Associations Between Prematurity, Birthweight, and Adolescence Blood Pressure in a Nationwide Cohort.

Introduction: Prematurity is associated with incomplete nephrogenesis and an increased incidence of acute kidney injury, that may increase the risk of future kidney disease, including hypertension, proteinuria and reduced glomerular filtration rate. The aim of this study was to evaluate the risk of hypertension or proteinuria in adolescents born prematurely or small for gestational age, in a nationwide cohort. Methods: The study cohort included potential recruits examined in the Israel Defense Forces (IDF) medical facilities, between November 2005 and October 2018. Clinical and anthropometric data, including blood pressure (BP) measurement, were retrieved from the IDF medical files. Adolescents born between January 1993 and December 2000 had additional data on gestational age at birth, retrieved from the Israeli Ministry of Health database. Results: The study cohort included 513,802 participants, aged 17.3 ± 0.9 years, of whom 48,994 had gestational age data. Adolescents born as very preterm, as extremely preterm infants, those born with very low birthweight (VLBW), or with extremely low birthweight (ELBW) had higher incidence of hypertensive-range BP (55%, 47%, 19% and 12%, respectively). No significant association between birthweight (BW) adjusted to gestational age and hypertension was observed. Within the overweight and obese adolescents, those born with VLBW and ELBW, had further increased hypertensive-range BP rate. Proteinuria was diagnosed in 0.33% of the study cohort, with no significant difference between BW or gestational age categories. Conclusion: Adolescents born with VLBW or as significant preterm were associated with high BP and should be monitored for hypertension development and its potential complications.

Treatment with Cobra Venom Factor Decreases Ischemic Tissue Damage in Mice.

Tissue ischemia, caused by the blockage of blood vessels, can result in substantial damage and impaired tissue performance. Information regarding the functional contribution of the complement system in the context of ischemia and angiogenesis is lacking. To investigate the influence of complement activation and depletion upon femoral artery ligation (FAL), Cobra venom factor (CVF) (that functionally resembles C3b, the activated form of complement component C3) was applied in mice in comparison to control mice. Seven days after induction of muscle ischemia through FAL, gastrocnemius muscles of mice were excised and subjected to (immuno-)histological analyses. H&E and apoptotic cell staining (TUNEL) staining revealed a significant reduction in ischemic tissue damage in CVF-treated mice compared to controls. The control mice, however, exhibited a significantly higher capillary-to-muscle fiber ratio and a higher number of proliferating endothelial cells (CD31+/CD45-/BrdU+). The total number of leukocytes (CD45+) substantially decreased in CVF-treated mice versus control mice. Moreover, the CVF-treated group displayed a shift towards the M2-like anti-inflammatory and regenerative macrophage phenotype (CD68+/MRC1+). In conclusion, our findings suggest that treatment with CVF leads to reduced ischemic tissue damage along with decreased leukocyte recruitment but increased numbers of M2-like polarized macrophages, thereby enhancing tissue regeneration, repair, and healing.

Exploring complications following cranioplasty after decompressive hemicraniectomy: A retrospective bicenter assessment of autologous, PMMA and CAD implants.

Cranioplasty (CP) after decompressive hemicraniectomy (DHC) is a common neurosurgical procedure with a high complication rate. The best material for the repair of large cranial defects is unclear. The aim of this study was to evaluate different implant materials regarding surgery related complications after CP. Type of materials include the autologous bone flap (ABF), polymethylmethacrylate (PMMA), calcium phosphate reinforced with titanium mesh (CaP-Ti), polyetheretherketone (PEEK) and hydroxyapatite (HA). A retrospective, descriptive, observational bicenter study was performed, medical data of all patients who underwent CP after DHC between January 1st, 2016 and December 31st, 2022 were analyzed. Follow-up was until December 31st, 2023. 139 consecutive patients with a median age of 54 years who received either PMMA (56/139; 40.3%), PEEK (35/139; 25.2%), CaP-Ti (21/139; 15.1%), ABF (25/139; 18.0%) or HA (2/139; 1.4%) cranial implant after DHC were included in the study. Median time from DHC to CP was 117 days and median follow-up period was 43 months. Surgical site infection was the most frequent surgery-related complication (13.7%; 19/139). PEEK implants were mostly affected (28.6%; 10/35), followed by ABF (20%; 5/25), CaP-Ti implants (9.5%; 2/21) and PMMA implants (1.7%, 1/56). Explantation was necessary for 9 PEEK implants (25.7%; 9/35), 6 ABFs (24.0%; 6/25), 3 CaP-Ti implants (14.3%; 3/21) and 4 PMMA implants (7.1%; 4/56). Besides infection, a postoperative hematoma was the most common cause. Median surgical time was 106 min, neither longer surgical time nor use of anticoagulation were significantly related to higher infection rates (p = 0.547; p = 0.152 respectively). Ventriculoperitoneal shunt implantation prior to CP was noted in 33.8% (47/139) and not significantly associated with surgical related complications. Perioperative lumbar drainage, due to bulging brain, inserted in 38 patients (27.3%; 38/139) before surgery was protective when it comes to explantation of the implant (p = 0.035). Based on our results, CP is still related to a relatively high number of infections and further complications. Implant material seems to have a high effect on postoperative infections, since surgical time, anticoagulation therapy and hydrocephalus did not show a statistically significant effect on postoperative complications in this study. PEEK implants and ABFs seem to possess higher risk of postoperative infection. More biocompatible implants such as CaP-Ti might be beneficial. Further, prospective studies are necessary to answer this question.

Oxytocin attenuates racial categorization in 14-month-old infants.

Intergroup bias - the preferential attitudes one holds towards one's social group - is a ubiquitous socio-cognitive phenomenon. In fact, studies show that already in the first months of life, infants manifest a preference for members of their own social group. This points to the possibility of inborn mechanisms involved in social group cognition. Here we assess the effect of a biological activation of infants' affiliative motivation on their social categorization capacity. In a first visit to the lab, mothers self-administered either Oxytocin (OT) or placebo (PL) via a nasal spray and then engaged in a face-to-face interaction with their 14-month-old infants, a procedure previously shown to increase OT levels in infants. Infants then performed a racial categorization task presented on an eye-tracker. Mothers and infants returned a week later and repeated the procedure while self-administering the complementary substance (i.e., PL or OT, respectively). In total, 24 infants completed the two visits. We found that whereas infants in the PL condition on the first visit exhibited racial categorization, infants in the OT condition in their first visit did not. Moreover, these patterns remained a week later despite the change in substance. Thus, OT inhibited racial categorization when infants first encountered the to-be-categorized faces. These findings highlight the role of affiliative motivation in social categorization, and suggest that the neurobiology of affiliation may provide insights on mechanisms that may be involved in the downstream prejudicial consequences of intergroup bias.

Central FGF21 production regulates memory but not peripheral metabolism.

Fibroblast growth factor 21 (FGF21) is a liver-derived endocrine hormone that functions to regulate energy homeostasis and macronutrient intake. Recently, FGF21 was reported to be produced and secreted from hypothalamic tanycytes, to regulate peripheral lipid metabolism; however, rigorous investigation of FGF21 expression in the brain has yet to be accomplished. Using a mouse model that drives CRE recombinase in FGF21-expressing cells, we demonstrate that FGF21 is not expressed in the hypothalamus, but instead is produced from the retrosplenial cortex (RSC), an essential brain region for spatial learning and memory. Furthermore, we find that central FGF21 produced in the RSC enhances spatial memory but does not regulate energy homeostasis or sugar intake. Finally, our data demonstrate that administration of FGF21 prolongs the duration of long-term potentiation in the hippocampus and enhances activation of hippocampal neurons. Thus, endogenous and pharmacological FGF21 appear to function in the hippocampus to enhance spatial memory.

Pharmacological FGF21 signals to glutamatergic neurons to enhance leptin action and lower body weight during obesity.

OBJECTIVE: Fibroblast growth factor 21 (FGF21) is a peripherally-derived endocrine hormone that acts on the central nervous system (CNS) to regulate whole body energy homeostasis. Pharmacological administration of FGF21 promotes weight loss in obese animal models and human subjects with obesity. However, the central targets mediating these effects are incompletely defined. METHODS: To explore the mechanism for FGF21's effects to lower body weight, we pharmacologically administer FGF21 to genetic animal models lacking the obligate FGF21 co-receptor, ß-klotho (KLB), in either glutamatergic (Vglut2-Cre) or GABAergic (Vgat-Cre) neurons. In addition, we abolish FGF21 signaling to leptin receptor (LepR-Cre) positive cells. Finally, we examine the synergistic effects of FGF21 and leptin to lower body weight and explore the importance of physiological leptin levels in FGF21-mediated regulation of body weight. RESULTS: Here we show that FGF21 signaling to glutamatergic neurons is required for FGF21 to modulate energy expenditure and promote weight loss. In addition, we demonstrate that FGF21 signals to leptin receptor-expressing cells to regulate body weight, and that central leptin signaling is required for FGF21 to fully stimulate body weight loss during obesity. Interestingly, co-administration of FGF21 and leptin synergistically leads to robust weight loss. CONCLUSIONS: These data reveal an important endocrine crosstalk between liver- and adipose-derived signals which integrate in the CNS to modulate energy homeostasis and body weight regulation.

Cobra Venom Factor Boosts Arteriogenesis in Mice.

Arteriogenesis, the growth of natural bypass blood vessels, can compensate for the loss of arteries caused by vascular occlusive diseases. Accordingly, it is a major goal to identify the drugs promoting this innate immune system-driven process in patients aiming to save their tissues and life. Here, we studied the impact of the Cobra venom factor (CVF), which is a C3-like complement-activating protein that induces depletion of the complement in the circulation in a murine hind limb model of arteriogenesis. Arteriogenesis was induced in C57BL/6J mice by femoral artery ligation (FAL). The administration of a single dose of CVF (12.5 µg) 24 h prior to FAL significantly enhanced the perfusion recovery 7 days after FAL, as shown by Laser Doppler imaging. Immunofluorescence analyses demonstrated an elevated number of proliferating (BrdU+) vascular cells, along with an increased luminal diameter of the grown collateral vessels. Flow cytometric analyses of the blood samples isolated 3 h after FAL revealed an elevated number of neutrophils and platelet-neutrophil aggregates. Giemsa stains displayed augmented mast cell recruitment and activation in the perivascular space of the growing collaterals 8 h after FAL. Seven days after FAL, we found more CD68+/MRC-1+ M2-like polarized pro-arteriogenic macrophages around growing collaterals. These data indicate that a single dose of CVF boosts arteriogenesis by catalyzing the innate immune reactions, relevant for collateral vessel growth.

Multicenter Study of the Impact of COVID-19 Shelter-In-Place on Tertiary Hospital-based Care for Pediatric Neurologic Disease.

Objective: To describe changes in hospital-based care for children with neurologic diagnoses during the initial 6 weeks following regional Coronavirus 2019 Shelter-in-Place orders. Methods: This retrospective cross-sectional study of 7 US and Canadian pediatric tertiary care institutions included emergency and inpatient encounters with a neurologic primary discharge diagnosis code in the initial 6 weeks of Shelter-in-Place (COVID-SiP), compared to the same period during the prior 3 years (Pre-COVID). Patient demographics, encounter length, and neuroimaging and electroencephalography use were extracted from the medical record. Results: 27,900 encounters over 4 years were included. Compared to Pre-COVID, there was a 54% reduction in encounters during Shelter-in-Place. COVID-SiP patients were younger (median 5 years vs 7 years). The incidence of encounters for migraine fell by 72%, and encounters for acute diagnoses of status epilepticus, infantile spasms, and traumatic brain injury dropped by 53%, 55%, and 56%, respectively. There was an increase in hospital length of stay, relative utilization of intensive care, and diagnostic testing (long-term electroencephalography, brain MRI, and head CT (all P<.01)). Conclusion: During the initial 6 weeks of SiP, there was a significant decrease in neurologic hospital-based encounters. Those admitted required a high level of care. Hospital-based neurologic services are needed to care for acutely ill patients. Precise factors causing these shifts are unknown and raise concern for changes in care seeking of patients with serious neurologic conditions. Impacts of potentially delayed diagnosis or treatment require further investigation.

Synthesis of Poly(acrylic acid)-Cysteine-Based Hydrogels with Highly Customizable Mechanical Properties for Advanced Cell Culture Applications.

The fabrication of highly customizable scaffolds is a key enabling technology in the development of predictive in vitro cell models for applications in drug discovery, cancer research, and regenerative medicine. Naturally derived and synthetic hydrogels are good candidates for in vitro cell growth studies, owing to their soft and biocompatible nature; however, they are often hindered by limited ranges of stiffness and the requirement to modify the gel with additional extracellular matrix (ECM) proteins for cell adherence. Here, we report on the synthesis of a printable synthetic hydrogel based on cysteine-modified poly(acrylic acid) (PAA-Cys) with tuneable mechanical and swelling properties by incorporating acrylic acid into the PAA-Cys network and subsequent photoinitiated thiol-acrylate cross-linking. Control of the acrylic acid concentration and UV curing time produces a series of hydrogels with swelling ratios in excess of 100% and Young's modulus values ranging from ∼2 to ∼35 kPa, of which most soft tissues fall within. Biocompatibility studies with RPE1 cells showed excellent cell adhesion and cell viability without the need for further modification with ECM proteins, but still can be modified as needed. The versatility of the hydrogel tuneable properties is demonstrated by culturing with RPE1 cells, which in vivo perform an important function in the visual process and the dysfunction of which may lead to various retinal abnormalities, such as glaucoma.

FGF21 suppresses alcohol consumption through an amygdalo-striatal circuit.

Excessive alcohol consumption is a major health and social issue in our society. Pharmacologic administration of the endocrine hormone fibroblast growth factor 21 (FGF21) suppresses alcohol consumption through actions in the brain in rodents, and genome-wide association studies have identified single nucleotide polymorphisms in genes involved with FGF21 signaling as being associated with increased alcohol consumption in humans. However, the neural circuit(s) through which FGF21 signals to suppress alcohol consumption are unknown, as are its effects on alcohol consumption in higher organisms. Here, we demonstrate that administration of an FGF21 analog to alcohol-preferring non-human primates reduces alcohol intake by 50%. Further, we reveal that FGF21 suppresses alcohol consumption through a projection-specific subpopulation of KLB-expressing neurons in the basolateral amygdala. Our results illustrate how FGF21 suppresses alcohol consumption through a specific population of neurons in the brain and demonstrate its therapeutic potential in non-human primate models of excessive alcohol consumption.

Conditional gene targeting using UCP1-Cre mice directly targets the central nervous system beyond thermogenic adipose tissues.

OBJECTIVE: Uncoupling protein 1 (UCP1) is a mitochondrial protein critical for adaptive thermogenesis in adipose tissues, and it is typically believed to be restricted to thermogenic adipose tissues. UCP1-Cre transgenic mice are utilized in numerous studies to provide "brown adipose-specific" conditional gene targeting. Here, we examined the distribution of Cre and UCP1 throughout the body in UCP1-Cre reporter mice. METHODS: UCP1-Cre mice crossed to Ai14-tdTomato and Ai9-tdTomato reporter mice were used to explore the tissue distribution of Cre recombinase and Ucp1 mRNA in various tissues. UCP1-Cre mice were independently infected with either a Cre-dependent PHP.eB-tdTomato virus or a Cre-dependent AAV-tdTomato virus to determine whether and where UCP1 is actively expressed in the adult central nervous system. In situ analysis of the deposited single cell RNA sequencing data was used to evaluate Ucp1 expression in the hypothalamus. RESULTS: As expected, Ucp1 expression was detected in both brown and inguinal adipose tissues. Ucp1 expression was also detected in the kidney, adrenal glands, thymus, and hypothalamus. Consistent with detectable Ucp1 expression, tdTomato expression was also observed in brown adipose tissue, inguinal white adipose tissue, kidney, adrenal glands, and hypothalamus of both male and female UCP1-Cre; Ai14-tdTomato and UCP1-Cre; Ai9-tdTomato mice by fluorescent imaging and qPCR. Critically, expression of tdTomato, and thus UCP1, within the central nervous system was observed in regions of the brain critical for the regulation of energy homeostasis, including the ventromedial hypothalamus (VMH). CONCLUSIONS: TdTomato expression in UCP1-Cre; tdTomato mice is not restricted to thermogenic adipose tissues. TdTomato was also expressed in the kidneys, adrenal glands, and throughout the brain, including brain regions and cell types that are critical for multiple aspects of central regulation of energy homeostasis. Collectively, these data have important implications for the utility of UCP1-Cre mice as genetic tools to investigate gene function specifically in brown adipose tissue.

Anti-SARS-CoV-2 and Autoantibody Profiles in the Cerebrospinal Fluid of 3 Teenaged Patients With COVID-19 and Subacute Neuropsychiatric Symptoms.

Importance: Neuropsychiatric manifestations of COVID-19 have been reported in the pediatric population. Objective: To determine whether anti-SARS-CoV-2 and autoreactive antibodies are present in the cerebrospinal fluid (CSF) of pediatric patients with COVID-19 and subacute neuropsychiatric dysfunction. Design, Setting, and Participants: This case series includes 3 patients with recent SARS-CoV-2 infection as confirmed by reverse transcriptase-polymerase chain reaction or IgG serology with recent exposure history who were hospitalized at the University of California, San Francisco Benioff Children's Hospital and for whom a neurology consultation was requested over a 5-month period in 2020. During this period, 18 total children were hospitalized and tested positive for acute SARS-CoV-2 infection by reverse transcriptase-polymerase chain reaction or rapid antigen test. Main Outcomes and Measures: Detection and characterization of CSF anti-SARS-CoV-2 IgG and antineural antibodies. Results: Of 3 included teenaged patients, 2 patients had intrathecal anti-SARS-CoV-2 antibodies. CSF IgG from these 2 patients also indicated antineural autoantibodies on anatomic immunostaining. Autoantibodies targeting transcription factor 4 (TCF4) in 1 patient who appeared to have a robust response to immunotherapy were also validated. Conclusions and Relevance: Pediatric patients with COVID-19 and prominent subacute neuropsychiatric symptoms, ranging from severe anxiety to delusional psychosis, may have anti-SARS-CoV-2 and antineural antibodies in their CSF and may respond to immunotherapy.

The role of oxytocin in regulating loneliness in old age.

Loneliness is prevalent in old age and is associated with reduced positive social interactions. Building on studies showing that oxytocin (OT) levels rise during social interactions, we hypothesized that following participation in positive social interaction involving synchronized movements, OT levels would increase, while state loneliness levels would diminish. A total of 63 older adults (aged M = 78.93, SD = 9.99; Range = 65-101) participated in the study. Participants completed emotional and social loneliness scales and provided saliva samples pre- and post-participation in the "mirror game", which requires movement synchronization and is known to promote connectedness and closeness. Results indicate a reduced state of loneliness following the mirror game. Importantly, the change in OT levels predicted the change in social loneliness, defined as the absence of social interactions with people in the social network. On the other hand, emotional loneliness, marked by deficient emotional contact, only decreased among participants who experienced high levels of closeness with their partner in the mirror game. Findings suggest that context-dependent change in endogenous OT may serve as biomarker for the social effects of oxytocin on loneliness in old age and can help in the development of targeted interventions for treating loneliness in old age.

Extensive pleiotropism and allelic heterogeneity mediate metabolic effects of IRX3 and IRX5.

Whereas coding variants often have pleiotropic effects across multiple tissues, noncoding variants are thought to mediate their phenotypic effects by specific tissue and temporal regulation of gene expression. Here, we investigated the genetic and functional architecture of a genomic region within the FTO gene that is strongly associated with obesity risk. We show that multiple variants on a common haplotype modify the regulatory properties of several enhancers targeting IRX3 and IRX5 from megabase distances. We demonstrate that these enhancers affect gene expression in multiple tissues, including adipose and brain, and impart regulatory effects during a restricted temporal window. Our data indicate that the genetic architecture of disease-associated loci may involve extensive pleiotropy, allelic heterogeneity, shared allelic effects across tissues, and temporally restricted effects.

Hepatokines and metabolism: Deciphering communication from the liver.

BACKGROUND: The liver is a key regulator of systemic energy homeostasis and can sense and respond to nutrient excess and deficiency through crosstalk with multiple tissues. Regulation of systemic energy homeostasis by the liver is mediated in part through regulation of glucose and lipid metabolism. Dysregulation of either process may result in metabolic dysfunction and contribute to the development of insulin resistance or fatty liver disease. SCOPE OF REVIEW: The liver has recently been recognized as an endocrine organ that secretes hepatokines, which are liver-derived factors that can signal to and communicate with distant tissues. Dysregulation of liver-centered inter-organ pathways may contribute to improper regulation of energy homeostasis and ultimately metabolic dysfunction. Deciphering the mechanisms that regulate hepatokine expression and communication with distant tissues is essential for understanding inter-organ communication and for the development of therapeutic strategies to treat metabolic dysfunction. MAJOR CONCLUSIONS: In this review, we discuss liver-centric regulation of energy homeostasis through hepatokine secretion. We highlight key hepatokines and their roles in metabolic control, examine the molecular mechanisms of each hepatokine, and discuss their potential as therapeutic targets for metabolic disease. We also discuss important areas of future studies that may contribute to understanding hepatokine signaling under healthy and pathophysiological conditions.

Selenium nanoparticles and metformin ameliorate streptozotocin-instigated brain oxidative-inflammatory stress and neurobehavioral alterations in rats.

Selenium nanoparticles (SeNPs) are well reported to exhibit pharmacological activities both in vitro and in vivo. However, literature is devoid of studies on the impact of SeNPs and/or metformin (M) against streptozotocin (STZ)-mediated oxidative brain injury and behavioral impairment. Consequently, to fill this gap, diabetes was induced in male Wistar rats by feeding with 10% fructose solution for 2 weeks, followed by a single dose intraperitoneal injection of STZ (40 mg/kg body weight [bwt]). After rats were confirmed diabetic, they were treated orally with 0.1 mg/kg bwt of SeNPs ± M (50 mg/kg bwt), and normal control (NC) received citrate buffer (2 mg/mL) for 5 weeks. In comparison with the diabetic control (DC), SeNPs, and/or M significantly (p < 0.05) lowered blood glucose levels, but increased insulin secretion and pancreatic ß-cell function. An increase in locomotor and motor activities evidenced by improved spontaneous alternation, locomotor frequency, hinding, and increased mobility time were observed in treated groups. In addition, there was enhanced brain antioxidant status with a lower acetylcholinesterase (AChE) activity and oxidative-inflammatory stress biomarkers. A significant downregulation of caspase 3 and upregulation of parvalbumin and Nrf2 protein expressions was observed in treated groups. In some of the studied parameters, treated groups were statistically (p < 0.05) insignificant compared with the normal control (NC) group. Overall, co-treatment elicited more efficacy than that of the individual regimen.

FGF21 signaling in glutamatergic neurons is required for weight loss associated with dietary protein dilution.

Alterations in macronutrient intake can have profound effects on energy intake and whole-body metabolism. For example, reducing protein intake increases energy expenditure, increases insulin sensitivity and decreases body weight in rodents. Fibroblast growth factor 21 (FGF21) signaling in the brain is necessary for the metabolic effects of dietary protein restriction and has more recently been proposed to promote protein preference. However, the neuron populations through which FGF21 elicits these effects are unknown. Here, we demonstrate that deletion of ß-klotho in glutamatergic, but not GABAergic, neurons abrogated the effects of dietary protein restriction on reducing body weight, but not on improving insulin sensitivity in both diet-induced obese and lean mice. Specifically, FGF21 signaling in glutamatergic neurons is necessary for protection against body weight gain and induction of UCP1 in adipose tissues associated with dietary protein restriction. However, ß-klotho expression in glutamatergic neurons was dispensable for the effects of dietary protein restriction to increase insulin sensitivity. In addition, we report that FGF21 administration does not alter protein preference, but instead promotes the foraging of other macronutrients primarily by suppressing simple sugar consumption. This work provides important new insights into the neural substrates and mechanisms behind the endocrine control of metabolism during dietary protein dilution.

FGF21 Signals to Glutamatergic Neurons in the Ventromedial Hypothalamus to Suppress Carbohydrate Intake.

Fibroblast growth factor 21 (FGF21) is an endocrine hormone produced by the liver that regulates nutrient and metabolic homeostasis. FGF21 production is increased in response to macronutrient imbalance and signals to the brain to suppress sugar intake and sweet-taste preference. However, the central targets mediating these effects have been unclear. Here, we identify FGF21 target cells in the hypothalamus and reveal that FGF21 signaling to glutamatergic neurons is both necessary and sufficient to mediate FGF21-induced sugar suppression and sweet-taste preference. Moreover, we show that FGF21 acts directly in the ventromedial hypothalamus (VMH) to specifically regulate sucrose intake, but not non-nutritive sweet-taste preference, body weight, or energy expenditure. Finally, our data demonstrate that FGF21 affects neuronal activity by increasing activation and excitability of neurons in the VMH. Thus, FGF21 signaling to glutamatergic neurons in the VMH is an important component of the neurocircuitry that functions to regulate sucrose intake.

Prevalence of tumor BRCA1 and BRCA2 dysfunction in unselected patients with ovarian cancer

Objective@#The therapeutic benefits of poly(ADP-ribose) polymerase inhibitors highlight the need to evaluate BRCA1/2 defects in tubal/ovarian cancer (OC). We sought to determine the pattern and disease characteristics associated with tumor BRCA1/2 mutations and BRCA1 methylation in women with OC. @*Methods@#We obtained 111 OC specimens from 2 university hospitals and assessed BRCA1/2 mutations and BRCA1 methylation in tumor DNA. The frequency and pattern of BRCA1/2 defects were examined. Associations between patient/disease characteristics and BRCA1/2 defects were ascertained (Fisher’s exact test). Platinum-free interval (PFI), progression-free survival (PFS), and overall survival (OS) based on the underlying BRCA1/2 defect were determined (Kaplan-Meier analysis [log-rank test]). @*Results@#We observed a BRCA1/2 dysfunction rate of 40% (28/70) in high-grade serous tubal/ovarian cancer (HGSC), including 14.3% BRCA1 methylation (n=10), 7.1% BRCA1 mutation (n=5), and 18.6% BRCA2 mutation (n=13). Defects in BRCA1/2 genes were associated with stage III/IV HGSC (BRCA1 methylation: P=0.005 [stage III/IV] and P=0.004 [HGSC]; BRCA1/2 mutation: P=0.03 [stage III/IV] and P<0.001 [HGSC]). Patients with BRCA1/2-mutated cancers showed improved OS (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.43–0.99; P=0.045) and a trend toward improved PFI (HR, 0.48; 95% CI, 0.22–1.06; P=0.07) and PFS (HR, 0.72; 95% CI, 0.51–1.03; P=0.07). No survival differences were observed between BRCA1-methylated and BRCA1/2 wild-type non-BRCA1-methylated cancers. @*Conclusion@#We observed a high tumor BRCA1/2 dysfunction rate in HGSC with a unique predominance of BRCA2 over BRCA1 mutations. While BRCA1/2 mutations conferred survival benefits in OC, no such association was observed with BRCA1 methylation.

Prevalence of tumor BRCA1 and BRCA2 dysfunction in unselected patients with ovarian cancer

Objective@#The therapeutic benefits of poly(ADP-ribose) polymerase inhibitors highlight the need to evaluate BRCA1/2 defects in tubal/ovarian cancer (OC). We sought to determine the pattern and disease characteristics associated with tumor BRCA1/2 mutations and BRCA1 methylation in women with OC. @*Methods@#We obtained 111 OC specimens from 2 university hospitals and assessed BRCA1/2 mutations and BRCA1 methylation in tumor DNA. The frequency and pattern of BRCA1/2 defects were examined. Associations between patient/disease characteristics and BRCA1/2 defects were ascertained (Fisher’s exact test). Platinum-free interval (PFI), progression-free survival (PFS), and overall survival (OS) based on the underlying BRCA1/2 defect were determined (Kaplan-Meier analysis [log-rank test]). @*Results@#We observed a BRCA1/2 dysfunction rate of 40% (28/70) in high-grade serous tubal/ovarian cancer (HGSC), including 14.3% BRCA1 methylation (n=10), 7.1% BRCA1 mutation (n=5), and 18.6% BRCA2 mutation (n=13). Defects in BRCA1/2 genes were associated with stage III/IV HGSC (BRCA1 methylation: P=0.005 [stage III/IV] and P=0.004 [HGSC]; BRCA1/2 mutation: P=0.03 [stage III/IV] and P<0.001 [HGSC]). Patients with BRCA1/2-mutated cancers showed improved OS (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.43–0.99; P=0.045) and a trend toward improved PFI (HR, 0.48; 95% CI, 0.22–1.06; P=0.07) and PFS (HR, 0.72; 95% CI, 0.51–1.03; P=0.07). No survival differences were observed between BRCA1-methylated and BRCA1/2 wild-type non-BRCA1-methylated cancers. @*Conclusion@#We observed a high tumor BRCA1/2 dysfunction rate in HGSC with a unique predominance of BRCA2 over BRCA1 mutations. While BRCA1/2 mutations conferred survival benefits in OC, no such association was observed with BRCA1 methylation.