Mechanoreceptor synapses in the brainstem shape the central representation of touch.

Mammals use glabrous (hairless) skin of their hands and feet to navigate and manipulate their environment. Cortical maps of the body surface across species contain disproportionately large numbers of neurons dedicated to glabrous skin sensation, in part reflecting a higher density of mechanoreceptors that innervate these skin regions. Here, we find that disproportionate representation of glabrous skin emerges over postnatal development at the first synapse between peripheral mechanoreceptors and their central targets in the brainstem. Mechanoreceptor synapses undergo developmental refinement that depends on proximity of their terminals to glabrous skin, such that those innervating glabrous skin make synaptic connections that expand their central representation. In mice incapable of sensing gentle touch, mechanoreceptors innervating glabrous skin still make more powerful synapses in the brainstem. We propose that the skin region a mechanoreceptor innervates controls the developmental refinement of its central synapses to shape the representation of touch in the brain.

Establishing connectivity through microdissections of midbrain stimulation-related neural circuits.

Comprehensive understanding of the neural circuits involving the ventral tegmental area is essential for elucidating the anatomo-functional mechanisms governing human behaviour as well as the therapeutic and adverse effects of deep brain stimulation for neuropsychiatric diseases. While the ventral tegmental area has been successfully targeted with deep brain stimulation for different neuropsychiatric diseases, the axonal connectivity of the region has not been fully understood. Here using fiber micro-dissections in human cadaveric hemispheres, population-based high-definition fiber tractography, and previously reported deep brain stimulation hotspots, we find that the ventral tegmental area participates in an intricate network involving the serotonergic pontine nuclei, basal ganglia, limbic system, basal forebrain, and prefrontal cortex, which is implicated in the treatment of obsessive-compulsive disorder, major depressive disorder, Alzheimer's disease, cluster headaches, and aggressive behaviors.

Metal-Solvent Complex Formation at the Surface of InP Colloidal Quantum Dots.

The surface chemistry of colloidal semiconductor nanocrystals (QDs) profoundly influences their physical and chemical attributes. The insulating organic shell ensuring colloidal stability impedes charge transfer, thus limiting optoelectronic applications. Exchanging these ligands with shorter inorganic ones enhances charge mobility and stability, which is pivotal for using these materials as active layers for LEDs, photodetectors, and transistors. Among those, InP QDs also serve as a model for surface chemistry investigations. This study focuses on group III metal salts as inorganic ligands for InP QDs. We explored the ligand exchange mechanism when metal halide, nitrate, and perchlorate salts of group III (Al, In Ga), common Lewis acids, are used as ligands for the conductive inks. Moreover, we compared the exchange mechanism for two starting model systems: InP QDs capped with myristate and oleylamine as X- and L-type native organic ligands, respectively. We found that all metal halide, nitrate, and perchlorate salts dissolved in polar solvents (such as n-methylformamide, dimethylformamide, dimethyl sulfoxide, H2O) with various polarity formed metal-solvent complex cations [M(Solvent)6]3+ (e.g., [Al(MFA)6]3+, [Ga(MFA)6]3+, [In(MFA)6]3+), which passivated the surface of InP QDs after the removal of the initial organic ligand. All metal halide capped InP/[M(Solvent)6]3+ QDs show excellent colloidal stability in polar solvents with high dielectric constant even after 6 months in concentrations up to 74 mg/mL. Our findings demonstrate the dominance of dissociation-complexation mechanisms in polar solvents, ensuring colloidal stability. This comprehensive understanding of InP QD surface chemistry paves the way for exploring more complex QD systems such as InAs and InSb QDs.

PTEN Regulates Dendritic Arborization by Decreasing Microtubule Polymerization Rate.

Phosphatase and tensin homolog (PTEN) is a major negative regulator of the phosphatidylinositol-3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway. Loss-of-function mutations in PTEN have been found in a subset of patients with macrocephaly and autism spectrum disorder (ASD). PTEN loss in neurons leads to somal hypertrophy, aberrant migration, dendritic overgrowth, increased spine density, and hyperactivity of neuronal circuits. These neuronal overgrowth phenotypes are present on Pten knock-out (KO) and reconstitution with autism-associated point mutations. The mechanism underlying dendritic overgrowth in Pten deficient neurons is unclear. In this study, we examined how Pten loss impacts microtubule (MT) dynamics in both sexes using retroviral infection and transfection strategies to manipulate PTEN expression and tag the plus-end MT binding protein, end-binding protein 3 (EB3). We found Pten KO neurons sprout more new processes over time compared with wild-type (WT) neurons. We also found an increase in MT polymerization rate in Pten KO dendritic growth cones. Reducing MT polymerization rate to the WT level was sufficient to reduce dendritic overgrowth in Pten KO neurons in vitro and in vivo Finally, we found that rescue of dendritic overgrowth via inhibition of MT polymerization was sufficient to improve the performance of Pten KO mice in a spatial memory task. Taken together, our data suggests that one factor underlying PTEN loss dependent dendritic overgrowth is increased MT polymerization. This opens the possibility for an intersectional approach targeting MT polymerization and mTOR with low doses of inhibitors to achieve therapeutic gains with minimal side effects in pathologies associated with loss of neuronal PTEN function.SIGNIFICANCE STATEMENT Loss of Pten function because of genetic deletion or expression of mutations associated with autism spectrum disorder (ASD), results in overgrowth of neurons including increased total dendritic length and branching. We have discovered that this overgrowth is accompanied by increased rate of microtubule (MT) polymerization. The increased polymerization rate is insensitive to acute inhibition of mechanistic target of rapamycin (mTOR)C1 or protein synthesis. Direct pharmacological inhibition of MT polymerization can slow the polymerization rate in Pten knock-out (KO) neurons to rates seen in wild-type (WT) neurons. Correction of the MT polymerization rate rescues increased total dendritic arborization and spatial memory. Our studies suggest that phosphatase and tensin homolog (PTEN) inhibits dendritic growth through parallel regulation of protein synthesis and cytoskeletal polymerization.

Race and Ethnicity and the Utilization of Security Responses in a Hospital Setting.

BACKGROUND: Security emergency responses (SERs) are utilized by hospitals to ensure the safety of patients and staff but can cause unintended morbidity. The presence of racial and ethnic inequities in SER utilization has not been clearly elucidated. OBJECTIVE: To determine whether Black and Hispanic patients experience higher rates of SER and physical restraints in a non-psychiatric inpatient setting. DESIGN: Retrospective cohort study. PARTICIPANTS: All patients discharged from September 2018 through December 2019. EXPOSURE: Race and ethnicity, as reported by patients at time of registration. MAIN OUTCOMES: The primary outcome was whether a SER was called on a patient. The secondary outcome was the incidence of physical restraints among patients who experienced a SER. KEY RESULTS: Among 24,212 patients, 18,755 (77.5%) patients identified as white, 2,346 (9.7%) as Black, and 2,425 (10.0%) identified with another race. Among all patients, 1,827 (7.6%) identified as Hispanic and 21,554 (89.0%) as non-Hispanic. Sixty-six (2.8%) Black patients had a SER activated during their first admission, compared to 295 (1.6%) white patients. In a Firth logit multivariable model, Black patients had higher adjusted odds of a SER than white patients (adjusted odds ratio (aOR) 1.37 [95% confidence interval: 1.02, 1.81], p = 0.037). Hispanic patients did not have higher odds of having a SER called than non-Hispanic patients. In a Poisson multivariable model among patients who had a SER called, race and ethnicity were not found to be significant predictors of restraint. CONCLUSION: Black patients had higher odds of a SER compared to white patients. No significant differences were found between Hispanic and non-Hispanic patients. Future efforts should focus on assessing the generalizability of these findings, the underlying mechanisms driving these inequities, and effective interventions to address them.

Emerging drugs for the treatment of major depressive disorder.

INTRODUCTION: Major depressive disorder (MDD) continues to be one of the highest contributors to disease burden and years lived with disability in the world. Current existing treatments have been associated with intolerable side effects, long onset of action and suboptimal remission rates. Newer agents are being developed that will be reviewed here, such as glutamate and gamma-aminobutyric acid (GABA) and the reinvigorated testing of psychedelic drugs. This review will summarize the target mechanisms of the newer ADTs currently in development and available on the market. AREAS COVERED: It briefly covers the existing agents for MDD and treatment-resistant depression (TRD) and the need for new agents with higher efficacy. Therapeutic agents currently in Phase II or later clinical trials are listed and discussed, based on a thorough review of the US National Institutes of Health clinicaltrials.gov index and a search of the Informa Pharmaprojects database. Compounds of interest are grouped into scientific rationale and include atypical antipsychotics, GABA positive allosteric modulators, glutamatergic agents, opioids, orexin 2 receptor antagonists, and psychedelics. EXPERT OPINION: New therapeutic agents currently in development are promising, with a more rapid onset of action and the ability to augment and treat TRD.

General Method to Increase Carboxylic Acid Content on Nanodiamonds.

Carboxylic acid is a commonly utilized functional group for covalent surface conjugation of carbon nanoparticles that is typically generated by acid oxidation. However, acid oxidation generates additional oxygen containing groups, including epoxides, ketones, aldehydes, lactones, and alcohols. We present a method to specifically enrich the carboxylic acid content on fluorescent nanodiamond (FND) surfaces. Lithium aluminum hydride is used to reduce oxygen containing surface groups to alcohols. The alcohols are then converted to carboxylic acids through a rhodium (II) acetate catalyzed carbene insertion reaction with tert-butyl diazoacetate and subsequent ester cleavage with trifluoroacetic acid. This carboxylic acid enrichment process significantly enhanced nanodiamond homogeneity and improved the efficiency of functionalizing the FND surface. Biotin functionalized fluorescent nanodiamonds were demonstrated to be robust and stable single-molecule fluorescence and optical trapping probes.

The effect of melatonin on ultrasound markers of follicular development: A double-blind placebo-controlled randomised trial.

BACKGROUND: Melatonin is a potent oxygen scavenger and is capable of altering blood flow in various vascular beds. AIMS: We aimed to determine the effect of melatonin on ovarian vascular indices during ovarian stimulation for in vitro fertilisation (IVF). MATERIALS AND METHODS: This is a pilot double-blind placebo-controlled randomised trial. Sixty-nine women (mean age 35.8 ± 4.3 years) undergoing their first cycle of IVF were randomised to receive either placebo, 2, 4 or 8 mg of melatonin, twice a day. Each participant underwent a transvaginal ultrasound at days 6-10 assessing follicular number and size. The vascularisation index (VI), flow index (FI) and vascularisation-flow index (VFI) were measured. These indices were then correlated with embryological outcomes. Informed consent was obtained from participants. This trial was registered with the Australia New Zealand Clinical Trials Registry (ACTRN12613001317785). RESULTS: The number of follicles did not differ between groups (P = 0.4). There were no differences in the VI (P = 0.4), FI (P = 0.1) or VFI (P = 0.3) in the right ovary or the FI (P = 0.3) or VFI (P = 0.3) in the left ovary between groups. When comparing placebo to any dose of melatonin, there were no differences in any measured parameter. While there was correlation between the number of follicles on ultrasound and all measured embryological outcomes, there was no correlation between ovarian vascular indices and these important clinical outcomes. CONCLUSIONS: Melatonin does not appear to change ovarian vascular indices during ovarian stimulation. In addition, such vascular indices cannot predict the number or quality of oocytes or embryos obtained in an IVF cycle. These findings require confirmation in future larger studies.

Saccharin increases perception of bladder filling in a forced diuresis experiment.

AIMS: To study bladder sensation during a forced diuresis protocol and to assess differences in sensation perceived by different ethnic groups and after drinking artificially sweetened water. METHODS: Female Caucasian and south Indian Asian volunteers performed the diuresis protocol drinking water, or water sweetened with saccharin (5 mg/kg body weight). Participants recorded filling sensation every 5 min while drinking 250-350 mL/15 min. They were asked to record the strongest sensation before voiding as maximum sensation, before voiding. The void was measured and sensation immediately recorded as minimum. The process was repeated. Voided volume and time required to achieve maximum sensation during cycle 2 were compared by water and sweetener, ethnic group, and age. RESULTS: Twenty Asian and 20 Caucasian volunteers participated. No differences in maximum voided volume or diuresis rate was seen by ethnicity. Median diuresis with sweetener was 16.7 mL/min (8.6-35) compared to 13.2 (7.1-25) with water (P = 0.008), a difference accounted for by 16 women with >5 mL/min difference in diuresis rate. These were excluded to leave 24 women with similar diuresis rates with both sweetener and water (14.8 mL/min (8.6-28.0) and 13.2 mL/min (7.1-25.0). In these women, time to achieve maximum sensation was lower with sweetener than water: 37.5 min (20-85) versus 50.0 min (20-80), P = 0.002, with no difference in voided volume. CONCLUSIONS: Water sweetened with saccharin produced an increased diuresis rate in some women. After controlling for this, time to recording maximum sensation was decreased with sweetened water, suggesting saccharin has an effect upon perceived sensation.

Abrogation of Nrf2 impairs antioxidant signaling and promotes atrial hypertrophy in response to high-intensity exercise stress.

BACKGROUND: Anomalies in myocardial structure involving myocyte growth, hypertrophy, differentiation, apoptosis, necrosis etc. affects its function and render cardiac tissue more vulnerable to the development of heart failure. Although oxidative stress has a well-established role in cardiac remodeling and dysfunction, the mechanisms linking redox state to atrial cardiomyocyte hypertrophic changes are poorly understood. Here, we investigated the role of nuclear erythroid-2 like factor-2 (Nrf2), a central transcriptional mediator, in redox signaling under high intensity exercise stress (HIES) in atria. METHODS: Age and sex-matched wild-type (WT) and Nrf2(-/-) mice at >20 months of age were subjected to HIES for 6 weeks. Gene markers of hypertrophy and antioxidant enzymes were determined in the atria of WT and Nrf2(-/-) mice by real-time qPCR analyses. Detection and quantification of antioxidants, 4-hydroxy-nonenal (4-HNE), poly-ubiquitination and autophagy proteins in WT and Nrf2(-/-) mice were performed by immunofluorescence analysis. The level of oxidative stress was measured by microscopical examination of di-hydro-ethidium (DHE) fluorescence. RESULTS: Under the sedentary state, Nrf2 abrogation resulted in a moderate down regulation of some of the atrial antioxidant gene expression (Gsr, Gclc, Gstα and Gstµ) despite having a normal redox state. In response to HIES, enlarged atrial myocytes along with significantly increased gene expression of cardiomyocyte hypertrophy markers (Anf, Bnf and ß-Mhc) were observed in Nrf2(-/-) when compared to WT mice. Further, the transcript levels of Gclc, Gsr and Gstµ and protein levels of NQO1, catalase, GPX1 were profoundly downregulated along with GSH depletion and increased oxidative stress in Nrf2(-/-) mice when compared to its WT counterparts after HIES. Impaired antioxidant state and profound oxidative stress were associated with enhanced atrial expression of LC3 and ATG7 along with increased ubiquitination of ATG7 in Nrf2(-/-) mice subjected to HIES. CONCLUSIONS: Loss of Nrf2 describes an altered biochemical phenotype associated with dysregulation in genes related to redox state, ubiquitination and autophagy in HIES that result in atrial hypertrophy. Therefore, our findings direct that preserving Nrf2-related antioxidant function would be one of the effective strategies to safeguard atrial health.

Suicidal ideation and sex differences in relation to 18 major psychiatric disorders in college and university students: anonymous web-based assessment.

College/university students are at high risk for psychiatric disorder and suicide secondary to age, campus stressors, and social pressures. We therefore report frequencies of 18 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision disorders and suicidal ideation (SI) acquired anonymously from a Web site receiving 113,181 visits from more than 1,500 predominantly US colleges/universities. Depression was foremost, followed by social phobia and eating disorders. Substance-related disorders were less frequent than expected. SI occurred in 47.1% of students, with women evidencing somewhat stronger findings than men. SI was more associated with substance, bipolar, and panic disorders than depression. Self-reported emotional volatility exceeded thoughts of self-harm for all disorders. The results support two subtypes of suicide risk: dysphoric premeditators and those primarily angry and/or impulsive. Clinicians and researchers should therefore consider suicide as an independent psychopathological phenomenon that includes emotional volatility as a risk factor and thoroughly evaluate psychiatric disorders potentially conferring greater suicidal propensity than depression.

Submammary Placement With Mastopexy for Implantable Pulse Generator Site Pain in Thin Women.

OBJECTIVE: Implantable pulse generators for neurostimulation and other indications are becoming more widespread. Pain at the generator site, erosion through the subcutaneous issues, and migration of the generator are frequent post-operative complications that result in high rates of re-operation. We report a case where a submammary combined approach with plastic surgery for improved soft tissue coverage resulted in better esthetic and functional outcomes in a thin woman. MATERIALS AND METHODS: A 40-year-old thin woman presented for revision of spinal cord stimulator due to pain at the bilateral infraclavicular generator sites secondary to lack of soft tissue coverage. She underwent revision of the implantable generator site with placement of the generator in the submammary location and concurrent mastopexy with plastic surgery. RESULTS: At two-year follow-up she continues to be pain-free after surgery and is very satisfied by the cosmetic outcome. CONCLUSION: Submammary placement of implantable pulse generators in thin women combined with mastopexy may result in improved soft tissue coverage, decreased pain at the generator site, and a low rate of complications.

Neuronal and epithelial cell rescue resolves chronic systemic inflammation in the lipid storage disorder Niemann-Pick C.

Chronic systemic inflammation is thought to be a major contributor to metabolic and neurodegenerative diseases. Since inflammatory components are shared among different disorders, targeting inflammation is an attractive option for mitigating disease. To test the significance of inflammation in the lipid storage disorder (LSD) Niemann-Pick C (NPC), we deleted the macrophage inflammatory gene Mip1a/Ccl3 from NPC diseased mice. Deletion of Ccl3 had been reported to delay neuronal loss in Sandhoff LSD mice by inhibiting macrophage infiltration. For NPC mice, in contrast, deleting Ccl3 did not retard neurodegeneration and worsened the clinical outcome. Depletion of visceral tissue macrophages also did not alter central nervous system (CNS) pathology and instead increased liver injury, suggesting a limited macrophage infiltration response into the CNS and a beneficial role of macrophage activity in visceral tissue. Prevention of neuron loss or liver injury, even at late stages in the disease, was achieved through specific rescue of NPC disease in neurons or in liver epithelial cells, respectively. Local epithelial cell correction was also sufficient to reduce the macrophage-associated pathology in lung tissue. These results demonstrate that elevated inflammation and macrophage activity does not necessarily contribute to neurodegeneration and tissue injury, and LSD defects in immune cells may not preclude an appropriate inflammatory response. We conclude that inflammation remains secondary to neuronal and epithelial cell dysfunction and does not irreversibly contribute to the pathogenic cascade in NPC disease. Without further exploration of possible beneficial roles of inflammatory mediators, targeting inflammation may not be therapeutically effective at ameliorating disease severity.

Abnormal cervical cancer screening in pregnancy and preterm delivery.

BACKGROUND: Preterm delivery is a major cause of neonatal morbidity and mortality. Human papillomavirus (HPV) infection is common in reproductive-aged women. We hypothesised that abnormal cervical cancer screening tests, as a proxy for HPV infection, would be associated with preterm delivery. METHODS: We conducted a retrospective cohort study of women delivering liveborn singletons beyond 20 weeks gestation, who had a Papanicolaou (Pap) test within 1 year prior to delivery. Women with abnormal Pap or positive high-risk HPV tests, classified as having 'abnormal screening', were compared with women classified as having 'normal screening' in bivariate analysis for overall preterm delivery at less than 37 weeks gestation. Using Poisson regression, we report unadjusted (RR) and adjusted (aRR) risk ratios for spontaneous preterm delivery due to preterm labour and preterm premature rupture of membranes. RESULTS: Among 2686 women meeting criteria for analysis, 213 (8%) had abnormal screening. Women with abnormal screening, compared with normal screening, were not more likely to deliver preterm (12.2% vs. 9.8%, RR 1.3 [95% confidence interval (CI) 0.9, 1.8], aRR 1.2 [95% CI 0.8, 1.7]). Women with abnormal screening, however, were at greater risk for spontaneous preterm delivery in unadjusted and adjusted analysis (8.9% vs. 4.5%; RR 2.0 [95% CI 1.2, 3.2], aRR 1.8 [95% CI 1.1, 2.9]). CONCLUSIONS: There was no difference in risk of overall preterm delivery in women with abnormal compared with normal cervical cancer screening tests. Our data suggest, however, that abnormal screening in pregnancy may be associated with spontaneous preterm delivery.

The surgical treatment of headache.

Medically refractory headache is an uncommon but difficult-to-treat clinical problem. Patients who fail maximal medical management may be candidates for invasive treatment. In this review, we critically examine the literature on the range of surgical treatments currently available for migraine, trigeminal autonomic cephalalgias, idiopathic intracranial hypertension and Chiari malformation type 1, with particular attention to patient selection, treatment efficacy, and complications.

Neurostimulation for neck pain and headache.

Patients with medically refractory headache disorders are a rare and challenging-to-treat group. The introduction of peripheral neurostimulation (PNS) has offered a new avenue of treatment for patients who are appropriate surgical candidates. The utility of PNS for headache management is actively debated. Preliminary reports suggested that 60-80% of patients with chronic headache who have failed maximum medical therapy respond to PNS. However, complications rates for PNS are high. Recent publication of 2 large randomized clinical trials with conflicting results has underscored the need for further research and careful patient counseling. In this review, we summarize the current evidence for PNS in treatment of chronic migraine, trigeminal autonomic cephalagias and occipital neuralgia, and other secondary headache disorders.

Comparison of Postoperative Seizures Between Burr-Hole Evacuation and Craniotomy in Patients With Nonacute Subdural Hematomas: A Bi-Institutional Propensity Score-Matched Analysis.

BACKGROUND AND OBJECTIVES: Postoperative seizures are a common complication after surgical drainage of nonacute chronic subdural hematomas (SDHs). The literature increasingly supports the use of prophylactic antiepileptic drugs for craniotomy, a procedure that is often associated with larger collections and worse clinical status at admission. This study aimed to compare the incidence of postoperative seizures in patients treated with burr-hole drainage and those treated with craniotomy through propensity score matching (PSM). METHODS: A retrospective cohort analysis was conducted on patients with surgical drainage of nonacute SDHs (burr-holes and craniotomies) between January 2017 to December 2021 at 2 academic institutions in the United States. PSM was performed by controlling for age, subdural thickness, subacute component, and preoperative Glasgow Coma Scale. Seizure rates and accompanying abnormalities on electroencephalographic tracing were evaluated postmatching. RESULTS: A total of 467 patients with 510 nonacute SDHs underwent 474 procedures, with 242 burr-hole evacuations (51.0%) and 232 craniotomies (49.0%). PSM resulted in 62 matched pairs. After matching, univariate analysis revealed that burr-hole evacuations exhibited lower rates of seizures (1.6% vs 11.3%; P = .03) and abnormal electroencephalographic findings (0.0% vs 4.8%; P = .03) compared with craniotomies. No significant differences were observed in postoperative Glasgow Coma Scale (P = .77) and length of hospital stay (P = .61). CONCLUSION: Burr-hole evacuation demonstrated significantly lower seizure rates than craniotomy using a propensity score-matched analysis controlling for significant variables.