IAPP Marks Mono-hormonal Stem-cell Derived ß Cells that Maintain Stable Insulin Production in vitro and in vivo.

Islet transplantation for treatment of diabetes is limited by availability of donor islets and requirements for immunosuppression. Stem cell-derived islets might circumvent these issues. SC-islets effectively control glucose metabolism post transplantation, but do not yet achieve full function in vitro with current published differentiation protocols. We aimed to identify markers of mature subpopulations of SC-ß cells by studying transcriptional changes associated with in vivo maturation of SC-ß cells using RNA-seq and co-expression network analysis. The ß cell-specific hormone islet amyloid polypeptide (IAPP) emerged as the top candidate to be such a marker. IAPP+ cells had more mature ß cell gene expression and higher cellular insulin content than IAPP- cells in vitro. IAPP+ INS+ cells were more stable in long-term culture than IAPP- INS+ cells and retained insulin expression after transplantation into mice. Finally, we conducted a small molecule screen to identify compounds that enhance IAPP expression. Aconitine up-regulated IAPP and could help to optimize differentiation protocols.

Insights into neuroinflammatory mechanisms of deep brain stimulation in Parkinson's disease.

Parkinson's disease, a progressive neurodegenerative disorder, involves gradual degeneration of the nigrostriatal dopaminergic pathway, leading to neuronal loss within the substantia nigra pars compacta and dopamine depletion. Molecular factors, including neuroinflammation, impaired protein homeostasis, and mitochondrial dysfunction, contribute to the neuronal loss. Deep brain stimulation, a form of neuromodulation, applies electric current through stereotactically implanted electrodes, effectively managing motor symptoms in advanced Parkinson's disease patients. Deep brain stimulation exerts intricate effects on neuronal systems, encompassing alterations in neurotransmitter dynamics, microenvironment restoration, neurogenesis, synaptogenesis, and neuroprotection. Contrary to initial concerns, deep brain stimulation demonstrates antiinflammatory effects, influencing cytokine release, glial activation, and neuronal survival. This review investigates the intricacies of deep brain stimulation mechanisms, including insertional effects, histological changes, and glial responses, and sheds light on the complex interplay between electrodes, stimulation, and the brain. This exploration delves into understanding the role of neuroinflammatory pathways and the effects of deep brain stimulation in the context of Parkinson's disease, providing insights into its neuroprotective capabilities.

The interplay between neuroinflammatory pathways and Parkinson's disease.

Parkinson's disease, a progressive neurodegenerative disorder predominantly affecting elderly, is marked by the gradual degeneration of the nigrostriatal dopaminergic pathway, culminating in neuronal loss within the substantia nigra pars compacta (SNpc) and dopamine depletion. At the molecular level, neuronal loss in the SNpc has been attributed to factors including neuroinflammation, impaired protein homeostasis, as well as mitochondrial dysfunction and the resulting oxidative stress. This review focuses on the interplay between neuroinflammatory pathways and Parkinson's disease, drawing insights from current literature.

Co-loading of Temozolomide with Oleuropein or rutin into polylactic acid core-shell nanofiber webs inhibit glioblastoma cell by controlled release.

Glioblastoma (GB) has susceptibility to post-surgical recurrence. Therefore, local treatment methods are required against recurrent GB cells in the post-surgical area. In this study, we developed a nanofiber-based local therapy against GB cells using Oleuropein (OL), and rutin and their combinations with Temozolomide (TMZ). The polylactic acid (PLA) core-shell nanofiber webs were encapsulated with OL (PLAOL), rutin (PLArutin), and TMZ (PLATMZ) by an electrospinning process. A SEM visualized the morphology and the total immersion method determined the release characteristics of PLA webs. Real-time cell tracking analysis for cell growth, dual Acridine Orange/Propidium Iodide staining for cell viability, a scratch wound healing assay for migration capacity, and a sphere formation assay for tumor spheroid aggressiveness were used. All polymeric nanofiber webs had core-shell structures with an average diameter between 133 ± 30.7-139 ± 20.5 nm. All PLA webs promoted apoptotic cell death, suppressed cell migration, and spheres growth (p < 0.0001). PLAOL and PLATMZ suppressed GB cell viability with a controlled release that increased over 120 h, while PLArutin caused rapid cell inhibition (p < 0.0001). Collectively, our findings suggest that core-shell nano-webs could be a novel and effective therapeutic tool for the controlled release of OL and TMZ against recurrent GB cells.

Hemorrhagic presentation of previously silent brain tumors / Presentación hemorrágica de tumores cerebrales anteriormente silenciosos

Introduction and objectives Acute presentation with intracranial hemorrhage owing to a previously silent brain tumor (BT) is rare. Although any BT can bleed, the frequency and type of bleeding varies across tumor types. Materials and methods We aimed to retrospectively review our experience with 55 patients with BTs presenting with ICH. Results Signs of increased intracranial pressure were the most common symptoms. The temporal lobe was the most common lesion site (n=22). Hemorrhages were mainly confined to the tumor margins (HCTs) (n=34). Extensive intraparenchymal hemorrhages (EIHs) were mainly associated with moderately/severely decreased levels of consciousness (LOCs) (n=15/16). High-grade glioma (HGGT) (n=25) was the leading pathological diagnosis followed by metastasis (MBT) (n=16/55). The hemorrhage type was associated with the pathological diagnosis of the tumor. Patients with HGGT (n=19/25) and MBT (n=9/16) mainly presented with HCTs, whereas low-grade gliomas (LGGT) primarily caused EIHs (n=6/7). Conclusions Hemorrhagic presentation is a rare occurrence in BTs. Among all, MBT and HGGT are responsible for majority of the cases. Importantly, despite their relatively benign characteristics, LGGTs mainly result in extensive parenchymal destruction once they bleed. Maximum surgical resection of hemorrhagic BTs and decompression of the affected brain regions followed by histological confirmation of the diagnosis should be the main goals of treatment in cases with hemorrhagic BTs (AU)

Introducción y objetivos La presentación aguda con hemorragia intracraneal debida a un tumor cerebral (BT) anteriormente silencioso es rara. A pesar de que cualquier BT puede sangrar, la frecuencia y el tipo de sangrado varían según el tipo de tumor. Materiales y métodos Nuestro objetivo fue reexaminar retrospectivamente nuestra experiencia con 55 pacientes con los BT que presentaban HIC. Resultados Los síntomas más comunes fueron signos de aumento de la presión intracraneal. El lóbulo temporal fue el sitio de lesión más común (n=22). Las hemorragias se limitaron especialmente a los márgenes tumorales (HCT) (n=34). Las hemorragias intraparenquimatosas extensas (HIE) se asociaron mayormente con niveles de conciencia moderada/severamente disminuidos (LOC) (n=15/16). El glioma de alto grado (HGGT) (n=25) fue el principal diagnóstico patológico después de la metástasis (MBT) (n=16/55). El tipo de hemorragia se asoció con el diagnóstico patológico del tumor. Los pacientes con HGGT (n=19/25) y MBT (n=9/16) presentaron mayormente con HCT, mientras que los gliomas de bajo grado (LGGT) causaron principalmente HIE (n=6/7). Conclusiones La presentación hemorrágica es una ocurrencia rara en los BT. Entre todos, MBT y HGGT son responsables de la mayoría de los casos. Más importante aún, pese a sus características relativamente benignas, los LGGT resultan mayormente una destrucción extensa del parénquima una vez que sangran. La resección quirúrgica máxima de BT hemorrágicos y la descompresión de las regiones cerebrales afectadas con la confirmación histológica del diagnóstico deben ser los objetivos principales del tratamiento en casos con BT hemorrágicos (AU)

Posterior Transdural Discectomy for Thoracic Disc Herniation.

AIM: To evaluate the safety and efficacy of posterior transdural discectomy for thoracic disc herniation. MATERIAL AND METHODS: The medical records of seven patients who underwent posterior transdural discectomy for thoracic disc herniation were retrospectively evaluated. RESULTS: Between 2012 and 2020, seven patients (five men and two women) who were aged between 17 and 74 years underwent posterior transdural discectomy. Numbness is the most common presenting symptom, and two patients complained of urinary incontinence. T10-11 was the most affected level. All patients underwent at least 6 months of follow-up. There were no postoperative cerebrospinal fluid leaks and neurological complications postoperatively. All patients maintained their baseline neurological status or improved after surgery. No patient had secondary neurological deterioration or need for further surgical treatment. CONCLUSION: The posterior transdural approach is a safe procedure that should be considered in lateral and paracentral thoracic disc herniations providing a more direct surgical intervention.

Hemorrhagic presentation of previously silent brain tumors.

INTRODUCTION AND OBJECTIVES: Acute presentation with intracranial hemorrhage owing to a previously silent brain tumor (BT) is rare. Although any BT can bleed, the frequency and type of bleeding varies across tumor types. MATERIALS AND METHODS: We aimed to retrospectively review our experience with 55 patients with BTs presenting with ICH. RESULTS: Signs of increased intracranial pressure were the most common symptoms. The temporal lobe was the most common lesion site (n=22). Hemorrhages were mainly confined to the tumor margins (HCTs) (n=34). Extensive intraparenchymal hemorrhages (EIHs) were mainly associated with moderately/severely decreased levels of consciousness (LOCs) (n=15/16). High-grade glioma (HGGT) (n=25) was the leading pathological diagnosis followed by metastasis (MBT) (n=16/55). The hemorrhage type was associated with the pathological diagnosis of the tumor. Patients with HGGT (n=19/25) and MBT (n=9/16) mainly presented with HCTs, whereas low-grade gliomas (LGGT) primarily caused EIHs (n=6/7). CONCLUSIONS: Hemorrhagic presentation is a rare occurrence in BTs. Among all, MBT and HGGT are responsible for majority of the cases. Importantly, despite their relatively benign characteristics, LGGTs mainly result in extensive parenchymal destruction once they bleed. Maximum surgical resection of hemorrhagic BTs and decompression of the affected brain regions followed by histological confirmation of the diagnosis should be the main goals of treatment in cases with hemorrhagic BTs.

Olea europaea Leaf Phenolics Oleuropein, Hydroxytyrosol, Tyrosol, and Rutin Induce Apoptosis and Additionally Affect Temozolomide against Glioblastoma: In Particular, Oleuropein Inhibits Spheroid Growth by Attenuating Stem-like Cell Phenotype.

The effects of Olea europaea leaf extract (OLE) phenolics, including oleuropein (OL), hydroxytyrosol (HT), tyrosol (TYR), and rutin against glioblastoma (GB), independently and in combination with temozolomide (TMZ), were investigated in T98G and A172 cells. Cell growth was assessed by WST-1, real-time cell analysis, colony formation, and cell cycle distribution assays. A dual acridine orange propidium iodide (AO/PI) staining and annexin V assay determined cell viability. A sphere-forming assay, an intracellular oxidative stress assay, and the RNA expression of CD133 and OCT4 investigated the GB stem-like cell (GSC) phenotype. A scratch wound-healing assay evaluated migration capacity. OL was as effective as OLE in terms of apoptosis promotion (p < 0.001) and GSC inhibition (p < 0.001). HT inhibited cell viability, GSC phenotype, and migration rate (p < 0.001), but its anti-GB effect was less than the total effect of OLE alone. Rutin decreased reactive oxygen species production and inhibited colony formation and cell migration (p < 0.001). TYR demonstrated the least effect. The additive effects of OL, HT, TYR and rutin with TMZ were significant (p < 0.001). Our data suggest that OL may represent a novel therapeutic approach against GB cells, while HT and rutin show promise in increasing the efficacy of TMZ therapy.

Oxidative Stress and Intracranial Hypertension after Aneurysmal Subarachnoid Hemorrhage.

Intracranial hypertension is a common phenomenon in patients with aneurysmal subarachnoid hemorrhage (aSAH). Elevated intracranial pressure (ICP) plays an important role in early brain injuries and is associated with unfavorable outcomes. Despite advances in the management of aSAH, there is no consensus about the mechanisms involved in ICP increases after aSAH. Recently, a growing body of evidence suggests that oxidative stress (OS) may play a crucial role in physio-pathological changes following aSAH, which may also contribute to increased ICP. Herein, we discuss a potential relation between increased ICP and OS, and resultantly propose antioxidant mechanisms as a potential therapeutic strategy for the treatment of ICP elevation following aSAH.

Activation of Tumor-Cell STING Primes NK-Cell Therapy.

Activation of the stimulator of interferon genes (STING) pathway promotes antitumor immunity but STING agonists have yet to achieve clinical success. Increased understanding of the mechanism of action of STING agonists in human tumors is key to developing therapeutic combinations that activate effective innate antitumor immunity. Here, we report that malignant pleural mesothelioma cells robustly express STING and are responsive to STING agonist treatment ex vivo. Using dynamic single-cell RNA sequencing of explants treated with a STING agonist, we observed CXCR3 chemokine activation primarily in tumor cells and cancer-associated fibroblasts, as well as T-cell cytotoxicity. In contrast, primary natural killer (NK) cells resisted STING agonist-induced cytotoxicity. STING agonists enhanced migration and killing of NK cells and mesothelin-targeted chimeric antigen receptor (CAR)-NK cells, improving therapeutic activity in patient-derived organotypic tumor spheroids. These studies reveal the fundamental importance of using human tumor samples to assess innate and cellular immune therapies. By functionally profiling mesothelioma tumor explants with elevated STING expression in tumor cells, we uncovered distinct consequences of STING agonist treatment in humans that support testing combining STING agonists with NK and CAR-NK cell therapies.

The association between hematologic parameters and intracranial injuries in pediatric patients with traumatic brain injury.

OBJECTIVE: Analyzing the association between hematologic parameters and abnormal cranial computerized tomography (CT) findings after head trauma. MATERIAL AND METHODS: A total of 287 children with isolated traumatic brain injury (TBI) were divided into the 'normal' (NG), 'linear fracture' (LFG) and 'intraparenchymal injury' groups (IPG) based on head CT findings. Demographical/clinical data and laboratory results were obtained from medical records. RESULTS: The neutrophil-lymphocyte ratio was markedly higher in the LFG (p = 0.010 and p = 0.016, respectively) and IPG (p = 0.004 and p < 0.001, respectively) compared with NG. Lower lymphocyte-monocyte ratio (p = 0.044) and higher red cell distribution width-platelet ratio (RPR) (p = 0.030) were associated with intraparenchymal injuries. Patients requiring neurosurgical intervention had higher neutrophil-lymphocyte ratio (p = 0.026) and RPR values (p = 0.031) and lower platelet counts (p = 0.035). Lower levels of erythrocytes (p = 0.005), hemoglobin (p = 0.003) and hematocrit (p = 0.002) were associated with severe TBI and unfavorable outcome (p = 0.012, p = 0.004 and p = 0.006, respectively). CONCLUSIONS: Hematologic parameters are useful in predicting the presence of abnormal cranial CT findings in children with TBI in association with injury severity; surgery need and clinical outcome.

A Novel HER2-Selective Kinase Inhibitor Is Effective in HER2 Mutant and Amplified Non-Small Cell Lung Cancer.

In-frame insertions in exon 20 of HER2 are the most common HER2 mutations in patients with non-small cell lung cancer (NSCLC), a disease in which approved EGFR/HER2 tyrosine kinase inhibitors (TKI) display poor efficiency and undesirable side effects due to their strong inhibition of wild-type (WT) EGFR. Here, we report a HER2-selective covalent TKI, JBJ-08-178-01, that targets multiple HER2 activating mutations, including exon 20 insertions as well as amplification. JBJ-08-178-01 displayed strong selectivity toward HER2 mutants over WT EGFR compared with other EGFR/HER2 TKIs. Determination of the crystal structure of HER2 in complex with JBJ-08-178-01 suggests that an interaction between the inhibitor and Ser783 may be responsible for HER2 selectivity. The compound showed strong antitumoral activity in HER2-mutant or amplified cancers in vitro and in vivo. Treatment with JBJ-08-178-01 also led to a reduction in total HER2 by promoting proteasomal degradation of the receptor. Taken together, the dual activity of JBJ-08-178-01 as a selective inhibitor and destabilizer of HER2 represents a combination that may lead to better efficacy and tolerance in patients with NSCLC harboring HER2 genetic alterations or amplification. SIGNIFICANCE: This study describes unique mechanisms of action of a new mutant-selective HER2 kinase inhibitor that reduces both kinase activity and protein levels of HER2 in lung cancer.

A Rare Cause of Epilepsy: Ulegyria Revisited in a Series of 10 Patients.

Introduction. Ulegyria results from perinatal hypoxic-ischemic brain injury in term infants. The specific mushroom-shaped configuration of ulegyria results from small atrophic circumvolutions at the bottom of a sulcus underlying an intact gyral apex. Clinically, ulegyria is generally associated with epilepsy. Here, we aimed to delineate the characteristics of patients with ulegyria and the epileptic seizures they experience. Material and methods. Medical records including radiology and pathology reports, video-electroencephalographic (EEG) analysis, operative notes, hospital progress and outpatient clinic notes were reviewed retrospectively in a total of 10 ulegyria patients. Results. Patients ages ranged between 24 and 58 years (mean, 32 ± 9.8 years). Past medical history was confirmed for neonatal asphyxia in 2 (20%). Neurological examination was remarkable for spastic hemiparesis in 1 (10%) patient with perisylvian ulegyria and for visual field deficits in 2 patients (20%) with occipital ulegyria. Ulegyria most commonly involved the temporoparietal region (n = 5, 50%) followed by the perisylvian area (n = 2, 20%). Except the one with bilateral perisylvian ulegyria, all patients had unilateral lesions (n = 9, 90%). Hippocampal sclerosis accompanied ulegyria in 2 patients (20%). All patients experienced epileptic seizures. Mean age at seizure onset was 8.8 ± 5.4 years (range, 2-20 years). Interictal scalp EEG and EEG-video monitoring records demonstrated temporoparietal and frontotemporal activities in 5 (50%) and 2 (20%) patients, respectively. The seizures were successfully controlled by antiepileptic medication in 8 patients (n = 8, 80%). The remaining 2 patients (%20) with concomitant hippocampal sclerosis required microsurgical resection of the seizure foci due to medically resistant seizures. Discussion. Ulegyria is easily recognized with its unique magnetic resonance imaging characteristics and clinical presentation in the majority of cases. It is highly associated with either medically resistant or medically controllable epileptic seizures. The treatment strategy depends on the age at onset and extends of the lesion that has a significant impact on the severity of the clinical picture.

EGFR Inhibition Enhances the Cellular Uptake and Antitumor-Activity of the HER3 Antibody-Drug Conjugate HER3-DXd.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are the standard-of-care treatment for EGFR-mutant non-small cell lung cancers (NSCLC). However, most patients develop acquired drug resistance to EGFR TKIs. HER3 is a unique pseudokinase member of the ERBB family that functions by dimerizing with other ERBB family members (EGFR and HER2) and is frequently overexpressed in EGFR-mutant NSCLC. Although EGFR TKI resistance mechanisms do not lead to alterations in HER3, we hypothesized that targeting HER3 might improve efficacy of EGFR TKI. HER3-DXd is an antibody-drug conjugate (ADC) comprised of HER3-targeting antibody linked to a topoisomerase I inhibitor currently in clinical development. In this study, we evaluated the efficacy of HER3-DXd across a series of EGFR inhibitor-resistant, patient-derived xenografts and observed it to be broadly effective in HER3-expressing cancers. We further developed a preclinical strategy to enhance the efficacy of HER3-DXd through osimertinib pretreatment, which increased membrane expression of HER3 and led to enhanced internalization and efficacy of HER3-DXd. The combination of osimertinib and HER3-DXd may be an effective treatment approach and should be evaluated in future clinical trials in EGFR-mutant NSCLC patients. SIGNIFICANCE: EGFR inhibition leads to increased HER3 membrane expression and promotes HER3-DXd ADC internalization and efficacy, supporting the clinical development of the EGFR inhibitor/HER3-DXd combination in EGFR-mutant lung cancer.See related commentary by Lim et al., p. 18.

Oncogenic switch and single-agent MET inhibitor sensitivity in a subset of EGFR-mutant lung cancer.

The clinical efficacy of epidermal growth factor receptor (EGFR)­targeted therapy in EGFR-mutant non­small cell lung cancer is limited by the development of drug resistance. One mechanism of EGFR inhibitor resistance occurs through amplification of the human growth factor receptor (MET) proto-oncogene, which bypasses EGFR to reactivate downstream signaling. Tumors exhibiting concurrent EGFR mutation and MET amplification are historically thought to be codependent on the activation of both oncogenes. Hence, patients whose tumors harbor both alterations are commonly treated with a combination of EGFR and MET tyrosine kinase inhibitors (TKIs). Here, we identify and characterize six patient-derived models of EGFR-mutant, MET-amplified lung cancer that have switched oncogene dependence to rely exclusively on MET activation for survival. We demonstrate in this MET-driven subset of EGFR TKI-refractory cancers that canonical EGFR downstream signaling was governed by MET, even in the presence of sustained mutant EGFR expression and activation. In these models, combined EGFR and MET inhibition did not result in greater efficacy in vitro or in vivo compared to single-agent MET inhibition. We further identified a reduced EGFR:MET mRNA expression stoichiometry as associated with MET oncogene dependence and single-agent MET TKI sensitivity. Tumors from 10 of 11 EGFR inhibitor­resistant EGFR-mutant, MET-amplified patients also exhibited a reduced EGFR:MET mRNA ratio. Our findings reveal that a subset of EGFR-mutant, MET-amplified lung cancers develop dependence on MET activation alone, suggesting that such patients could be treated with a single-agent MET TKI rather than the current standard-of-care EGFR and MET inhibitor combination regimens.

Does intraurethral erythropoietin administration effect wound healing after hypospadias correction? an experimental rat study.

OBJECTIVES: To analyze effects of intraurethral EPO application on urethral wound healing by defining hystopathologic changes in a rat model of hypospadias. METHODS: A hypospadias model was created in 30 rats and randomized into 3 groups of 10. For 14 days, the first group was administered 25 iu EPO instillation intraurethrally once a day, while group 2 was administered with 50 iu EPO in the same manner. The third group was assigned as control group. On the day 15, rats were sacrificed and penectomies were performed. One independent pathologist who is blinded to groups and treatments evaluated the penis samples. RESULTS: Histopathologic examinations yielded the mean fibrosis scores (± SD) as 1.9 ± 0.568, 1.1 ± 0.786 and 2.5 ± 0.535 in groups I, II and III, respectively. There was significant difference between the EPO groups and the control group (p = 0.04-I, p = 0.003-II). The mean inflammation scar scores (± SD) were determined as 1 ± 1.054, 2 ± 1.247, 2.63 ± 0.744 in groups I, II and III, respectively. There was a significant difference in terms of inflammation between control group and group I (p = 0.005). Mean congestion scores (± SD) were found 1.2 ± 0.789 in groups I-II and 0.75 ± 0.463 in group III (p = 0.310). Hyperemia was seen in 60% 70% and 37.5% in groups I, II and III, respectively (p = 0.387). CONCLUSION: Intraurethral EPO therapy effected urethral wound healing in a good way. Thus it could be feasible to treat the patients with after hypospadias surgeries and to improve success rates.

Bridging the Divide: Student Grand Rounds at the Interface of Basic Science and Clinical Medicine.

PROBLEM: As biomedical research and clinical medicine become increasingly complex, physician-scientists and clinically oriented biomedical researchers play important roles in bridging the gap between disciplines. A lack of educational programming that addresses the unique needs of students preparing for careers at the interface of basic science and clinical medicine may contribute to trainee attrition. APPROACH: The MD-PhD/LHB Grand Rounds was introduced in 2008 as a trainee-driven collaborative effort of the Harvard/Massachusetts Institute of Technology MD-PhD program at Harvard Medical School (HMS MD-PhD program), Harvard's Leder Human Biology and Translational Medicine (LHB) program, and the Brigham and Women's Hospital (BWH) Internal Medicine Department. Each of the program's approximately 4 sessions per year begins with dinner, followed by a clinical case presentation led by a BWH MD-PhD resident with a master clinician faculty discussant, then a research presentation by an LHB PhD student or an MD-PhD student on a basic science topic related to the clinical case, and time for socialization. OUTCOMES: In a July 2017 survey of participating students and residents, respondents reported being highly satisfied with the program. Mean satisfaction ratings were 4.3 (SD 0.5) for 12 MD-PhD students, 4.2 (SD 0.7) for 31 LHB students, and 4.4 (SD 0.9) for 5 residents on a 5-point scale (5 = very satisfied). Free-text responses suggested MD-PhD students valued opportunities for active engagement with the resident presenter and faculty discussant. LHB students appreciated the absence of medical jargon in the clinical presentations. Residents' reported reasons for participating included enjoyment of teaching and interaction with students. NEXT STEPS: The Harvard MD-PhD/LHB Grand Rounds can serve as a template for developing similar programs at other institutions. Research is needed to determine whether such grand rounds programs can help fix the leaky pipeline in the training of future physician-scientists and clinically oriented biomedical researchers.

Intraurethral Erythropoietin to Prevent Fibrosis and Improve Urethral Healing: An Experimental Study in a Rat Model.

OBJECTIVE: To determine the effects of intraurethral erythropoietin (EPO) on an experimentally induced urethral injury in a rat model with respect to wound healing enhancement and the prevention of spongiofibrosis MATERIAL AND METHODS: A urethral injury model was created by traumatizing the urethra of male rats with a tilted-tip insulin injector. Thirty rats were randomly separated into 3 groups of 10; Group 1 (control) received 0.9% saline solution twice a day, Group II received EPO 25 IU/kg once a day and 0.9% saline solution once a day, and Group III received EPO 25 IU/kg twice a day. All applications were made intraurethrally via a 24 ga catheter sheath. To investigate inflammation and spongiofibrosis and congestion of vessels in the lamina propria, the penises of the rats were harvested for histopathologic evaluation after a follow-up period of 14 days. RESULTS: Histopathologic analysis revealed less fibrosis and inflammation and higher congestion of vessels in Group III that had received high-dose EPO. There was a significant decrease in both spongiofibrosis and inflammation and an increase in congestion in Groups II and III compared to the control group (P = .001, for all). In the comparison of Group II with Group III, no statistically significant differences were found in terms of these 3 parameters (P = .5, P = .6, P = .27, respectively). CONCLUSION: The results of this study have shown that EPO has a preventive effect on spongiofibrosis and improve urethral wound healing in a rat model of urethral injury.