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The article discusses the results of a study that evaluated the early effects of systemic metabolic changes, renal histologic morphology and histological changes of rats' ileal patch after experimental ileocystoplasty. The study developed an animal model of female Wistar species of rats in which bladder augmentation using ileum and a sham operation were performed. It showed that the augmented group's urinary pH was higher in treated rats than in shams while the bladder calculi was formed in 28.6 percent of ileocystoplasty. It concludes that treated rats showed significant improvement of serum creatine, sign of glomerular overload and depletion.

Purpose: Delayed structural and functional recovery after a 20 km graded running race was analyzed with respect to the sex effect., Methods: Thirteen female and 14 male recreational runners completed the race and three test sessions: one before (PRE) and two after, once on Day 1 or 2 (D1-2) and then on Day 3 or 4 (D3-4). Muscle damage was assessed indirectly using ultrasonography to quantify changes in cross-sectional area (CSA) of 10 lower-limb muscles. Delayed onset of muscle soreness (DOMS) was assessed for three muscle groups. Functional recovery was quantified by kinetic analysis of a squat jump (SJ) and a drop jump (DJ) test performed on a sledge ergometer. Linear mixed models were used to assess control group reproducibility and recovery patterns according to sex., Results: Regardless of sex, DOMS peaked at D1-2 for all muscle groups and resolved at D3-4. CSA was increased in each muscle group until D3-4, especially in the semimembranosus muscle. A specific increase was found in the short head of the biceps femoris in women. Regardless of sex, SJ and DJ performances declined up to D3-4. Depending on the muscle, positive and/or negative correlations were found between structural and functional changes. Some of these were sex-specific., Conclusion: Structural and functional recovery was incomplete in both sexes up to D3-4, although DOMS had disappeared. More emphasis should be placed on hamstring muscle recovery. Highlighting the intermuscular compensations that can occur during multi-joint testing tasks, the structural-functional relationships were either positive or negative, muscle- and sex-dependent., (© 2024 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Introduction: Biomarker testing is mandatory for the clinical management of patients with advanced non-small cell lung cancer (NSCLC). Myriads of technical platforms are now available for biomarker analysis with differences in terms of multiplexing capability, analytical sensitivity, and turnaround time (TAT). We evaluated the technical performance of the diagnostic workflows of 24 representative Italian institutions performing molecular tests on a series of artificial reference specimens built to mimic routine diagnostic samples., Methods: Sample sets of eight slides from cell blocks of artificial reference specimens harboring exon 19 EGFR (epidermal growth factor receptor) p.E746_AT50del, exon 2 KRAS (Kirsten rat sarcoma viral oncogene homologue) p.G12C, ROS1 (c-ros oncogene 1)-unknown gene fusion, and MET (MET proto-oncogene, receptor tyrosine kinase) Δ exon 14 skipping were distributed to each participating institution. Two independent cell block specimens were validated by the University of Naples Federico II before shipment. Methodological and molecular data from reference specimens were annotated., Results: Overall, a median DNA concentration of 3.3 ng/µL (range 0.1-10.0 ng/µL) and 13.4 ng/µL (range 2.0-45.8 ng/µL) were obtained with automated and manual technical procedures, respectively. RNA concentrations of 5.7 ng/µL (range 0.2-11.9 ng/µL) and 9.3 ng/µL (range 0.5-18.0 ng/µL) were also detected. KRAS exon 2 p.G12C, EGFR exon 19 p.E736_A750del hotspot mutations, and ROS1 aberrant transcripts were identified in all tested cases, whereas 15 out of 16 (93.7%) centers detected MET exon 14 skipping mutation., Conclusions: Optimized technical workflows are crucial in the decision-making strategy of patients with NSCLC. Artificial reference specimens enable optimization of diagnostic workflows for predictive molecular analysis in routine clinical practice., (© 2024. The Author(s).)

With human space exploration back in the spotlight, recent studies have investigated the neuromuscular adjustments to simulated hypogravity running. They have examined the activity of individual muscles, whereas the central nervous system may rather activate groups of functionally related muscles, known as muscle synergies. To understand how locomotor control adjusts to simulated hypogravity, we examined the temporal (motor primitives) and spatial (motor modules) components of muscle synergies in participants running sequentially at 100%, 60%, and 100% body weight on a treadmill. Our results highlighted the paradoxical nature of simulated hypogravity running: The reduced mechanical constraints allowed for a more flexible locomotor control, which correlated with the degree of spatiotemporal adjustments. Yet, the increased temporal (shortened stance phase) and sensory (deteriorated proprioceptive feedback) constraints required wider motor primitives and a higher contribution of the hamstring muscles during the stance phase. These results are a first step towards improving astronaut training protocols., (© 2024. The Author(s).)

Introduction: Originally developed for astronauts, lower body positive pressure treadmills (LBPPTs) are increasingly being used in sports and clinical settings because they allow for unweighted running. However, the neuromuscular adjustments to unweighted running remain understudied. They would be limited for certain lower limb muscles and interindividually variable. This study investigated whether this might be related to familiarization and/or trait anxiety. Methods: Forty healthy male runners were divided into two equal groups with contrasting levels of trait anxiety (high, ANX + , n = 20 vs. low, ANX - , n = 20). They completed two 9-min runs on a LBPPT. Each included three consecutive 3-min conditions performed at 100%, 60% (unweighted running), and 100% body weight. Normal ground reaction force and electromyographic activity of 11 ipsilateral lower limb muscles were analyzed for the last 30 s of each condition in both runs. Results: Unweighted running showed muscle- and stretch-shortening cycle phase-dependent neuromuscular adjustments that were repeatable across both runs. Importantly, hamstring (BF, biceps femoris; STSM, semitendinosus/semimembranosus) muscle activity increased during the braking (BF: +44 ± 18%, p < 0.001) and push-off (BF: +49 ± 12% and STSM: +123 ± 14%, p < 0.001 for both) phases, and even more so for ANX + than for ANX - . During the braking phase, only ANX + showed significant increases in BF (+41 ± 15%, p < 0.001) and STSM (+53 ± 27%, p < 0.001) activities. During the push-off phase, ANX + showed a more than twofold increase in STSM activity compared to ANX - (+119 ± 10% vs. +48 ± 27, p < 0.001 for both). Conclusion: The increase in hamstring activity during the braking and push-off phases may have accelerated the subsequent swing of the free-leg, likely counteracting the unweighting-induced slowing of stride frequency. This was even more pronounced in ANX + than in ANX - , in an increased attempt not to deviate from their preferred running pattern. These results highlight the importance of individualizing LBPPT training and rehabilitation protocols, with particular attention to individuals with weak or injured hamstrings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fazzari, Macchi, Ressam, Kunimasa, Nicol, Martha, Bolmont, Sainton, Hays, Vercruyssen, Lapole, Bossard, Casanova, Bringoux and Chavet.)

Background/aim: Triple-negative breast cancers represent 15% of all mammary malignancies and encompass several entities with different genomic characteristics. Among these, luminal androgen receptor (LAR) tumors express the androgen receptor (AR) and are characterized by a genomic profile which resembles luminal breast cancers. Moreover, LAR malignancies are usually enriched in PIK3CA, KMTC, CDH, NF1, and AKT1 alterations. Still, molecular features, clinical behavior and prognosis of this variant remain controversial, while identification of effective treatments represents an unmet medical need. Additionally, the predictive role of the AR is unclear., Materials and Methods: We performed an extensive next generation sequencing analysis using a commercially available panel in a cohort of patients with LAR breast cancer followed at two local Institutions. We next employed bioinformatic tools to identify signaling pathways involved in LAR pathogenesis and looked for potentially targetable alterations., Results: Eight patients were included in the study. In our cohort we found 26 known genetic alterations (KGAs) in 15 genes and 64 variants of unknown significance (VUS) in 59 genes. The most frequent KGAs were single nucleotide variants in PIK3CA, HER2, PTEN and TP53. Among VUS, CBFB, EP300, GRP124, MAP3K1, RANBP2 and TSC2 represented recurrently altered genes. We identified five signaling pathways (MAPK, PI3K/AKT, TP53, apoptosis and angiogenesis) involved in the pathogenesis of LAR breast cancer. Several alterations, including those in PIK3CA, ERBB2 and PI3K/AKT/mTOR signaling, were potentially targetable., Conclusion: Our findings confirm a role for PI3K/AKT/mTOR signaling in the pathogenesis of LAR breast cancers and indicate that targeting this pathway, along with ERBB2 mutations, may represent an additional therapeutic strategy which deserves further exploration in larger studies., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Stem cell factor receptor (c-kit) plays a crucial role in regulating proliferation and survival of germ cells. The aim of this study was to find the correlation between the number of c-kit positive germ cells, testicular asymmetry and histological grade in varicocele affected testis samples of adolescents., Materials and Methods: Twenty testicular biopsy samples of adolescents affected by varicocele and eight normal control testes were included. The relationship between percentage of testicular asymmetry, number of tubular c-kit positive germ cells and severity of spermatogenic failure was assessed., Results: The mean (SD; median) histological grade for spermatogenic failure in controls was 1.37(0.52; 1), while in the varicocele group, it was 2.70(1.08; 3) (P = .0052). Mean(SD; median) number c-kit positive germ cells in the control group were 20.1(2.52; 20), while in the varicocele group it was 12.35(7.16; 12.5) (P = .0059). Spearman test documented a significant positive correlation between percentage of hypotrophy and histological grade of spermatogenic failure (r = 0.5544 , 95% CI: 0.1345 to 0.8055, P = .0112) but a negative correlation with the number of c-kit positive cells (r = - 0.5871, 95% CI: - 0.8219 to -0.1817, P = .0065). Moreover, a significant negative correlation was found between grade of histological changes and number of c-kit positive germ cells (P < .0001)., Conclusion: A significant correlation between hypotrophy, histological lesions and c-kit positive germ cells exists in varicocele testes. This finding suggests a possible role for c-kit in the pathogenesis of germ cell impairment in varicocele. Histological changes and lack of c-kit germ cells were also noted in testes not displaying hypotrophy. We believe that reliable markers should be found as better predictors of testicular function in adolescent with varicocele.

Thyroid cancer incidence is increased in volcanic areas where environment pollution biocontaminates residents. Tungsten (W) is the most increased heavy metal in drinking water of Mount Etna volcanic area where it exceeds the normal range in the urine of 27% inhabitants. The possible connection between increased tungsten and thyroid cancer has never been studied. We investigated in vitro the effect tungsten on both human thyrocytes in primary culture, thyrospheres (aggregates of stem/precursor thyroid cells) and thyrocytes differentiated from tungsten-exposed thyrospheres. Chronic exposure to low-dose (nanomolar range, as in the urines of volcanic area residents) soluble tungsten had major biological effects on thyroid stem/precursor cells, promoting growth with a biphasic (hormetic) dose-response and reducing apoptosis. No such effects were observed in mature thyrocytes. In addition, tungsten-exposed thyrospheres had abnormal expression of genes commonly altered also in thyroid cancer and increased activation of the DNA-repair proteins H2AX and 53BP1. Moreover, exposure to tungsten decreased thyrosphere differentiation, as indicated by the reduced expression of thyroid-specific genes in derived thyrocytes that also showed preneoplastic changes such as increased anchorage-independent growth, clonogenic growth and migration capacity. The mechanism of action of tungsten on thyroid stem/precursor cells is unclear but involves membrane G-proteins and activation of the ERK signaling pathway. These data indicate that chronic exposure to slightly increased tungsten, harmless for mature thyrocytes, importantly affects the biology of stem/precursor thyroid cells and of their progeny, inducing characteristics of preneoplastic transformation.

[This corrects the article DOI: 10.18632/oncotarget.20293.].

Background: Triple Negative Breast Cancer (TNBC) represents a heterogeneous group of tumors with poor prognosis owing to aggressive tumor biology and lack of targeted therapies. No clear prognostic biomarkers have been identified to date for this subgroup., Materials and Methods: In this retrospective study we evaluated the prognostic role of 4 different molecular determinants, including androgen receptor (AR), E-cadherin (CDH1), Ki67 index, and basal cytokeratins (CKs) 5/6, in a cohort of 99 patients with TNBC. All patients received neo/adjuvant chemotherapy (mostly anthracycline/taxane-based). Immunohistochemistry (IHC) was performed in formalin-fixed paraffin-embedded primary tumor samples. CDH1 expression was considered positive as ≥ 30% of the membrane cells staining. AR positivity was defined as > 10% of positive tumor cells. High Ki67 was defined as ≥20% positive tumor cells. CK5/6 expression was judged positive if the score was ≥1., Results: The absence of AR expression was significantly associated with highly undifferentiated tumors. Univariate analyses showed that lack of expression of CDH1, tumor size and nodal status were significantly correlated with worse RFS and OS (p< 0.05). AR expression and low Ki67 showed a trend towards better RFS and OS. Patients with absent CK5/6 expression in univariate and multivariate analyses had poorer RFS (p=0.02 and p=0.002, respectively) and OS (p=0.05 and p=0.02, respectively). Multivariate analysis showed an independent association between CDH1 expression and better RFS and OS (p< 0.05) beyond tumor size, nodal status, and grade. The Kaplan-Meier curves showed that patients with AR and CDH1 negative expression and high Ki-67 levels have a significant correlation with poor outcome., Conclusions: Our study supports the use of IHC expression of AR, CDH1, Ki67, and CK5/6 as prognostic markers in TNBCs and suggests a link between their expression and prognosis and may help to stratify TNBC patients in different prognostic classes., Competing Interests: CONFLICTS OF INTEREST No potential conflicts of interest declared.

Triple-negative breast cancer (TNBC) indicates a subset of breast carcinomas that does not express estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). According to the literature, TNBCs are aggressive tumors, characterized by a high incidence of recurrence and a high risk of disease progression. Lactoferrin (LF) is a single-chain, iron-binding glycoprotein of ~700 amino acids, which is involved in a wide range of biological activities, including iron-trafficking and carcinogenesis. The present study aimed to assess LF expression in human TNBC samples and the possible correlation with clinico-pathological parameters associated with biological aggressiveness. LF immunohistochemical expression was investigated in formalin-fixed, paraffin-embedded samples of human TNBC. Cases were analyzed according to an intensity distribution (ID) score, and only those showing an ID score of >2 were considered as positive for LF. LF immunostaining was encountered in 26.15% cases. A significant correlation was found between LF expression and a low Ki-67 labeling index (P=0.040), the absence of recurrence (P=0.010) and alive status (P=0.020). LF may assist in identifying a subset of TNBC with less aggressive biological behavior. The meaning of LF expression in TNBC remains unclear and is controversial. The present findings indicated that LF expression is correlated with a low growth fraction in these tumors. Thus, it is possible that the inhibition of the LF axis may be a valid therapeutic target for TNBC, and this should be confirmed by future studies.

Objective: An animal model of female Wistar species of rats was developed to study the early effects of ileocystoplasty., Materials and Methods: Bladder augmentation using ileum and a sham operation (cistostomy) were performed in 14 and 6 female Wistar rats, rispectively. Urine was obtained for culture and urinalysis in all rats at the time of operation and at the time of the sacrifice. Seven rats underwent ileocystoplasty and three shams were sacrificed after one and three months. In all rats sacrificed three months after ileocystoplasty, blood sample drawn for serum electrolytes, blood urea, nitrogen creatine and bicarbonate was performed. Post mortem histopathological examination of the ileal patch and of kidneys was performed., Results: The cultures of the urine were positive in 1 out 7 (14.3%) and in 4 out 7 (57%) after one and three months after ileocystoplasty, respectively. Urinary pH of the augmented group was significantly higher in treated rats than in shams (p < 0.05). At sacrifice three months post operatively, the serum chloride concentration was significantly higher in augmented than shams (p < 0.05). Bladder calculi were formed in 28.6% of ileocystoplasty. Histopathological examination of the enteropatch showed urothelialization of the graft and kidneys showed a significant glomerular depletion., Conclusion: Our data confirm an early significant enhancement of urinary pH in rats underwent ileocystoplasty and the stone formation is a frequent event. Already three months after ileocystoplasty urothelialization extended from the side of anastomosis towards the central portion of the ileal graft. Moreover, a significant improvement of serum creatine, sign of glomerular overload and progressive glomerular depletion were recorded in treated rats, probably as a consequence of water and electrolyte resoption through the intestinal graft.

Objective: Acute pancreatitis is an inflammatory condition that may lead to multisystemic organ failure. Melanocortin peptides have been successfully used in experimental models of organ failure and shock, and their protective effect occurs through the activation of a vagus nerve-mediated cholinergic anti-inflammatory pathway by acting at brain melanocortin 4 receptors. In the light of these observations, we studied the effects of the selective melanocortin 4 receptor agonist RO27-3225 in an experimental model of cerulein-induced pancreatitis., Design: Randomized experiment., Setting: Research laboratory at a university hospital., Subject: Experimental pancreatitis in rats., Interventions: Acute pancreatitis was induced in male Sprague-Dawley rats by intraperitoneal injections of cerulein (80 μg/kg, four injections at hourly intervals). Before pancreatitis induction, groups of animals were subjected to bilateral cervical vagotomy, pretreated with the nicotinic acetylcholine receptor antagonist chlorisondamine or the selective melanocortin 4 receptor antagonist HS024, or not pretreated. Thirty minutes after the first cerulein injection, rats were intraperitoneally treated with a nanomolar dose of RO27-3225 or vehicle. Some experimental groups were prepared for neural efferent activity recording along the vagus nerve starting 30 mins after treatment with RO27-3225 or vehicle, and for a 30-min period., Measurements and Main Results: Serum lipase and amylase activity, tumor necrosis factor-α and interleukin-6 expression, pancreatic myeloperoxidase activity, and histologic damage were evaluated; neural efferent activity of vagal fibers was also assessed. RO27-3225 reduced cerulein-induced serum lipase and amylase activity, blunted the expression of tumor necrosis factor-α and interleukin-6, abated the increase in pancreatic myeloperoxidase activity, and protected against histologic damage. Furthermore, RO27-3225 markedly increased neural efferent activity along the vagus nerve. Vagotomy, chlorisondamine, and HS024 abated these protective effects of RO27-3225., Conclusions: Our data show that melanocortin 4 receptor agonists reduce pancreatitis severity through the activation of the cholinergic anti-inflammatory pathway. These findings could be of particular interest in the clinical setting.

In rat experimental varicocele, polydeoxyribonucleotide (PDRN) induces vascular endothelial growth factor (VEGF) production, thereby enhancing testicular function. This may point to a new therapeutic approach in human varicocele., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Bladder augmentation predisposes humans to many metabolic, renal and enteropatch changes. Our aim was to evaluate in a rat model of ileocystoplasty mid- and long-term urinary, metabolic, renal and graft changes., Materials and Methods: We performed an ileocystoplasty and a sham operation in 30 rats. Seven augmented rats and 3 sham-operated animals were euthanized after 1, 3 and 6 months. We performed urinalysis, urine culture and blood sampling for serum electrolytes and urea. Histopathological changes of the ileal patch and kidneys were also evaluated., Results: The urine cultures were positive in 14.3, 57 and 71%, respectively, 1, 3 and 6 months after surgery. Urinary pH, serum chloride and urea of the augmented group were significantly higher. Bladder calculi were formed in 23.8% of ileocystoplasty. Histopathological examination showed urothelialization of the graft with hyperplastic/metaplastic changes. The kidneys showed glomerular depletion and a marked distal tubular ectasia., Conclusions: Our data showed that, in a mid- and long-term follow-up, rat bladders subjected to ileocystoplasty displayed hyperchloremic metabolic acidosis, electrolyte imbalance, enhanced serum blood urea levels and glomerular/tubular changes. Hyperplastic and/or metaplastic changes at the junctional zone were observed. Our experimental results suggest that frequent monitoring of renal function and surveillance of humans who have undergone ileocystoplasty are recommended., (Copyright © 2011 S. Karger AG, Basel.)

Giant cell tumor of soft tissue is a rare neoplasm named for its resemblance to giant cell tumor of bone. According to World Health Organization classification of soft tissue tumors, it belongs to the category of the so-called fibrohistiocytic tumors of intermediate malignancy, characterized by frequent local recurrences unless widely excised, but only rarely metastases to lymph nodes and lungs. Cutaneous presentation is extremely rare. We described a case occurring in a 79-year-old woman who presented with a nodular, polypoid, ulcerated lesion on the paranasal region. The histomorphological features were consistent with the diagnosis of primary giant cell tumor of the skin. Clinical informations and immunohistochemistry are useful in distinguishing this neoplasm from other neoplastic and reactive lesions of the superficial soft tissues containing giant cells.

Introduction: Wnt-1 is capable of inducing metanephric mesenchyme to undergo tubulogenesis. A relationship between the degree of cystogenesis and reduced E-cadherin (E-cad) expression was described. Syndecan-1 (Sdc-1) has a critical role in kidney development., Materials and Methods: Ten multicystic dysplastic kidneys (MCDKs) were stained with hematoxylin and eosin and immunohistochemistry was performed using Wnt-1, E-cad and Sdc-1 antibodies. Eight unaffected kidneys were used as controls., Results: Strong Wnt-1 immunostaining occurred inside cystic/tubular epithelial cells and in blastematous foci. An immunoreaction was observed in glomerular epithelial cells. In controls, just weak cytoplasmic Wnt-1 positivity was seen in tubular epithelial cells. E-cad reaction was negative in MCDKs while strong immunostaining was common in tubular cells of controls. A strong Sdc-1 immunoreaction depicted cystic, tubular and glomerular epithelial cells in MCDKs while Sdc-1 expression documented weak positivity in tubular epithelium alone., Conclusions: Our data are in accordance with an involvement of Wnt-1 in normal nephrogenesis and with its role in altered epithelial differentiation of metanephric mesenchyme in MCDKs. Wnt-1 signal may function to suppress E-cad expression, a predisposing event for cystogenesis. High expression of Sdc-1 in tubular/cystic epithelial cells of MCDKs might alter the normal transition of stages of the developmental process and modify the anion charge of the glomerular barrier., (Copyright (c) 2010 S. Karger AG, Basel.)

Purpose: Dextranomer/hyaluronic acid implantation is associated with a granulomatous inflammatory reaction, replaced by fibrosis. Appearance of myofibroblasts is considered a crucial event in fibrosis, and CD68 positive cells and other factors are implied in their activation. Mast cells are a source of these factors and tryptase can induce fibroblast to express alpha-smooth muscle actin, which is characteristic of myofibroblasts. We evaluated histological changes in refluxing ureters treated with dextranomer/hyaluronic acid and immunolocalized CD68 positive cells, tryptase mast cells and myofibroblasts., Materials and Methods: We performed histological, histochemical and immunohistochemical analyses in 22 refluxing ureters treated with dextranomer/hyaluronic acid in comparison with 17 refluxing ureters who underwent ureteral reimplantation but did not receive endoscopic bulking agent. We used CD68 antibody for monocytes/macrophages and epithelioid cells, mast cell tryptase mouse antibody for mast cells, and alpha-smooth muscle actin and vimentin antibodies for myofibroblasts. The area of the ureteral lumen in dextranomer/hyaluronic acid treated and untreated ureteral endings was measured., Results: Sirius red documented a major grade of histological lesions in dextranomer/hyaluronic acid treated refluxing ureters. CD68 and tryptase mast cell staining showed a significant enhancement of positive cells in dextranomer/hyaluronic acid treated refluxing ureters. Immunostaining for alpha-smooth muscle actin and vimentin displayed a myofibroblastic invasion in dextranomer/hyaluronic acid. Measurement of surface in treated refluxing ureters was significantly less than in untreated refluxing ureters., Conclusions: Our data documented a recruitment of CD68 and tryptase positive cells, abnormal accumulation of collagenous stroma and successive extracellular matrix remodeling through differentiation of myofibroblasts. Myofibroblasts might provoke tissue contraction, decreasing the ureteral diameter and modifying the ureteral length-to-diameter ratio, preventing urine reflux.

Purpose: Testicular torsion is a medical emergency that requires immediate diagnosis and treatment to avoid subsequent testicular injury and infertility. PPARs are a family of nuclear hormone receptors belonging to the steroid receptor superfamily. Three PPAR isotypes (alpha, beta/delta and gamma) encoded by separate genes and showing different tissue distribution patterns have been identified. PPARbeta/delta is expressed in testis and its role is largely unknown. We tested whether pharmacological activation of PPARbeta/delta might protect the testis from ischemia and reperfusion injury., Materials and Methods: Adult male Sprague-Dawley rats were subjected to 1-hour testicular ischemia, followed by 24 hours of reperfusion. Sham testicular ischemia-reperfusion rats served as controls. The animals were randomized to receive immediately after detorsion 1) L-165,041 (4 mg/kg intraperitoneally), a potent agonist of PPARbeta/delta, 2) GW9662 (Calbiochem(R)) (4 mg/kg intraperitoneally), an antagonist of PPAR, 3) L-165,041 (4 mg/kg intraperitoneally) plus GW9662 (4 mg/kg intraperitoneally) concomitantly or 4) vehicle (1 ml/kg 10% dimethyl sulfoxide/NaCl solution). We evaluated testicular extracellular signal regulated kinase, tumor necrosis factor-alpha and interleukin-6 by Western blot. We also investigated PPARbeta/delta activation by Western blot, mRNA expression and organ damage., Results: Testicular ischemia-reperfusion injury caused a significant increase in extracellular signal regulated kinase, tumor necrosis factor-alpha and interleukin-6 expression in each testis. Furthermore, histological examination revealed marked damage. L-165,041 administration increased the PPARbeta/delta message and protein, inhibited extracellular signal regulated kinase, tumor necrosis factor-alpha and interleukin-6 expression, and decreased histological damage. Concomitant administration of GW9662 reversed the protection exerted by PPARbeta/delta agonist., Conclusions: These findings indicate that PPARbeta/delta agonists might be an attractive therapeutic candidate for managing testicular torsion.

Nuclear factor kappa-B (NF-kappaB), mitogen-activated protein kinase3/MAPK1 and MAPK8 are involved in testicular ischemia reperfusion injury (testicular-I/R). NF-kappaB knock-out mice (KO) subjected to testicular-I/R have a reduced testicular damage, blunted MAPK8 activation and enhanced MAPK3/MAPK1 activity. To better understand the role of MAPK3/MAPK1 up-regulation during testicular-I/R, we investigated the effects of PD98059, an inhibitor of MAPK3/MAPK1, in KO mice during testicular-I/R. KO and wild-type (WT) animals underwent 1 h testicular ischemia followed by 24 h reperfusion or a sham testicular-I/R. Animals received either PD98059 (5 mg/kg/ip) or its vehicle. MAPK3/MAPK1, BAX, caspase-3 and -9 and TNF-alpha expression were assessed along with histological examination and an immunostaining for protein of apoptosis. Testicular-I/R caused a greater increase in MAPK3/MAPK1 in KO than in WT animals in both testes. KO mice had a lower expression of the apoptotic proteins and TNF-alpha as well as reduced histological damage compared to WT. Immunostaining confirmed the lower expression of BAX in the Leydig cells of KO mice. Administration of PD98059, abrogated MAPK3/MAPK1 expression and slightly reduced TNF-alpha but did not improve or reverse the histological damage in KO. PD98059 significantly reduced the histological damage in WT mice and markedly reduced the apoptotic proteins in KO and WT mice. These results suggest that testicular-I/R triggers also a pathway of organ damage involving MAPK3/MAPK1, TNF-alpha, BAX, caspase-3 and -9 that activates an apoptotic machinery in an NF-kappaB independent manner. These findings should contribute to better understand testicular torsion-induced damage.

Introduction and Aim. Disorders of esophageal motility causing dysphagia and gastroesophageal reflux are frequent in survivors to esophageal atresia (EA) and distal tracheoesophageal fistula (TEF). The aim of the present study was to investigate the histologic and immunohistochemical features in both esophageal atretic segments to further understand the nature of the motor disorders observed in these patients. Material and Methods. Esophageal specimens from 12 newborns with EA/TEF and 5 newborns dead of unrelated causes were examined. The specimens were fixed in 5% buffered formalin, included in paraffin and cut in 5 micron sections that were stained with hematoxilin and eosin (H and E), and immunohistochemical stainings for Actin, S-100 protein, Neurofilament, Neuron-Specific-Enolase, Chromogranin A and Peripherin were evaluated under the microscope. Results. In controls, the distribution of the neural elements was rather homogenous at both levels of the esophagus. In contrast, the atretic segments showed quantitative and qualitative differences between them with sparser nervous tissue in the distal one in comparison with the proximal one and with controls. Conclusions. These results further support the assumption that histomorphological alterations of the muscular and nervous elements within the esophageal wall might contribute to esophageal dysmotility in patients surviving neonatal operations for EA/TEF.

A rare case of a 46-year-old woman with bilateral Krukenberg tumours is reported. Histologically, oedematous ovarian stroma was infiltrated by signet-ring cells arranged singly, in cords or in nests. Immunoreactivity for cytokeratin-7, carcinoembryonic antigen as well as histochemical positivity for mucins demonstrated the epithelial nature of the tumour. The gastric primary site was suggested by the cytoplasmic immunoreactivity for MUC-5AC and by ultrastructural evidence of gastric differentiation in signet-ring cells such as mucous granules with eccentric dense cores and intracellular microcysts, lined by sparse microvilli. Gastric biopsy, performed after pathological diagnosis, revealed a signet-ring cell carcinoma similar to that in the ovaries, confirming the gastric origin of the Krukenberg tumour. Because none of the individual immunohistochemical markers used for tissue identification is both site specific and site sensitive, electron microscopy in combination with immunohistochemistry is a valuable tool for the pathologist in the diagnosis of the tissue origin of a Krukenberg tumour.