Competitive clonal hematopoiesis in mouse chimeras explained by a stochastic model of stem cell organization

Many current experimental results show the necessity of new conceptual approaches to understand hematopoietic stem cell organization. Recently, we proposed a novel theoretical concept and a corresponding quantitative model based on microenvironment-dependent stem cell plasticity. The objective of our present work is to subject this model to an experimental test for the situation of chimeric hematopoiesis. Investigating clonal competition processes in DBA/2-C57BL/6 mouse chimeras, we observed biphasic chimerism development with initially increasing but long-term declining DBA/2 contribution. These experimental results were used to select the parameters of the mathematical model. To validate the model beyond this specific situation, we fixed the obtained parameter configuration to simulate further experimental settings comprising variations of transplanted DBA/2-C57BL/6 proportions, secondary transplantations, and perturbation of stabilized chimeras by cytokine and cytotoxic treatment. We show that the proposed model is able to consistently describe the situation of chimeric hematopoiesis. Our results strongly support the view that the relative growth advantage of strain-specific stem cells is not a fixed cellular property but is sensitively dependent on the actual state of the entire system. We conclude that hematopoietic stem cell organization should be understood as a flexible, self-organized rather than a fixed, preprogrammed process.     

The effect of thyroid status on the calmodulin content of several tissues in the rat

The present studies represent an initial effort to evaluate a possible relationship between thyroid status and calmodulin and were undertaken because of evidence that some actions of the thyroid hormones are calmodulin mediated. To this end, the effects of hypothyroidism and of thyroid hormone excess on the concentration of calmodulin in several tissues of the rat were evaluated. In thymocytes, liver, heart, and brain, but not in skeletal muscle, calmodulin concentrations were markedly increased in the thyrotoxic rat (140-203% of values in normal controls); values were unchanged in hypothyroid animals. These changes were evident regardless of whether calmodulin concentrations were expressed per cell (thymocytes), or in relation to either the wet wt or protein content of the tissues. These findings are apparently the first to demonstrate that thyroid hormone, unlike other hormones tested thus far, can influence tissue calmodulin content. In view of the fact that many metabolic systems that are influenced by calmodulin are similarly affected by thyroid hormones, the findings support the possibility that some actions of thyroid hormone are calmodulin mediated.     

Avascular necrosis after treatment of DDH: the protective influence of the ossific nucleus

We retrospectively reviewed the results of open or closed reduction for developmental dysplasia of the hip (DDH) in 49 children younger than 12 months old, who had 57 hip dislocations. Group A (18 hips) developed partial or complete avascular necrosis (AVN), and group B (39 hips) did not develop AVN. Thirty-eight hips were treated by closed reduction, and 17 had open reduction. One patient with bilateral hip dislocation initially had closed reductions followed by bilateral open reduction 3 months later. With the numbers available for study, there was no significant difference in the occurrence of AVN with respect to variables such as preliminary traction, closed versus open reduction, Pavlik harness use, and age at the time of operative intervention. However, the presence of the ossific nucleus before reduction, detected either by radiographs (p < 0.001) or ultrasonography (p = 0.033) was statistically significant in predicting AVN. Only one (4%) of 25 hips with an ossific nucleus developed AVN, whereas 17 (53%) of 32 hips without an ossific nucleus before reduction developed AVN. Our results suggest that the presence of the ossific nucleus before closed or open reduction for DDH may decrease the risk of AVN.     

The predominance of benign histology in small testicular masses

ObjectivesTo evaluate the concordance between testicular tumor size and benign histology in order to identify a cut-off size, below which the rate of benign lesions would be highest.Methods and materialsDuring the years 1995–2008, we performed 131 consecutive testicular operations for testicular tumors. Ten of these were testicular preserving surgery, whereas the other 121 patients had radical orchiectomy. We searched for the rate of benign lesions in the following 3 groups of tumor diameter: 10 mm or less, 11–20 mm, and greater than 20 mm. ROC analysis was used to find the optimal size cut-off below which the rate of benign lesions would be highest.ResultsBenign lesions were found in 11 patients (8%), including epidermoid cyst (n = 4), Leydig cell tumor (n = 3), fibrosis (n = 1), adenomatoid tumor (n = 2), and 1 patient with a simple cyst. Small tumor size strongly correlated with benign histology. The mean diameter of benign vs. malignant lesions was 15 mm and 41 mm, respectively (P < 0.05). The rate of benign lesions in tumors with a diameter of 10 mm or less, 11–20 mm and greater than 20 mm was 50%, 17%, and 2%, respectively. Receiver Operating characteristic (ROC) analysis with 87% sensitivity and 83% specificity revealed a cut-off value of 18.5 mm tumor diameter below which the proportion of benign lesions was 38.5% compared with 2% above it (P < 0.05).ConclusionsWhile benign lesions comprise only 8% of all testicular tumors, their proportion among small lesions is much higher. With a size cut-off of 18.5 mm, 38.5% of smaller lesions are benign. These findings support consideration of testicular exploration for small testicular lesions aiming at preservation rather than predetermined radical orchiectomy.     

Irbesartan promotes erection recovery after nerve‐sparing radical retropubic prostatectomy: a retrospective long‐term analysis

Study Type – Therapy (retrospective cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Erectile dysfunction following radical prostatectomy (RP) is among the most common and dreaded adverse effects of the surgery. Multiple studies confirm the potential benefit of various drug classes to accelerate the return of erectile function (EF) after RP. There is pre‐clinical evidence supporting the use of angiotensin‐receptor blockers (ARBs) for this purpose, although this has not been studied in humans. The present study shows that there may be a benefit in the recovery of EF post‐RRP in patients taking a daily dose of irbesartan, an ARB, following RRP. In addition, the use of irbesartan may curb the loss of stretched penile length which occurs postoperatively. Further study in the form of prospective, randomized, placebo‐controlled clinical trials are necessary to confirm these findings.

OBJECTIVE

• ? To evaluate retrospectively the potential benefit of administering irbesartan, an angiotensin‐receptor blocker, to improve erectile function (EF) recovery after nerve‐sparing radical retropubic prostatectomy (RRP).

PATIENTS AND METHODS

• ? Before surgery potent patients who underwent nerve‐sparing RRP between April and December 2009 elected to start daily oral irbesartan 300 mg on postoperative day 1 (n= 17). A contemporaneously clinically matched cohort consisting of patients who declined irbesartan use served as the control group (n= 12).
• ? Postoperative ‘on demand’ use of erectile aids (phosphodiesterase type 5 [PDE5] inhibitors and intracavernous injections) was adopted.
• ? Potency was monitored by the administration of International Index of Erectile Function‐5 (IIEF‐5) questionnaires before surgery and at early (3 months) and long‐term (12 and 24 months) postoperative intervals.
• ? Stretched penile length (SPL) was measured both immediately and 3 months after surgery.

RESULTS

• ? EF status was no different between groups at baseline (P > 0.05).
• ? While the IIEF‐5 scores at 24 months after surgery were statistically similar between the two groups (control = 15.2 ± 2.0, irbesartan = 14.1 ± 3.1, P= 0.77), at 12 months the IIEF‐5 scores of the irbesartan group were significantly higher than those of the control group (14 ± 2.6 vs. 7.2 ± 1.6, P < 0.05).
• ? The proportional loss of SPL after RRP was less in the irbesartan than in the control group at 3 months (–0.9 ± 1.5% vs –5.6 ± 1.5, P < 0.05).

CONCLUSION

• ? Regular irbesartan use after nerve‐sparing RRP in patients with normal preoperative erectile function could improve EF recovery after surgery and mitigate early loss of SPL.

     

The prognostic value of elevated neutrophil–lymphocyte ratio for cardiac surgery-associated acute kidney injury: A systematic review and meta-analysis

Background

Patients undergoing cardiac surgery are at significant risk of developing postoperative acute kidney injury (AKI). Neutrophil–lymphocyte ratio (NLR) is a widely available inflammatory biomarker which may be of prognostic value in this setting.

Methods

We conducted a systematic review and meta-analysis of studies reporting associations between perioperative NLR with postoperative AKI. We searched Medline, Embase and the Cochrane Library, without language restriction, from inception to May 2022 for relevant studies. We meta-analysed the reported odds ratios (ORs) with 95% confidence intervals (CIs) for both elevated preoperative and postoperative NLR with risk of postoperative AKI and need for renal replacement therapy (RRT). We conducted a meta-regression to explore inter-study statistical heterogeneity.

Results

Twelve studies involving 10,724 participants undergoing cardiac surgery were included, with eight studies being deemed at high risk of bias using PROBAST modelling. We found statistically significant associations between elevated preoperative NLR and postoperative AKI (OR 1.45, 95% CI 1.18–1.77), as well as postoperative need for RRT (OR 2.37, 95% CI 1.50–3.72). Postoperative NLR measurements were not of prognostic significance.

Conclusions

Elevated preoperative NLR is a reliable inflammatory biomarker for predicting AKI following cardiac surgery.