Age-specific and compartment-dependent changes in mitochondrial homeostasis and cytoplasmic viscosity in mouse peripheral neurons.

Mitochondria are dynamic bioenergetic hubs that become compromised with age. In neurons, declining mitochondrial axonal transport has been associated with reduced cellular health. However, it is still unclear to what extent the decline of mitochondrial transport and function observed during ageing are coupled, and if somal and axonal mitochondria display compartment-specific features that make them more susceptible to the ageing process. It is also not known whether the biophysical state of the cytoplasm, thought to affect many cellular functions, changes with age to impact mitochondrial trafficking and homeostasis. Focusing on the mouse peripheral nervous system, we show that age-dependent decline in mitochondrial trafficking is accompanied by reduction of mitochondrial membrane potential and intramitochondrial viscosity, but not calcium buffering, in both somal and axonal mitochondria. Intriguingly, we observe a specific increase in cytoplasmic viscosity in the neuronal cell body, where mitochondria are most polarised, which correlates with decreased cytoplasmic diffusiveness. Increasing cytoplasmic crowding in the somatic compartment of DRG neurons grown in microfluidic chambers reduces mitochondrial axonal trafficking, suggesting a mechanistic link between the regulation of cytoplasmic viscosity and mitochondrial dynamics. Our work provides a reference for studying the relationship between neuronal mitochondrial homeostasis and the viscoelasticity of the cytoplasm in a compartment-dependent manner during ageing.

Differential Expression of SRY-Related HMG-Box Transcription Factor 2, Oligodendrocyte Lineage Transcription Factor 2, and Zinc Finger E-Box Binding Homeobox 1 in Serum-Derived Extracellular Vesicles: Implications for Mithramycin Sensitivity and Targeted Therapy in High-Grade Glioma.

Glioblastoma multiforme (GBM) is the most aggressive type of glioma and is often resistant to traditional therapies. Evidence suggests that glioma stem cells (GSCs) contribute to this resistance. Mithramycin (Mit-A) targets GSCs and exhibits antitumor activity in GBM by affecting transcriptional targets such as SRY-related HMG-box transcription factor 2 (SOX2), oligodendrocyte lineage transcription factor 2 (OLIG2), and zinc finger E-box binding homeobox 1 (ZEB1). However, its clinical use has been limited by toxicity. This study explored the diagnostic potential of serum extracellular vesicles (EVs) to identify Mit-A responders. Serum EVs were isolated from 70 glioma patients, and targeted gene expression was analyzed using qRT-PCR. Using chemosensitivity assay, we identified 8 Mit-A responders and 17 nonresponders among 25 glioma patients. The M-score showed a significant correlation (p = 0.045) with isocitrate dehydrogenase 1 mutation but not other clinical variables. The genes SOX2 (p = 0.005), OLIG2 (p = 0.003), and ZEB1 (p = 0.0281) were found to be upregulated in the responder EVs. SOX2 had the highest diagnostic potential (AUC = 0.875), followed by OLIG2 (AUC = 0.772) and ZEB1 (AUC = 0.632).The combined gene panel showed significant diagnostic efficacy (AUC = 0.956) through logistic regression analysis. The gene panel was further validated in the serum EVs of 45 glioma patients. These findings highlight the potential of Mit-A as a targeted therapy for high-grade glioma based on differential gene expression in serum EVs. The gene panel could serve as a diagnostic tool to predict Mit-A sensitivity, offering a promising approach for personalized treatment strategies and emphasizing the role of GSCs in therapeutic resistance.

Healthcare costs and resource utilization in patients with migraine treated with erenumab: A retrospective, non-interventional study using claims data from the United States.

OBJECTIVE: To assess healthcare costs and healthcare resource utilization (HCRU) among adult patients who newly initiated erenumab in the United States. METHODS: This retrospective, non-interventional analysis included adult patients (aged ≥18 years) newly initiating erenumab and who had three consecutive monthly claims for erenumab (11/1/2017-9/1/2019) from the Komodo Health database. Outcomes included migraine-related and all-cause costs, use of other preventive/acute migraine medications, and HCRU. All outcomes were compared during the 180-day pre- versus the 180-day post-index periods. Cost outcomes were also assessed for longer periods including post-index Days 91-270 and monthly mean post-index costs for the longest time of continuous insurance enrollment. RESULTS: Overall, 1839 patients with migraine were included for analysis. Compared to the 180-day pre-index period, an increase in total migraine-related costs (+$2639; p < 0.0001), migraine-related prescription costs (+$3435, p < 0.0001), all-cause total costs (+$2977; p < 0.001), and all-cause prescription costs (+$4102; p < 0.0001) were observed during the 180-day post-index period after adjusting for covariates. Conversely, reduction in migraine-related medical costs (-$896; p < 0.0001), and significantly lower odds of migraine-related emergency room visits (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.44-0.82; p = 0.001), migraine-related office visits (OR 0.58, 95% CI 0.53-0.64; p < 0.0001), and migraine-related neurologist visits (OR 0.69, 95% CI 0.63-0.75; p < 0.0001) were observed during the 180-days post-index period. There were significant decreases in the odds of having overall preventive migraine medications (OR 0.81, 95% CI 0.75-0.87; p < 0.0001), acute-migraine medications (OR 0.92, 95% CI 0.85-1.00; p = 0.038), and triptan (OR 0.79, 95% CI 0.73-0.85; p < 0.0001) during the 180-day post-index period. Sensitivity analyses on cost outcomes found no statistically significant differences in pre-index migraine-related costs compared to post-index migraine-related costs when assessing longer post-index follow-up periods. CONCLUSION: Initiation of therapy with a novel treatment is often associated with an increase in overall healthcare costs due to the entrance costs associated with novel therapy. For a chronic condition such as migraine, cost versus health benefits should be evaluated over a long period (e.g., ≥2 years) to better understand the true benefits of therapy. Data from this study suggest that the entrance cost for erenumab, the primary driver of the high post-index prescription costs gets mitigated by reduced medical costs over long-term follow-up. The results indicate better disease management in adult patients with migraine, which should be an important consideration for both patients and payors, as these findings have shown an offset between migraine-related prescription and medical costs.

In-utero Diagnosis of Prostatic Embryonal Rhabdomyosarcoma.

Though rhabdomyosarcoma is the most common soft-tissue tumor diagnosed in children there are no reported cases of prenatally detected prostatic embryonal rhabdomyosarcoma. This report demonstrates the first reported case of this phenomenon and its subsequent workup, diagnosis, and treatment.

Standardization of Particle Size for Floating Particle Wettability Measurement for Carbonate Rocks.

Misrepresentation of the wettability of a reservoir can lead to potentially low ultimate hydrocarbon recovery resulting in substantial economic losses. At the same time, it is impossible to determine the wettability of a reservoir across its length and breadth on a continuous basis using standard procedures. This work presents the development and standardization of a quick, easy, and low-cost wettability measurement method using the adherence tendency of rock particles in the oil or aqueous phase. The most important aspect of this study was establishing the optimum particle size for sustained floatation and balancing the buoyancy and gravity effect. The results show that the particles sink with a larger than optimum particle size because of the gravity effect. Similarly, the particles would float if they are smaller than optimum due to buoyancy and viscosity advantages. A new scale is designed, and the midpoint analysis shows that a 63-90 µm particle size is the ideal size range for the carbonate reservoir's wettability measurements, as the midpoint of the size distribution coincides with the standard Amott-Harvey (A-H) index. However, this size range is found to be wider for oil-wet particles. The floating particle method has several advantages over the established methods once standardized against a reliable process. Not only is the process fast but it can be performed with basic laboratory tools and does not require a high skill set. Most importantly, reliable wettability information can be obtained from drill cuttings and core fragments, enabling the determination of reservoir wettability on a continuum basis and not as a point basis, thus providing a more reliable average value, particularly for heterogeneous and unconsolidated reservoirs.

Corneal stromal regeneration-keratoconus cell therapy: a review.

BACKGROUND: Keratoconus is a corneal ectatic disease caused by stromal thinning leading to astigmatism and progressive loss of vision. Loss of the keratocytes and excessive degradation of collagen fibres by matrix metalloproteinases are the molecular signatures of the disease. Despite several limitations, corneal collagen cross-linking and keratoplasty are the most widely used treatment options for keratoconus. In the pursuit of alternative treatment modalities, clinician scientists have explored cell therapy paradigms for treating the condition. METHODS: Articles pertaining to keratoconus cell therapy with relevant key words were used to search in PubMed, Researchgate, and Google Scholar. The articles were selected based on their relevance, reliability, publication year, published journal, and accessibility. RESULTS: Various cellular abnormalities have been reported in keratoconus. Diverse cell types such as mesenchymal stromal cells, dental pulp cells, bone marrow stem cells, haematopoietic stem cells, adipose-derived stem cells apart from embryonic and induced pluripotent stem cells can be used for keratoconus cell therapy. The results obtained show that there is a potential for these cells from various sources as a viable treatment option. CONCLUSION: There is a need for consensus with respect to the source of cells, mode of delivery, stage of disease, and duration of follow-up, to establish a standard operating protocol. This would eventually widen the cell therapy options for corneal ectatic diseases beyond keratoconus.

Resveratrol for dry eye disease - Hope or Hype?

Dry eye disease (DED) is a multifactorial and common ophthalmic disease that has a tremendous effect on the quality of life. It is now becoming a public health concern because of our changing lifestyle and environment. The current treatment modalities, artificial tear substitutes, and anti-inflammatory therapy are directed at dry eye symptoms. One of the major drivers for DED is oxidative stress, and the polyphenol group of natural compounds has the potential to reduce the same. Resveratrol, widely found in the skin of grapes and nuts, has antioxidative and anti-inflammatory properties. It has been shown to have beneficial effects in glaucoma, age-related macular degeneration, retinopathy of prematurity, uveitis, and diabetic retinopathy. Studies have also explored the beneficial effects of resveratrol in DED, making it as a promising therapeutic molecule. Resveratrol has not yet reached clinical application because of difficulty in deliverability and low bioavailability. In this review, we explore the potential of resveratrol in DED treatment based on various in vitro and in vivo studies.

Real-world treatment satisfaction with erenumab in migraine: analysis of the US National Health and Wellness Survey.

OBJECTIVE: The treatment landscape for the prevention of migraine has rapidly evolved in recent years with the advent of calcitonin gene-related peptide therapy, including erenumab. The objective of this study was to assess patient-reported treatment satisfaction among erenumab users. METHODS: This retrospective, cross-sectional study used data from the 2019 US National Health and Wellness Survey collected during March-July 2019. Respondents self-reporting physician-diagnosed migraine and currently using erenumab were analyzed. Treatment satisfaction was measured on a seven-point Likert scale. Data were further reported by the duration of erenumab treatment. Data on respondents' socio-demographic characteristics and treatment patterns were also collected. RESULTS: Overall, 67 respondents using erenumab with or without other migraine preventives for up to 1 year were included in the analysis. The mean (standard deviation) age was 46.7 (12.9) years. Most of the respondents were women (86.6%), White (74.6%), and commercially-insured (67.2%). Notably, 40.3% had ≥1 comorbidity per the Charlson Comorbidity Index. Approximately half of the respondents were college graduates and employed (49.3% each). Among the 67 respondents, 46 received erenumab exclusively. Across both cohorts, the percentage of respondents who were satisfied with erenumab treatment was slightly higher among those with a longer treatment duration (overall erenumab cohort: 63.6%, 69.6%, and 75.8% for 0-<3, 3-<6, and 6-12 months, respectively; erenumab monotherapy cohort: 62.5%, 71.4%, and 87.5% for 0-<3, 3-<6, and 6-12 months, respectively). Treatment patterns before switching to erenumab revealed that most respondents had used ≥1 preventive treatment for migraine (80.6%; 54/67), over two-thirds (33/54) of whom had ≥2 treatment failures owing to nonresponse. CONCLUSION: Satisfaction was high among long-term erenumab users, indicating that those using erenumab for a longer duration are more satisfied. Furthermore, this study provided insights on the basic socio-demographics, disease characteristics, and health behaviors of erenumab users as well as their treatment patterns before switching to erenumab.

Effect of Prostate Volume and Minimum Tumor Temperature on 4-Year Quality-of-Life After Focal Cryoablation Compared with Active Surveillance in Men with Prostate Cancer.

Background: The purpose of this study is to analyze quality-of-life (QoL) metrics in men treated with focal cryoablation (FC) compared with active surveillance (AS) for localized prostate cancer over a 4-year follow-up period. We further investigated the effect of prostate size and minimum tumor temperature on QoL outcomes. Methods: An Institutional Review Board-approved database was reviewed for patients who underwent FC or AS. QoL questionnaire responses were collected and scores were analyzed for differences between FC and AS, between prostate volume <50 cc and ≥50 cc, and "cold" (<-78°C) and "warm" (≥-78°C) tumor temperatures. Results: One hundred forty-eight AS and 60 FC patients were included. Compared with AS, no significant difference existed in urinary function (UF) measured by Expanded Prostate Cancer Index Composite (EPIC) (p = 0.593) and International Prostate Symptom Score (IPSS) (p = 0.241), bowel habits (p = 0.370), or anxiety (p = 0.672) across time post-FC. FC had significantly worse sexual function (SF) compared with AS measured by EPIC (p < 0.0001) and International Index of Erectile Function (IIEF) (p < 0.0001). Patients with prostate volume <50 cc did not demonstrate differences between AS and FC in UF on EPIC (p = 0.459) or IPSS (p = 0.628), but FC patients had worse SF on EPIC (p < 0.001) and IIEF (p < 0.001). FC patients with a prostate volume ≥50 cc had better UF measured by IPSS (p < 0.05) and similar SF on EPIC (p = 0.162) and IIEF (p = 0.771) compared with AS. UF over time measured by EPIC (0.825) and IPSS (p = 0.658) was the same between AS, "warm," and "cold" FC groups. AS had significantly better SF than the "warm" and "cold" FC groups on EPIC (p < 0.001) and IIEF (p < 0.05). Conclusions: No differences were found in anxiety, urinary, or bowel function between AS and FC. Despite differences in SF, patients with larger prostates had no difference in SF and improved UF compared with AS. Future studies with larger cohorts are needed.

Sexual Addiction as a Legal Defense.

The term sexual addiction is used to describe a range of behaviors involving compulsive and maladaptive sexual behavior. There are mixed opinions in the medical literature regarding whether sexual addiction represents a valid psychiatric diagnosis or instead pathologizes behaviors in the expected range of human behavior. The opinions on sexual addiction in case law are similarly mixed. The condition has at times been used as a successful mitigating factor and at other times been rejected for lack of scientific evidence. The authors searched the LexisNexis database for legal cases that involved the use of sexual addiction as a mitigating or aggravating factor to provide an overview of the available case law. This article is focused on the uncertainty surrounding the diagnosis of sexual addiction and how it has been interpreted by the legal system.

Capillary hemangioma of the bladder in a pediatric patient.

We report a case of a bladder hemangioma in a pediatric patient. A 2-year-old Caucasian female presented with intermittent gross hematuria and protrusion of beefy red tissue near the vaginal introitus when straining. On cystoscopy, we discovered a wide-based vermiform mass. Transurethral resection of the bladder mass was performed. Based on the histological findings of the tissue resected, a diagnosis of capillary hemangioma of the bladder was made. Despite their rarity, bladder hemangiomas should be considered in the differential in children with gross hematuria.

Postnatal expression of the lysine methyltransferase SETD1B is essential for learning and the regulation of neuron-enriched genes.

In mammals, histone 3 lysine 4 methylation (H3K4me) is mediated by six different lysine methyltransferases. Among these enzymes, SETD1B (SET domain containing 1b) has been linked to syndromic intellectual disability in human subjects, but its role in the mammalian postnatal brain has not been studied yet. Here, we employ mice deficient for Setd1b in excitatory neurons of the postnatal forebrain, and combine neuron-specific ChIP-seq and RNA-seq approaches to elucidate its role in neuronal gene expression. We observe that Setd1b controls the expression of a set of genes with a broad H3K4me3 peak at their promoters, enriched for neuron-specific genes linked to learning and memory function. Comparative analyses in mice with conditional deletion of Kmt2a and Kmt2b histone methyltransferases show that SETD1B plays a more pronounced and potent role in regulating such genes. Moreover, postnatal loss of Setd1b leads to severe learning impairment, suggesting that SETD1B-dependent regulation of H3K4me levels in postnatal neurons is critical for cognitive function.

Kidney Autotransplantation for Treatment of Ureteric Obstruction: A Case Report and Brief Review of the Literature.

Autologous kidney transplantation is a relatively rare procedure that has been used as an alternative treatment for a variety of complex genitourinary problems, in particular for the treatment of complex proximal ureteral strictures. In this case report, a 47-year-old male, who had undergone a living donor nephrectomy 14 years earlier, presented with episodes of acute kidney injury on chronic kidney disease. He was found to have a complex proximal ureter stricture of his solitary right kidney. He underwent nephrectomy with subsequent autotransplantation of the kidney into the right iliac fossa. His renal function improved significantly after surgery. Renal autotransplantation may be considered for the management of proximal ureteral obstruction when alternative options are contraindicated.

Real-world migraine-related healthcare resource utilization and costs associated with improved vs. worsened/stable migraine: a panel-based chart review in France, Germany, Italy, and Spain.

OBJECTIVE: To estimate the migraine-related healthcare resource utilization (HRU) and costs among patients with improved vs. worsened/stable migraine. METHODS: This was a follow-up to a retrospective, panel-based chart review conducted in France, Germany, Italy, and Spain among a panel of physicians (neurologists, headache specialists, and pain specialists) who agreed to participate in patient studies and had treated ≥10 migraine patients in 2017. Eligible physicians extracted data for up to five adults with ≥4 monthly migraine days (MMDs) who initiated a preventive treatment on or after 1 January 2013 and received physician care for ≥6 months after the date of the most recent preventive treatment initiation (index date). Based on the trajectory of migraine severity from the 1-month pre-index period to the 6-month post-index period, cohorts were classified as improved (converting from chronic to episodic or from chronic/episodic to <4 MMDs) or stable/worsened (remaining chronic/episodic or transforming from episodic to chronic) migraine. Migraine-related HRU and costs (2017 €) during the 6-month post-index period were compared between patients with improved vs. stable/worsened migraine. RESULTS: Overall, 470 patient charts were analyzed, with 339 classified as improved migraine and 131 classified as stable/worsened migraine. After adjusting for within-physician correlation, country, sex, and presence of comorbidities before the index date, the improved migraine cohort had significantly fewer migraine-related physician office visits (-0.81; p < .001), emergency room/accident & emergency (ER/A&E) visits (-0.67; p < .001), and hospitalizations (-0.12; p < .001) in the 6-month post-index period vs. the stable/worsened migraine cohort. Consistent with HRU patterns, the adjusted migraine-related costs for physician office visits (-€42.23; p < .05), hospitalizations (-€215.56; p < .05), and total costs (-€396.81; p < .01) in the 6-month post-index period were significantly reduced for the improved migraine cohort vs. the stable/worsened migraine cohort. CONCLUSIONS: Over a 6-month period following initiation of preventive migraine treatment, patients with improved migraine had significantly lower migraine-related HRU and costs than those with stable/worsened migraine.

Follow the Shoestring: A Unique Case of Bullet Extraction.

Firearm-related injuries and deaths remain a major issue in the United States. Gunshot injuries to the foot can be particularly difficult to manage when they occur as they can cause fractures or devastating neurovascular damage. There are limited reasons for routine bullet removal in most cases. Acute indications include wounds involving joints, palms, and soles as well as increased risk of infection, persistent pain, and lead intoxication. Here, we bring attention to a case of a gunshot wound to the left foot of a 53-year-old male, in which the bullet was able to be extracted using a shoe fiber that had become wrapped around the bullet.

Healthcare resource use and indirect costs associated with migraine in Italy: results from the My Migraine Voice survey.

AIMS: To evaluate the healthcare resource use (HRU) and cost of lost productivity due to migraine among Italians with ≥4 monthly migraine days (MMDs), with a focus on those with ≥2 prior preventive treatment failures (TFs). MATERIALS AND METHODS: Data from Italian participants from the My Migraine Voice survey were used to assess migraine-related HRU and migraine's impact on work productivity and daily activities using the Work Productivity and Activity Impairment questionnaire. The mean, annualized cost of lost productivity was estimated using the Human Capital Approach and extrapolated to employed Italian population with ≥4 MMDs to calculate the overall migraine-related indirect cost burden in Italy. RESULTS: Data of 420 participants, enrolled between September 2017 and February 2018, were analyzed (mean age: 38.5 years, 81.2% women, 37.8% with ≥2 TF). During a 6-month period, 57.6% of participants visited general practitioners (mean visits: 4.5), 31.9% neurologists (mean visits: 2.6), and 26.4% headache specialists (mean visits: 2.8). Overall, 32.0% of participants had ≥1 emergency room visit (mean visits: 2.8) and 15.0% had ≥1 hospitalization (mean visits: 2.9) because of migraine in the past 12 months. Participants who were employed (N = 215) reported 15.5% absenteeism, 45.3% presenteeism, 53.8% overall work impairment, and 52.6% activity impairment. The mean annualized indirect cost was estimated to be €14,368. The annual indirect cost burden was estimated to be €7.6 billion for the employed Italian population with ≥4 MMDs. The impact of migraine was particularly high among the ≥2 TF subgroups on all parameters. The indirect cost was estimated to be €15,881 (€5,007 attributed to absenteeism). CONCLUSION: Migraine-related HRU and indirect costs are high among individuals with ≥4 MMDs (particularly those with ≥2 TF). There is a need for more effective treatments and better management of migraines to reduce the functional and economic burden among this difficult-to-treat population.

Treatment of obstructive sleep apnea does not treat primary nocturnal enuresis.

INTRODUCTION: Primary Nocturnal Enuresis (PNE), obesity, and obstructive sleep apnea (OSA) are suggested to share a complex interaction whereby risk for PNE is increased when obesity and airway obstruction are present. We aimed to evaluate whether surgical or medical management of OSA in the treatment of patients with PNE and improves PNE outcomes. STUDY DESIGN: Our institutions electronic medical record was queried for patients who underwent a pediatric diagnostic polysomnogram (PDPSG) for the complaint of PNE between October 2010 and September 2020 and were diagnosed with OSA. Retrospective chart review was performed of the 59 patients identified. Patients were divided based on therapy type for their OSA. Groups included those no therapy, any therapy which includes patients undergoing tonsillectomy and adenoidectomy (T&A) and/or continuous positive airway pressure (CPAP) and those who chose T&A. Primary outcome was to evaluate effects of treating OSA with T&A and effects on PNE outcome based on International Children's Continence Society (ICCS) definitions of complete, partial or no improvement. Separate grouping based on ICCS PNE outcome were also made for evaluation of variables associated with each group. Secondary outcome evaluated role of BMI in success of treatments of PNE. Chi-squared and one-way ANOVA tests were performed. RESULTS: 59 patients (64.4% male, mean age at diagnosis 8.8 years old) underwent a PDPSG for PNE. Monosymptomatic PNE was diagnosed in 40.7% while 32.2% had non-monosymptomatic PNE and the remainder were unknown. Patients were predominantly Caucasian (47.5%), with an average BMI of 20.6 kg/m2 25 patients underwent no therapy for their OSA while the remaining 34 received treatment. No statistically significant difference between those receiving and those forgoing therapy were noted in age, race, gender, BMI, type of PNE or Apnea-Hypopnea Index. There was also so significant difference in ICCS defined enuresis outcomes (p = 0.871) with over 60% in both groups experiencing resolution or improvement. Follow up was significantly different between cohorts, measured at 43 months for those receiving therapy for OSA and 29.1 months for those forgoing therapy. When considering only those who chose T&A as their therapy for PNE, there were once again, no significant differences between groups including ICCS enuresis outcome. Sub-grouping based on ICCS enuresis outcome revealed no associations between variables measured and improvement of PNE (p > 0.05), other than defining type of PNE (p = 0.012). CONCLUSION: In patients with OSA and PNE, surgical treatment of airway obstruction had no effect on resolution of PNE.

Management of Testicular Torsion and a Contralateral Testicular Mass Presenting Synchronously.

Testicular masses found in prepubertal males are often benign in nature. This has led to an increase in the use of testis-sparing surgery. Testicular torsion is considered a urologic emergency that requires immediate surgical intervention. Based off literature review, it is rare for these unique entities to present synchronously in a single patient. This report demonstrates that in the pediatric population it is possible to safely treat a suspected benign testicular mass with testis sparing mass enucleation if it presents synchronously with testicular torsion in the contralateral testis.