bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blockade of endogenous insulin receptor signaling in the nucleus tractus solitarius potentiates exercise pressor reflex function in healthy male rats
Authors: Estrada Juan A. , Hotta Norio , Kim Han‐Kyul , Ishizawa Rie , Fukazawa Ayumi , Iwamoto Gary A. , Smith Scott A. , Vongpatanasin Wanpen , Mizuno Masaki 
Published: August 2023

AbstractInsulin not only regulates glucose and/or lipid metabolism but also modulates brain neural activity. The nucleus tractus solitarius (NTS) is a key central integration site for sensory input from working skeletal muscle and arterial baroreceptors during exercise. Stimulation of the skeletal muscle exercise pressor reflex (EPR), the responses of which are buffered by the arterial baroreflex, leads to compensatory increases in arterial pressure to supply blood to working muscle. Evidence suggests that insulin signaling decreases neuronal excitability in the brain, thus antagonizing insulin receptors (IRs) may increase neuronal excitability. However, the impact of brain insulin signaling on the EPR remains fully undetermined. We hypothesized that antagonism of NTS IRs increases EPR function in normal healthy rodents. In decerebrate rats, stimulation of the EPR via electrically induced muscle contractions increased peak mean arterial pressure (MAP) responses 30 min following NTS microinjections of an IR antagonist (GSK1838705, 100 μM; Pre: Δ16 ± 10 mmHg vs. 30 min: Δ23 ± 13 mmHg, n = 11, p = .004), a finding absent in sino‐aortic baroreceptor denervated rats. Intrathecal injections of GSK1838705 did not influence peak MAP responses to mechano‐ or chemoreflex stimulation of the hindlimb muscle. Immunofluorescence triple overlap analysis following repetitive EPR stimulation increased c‐Fos overlap with EPR‐sensitive nuclei and IR‐positive cells relative to sham operation (p < .001). The results suggest that IR blockade in the NTS potentiates the MAP response to EPR stimulation. In addition, insulin signaling in the NTS may buffer EPR stimulated increases in blood pressure via baroreflex‐mediated mechanisms during exercise.
Contribution of µ Opioid Receptor–expressing Dorsal Horn Interneurons to Neuropathic Pain–like Behavior in Mice
Authors: Qi Yanmei , Nelson Tyler S. , Prasoon Pranav , Norris Christopher , Taylor Bradley K. 
Published: August 2023

Background
Intersectional genetics have yielded tremendous advances in our understanding of molecularly identified subpopulations and circuits within the dorsal horn in neuropathic pain. The authors tested the hypothesis that spinal µ opioid receptor–expressing neurons (Oprm1-expressing neurons) contribute to behavioral hypersensitivity and neuronal sensitization in the spared nerve injury model in mice.

Methods
The authors coupled the use of Oprm1
Cre transgenic reporter mice with whole cell patch clamp electrophysiology in lumbar spinal cord slices to evaluate the neuronal activity of Oprm1-expressing neurons in the spared nerve injury model of neuropathic pain. The authors used a chemogenetic approach to activate or inhibit Oprm1-expressing neurons, followed by the assessment of behavioral signs of neuropathic pain.

Results
The authors reveal that spared nerve injury yielded a robust neuroplasticity of Oprm1-expressing neurons. Spared nerve injury reduced Oprm1 gene expression in the dorsal horn as well as the responsiveness of Oprm1-expressing neurons to the selective µ agonist (D-Ala2, N-MePhe4, Gly-ol)-enkephalin (DAMGO). Spared nerve injury sensitized Oprm1-expressing neurons, as reflected by an increase in their intrinsic excitability (rheobase, sham 38.62 ± 25.87 pA [n = 29]; spared nerve injury, 18.33 ± 10.29 pA [n = 29], P = 0.0026) and spontaneous synaptic activity (spontaneous excitatory postsynaptic current frequency in delayed firing neurons: sham, 0.81 ± 0.67 Hz [n = 14]; spared nerve injury, 1.74 ± 1.68 Hz [n = 10], P = 0.0466), and light brush-induced coexpression of the immediate early gene product, Fos in laminae I to II (%Fos/tdTomato+: sham, 0.42 ± 0.57% [n = 3]; spared nerve injury, 28.26 ± 1.92% [n = 3], P = 0.0001). Chemogenetic activation of Oprm1-expressing neurons produced mechanical hypersensitivity in uninjured mice (saline, 2.91 ± 1.08 g [n = 6]; clozapine N-oxide, 0.65 ± 0.34 g [n = 6], P = 0.0006), while chemogenetic inhibition reduced behavioral signs of mechanical hypersensitivity (saline, 0.38 ± 0.37 g [n = 6]; clozapine N-oxide, 1.05 ± 0.42 g [n = 6], P = 0.0052) and cold hypersensitivity (saline, 6.89 ± 0.88 s [n = 5] vs. clozapine N-oxide, 2.31 ± 0.52 s [n = 5], P = 0.0017).

Conclusions
The authors conclude that nerve injury sensitizes pronociceptive µ opioid receptor–expressing neurons in mouse dorsal horn. Nonopioid strategies to inhibit these interneurons might yield new treatments for neuropathic pain.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New
Multi-omics analysis of adamantinomatous craniopharyngiomas reveals distinct molecular subgroups with prognostic and treatment response significance
Authors: Wang Xianlong , Zhao Chuan , Lin Jincheng , Liu Hongxing , Zeng Qiuhong , Chen Huadong , Wang Ye , Xu Dapeng , Chen Wen , Xu Moping , Zhang En , Lin Da , Lin Zhixiong 
Published: August 2023

Abstract

Background:
Adamantinomatous craniopharyngioma (ACP) is the commonest pediatric sellar tumor. No effective drug is available and interpatient heterogeneity is prominent. This study aimed to identify distinct molecular subgroups of ACP based on the multi-omics profiles, imaging findings, and histological features, in order to predict the response to anti-inflammatory treatment and immunotherapies.

Methods:
Totally 142 Chinese cases diagnosed with craniopharyngiomas were profiled, including 119 ACPs and 23 papillary craniopharyngiomas. Whole-exome sequencing (151 tumors, including recurrent ones), RNA sequencing (84 tumors), and DNA methylome profiling (95 tumors) were performed. Consensus clustering and non-negative matrix factorization were used for subgrouping, and Cox regression were utilized for prognostic evaluation, respectively.

Results:
Three distinct molecular subgroups were identified: WNT, ImA, and ImB. The WNT subgroup showed higher Wnt/β-catenin pathway activity, with a greater number of epithelial cells and more predominantly solid tumors. The ImA and ImB subgroups had activated inflammatory and interferon response pathways, with enhanced immune cell infiltration and more predominantly cystic tumors. Mitogen-activated protein kinases (MEK/MAPK) signaling was activated only in ImA samples, while IL-6 and epithelial–mesenchymal transition biomarkers were highly expressed in the ImB group, mostly consisting of children. The degree of astrogliosis was significantly elevated in the ImA group, with severe finger-like protrusions at the invasive front of the tumor. The molecular subgrouping was an independent prognostic factor, with the WNT group having longer event-free survival than ImB (Cox, P = 0.04). ImA/ImB cases were more likely to respond to immune checkpoint blockade (ICB) therapy than the WNT group (P <0.01). In the preliminary screening of subtyping markers, CD38 was significantly downregulated in WNT compared with ImA and ImB (P = 0.01).

Conclusions:
ACP comprises three molecular subtypes with distinct imaging and histological features. The prognosis of the WNT type is better than that of the ImB group, which is more likely to benefit from the ICB treatment.
Changes Over Time in Outcomes of School-Age Children and Parents Receiving Integrated Mental Health Care in Federally Qualified Health Centers
Authors: Kim Jihye , Bair-Merritt Megan H. , Rosenberg Jessica , Feinberg Emily , Morris Anita , Durham Michelle P. , Estela Maria Guadalupe , Sheldrick R. Christopher 
Published: August 2023

ABSTRACT:

Objective:
The purpose of this study is to understand change in parent-reported outcomes of mental health symptoms, health-related quality of life (QoL), and school-related functioning among children receiving mental health care at 3 federally qualified health centers engaging in a comprehensive pediatric mental health integration model.

Methods:
Trained personnel enrolled English- or Spanish-speaking families of 6- to 12-year-old children who had recently started receiving integrated mental health care and surveyed their parent/caregiver at 3 time points: entry into the cohort, 6-month follow-up, and 12-month follow-up (unique N = 51). Primary outcomes included validated measures of child symptoms, child health-related QoL, and child school-related functioning. Secondary outcomes focused on parental functioning and included validated measures of parental stress and depressive and internalizing symptoms. A multilevel mixed-effects generalized linear model was used to estimate the change in parent-reported outcomes over time, with inverse probability weights used to address attrition. Additional analyses were conducted to determine the degree to which changes in symptoms over time were associated with improvements in school-related functioning.

Results:
Over 12 months, children's mental health symptoms, health-related QoL, and school-related functional outcomes significantly improved. No changes in parental functioning were observed. In addition, improvements in mental health symptoms and health-related QoL were associated with improvements in school-related functional outcomes over time.

Conclusion:
Findings demonstrate that outcomes of children who received integrated mental health care improved over time, both in regard to mental health and school functioning.
Cardiovascular Risk Management in Patients Treated With Janus Kinase Inhibitors
Authors: Shah Jill T. , Shah Keya T. , Femia Alisa N. , Lo Sicco Kristen I. , Merola Joseph F. , Weber Brittany , Garshick Michael S. 
Published: August 2023

Abstract:
The Janus kinase-signal transducer and activator of transcription pathway plays a critical role in the pathogenesis of many immune-mediated inflammatory diseases (IMIDs). Although Janus kinase inhibitors (JAKi) are an effective treatment for several IMIDs, they have come under scrutiny as a class because of a potential risk of venous thromboembolism and cardiovascular (CV) events, specifically noted with the oral JAKi, tofacitinib, as reported in the ORAL Surveillance Trial of a high CV risk rheumatoid arthritis population. This trial resulted in a black box warning from the Food and Drug Administration and European Medicines Agency regarding risk of venous thromboembolism and CV events that was extended across several types of JAKi (including topical ruxolitinib) when treating IMIDs, leading to considerable controversy. Included is an up-to-date review of the current and rapidly evolving literature on CV risk in patients with IMIDs on JAKi therapy, including identification of potential risk factors for future venous thromboembolism and CV events on JAKi therapy. We suggest a comprehensive, multimodal, and systematic approach for evaluation of CV risk in patients considering taking JAKi and emphasize that cardiologists play an important role in risk stratification and mitigation for patients with high CV risk factors or on long-term JAKi therapies.
Changing Faces: Factors Associated with the Intention to Pursue Plastic Surgery and Practice in Underserved Areas
Authors: Nguyen Mytien , Kaminaka Annette , Brutus Nicholas N. , Gonzalez Luis A. , Ratanpal Amit , Alperovich Michael , Jeffe Donna B. , Ata Ashar , Mason Hyacinth R. C. , Butler Paris D. 
Published: August 2023

Background:
Improving the number of plastic and reconstructive surgeons who provide care to patients in underserved communities is critical to achieving health equity. We aimed to identify factors associated with graduating medical students’ intentions to pursue plastic surgery and practice in underserved areas.

Methods:
De-identified data for US medical school graduates were obtained from the Association of American Medical Colleges for students who matriculated in academic years 2007–2008 and 2011–2012. Data collected included self-reported demographic and future practice intentions. Multivariate analysis was conducted to determine indicators of students’ interest in plastic surgery, and their intention to practice in underserved areas.

Results:
Of the 57,307 graduating US medical students in our cohort who completed the Graduation Questionnaire, 532 (0.9%) reported an intention to pursue plastic surgery. Hispanic [adjusted odds ratio (aOR): 1.45; 95% confidence interval (95% CI), 1.07–1.98] and multiracial (aOR: 1.59; 95% CI, 1.03–2.45) students were more likely to pursue plastic surgery compared with other surgical specialties. Among students interested in plastic surgery, compared with non-Hispanic White students, Black (aOR: 6.15; 95% CI, 1.96–19.26) students were more likely to report intention to practice in underserved areas. Students with community-engagement experiences were more likely to report intention to practice in underserved areas.

Conclusions:
Diversity among medical trainees pursuing plastic and reconstructive surgery is critical for maintaining and expanding plastic surgery services rendered in underserved areas. These findings suggest that student demographics and experiences with community-engagement experiences are positive indicators of practicing in underserved communities.
Effects of Tongmai Yangxin pills on ventricular remodeling in myocardial ischemia-reperfusion rats
Authors: Chen Rui , Meng Ke , Wang Caijun , Lyu Qingbo , Jiang Di , Ding Xinya , Xu Jinpeng , Wang Lin , Wang Yujing , Zhou Kun , Wang Yi 
Published: August 2023

Objective:
This study aimed to determine whether Tongmai Yangxin pills (TM) can attenuate ventricular remodeling (VR) and to explore the underlying mechanisms.

Methods:
After the myocardial ischemia-reperfusion (I/R) injury model has been established, the rats were divided into seven groups: control, Sham, I/R, TM (1.0 g/kg), TM (2.0 g/kg), TM (4.0 g/kg), and Tongxinluo capsules, respectively. Experimental parameters were assessed on days 3 and 28 after drug administration. Cardiac structure and function were assessed by echocardiography. Myocardial ischemia was quantified using triphenyl tetrazolium chloride staining, and the cardiac pathology was evaluated using hematoxylin-eosin staining. Myocardial enzyme and oxidant activities were detected using an automatic biochemical analyzer and kit, respectively. Masson’s trichrome staining was used to analyze the degree of collagen deposition. The expression levels of inflammation and fibrosis-related proteins were detected using enzyme-linked immunosorbent assays.

Results:
After 3 days of administration, TM improved cardiac function and morphology. It effectively reduced the area of myocardial infarction in I/R rats, inhibited the abnormal activity of myocardial enzymes, and significantly reduced superoxide dismutase activity, as well as C-reactive protein, tumor necrosis factor-α, and interleukin-1β expression at the protein level. TM administration inhibited oxidative stress, inflammation, and myocardial pathological damage. After 28 d of administration, TM improved heart function; inhibited ventricular dilation and the thinning of the ventricular wall; significantly reduced the protein expression of connective tissue growth factor, matrix metalloproteinase 2, and matrix metalloproteinase 9; and decreased the degree of myocardial fibrosis.

Conclusions:
TM can effectively reduce the infarct size, improve the cardiac structure and function, reduce myocardial collagen deposition, and attenuate VR. The underlying mechanisms involve the inhibition of inflammatory responses in the early stages and a reduction of myocardial fibrosis in the late stages.

Graphical abstract:

http://links.lww.com/AHM/A60
Association Between Benefit Finding and Self-care Management in Heart Failure Patient-Caregiver Dyads
Authors: Fang Wenjie , Chen Cancan , Zhang Xiuting , Li Jinliang , Li Ximiao , Fan Xiuzhen 
Published: August 2023

Background
Inadequate self-care management has been reported in patients with heart failure (HF) and their family caregivers. However, evidence on the influencing factors and corresponding action paths for self-care management within a dyadic context is limited.

Objective
The aim of this study was to examine dyadic associations between benefit finding and self-care management in HF patient-caregiver dyads and the mediating role of mutuality in these associations.

Methods
This cross-sectional study was conducted in China, and a convenience sample of 253 HF patient-caregiver dyads was included in the analysis. Dyadic benefit finding and mutuality, patients' self-care management, and caregivers' contributions to self-care management were measured using self-reported questionnaires. The actor-partner interdependence model and actor-partner interdependence mediation model were adopted to analyze the data.

Results
Patients' benefit finding had an actor effect on their own self-care management (β = 0.134, P < .05) and a partner effect on caregivers' contributions to self-care management (β = 0.130, P < .05). Similarly, caregivers' benefit finding had an actor effect on their contributions to self-care management (β = 0.316, P < .01) and a partner effect on patients' self-care management (β = 0.187, P < .01). Moreover, patients' mutuality completely mediated the actor effect of their benefit finding on self-care management (β = 0.127; 95% confidence interval, 0.032–0.233), and caregivers' mutuality partially mediated the actor effect of their benefit finding on contributions to self-care management (β = 0.060; 95% confidence interval, 0.012–0.124). In addition, caregivers' mutuality completely mediated the partner effect of patients' benefit finding on caregivers' contributions to self-care management (β = 0.036; 95% confidence interval, 0.009–0.081).

Conclusions
The findings revealed the importance of benefit finding and mutuality, 2 modifiable factors positively associated with dyadic HF self-care management. Dyadic interventions targeting on enhancing benefit finding and mutuality should be designed and implemented to improve HF self-care management.
Planning and effectiveness of intensive rehabilitation as a treatment for a patient with neurosarcoidosis: A case report
Authors: Takeshima Shinichi , Furuya Toshiki , Yamamoto Mariko , Noma Marie , Kawate Nobuyuki 
Published: August 2023

Introduction:
Neurosarcoidosis tends to prolong the duration of treatment and may result in a decline in physical function requiring rehabilitation. Because of a rare disease, the adjustment of oral steroid dosage, which is the cornerstone of treatment, is highly dependent on professional experience in general. Therefore, the number of hospitals that can perform dosage adjustment is very limited, and it is difficult to provide concurrent intense rehabilitation at the same hospital over a long period of time, and there are no reports that mention this.

Patient concerns:
A 49-year-old man, who presented with impaired consciousness, dysphagia and right hemiplegia, was diagnosed with neurosarcoidosis based on a previous diagnosis of sarcoidosis, laboratory test results, and clinical symptoms. High-dose oral steroid therapy was initiated and he was transferred to our rehabilitation hospital for progressive disuse approximately 2 months after the disease onset.

Diagnoses:
This case was diagnosed as “probable” neurosarcoidosis.

Interventions:
The steroid dose was not reduced during rehabilitation treatment in our hospital considering the risk of relapse of the primary disease due to steroid reduction. His training regimen focused on minimum activities of daily living was performed, and its effectiveness was determined during approximately 60 days after the initiation of rehabilitation.

Outcomes:
Two months after admission, he was independently eating, transferring, and toileting under supervision. He was discharged home 3 months after admission.

Lessons:
Intensive rehabilitation can be one of the effective comprehensive treatment strategy for patients with neurosarcoidosis. On the other hand, since there is no consensus treatment method, the duration of rehabilitation and goal setting should be adjusted based on an understanding of the characteristics of the disease and the overall treatment plan.
Adult granulosa cell tumor of the testis with malignant tendency: A case report with genetic analysis using high-throughput sequencing
Authors: Deng Lili , Zeng Jingjing , Qiu Jin Feng , Yang Li Hua , Ma Jie 
Published: August 2023

Background:
The adult granulosa cell tumor of the testis is a rare sex-cord/stromal tumor, with a potentiality for late recurrence and metastasis. Because of its rarity, this tumor is poorly understood, particularly in terms of its molecular features. As a result, it is necessary to register each occurrence in order to study the evolution of this rare malignancy and develop therapeutic strategies.

Methods:
A 50-year-old man discovered a painless right testicular mass unexpectedly, and the mass steadily expanded for 2 months. Ultrasonography showed a 5.2 cm × 4.0 cm × 3.6 cm mass in the right testicle. A right radical orchiectomy was performed on September 7, 2016. The pathologic diagnosis was a testicular adult granulosa cell tumor. The post-computed tomography scans and bone scintigraphy ruled out distant metastases. A high-throughput sequencing of 520 cancer-related genes revealed FOXL2 C134W, CDKN2A E87Gfs*24, TP53 S183*, TERT c.-124C > T, and H3F3A K28R mutations in this case. Because the patient stated he would be unable to return to the hospital for a follow-up appointment on time, he elected to have 4 cycles of adjuvant chemotherapy BEP (bleomycin, etoposide, and cisplatin) after the right radical orchiectomy.

Results:
The patient has not had a clinical recurrence or metastasis in 6 years.

Conclusion:
Surgery together with adjuvant chemotherapy may be useful treatment options for these individuals with malignant tendencies who are unable to visit the hospital for a follow-up appointment on time. Adult testicular granulosa cell tumors have a relatively complex genetic profile; their etiology is linked to a number of common driver genes, including TERT, CDKN2A, TP53, and H3F3A.
Genetic analysis and management of a familial hypercholesterolemia pedigree with polygenic variants: Case report
Authors: Han Yu , Zhang Lin , Tao Huimin , Wu Jiebin , Zhai Jingfang 
Published: August 2023

Rationale:
Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder typically caused by low density lipoprotein receptor (LDLR) gene mutation. Herein, we reported a FH pedigree with polygenic variants: LDLR, apolipoprotein B (APOB), and epoxide hydrolase 2 (EPHX2).

Patient concerns:
A 10-year-old boy mainly presented multiple skin xanthomas and hypercholesterolemia. His family visited our hospital and was performed with pedigree whole exome sequencing (WES) at 20 + 3 weeks gestation of the mother’s second pregnancy.

Diagnoses:
Based on the clinical features and genetic analysis, the pedigree was diagnosed with familial hypercholesterolemia.

Interventions:
After genetic counseling, the couple opted to continue the pregnancy. Treatment advice and follow-up were offered to them.

Outcomes:
A novel compound heterozygous LDLR mutation: c.1009G>T and c.68-2A>G, derived from his parents respectively was revealed through pedigree WES, meanwhile, a maternal APOB gene variant: c.1670A>G and a paternal EPHX2 gene variant: c.548 dup of the proband were found together. Furthermore, the same compound heterozygous LDLR mutation as his was confirmed in his sister without APOB and EPHX2 variants in her fetal stage.

Lessons:
WES combined with clinical features is essential for the diagnosis of FH, however, prenatal genetic testing results might bring more challenges to prenatal genetic counseling. Furthermore, it is more important to provide the guidance and early intervention for such families in the long run.