Exosomal miR-128-3p reversed fibrinogen-mediated inhibition of oligodendrocyte progenitor cell differentiation and remyelination after cerebral ischemia

Aims

To investigate the role of exosomal miR-128-3p in promoting fibrinogen-mediated inhibition of oligodendrocyte progenitor cell (OPC) differentiation and the therapeutic potential of exosomal miR-128-3p in cerebral ischemia.

Methods

Mouse models of middle cerebral artery occlusion (MCAO) were established as described previously. MCAO was treated with fibrinogen and exosomes by stereotactically injecting into the left stratum. Mouse cortical OPCs were used for mRNA and miRNA sequencing analysis. Exosomes were isolated from neural stem cells (NSCs) of mice.

Results

Fibrinogen deposition suppressed remyelination after MCAO and inhibited OPC differentiation by activating ACVR1, the bone morphogenetic protein (BMP) signaling type I receptor. In vitro, miR-sequencing and verification studies revealed that miR-128-3p is associated with BMP signaling mediated by ACVR1. Additionally, transfer of NSC-derived exosomal miR-128-3p to OPCs significantly increased myelin basic protein expression and inhibited BMP signaling. Furthermore, NSC-derived exosomal miR-128-3p protected against fibrinogen-induced demyelination related to BMP signaling, reduced the infarct volume, and improved neurological function after MCAO.

Conclusions

Fibrinogen deposition inhibits remyelination after ischemic damage and NSC-derived exosomal miR-128-3p promotes OPC differentiation into OLs by suppressing BMP signaling, indicating that NSC-derived exosomal miR-128-3p represents a potential therapeutic target for ischemic stroke.     

Expression of histone acetylases p300 and PCAF in pediatric astrocytomas

Objects

The protein 300 (p300) and p300/CBP-binding protein-associated factor (PCAF) are enzymes with histone acetyltransferase (HAT) activity, a function that can become deregulated in different tumors and affect biological responses.

Methods

Due to the lack of information on the deregulation of these HATs in pediatric tumors, this study evaluated the expression of both the mRNA and proteins of p300 and PCAF in 54 samples of pediatric astrocytomas embedded in paraffin.

Results

PCAF was not expressed in normal brain tissue. In grade I tumors, the expression of p300 (1.1?±?0.1) and PCAF (1.2?±?0.11) was greater than those observed in grade III tumors: 0.72?±?0.15 for p300 and 0.55?±?0.11 for PCAF, and grade IV tumors: 0.74?±?0.13 for p300 and 0.55?±?0.13 for PCAF (p?<?0.05). Immunohistochemical staining revealed the same tendency towards a decrease in the expression of the protein as the degree of clinical severity increased. Patients with recurrent grades I, III, and IV tumors had the highest levels of PCAF, compared to those who showed no recurrence (p?<?0.05).

Conclusions

This work describes and confirms that these HATs play important roles in regulating genes and in the biological behavior of pediatric astrocytomas.     

Clinical and preclinical evaluation of miR-144-5p as a key target for major depressive disorder

Background

Neuronal abnormalities are closely associated with major depressive disorder (MDD). Available evidence suggests a role for microRNAs (miRNAs) in regulating the expression of genes involved in MDD. Hence, miRNAs that can be potential therapeutic targets need to be identified.

Methods

A mouse model of chronic unpredictable stress (CUS) was used to evaluate the function of miRNAs in MDD. miR-144-5p was screened from the hippocampi of CUS mice based on sequencing results. Adenovirus-associated vectors were used to overexpress or knockdown miR-144-5p in mice. BpV(pic) and LY294002 were used to determine the relationship between miR-144-5p target genes PTEN and TLR4 in neuronal impairment caused by miR-144-5p deficiency. Western blotting, immunofluorescence, ELISA immunosorbent assay, and Golgi staining were used to detect neuronal abnormalities. Serum samples from healthy individuals and patients with MDD were used to detect miR-144-5p levels in the serum and serum exosomes using qRT-PCR.

Results

miR-144-5p expression was significantly decreased within the hippocampal dentate gyrus (DG) of CUS mice. Upregulation of miR-144-5p in the DG ameliorated depression-like behavior in CUS mice and attenuated neuronal abnormalities by directly targeting PTEN and TLR4 expression. Furthermore, miR-144-5p knockdown in normal mice led to depression-like behavior via inducing neuronal abnormalities, including abnormal neurogenesis, neuronal apoptosis, altered synaptic plasticity, and neuroinflammation. miR-144-5p deficiency-mediated neuronal impairment was mediated by PI3K/Akt/FoxO1 signaling. Furthermore, miR-144-5p levels were downregulated in the sera of patients with MDD and associated with depressive symptoms. Consistently, serum exosome-derived miR-144-5p levels were decreased in patients with MDD.

Conclusion

miR-144-5p plays a vital role in regulating neuronal abnormalities in depression. Our findings provide translational evidence that miR-144-5p is a new potential therapeutic target for MDD.     

Circulating miR-126 and miR-130a levels correlate with lower disease risk,disease severity,and reduced inflammatory cytokine levels in acute ischemic stroke patients

To investigate the correlations of five angiogenesis-related miRNA (miR-126, miR-130a, miR-222, miR-218, and miR-185) expression levels with risk, severity, and inflammatory cytokines levels in acute ischemic stroke (AIS) patients. A total of 148 AIS patients and 148 age- and gender-matched controls were consecutively enrolled. Blood samples were collected from AIS patients and controls, and plasma was separated for miRNAs and cytokine level detection. Plasma levels of miRNAs were evaluated by real-time qPCR method, and inflammatory cytokine levels were detected using an enzyme-linked immunosorbent assay (ELISA). Plasma miR-126 and miR-130a expression levels in AIS patients were lower than those of controls, while the levels of miR-222, miR-218, and miR-185 were elevated in AIS patients compared with controls. After pooling the five miRNA expression levels together, the area under the curve (AUC) for predicting AIS risk was 0.840 (95% CI 0.795–0.885) with a sensitivity of 83.8% and a specificity of 69.6% at the best cut-off point. Plasma miR-126 (r?=???0.402, P?<?0.001) and miR-130a (r?=???0.161, P?=?0.050) levels were negatively correlated with NIHSS scores, while plasma miR-218 level was positively correlated with NIHSS scores (r?=?0.471, P?<?0.001). Most importantly, plasma miR-126 expression was negatively correlated with TNF-α (r?=???0.168, P?=?0.041), IL-1β (r?=???0.246, P?=?0.003), and IL-6 (r?=???0.147, P?=?0.035) levels, while miR-130a expression was negatively correlated with TNF-α (r?=???0.287, P?<?0.001), IL-1β (r?=???0.168, P?=?0.041), and IL-6 (r?=???0.239, P?=?0.003) expression levels and positively associated with IL-10 level (r?=?0.261, P?=?0.001). Circulating miR-126 and miR-130a levels correlate with lower disease risk, decreased disease severity, and reduced inflammatory cytokine levels in AIS patients.     

Downregulation of microRNA-330-5p induces manic-like behaviors in REM sleep-deprived rats by enhancing tyrosine hydroxylase expression

Aim

In our pilot study, we found an increase in tyrosine hydroxylase (Th) mRNA expression in the prefrontal cortex of 72-h REM sleep-deprived (SD) rats, a mania model. Additionally, the expression levels of miR-325-3p, miR-326-3p, and miR-330-5p, the predicted target miRNAs on TH, were significantly decreased. Based on these results, in this study, we investigated whether miRNA-325-3p, miR-326-3p, and miR-330-5p modulate TH and manic-like behaviors in SD rats.

Methods

Manic-like behaviors were assessed using the open field test (OFT) and elevated plus-maze (EPM) test. The direct binding activity of miRNAs to the 3′-untranslated region (3′-UTR) of the Th gene was measured in HEK-293 cells using a luciferase reporter system. We also examined mRNA and protein expression of TH after intracerebroventricular (ICV) injection of miR-330-5p agomir to SD rats, along with manic-like behaviors.

Results

We observed an upregulation in mRNA and protein expression of TH and downregulation in miRNA-325-3p, miR-326-3p, and miR-330-5p expressions in the prefrontal cortex of SD rats, together with increased manic-like behaviors. The luciferase reporter assay showed that miR-330-5p could repress TH expression through direct binding to its target site in the 3′-UTR of Th, whereas miR-326-3p and miR-330-5p could not. In addition, ICV injection of miR-330-5p agomir alleviated the increase in TH expression in the prefrontal cortex of SD rats and manic-like behaviors.

Conclusions

TH expression regulation through miR-330-5p may be implicated in the pathophysiology of mania in SD rats.     

SHH,WNT, and NOTCH pathways in medulloblastoma: when cancer stem cells maintain self-renewal and differentiation properties

Purpose

Infant medulloblastoma (MB) is a malignant neuroepithelial embryonal tumor of the cerebellum, believed to derive from precursor granule cells with stem or progenitor cells appearance, and caused by a change in expression profile of genes related to the development. This work aims to study the expression profile of these genes in MB tumors, correlating with clinicopathological characteristics.

Methods

We quantified, by qPCR in 40 MB tumor samples, the expression of genes in HH (PTCH1, PTCH2, and GLI1), WNT (APC, CTNNB1, WIF1, and DKK2), and NOTCH pathways (NOTCH2 and HES1), which have a crucial role in development, and genes as MYCC, MYCN, and TERT, correlating this findings to patient’s clinicopathological characteristics.

Results

Considering the universal RNA as our control sample, and considering the median of gene expression in the control samples as our cutoff, we observed that HES1 gene showed decreased expression compared to control (p?=?0.0059), but patients with HES1 overexpression were directly related to a shorter survival (p?=?0.0165). Individuals with higher GLI1 gene expression had significant shorter survival (p?=?0.0469), and high expression was prevalent in patients up to 5 years old (p?=?0.0479). Patients showing high PTCH2 expression were related to worse survival (p?=?0.0426), and it was correlated with GLI1 high expression (p?=?0.0094). We also observed a concomitant overexpression of WIF1 and DKK2 genes in a subgroup of MB samples (n?=?11, p?=?0.0118).

Conclusions

Our results suggest the presence of activated developmental signaling pathways in MB, which are important for cell proliferation and maintenance, and that may be targeted for novel therapeutic options.     

Exosomes Released from Bone-Marrow Stem Cells Ameliorate Hippocampal Neuronal Injury Through transferring miR-455-3p

BackgroundThe neuroprotective roles of mesenchymal stem cells (MSCs) in brain injury are elicited at least partially through the secretion exosomes containing microRNAs (miRNAs). We herein investigate the protective function of bone marrow MSCs (BMSCs)-derived exosomes harboring miR-455-3p against hippocampal neuronal injury in mouse and N2a cell damage model.MethodsFirst, BMSC surface markers were detected by flow cytometry, followed by extraction of BMSCs-derived exosomes (BMSCs-Exos). A mouse model of neuronal injury was induced by middle cerebral artery occlusion/reperfusion (MCAO/R), and N2a cells were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) for in vitro experiments. BMSCs-Exos were administrated in mice and N2a cells. We subsequently determined viability- and apoptosis-features using EdU staining, CCK-8, flow cytometry and Caspase-3 kits. Subsequently, we used RT-qPCR to assess miR-455-3p expression in brain tissues as well as N2a cells, and bioinformatic tools to predict the targeting mRNA of miR-455-3p, which was validated by dual-luciferase assays.ResultsBMSCs-Exos improved hippocampal neuronal injury in MCAO/R-treated mice and OGD/R-induced injury to N2a cells. BMSCs-Exos upregulated miR-455-3p expression in brain tissues of mice and OGD/R-treated N2a cells. miR-455-3p targeted and conversely regulated PDCD7 expression. The protective effect of BMSCs-Exos on OGD/R-treated N2a cells was markedly mitigated following miR-455-3p downregulation. Moreover, overexpression of miR-455-3p contributed to increased N2a cell activity and decreased apoptosis, while the rescue experiment results were opposite.ConclusionMSCs-derived exosomal miR-455-3p targeted PDCD7 to alleviate hippocampal neuronal injury in MCAO/R-treated mice and injury of OGD/R-treated N2a cells.     

Downregulation of miR-491-5p promotes neovascularization after traumatic brain injury

Micro RNA-491-5 p(miR-491-5 p) plays an important role in regulating cell proliferation and migration;however,the effect of miR-491-5 p on neovascularization after traumatic brain injury remains poorly understood.In this study,a controlled cortical injury model in C57 BL/6 mice and an oxygen-glucose deprivation model in microvascular endothelial cells derived from mouse brain were established to simulate traumatic brain injury in vivo and in vitro,respectively.In the in vivo model,quantitative real-time-polymerase chain reaction results showed that the expression of miR-491-5 p increased or decreased following the intracerebroventricular injection of an miR-491-5 p agomir or antagomir,respectively,and the expression of miR-491-5 p decreased slightly after traumatic brain injury.To detect the neuroprotective effects of miR-491-p,neurological severity scores,Morris water maze test,laser speckle techniques,and immunofluorescence staining were assessed,and the results revealed that miR-491-5 p downregulation alleviated neurological dysfunction,promoted the recovery of regional cerebral blood flow,increased the number of lectin-stained microvessels,and increased the survival of neurons after traumatic brain injury.During the in vitro experiments,the potential mechanism of miR-491-5 p on neovascularization was explored through quantitative real-time-polymerase chain reaction,which showed that miR-491-5 p expression increased or decreased in brain microvascular endothelial cells after transfection with an miR-491-5 p mimic or inhibitor,respectively.Dual-luciferase reporter and western blot assays verified that metallothionein-2 was a target gene for miR-491-5 p.Cell counting kit 8(CCK-8) assay,flow cytometry,and 2′,7′-dichlorofluorescein diacetate(DCFH-DA) assay results confirmed that the downregulation of miR-491-5 p increased brain microvascular endothelial cell viability,reduced cell apoptosis,and alleviated oxidative stress under oxygen-glucose deprivation conditions.Cell scratch assay,Transwell assay,tube formation assay,and western blot assay results demonstrated that miR-491-5 p downregulation promoted the migration,proliferation,and tube formation of brain microvascular endothelial cells through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor pathway.These findings confirmed that miR-491-5 p downregulation promotes neovascularization,restores cerebral blood flow,and improves the recovery of neurological function after traumatic brain injury.The mechanism may be mediated through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor signaling pathway and the alleviation of oxidative stress.All procedures were approved by Ethics Committee of the First Affiliated Hospital of Chongqing Medical University,China(approval No.2020-304) on June 22,2020.     

Preoperative and postoperative neurological, neuropsychological and behavioral impairment in children with posterior cranial fossa astrocytomas and medulloblastomas: the role of the tumor and the impact of the surgical treatment

Introduction

The aim of the present study was to prospectively investigate if a correlation might exist between preoperative and postoperative neurological conditions, neuroradiological/intraoperative findings and results of a complete neuropsychological evaluation in children with posterior fossa medulloblastomas and astrocytomas.

Materials and methods

Of the 65 children admitted at the Pediatric Neurosurgery of the UCSC of Rome between January 2005 and October 2009, 41 were selected; the only two exclusion criteria were represented by age under 24 months and severe neurological conditions, seen that in both cases it would not have been a possible reliable evaluation. All children underwent a preoperative and immediate postoperative complete MR study. Hydrocephalus was graded on the Evans score; brainstem infiltration was defined on intraoperative findings. Neuropsychological assessment consisted of a battery of tests tailored on the patient’s age, cognitive level, and level of cooperation. Post operative neuropsychological evaluation was performed at a mean time of 2.5 min (2 mos, max 4.5 mos) from the operation, before any eventually needed adjuvant treatment (i.e., chemotherapy, radiotherapy).

Results

Concerning neurological status, we found a statistically significant relation between the presence of oculomotor impairment and both verbal fluency deficits (p?=?0.044) and imagery disorders (p?=?0.03); also, the presence of ataxia/dysmetria was significantly correlated to attention dysfunction (p?=?0.01) and, more tightly, to planning dysfunction (p?=?0.006). For neuroradiological/intraoperative features, Intelligence Quotient (IQ) impairment was significantly correlated to the intraoperative evidence of tumor infiltration of the brainstem (p?=?0.003), a severe hydrocephalus at diagnosis (p?=?0.001) and the histological diagnosis of medulloblastoma (MB) (p?=?0.002). For selective skills, a significant correlation was found between linguistic processing deficits and the evidence of dentate nuclei infiltration (blindly defined on MR); procedural memory defects and imagery disorders related to the severity of the hydrocephalus (p?=?0.02), infiltration of the brain stem (p?=?0.01) and a histological diagnosis of MB (p?=?0.01). After surgery no patient showed a worsening of his/her cognitive profile; the relationships between clinical, intraoperative, and radiological findings were substantially confirmed.

Discussion

Our results support the hypothesis that when present, neuropsychological impairment is already present at diagnosis and that the most statistically significant factors, which might be related with cognitive deficits in the preoperative as well as in the postoperative period, are tumor infiltration of the brainstem, the severity of hydrocephalus, and a histological diagnosis of MB.     

Overexpression of miR-582-5p Inhibits the Apoptosis of Neuronal Cells after Cerebral Ischemic Stroke Through Regulating PAR-1/Rho/Rho Axis

Objective

The purpose of this study was to explore the role of miR-582-5p/proteinase-activated receptors type I (PAR-1)/Rho/Rho in neuronal cell apoptosis after cerebral ischemic stroke (CIS).

Plasma Levels of miR-125b-5p and miR-206 in Acute Ischemic Stroke Patients After Recanalization Treatment: A Prospective Observational Study

Introduction: Multiple microRNAs (miRNAs) participate in the response to hypoxic/ischemic and ischemia-reperfusion events. However, the expression of these miRNAs in circulation from patients with acute ischemic stroke (AIS) receiving recanalization treatment has not been examined, and whether they are associated with the severity and outcome of stroke is still unknown. Materials and methods: In this prospective cohort study, plasma levels of miR-125b-5p, miR-15a-3p, miR-15a-5p, and miR-206 were measured at 24 hours after thrombolysis with or without endovascular treatment in 94 patients with AIS, as determined by qRT-PCR. Stroke severity was assessed based on National Institutes of Health Stroke Scale (NIHSS) score and infarct lesion. Intracranial haemorrhage (ICH) was recorded. An unfavorable outcome was defined as a modified Rankin Scale score greater than 2 at day 90 after stroke. Results: miR-125b-5p and miR-206 levels were correlated with NIHSS scores (P = .014 and P = .002) and cerebral infarction volumes (P = .025 and P = .030). miR-125b-5p levels were significantly higher in patients with an unfavorable outcome than in patients with a favorable outcome (P = .002) and showed good diagnostic accuracy in discriminating the presence of an unfavorable outcome (area under the curve .735, 95% confidence interval .623-.829, P < .001). No association was found between different miRNAs and ICH. Conclusions: In AIS patients after thrombolysis with or without endovascular treatment, miR-125b-5p is a novel prognostic biomarker highly associated with an unfavorable outcome. miR-125b-5p and miR-206 levels are associated with stroke severity.     

Prognosis of pediatric high-grade gliomas with temozolomide treatment: a retrospective, multicenter study

Purpose

We analyzed the usefulness of initial or recurrent treatment of temozolomide (TMZ) in pediatric high-grade gliomas (HGGs).

Methods

Between 2002 and 2010, we performed surgery on 35 patients with 17 glioblastomas, 14 anaplastic astrocytomas, 3 anaplastic oligodendrogliomas, and 1 anaplastic oligoastrocytoma. The male-to-female ratio was 21:14, and the median age was 13?years (range, 3–18?years). The mean follow-up period was 15.9 (±1.8) months. As the TMZ treatment, 22 patients received the initial treatment and 13 patients at recurrence. We analyzed the prognostic significance of TMZ treatment, tumor location, extent of removal, pathology, and recurrence pattern.

Results

The median progression-free survival (PFS) and overall survival (OS) were 9.7 (±1.4) and 17.8 (±2.5) months, respectively. Based on univariate analysis, the median PFS was 9.9 (±1.6) months in the tumors located in the cerebral hemisphere and 5.6 (±1.3) months in the diencephalon (p?=?0.03). Median PFS was 12.5 (±1.7) months in the initial treatment and 6.8 (±0.8) months in the recurrent treatment (p?=?0.03). The median OS was 14.9 (±2.3) months in glioblastomas and 24.4 (±4.1) months in tumors with an anaplastic pathology (p?=?0.01). The median OS was 12.1 (±3.7) months in patients with cerebrospinal fluid (CSF) dissemination and 18.2 (±2.9) months in patients without CSF dissemination (p?=?0.02). Grades 3 and 4 treatment-related toxicity occurred in 7.7–9?% of the patients.

Conclusions

Initial or recurrent TMZ treatment in pediatric HGGs was safe and tolerable. Initial treatment showed improved PFS compared to recurrent treatment, and both showed similar OS.     

Does Affective Valence During and Immediately Following a 10-Min Walk Predict Concurrent and Future Physical Activity?

Background

Affect may be important for understanding physical activity behavior.

Purpose

To examine whether affective valence (i.e., good/bad feelings) during and immediately following a brief walk predicts concurrent and future physical activity.

Methods

At months?6 and 12 of a 12-month physical activity promotion trial, healthy low-active adults (N?=?146) reported affective valence during and immediately following a 10-min treadmill walk. Dependent variables were self-reported minutes/week of lifestyle physical activity at months?6 and 12.

Results

Affect reported during the treadmill walk was cross-sectionally (month?6: ???=?28.6, p?=?0.008; month 12: ???=?26.6, p?=?0.021) and longitudinally (???=?14.8, p?=?0.030) associated with minutes/week of physical activity. Affect reported during a 2-min cool down was cross-sectionally (month 6: ???=?21.1, p?=?0.034; month 12: ???=?30.3, p?<?0.001), but not longitudinally associated with minutes/week of physical activity. Affect reported during a postcool-down seated rest was not associated with physical activity.

Conclusions

During-behavior affect is predictive of concurrent and future physical activity behavior.     

Lithium/Valproic Acid Combination and l-Glutamate Induce Similar Pattern of Changes in the Expression of miR-30a-5p in SH-SY5Y Neuroblastoma Cells

It has been proposed that Lithium (Li) and valproic acid (VPA) may be useful to treat neurodegenerative disorders because they protect neurons against excitotoxic insults both in vitro and in vivo models. Moreover, these two drugs may exert their effects by regulating microRNAs (miRNAs), single-stranded and non-coding RNAs able to control gene expression. A subset of the miR-30a family (miR-30a-5p) is involved in the fine-tuning of neuroprotective molecules such as the neurotrophin brain-derived neurotrophic factor (BDNF). Thus, there is the possibility that Li and VPA may alter miR-30a-5p and in turn affect BDNF production. However, data on miR-30a-5p levels in presence of Li and VPA and/or a neurotoxic insult are not yet available. Thus, the aim of this study was to investigate whether exposure to Li and VPA may influence miR-30a-5p expression in an in vitro model of neurodegeneration generated by the exposure of a human neuroblastoma cell line (SH-SY5Y) to neurotoxic concentration of l-glutamate. The results showed that both l-glutamate and Li–VPA caused an increase in miR-30a-5p expression at 24 h of incubation and a decrease at 48 h. Moreover, Li–VPA alone caused a decrease in miR-30a-5p expression also in cells not exposed to the toxic effect of glutamate. These data indicate that changes in miR-30a-5p expression induced by Li–VPA are not related to the cytoprotective action of BDNF and suggest alternative function for this miR. These findings also indicate that miRNA changes are present in in vitro models of neurodegeneration, although the significance of these changes warrants further investigation.     

The Foramen magnum in isolated and syndromic brachycephaly

Background

Though the foramen magnum (FM) is often altered in complex craniosynostosis, no study analysed the FM dimensions in patients with brachycephaly specifically.

Patients and methods

We measured the FM area, sagittal and transverse diameters on preoperative CT scans in patients with bicoronal synostosis (n?=?40) and age-matched control group (n?=?18). Our study included 16 children with FGFR3 p.Pro250Arg mutation (mean age 6.1 months), 10 with TWIST-1 mutation (mean age7.6 months) and 14 patients with isolated bicoronal synostosis (mean age 6.1).

Results

We observed a significantly smaller FM area in FGFR3 group compared to control group and isolated brachycephaly group (p?=?0.001 and p?=?0.038, respectively). The mean FM area in FGFR3 group was 426.13 mm² (p?=?0.001), while in TWIST-1 group was 476.34 mm² (p?=?0.103), and in isolated brachycephaly group 489.43 mm² (p?=?0.129) compared to control group: 528.90 mm². The posterior segment of the sagittal diameter of the FM and its width as well as the bi-interoccipital synchondrosis diameters were significantly smaller in FGFR3 group compared to control group. In TWIST-1 group, the only altered dimension was the FM anterior segment of the sagittal diameter (p?=?0.008). We did not observe any significant alteration of FM in patients with isolated brachycephaly compared to control group.

Discussion and conclusions

The FM area is significantly altered in FGFR3-related brachycephaly, whereas in patients with Saethre–Chotzen syndrome (TWIST-1 mutation) the mean FM area is similar to control group. This study confirms the importance of FGFRs on FM growth whereas TWIST-1 seems to have a minor role.     

Civil commitment law, mental health services, and US homicide rates

Purpose

The study considers whether involuntary civil comment (ICC) statute provisions are associated with homicide rates. Do statutes based solely upon dangerousness criteria versus broader ICC-criteria—i.e. “need for treatment,” “protection of health and safety,” and family protection–have differential associations related to their goal of reducing the frequency of homicide?

Method

State-level data were obtained from online data bases and key-informant surveys. Ordinary-least-squares and Poisson regression were used to evaluate the association between statute characteristics, mental health system characteristics, and 2004 Homicide Rates after controlling for firearm-control-law restrictiveness and social-economic-demographic-geographic-and-political indicators historically related to homicide rate variation.

Results

Poisson and OLS models, respectively, were significant: likelihood ratio χ²?=?108.47, df?=?10; p?R ²?=?0.72; df?=?10, 25; F?=?10.21; p?p?p?≤?0.01), fewer inpatient-bed access problems (p?≤?0.03), and better mental health system ratings (p?≤?0.04). OLS results indicate that social-economic-demographic-geographic-and-political indicators accounted for 25% of homicide rate variation. Broader ICC-criteria were associated with 1.42 less homicides per 100,000. Less access to psychiatric inpatient-beds and more poorly rated mental health systems were associated with increases in the homicide rates of 1.08 and 0.26 per 100,000, respectively.

Conclusions

While social-economic-demographic-geographic-and-political indicators show the strongest association with homicide rate variation, the results show the importance and potentially preventive utility of broader ICC criteria, increased psychiatric inpatient-bed access, and better performing mental health systems as factors contributing to homicide rate variation.