning. We used simulated cases to explore relationships between sleep duration and diagnostic reasoning. METHODS: Residents were recruited for a 2-month study (inpatient/outpatient). Each participant's sleep was tracked (sleep diary/actigraphy). At the end of each month, residents watched 2 brief simulated clinical encounters and performed "think alouds" of their clinical reasoning. In each session, 1 video was straightforward and the other video contained distracting contextual factors. Sessions were recorded, transcribed, and interpreted. We conducted a thematic analysis using a constant comparative approach. Themes were compared based on sleep duration and contextual factors. RESULTS: Residents (n = 17) slept more during outpatient compared with inpatient months (450.5 ± 7.13 vs 425.6 ± 10.78 hours, P = .02). We found the following diagnostic reasoning themes: uncertainty, disorganized knowledge, error, semantic incompetence, emotional content, and organized knowledge. Themes reflecting suboptimal clinical reasoning (disorganized knowledge, error, semantic incompetence, uncertainty) were observed more in cases with contextual factors (distractors). "Think alouds" from cases with contextual factors following sleep restriction had a greater number of themes concerning for problematic diagnostic reasoning. CONCLUSIONS: Residents obtained significantly more sleep during outpatient compared with inpatient months. Several negative clinical reasoning themes emerged with less sleep combined with cases containing contextual distractors. Our findings reinforce the importance of adequate sleep and supervision in house officers, particularly in cases with distracting elements. CITATION: Collen J, Durning S, Berk J, Mang J, Alcover K, Jung E. Exploring sleep duration and clinical reasoning process in resident physicians: a thematic analysis. J Clin Sleep Med. 2024;20(8):1279-1289.

Systemic inflammation induced from remote extremity trauma is a critical driver of secondary brain injury.

Blast exposure, commonly experienced by military personnel, can cause devastating life-threatening polysystem trauma. Despite considerable research efforts, the impact of the systemic inflammatory response after major trauma on secondary brain injury-inflammation is largely unknown. The aim of this study was to identify markers underlying the susceptibility and early onset of neuroinflammation in three rat trauma models: (1) blast overpressure exposure (BOP), (2) complex extremity trauma (CET) involving femur fracture, crush injury, tourniquet-induced ischemia, and transfemoral amputation through the fracture site, and (3) BOP+CET. Six hours post-injury, intact brains were harvested and dissected to obtain biopsies from the prefrontal cortex, striatum, neocortex, hippocampus, amygdala, thalamus, hypothalamus, and cerebellum. Custom low-density microarray datasets were used to identify, interpret and visualize genes significant (p < 0.05 for differential expression [DEGs]; 86 neuroinflammation-associated) using a custom python-based computer program, principal component analysis, heatmaps and volcano plots. Gene set and pathway enrichment analyses of the DEGs was performed using R and STRING for protein-protein interaction (PPI) to identify and explore key genes and signaling networks. Transcript profiles were similar across all regions in naïve brains with similar expression levels involving neurotransmission and transcription functions and undetectable to low-levels of inflammation-related mediators. Trauma-induced neuroinflammation across all anatomical brain regions correlated with injury severity (BOP+CET > CET > BOP). The most pronounced differences in neuroinflammatory-neurodegenerative gene regulation were between blast-associated trauma (BOP, BOP+CET) and CET. Following BOP, there were few DEGs detected amongst all 8 brain regions, most were related to cytokines/chemokines and chemokine receptors, where PPI analysis revealed Il1b as a potential central hub gene. In contrast, CET led to a more excessive and diverse pro-neuroinflammatory reaction in which Il6 was identified as the central hub gene. Analysis of the of the BOP+CET dataset, revealed a more global heightened response (Cxcr2, Il1b, and Il6) as well as the expression of additional functional regulatory networks/hub genes (Ccl2, Ccl3, and Ccl4) which are known to play a critical role in the rapid recruitment and activation of immune cells via chemokine/cytokine signaling. These findings provide a foundation for discerning pathophysiological consequences of acute extremity injury and systemic inflammation following various forms of trauma in the brain.

Diagnostic performance of MRI and US in suspicion of penile fracture.

Background: Penile fracture (PF) is defined as rupture of the tunica albuginea of the corpora cavernosa. While most authors agree that rapid surgical therapy of this rare pathology leads to the best patient outcome, the role of imaging is highly controversial in the published literature. To obtain further evidence concerning the diagnostic accuracies of magnetic resonance imaging (MRI) and ultrasound (US) in the diagnostic assessment of patients with suspected PF. Methods: We systematically reviewed MRI and US examinations performed in our institution between 2000 and 2021 and correlated imaging reports with either intraoperative finding or final clinical diagnosis. Inclusion criteria were: (I) patient age ≥18 years, (II) examination between 2000 and 2021, (III) information available on patient's history and clinical presentation, and (IV) documented final diagnosis in discharge letter. Next to diagnostic accuracy, we describe typical imaging findings such as penile hematoma, tear of the tunica albuginea including location in terms of side and shaft segment affected, and involvement of corpus spongiosum. Results: Overall, 46 of 88 included patients (54.5%) had a confirmed diagnosis of PF. A total of 69 MRI and 31 US examinations were included. Sensitivity and specificity were 91.9% (95% CI: 78.7-97.2%) and 90.6% (95% CI: 75.8-96.8%) for MRI and 71.4% (95% CI: 45.4-88.3%) and 100.0% (95% CI: 81.6-100.0%) for US, respectively. Conclusions: The results of the present study suggest that MRI is more suitable to confirm PF and identify the site of the associated tunica albuginea tear while US is a good tool for ruling out PF.

Perioperative and oncologic outcome in patients treated for renal cell carcinoma with an extended inferior vena cava tumour thrombus level II-IV.

PURPOSE: Surgical treatment of patients with renal cell carcinoma (RCC) and an extended tumour thrombus (TT) in the inferior vena cava (IVC) is challenging and often requires a multidisciplinary approach. The aim of this study was to analyse results in the real-world management of RCC patients with an extended IVC TT (level II-IV according to the Mayo classification of macroscopic venous invasion in RCC) in terms of pre-, peri- and postoperative outcome, complications and oncologic outcome. METHODS: We investigated 61 patients with evidence of RCC and an extended TT in the IVC undergoing radical nephrectomy and tumour thrombectomy at our tertiary referral centre. Patients and operative characteristics were recorded and complications were analysed using the Clavien-Dindo classification. Follow-up data were retrieved by contacting the treating outpatient urologists, general practitioners and patients. RESULTS: The TT level was II in 36, III in 8 and IV in 17 patients. Complications grade IIIb and higher according to the Clavien-Dindo classification occurred in n = 3 (8.4 %), n = 2 (25.0 %) and n = 5 (29.5 %) patients with level II, III and IV TT, respectively. The overall survival of patients with TT level II, III and IV at 24 months (60 months) was 66.9 % (41.6 %), 83.3 % (83.3 %) and 64.1 % (51.3 %). Presence of primary metastatic disease was the only significant independent predictor for OS.  CONCLUSIONS: Radical nephrectomy with tumour thrombectomy appears to be a feasible and effective treatment option in the management of patients with RCC and an extended IVC TT.

Focal Segmental Glomerulosclerosis and Recurrence in Living Donor Recipients.

PURPOSE: Focal segmental glomerulosclerosis (FSGS) is a common cause for end-stage renal disease that can recur in the graft after kidney transplantation. The incidence of FSGS recurrence is reported in up to 47% of patients, predisposing those to possible poorer transplantation outcomes. Hence, we examined the incidence of FSGS recurrence and the effect on graft outcome in our patient cohort of living donor kidney transplantations (LDKT). PATIENTS AND METHODS: We analyzed 194 adult patients who received a LDKT between 2011 and 2017 of which 22 (11%) had FSGS as underlying disease. Demographic data and clinical outcomes, especially regarding recurrence of FSGS, were evaluated. RESULTS: FSGS recurrence was identified in three (14%) patients within three months after transplantation, of whom two patients (9%) lost their graft. There was no significant difference in graft survival comparing FSGS to other reasons for end-stage renal disease. CONCLUSION: Incidence of FSGS recurrence in the present patient cohort was within the range reported in the literature and comparatively low. Our data support LDKT as a treatment option in patients with end-stage renal disease due to FSGS.

Is a Retroaortic Vein a Risk Factor in Laparoscopic Living Donor Nephrectomy?

INTRODUCTION: In living donor transplantation choosing the right donor and donor side for laparoscopic donor nephrectomy is a challenging task in clinical practice. Knowledge about anomalies in renal blood supply are crucial to evaluate the feasibility of the operative procedure. Few data so far exist whether the existence of a retroaortic left renal vein has an impact on living kidney transplantation outcome for donor and recipient. MATERIALS AND METHODS: We retrospectively analyzed 221 patients who underwent laparoscopic living donor nephrectomy between 2011 and 2017 for existence of a retroaortic left renal vein. Clinical characteristics and operative outcomes for donors and recipients were analyzed. RESULTS: 221 patients underwent donor nephrectomy between 2011 and 2017; 11 patients (4.98%) showed the feature of a retroaortic left renal vein, and in 8 patients (72.7%) out of those 11 the left kidney was chosen for transplantation. Mean preoperative serum creatinine was 0.77 (0.49-0.98) mg/dL and 1.28 (0.97-1.64) mg/dL at discharge. In recipients mean serum creatinine preoperatively, after 1 week, 1 month,1 year, 2 and 3 years of follow-up was 10.36 (6.09-20.77) mg/dL, 1.71 (0.67-2.72), 1.33 (0.70-1.89), 1.31 (0.95-2.13), 1.31 (0.98-2.13) and 1.33 (1.03-1.84), respectively. Neither donors nor recipients suffered from any operative complications. CONCLUSIONS: Laparoscopic living donor nephrectomy of a left kidney with retroaortic renal vein is safe for the donor, without limitation in the outcome for the recipient.

Additive Value of Transrectal Systematic Ventral Biopsies in Combination with Magnet Resonance Imaging/Ultrasound Fusion-Guided Biopsy in Patients with 3 or More Negative Prostate Biopsies.

INTRODUCTION: Patients with consistent suspicion for prostate cancer (PCa) and multiple negative prebiopsies prior to multiparametric magnetic resonance imaging (mpMRI) are still frequently evaluated for an image-guided biopsy and are reported with heterogeneous detection rates. The inclusion of a systematic biopsy (SB) is also still recommended with predominant sampling within the posterior/peripheral zone of the prostate. The aim of this study was (I) to evaluate PCa detection rates using a modified 10 core SB template including anterior biopsies in combination with mpMRI/ultrasound fusion-guided targeted biopsy (TB) in patients with 3 or more negative prebiopsies and (II) to compare mpMRI index lesion localization with histologically confirmed locali-zation from associated prostatectomy samples. METHODS: Overall 1,337 consecutive patients underwent sensor-based registration TB of the prostate and a subsequent 10-core SB between January 2012 and December 2015 at our institution. For this study, 101 patients with ≥3 negative prebiopsies and prostate imaging - reporting data system lesions ≥3 were pooled prospectively and underwent TB and a modified SB including 2 ventral (anterior) biopsies. Detection rates were estimated for the modified SB, TB, and its combination. A subgroup analysis of 35 patients undergoing prostatectomy was performed by a head-to-head comparison of mpMRI index lesion and histologically confirmed PCa index lesion localization. RESULTS: The overall detection rate for PCa was 54.5%. The combination of TB and SB detected 14 (25.4%) more cases missed by TB alone (p < 0.001) and 7 (12.7%) more cases missed by SB alone (p = 0.016), respectively. A postoperative Gleason upgrade was seen in 12/35 (34.3%) cases within the TB group and in 14/35 (40.0%) in the SB group, respectively. The subgroup analysis showed a predominant location of PCa index lesions anteriorly at the level of the midgland. The MRI detection rate of the anteriorly located index lesions was 70.4% (15/21 cases) with a clinically significant Gleason score (≥3 + 4 = 7a [International Society of Urological Pathology grade 2]) in 80.9%. Interestingly a modified SB template detected 90.5% (19/21) of the anteriorly located index lesions. CONCLUSION: Our data suggest that in patients with multiple prebiopsies PCa seems to be predominantly located anteriorly. We suggest the general integration of anterior biopsies despite TB in repeat biopsy patients.

Molecular complexity of taxane-induced cytotoxicity in prostate cancer cells.

BACKGROUND: Taxanes are routinely used to treat men with advanced prostate cancer, yet their molecular mode of action is poorly characterized. Taxanes stabilize microtubules and may hence interfere with a plethora of cellular processes, most notably mitosis. However, prostate cancer is typically a slowly growing tumor suggesting that additional processes play a role in the response to taxanes. METHODS: Here, we analyzed the potential effect of taxanes on microtubuli-dependent intracellular transport and signaling processes, specifically, nuclear translocation of the androgen receptor and modulation of the RAS-RAF-MEK-ERK signaling cascade. RESULTS: We show that the androgen-driven nuclear translocation of the androgen receptor remains virtually undisturbed by docetaxel in prostate cancer cells. However, we found a striking down-regulation of activated ERK1/2 together with enhanced cytotoxicity in both docetaxel or cabazitaxel-treated cells that was comparable to direct MEK kinase inhibition. Remarkably, MEK inhibition alone was less effective in inducing cytotoxicity than taxanes indicating that a down-regulation of activated ERK1/2 may be necessary but is not sufficient for taxane-induced antitumoral effects. In line with this notion, we show in a xenograft mouse model that prostate cancer cells that are resistant to docetaxel overexpress activated ERK1/2. Taken together, our findings underscore that the modulation of ERK1/2 activation, in concert with other mechanisms, plays an important role in taxane-induced antineoplastic effects on prostate cancer cells. CONCLUSIONS: These results suggest at least partially nonoverlapping effects of docetaxel and androgen deprivation therapy and hence help to understand recent clinical findings. A further elucidation of the mode of action of docetaxel would have important implications to optimize current treatment strategies and biomarker development for men with metastatic prostate cancer.

Prognostic Significance and Functional Role of CEP57 in Prostate Cancer.

We have recently shown that centrosomal protein 57 (CEP57) is overexpressed in a subset of human prostate cancers. CEP57 is involved in intracellular transport processes, and its overexpression causes mitotic defects as well as abnormal microtubule nucleation and bundling. In the present study, we further characterized the prognostic and functional role of CEP57 in prostate cancer. Unexpectedly, we found that high CEP57 expression is an independent prognostic factor for a more favorable biochemical recurrence-free survival in two large patient cohorts. To reconcile this finding with the ability of CEP57 to cause cell division errors and thus potentially promote malignant progression, we hypothesized that alterations of microtubule-associated transport processes, in particular nuclear translocation of the androgen receptor (AR), may play a role in our finding. However, CEP57 overexpression and microtubule bundling had, surprisingly, no effect on the nuclear translocation of the AR. Instead, we found a significant increase of cells with disarranged microtubules and a cellular morphology suggestive of a cytokinesis defect. Because mitotic dysfunction leads to a reduced daughter cell formation, it can explain the survival benefit of patients with increased CEP57 expression. In contrast, we show that a reduced expression of CEP57 is associated with malignant growth and metastasis. Taken together, our findings underscore that high CEP57 expression is associated with mitotic impairment and less aggressive tumor behavior. Because the CEP57-induced microtubule stabilization had no detectable effect on AR nuclear translocation, our results furthermore suggest that microtubule-targeting therapeutics used in advanced prostate cancer such as docetaxel may have modes of action that are at least in part independent of AR transport inhibition.