Neuroprotective modulation of the unfolded protein response in Marinesco-Sj?gren syndrome: PERK signaling inhibition and beyond

<正>Individuals with Marinesco-Sj?gren syndrome(MSS;OMIM 248800),a genetic disease of infancy,suffer various disabilities,including loss of motor coordination due to cerebellar degeneration,and skeletal muscle weakness.After a progressive phase,symptoms stabilize and patients live to old age.Therefore,any pharmacological treatment that delays or attenuates cerebellar degeneration and/or muscle pathology can significantly improve their quality of life.We recently found that inhibiting the protein kinase RNA-like endoplasmic reticulum kinase     

Trabecular Bone Score Reference Values for Children and Adolescents According to Age,Sex, and Ancestry

Trabecular bone score (TBS) is used for fracture prediction in adults, but its utility in children is limited by absence of appropriate reference values. We aimed to develop reference ranges for TBS by age, sex, and population ancestry for youth ages 5 to 20 years. We also investigated the association between height, body mass index (BMI), and TBS, agreement between TBS and lumbar spine areal bone mineral density (aBMD) and bone mineral apparent density (BMAD) Z-scores, tracking of TBS Z-scores over time, and precision of TBS measurements. We performed secondary analysis of spine dual-energy X-ray absorptiometry (DXA) scans from the Bone Mineral Density in Childhood Study (BMDCS), a mixed longitudinal cohort of healthy children (n = 2014) evaluated at five US centers. TBS was derived using a dedicated TBS algorithm accounting for tissue thickness rather than BMI. TBS increased only during ages corresponding to pubertal development with an earlier increase in females than males. There were no differences in TBS between African Americans and non-African Americans. We provide sex-specific TBS reference ranges and LMS values for calculation of TBS Z-scores by age and means and SD for calculation of Z-scores by pubertal stage. TBS Z-scores were positively associated with height Z-scores at some ages. TBS Z-scores explained only 27% and 17% of the variance of spine aBMD and BMAD Z-scores. Tracking of TBS Z-scores over 6 years was lower (r = 0.47) than for aBMD or BMAD Z-scores (r = 0.74 to 0.79), and precision error of TBS (2.87%) was greater than for aBMD (0.85%) and BMAD (1.22%). In sum, TBS Z-scores provide information distinct from spine aBMD and BMAD Z-scores. Our robust reference ranges for TBS in a well-characterized pediatric cohort and precision error estimates provide essential tools for clinical assessment using TBS and determination of its value in predicting bone fragility in childhood and adolescence. © 2022 American Society for Bone and Mineral Research (ASBMR).     

Sexual dimorphism in shape and size of the neurocranium

International Journal of Legal Medicine - Sex identification is a primary step in forensic analysis of skeletal remains. The accuracy of sex estimation methods greatly depends on the sexual...     

Serotonin-induced increase in cAMP in ganglia isolated from the myenteric plexus of the guinea pig small intestine: Mediation by a novel 5-HT receptor

Serotonin (5-HT) is a mediator (through 5-HT_1P receptors) of slow EPSPs in myenteric ganglia of the small intestine. The effect of 5-HT can be mimicked by elevating cAMP; therefore, we tested the hypothesis that the slow EPSP-like response to 5-HT is cAMP-mediated. Guinea pig gut was enzymatically dissociated; myenteric ganglia remained intact and were collected by filtration. Neurons in the isolated ganglia retained their ability to manifest the slow EPSP-like response to 5-HT. Exposure to 5-HT raised the ganglionic level of cAMP (ED₅₀ 0.3 μM). This effect was not antagonized by the 5-HT_1P antagonist, N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide (100.0 μM), or mimicked by the 5-HT_1P agonist, 5-hydroxyindalpine (10.0 μM). Increases in cAMP were also evoked by the 5-HT₁ agonist, 5-carboxyamidotryptamine (10.0 μM), the 5-HT₂ agonist, (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 1.0–10.0 μM), and by the 5-HT₄ agonists, renzapride (1.0–10.0 μM) and 5-methoxytryptamine (1.0–10.0 μM); however, neither the 5-HT₁/5-HT₂ antagonists, spiperone, methysergide, and methiothepin, nor the 5-HT₄ antagonist, tropisetron (ICS 205–930; 10.0 μM), were able to inhibit the rise in cAMP evoked by these compounds or by 5-HT (0.1–10.0 μM). The 5-HT-evoked elevation of cAMP was antagonized by ketanserin (10.0 μM), which also blocked the effects of 5-methoxytryptamine and DOI, but not those of renzapride. The effective concentration of DOI, however, was higher than that needed for activation of 5-HT₂ receptors, and Northern analysis using a cDNA probe encoding the rat 5-HT₂ receptor failed to reveal the presence of 5-HT₂ mRNA in myenteric ganglia, although it hybridizes with mRNA of the right size in the guinea pig brain. Compounds that failed to change levels of cAMP or to antagonize the action of 5-HT included 8-hydroxy-di-n-propylamino tetralin, R58639, R88226, and sumatriptan. It is concluded that the receptor responsible for the 5-HT-induced rise in cAMP in ganglia isolated from the guinea pig myenteric plexus is not a known subtype of 5-HT receptor. Since the pharmacology of this novel receptor is different from that of the slow EPSP-like response to 5-HT, the receptor probably does not mediate the slow EPSP. © 1993 Wiley-Liss, Inc.     

Nucleolin protein expression in cutaneous melanocytic lesions

Background:  Nucleolin is a major nucleolar argyrophilic protein involved in carcinogenesis. There are only few studies on its tissue expression in human cancer and none in melanoma. We aimed at exploring this protein and its prognostic impact in cutaneous melanocytic lesions.
Methods:  We studied 193 cases including benign, dysplastic and malignant melanocytic lesions. Nuclear positivity was evaluated by immunohistochemistry and quantified by automated image analysis.
Results:  Most dysplastic and malignant lesions showed high percentages of cells with abnormal patterns of nuclear positivity (Abn+N) consisting in multiple, irregular, positive dots (ID+) and a coarse, irregularly positive nucleoplasm (CNpl+) or both (ID+CNpl+). The patterns CNpl+ and/or ID+CNpl+ were never observed in benign lesions, in which ID+ were also virtually absent. Abn+N% was significantly lower in dysplastic nevi than in primary melanomas and metastases and in primary melanomas than in metastases (p < 0.05). Furthermore, Abn+N was the second powerful prognostic discriminator, after melanoma thickness, and a significantly lower survival was observed in vertical growth phase melanoma patients showing Abn+N in more than 50% of melanoma cells.
Conclusion:  An altered nuclear nucleolin expression seems to accompany melanoma progression. Further investigation on nucleolin functionality and subcellular trafficking could add information on its altered role in melanoma.     

Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32

Some MCP SNP and aHUS-associated MCP mutation     

Spinal canal narrowing during simulated frontal impact

Between 23 and 70% of occupants involved in frontal impacts sustain cervical spine injuries, many with neurological involvement. It has been hypothesized that cervical spinal cord compression and injury may explain the variable neurological profile described by frontal impact victims. The goals of the present study, using a biofidelic whole cervical spine model with muscle force replication, were to quantify canal pinch diameter (CPD) narrowing during frontal impact and to evaluate the potential for cord compression. The biofidelic model and a sled apparatus were used to simulate frontal impacts at 4, 6, 8, and 10 g horizontal accelerations of the T1 vertebra. The CPD was measured in the intact specimen in the neutral posture (neutral posture CPD), under static sagittal pure moments of 1.5 Nm (pre-impact CPD), during dynamic frontal impact (dynamic impact CPD), and again under static pure moments following each impact (post-impact CPD). Frontal impact caused significant (P<0.05) dynamic CPD narrowing at C0-dens, C2-C3, and C6-C7. The narrowest dynamic CPD was observed at C0-dens during the 10 g impact and was 25.9% narrower than the corresponding neutral posture CPD. Interpretation of the present results indicate that the neurological symptomatology reported by frontal impact victims is most likely not due to cervical spinal cord compression. Cord compression due to residual spinal instability is also not likely.     

Pulp and periodontal healing of laterally luxated permanent teeth: results after 4 years

Abstract – Aim: To evaluate the pulp and periodontal healing of laterally luxated permanent teeth. Material and methods: Patients presenting with lateral luxation of permanent teeth during 2001–2002 were enrolled in this clinical study. Laterally luxated teeth were repositioned and splinted with a TTS/composite resin splint for 4 weeks. Immediate (prophylactic) root‐canal treatment was performed in severely luxated teeth with radiographically closed apices. All patients received tetracycline for 10 days. Re‐examinations were performed after 1, 2, 3, 6, 12 and 48 months. Results: All 47 laterally luxated permanent teeth that could be followed over the entire study period survived. In 10 teeth (21.3%), a prophylactic root‐canal treatment was performed within 2 weeks following injury. The remaining 37 teeth showed the following characteristics at the 4‐year re‐examination: 19 teeth (51.4%) had pulp survival (no clinical or radiographic signs or symptoms), nine teeth (24.3%) presented with pulp canal calcification, and pulp necrosis was seen in another nine teeth (24.3%), within the first year after trauma. None of the teeth with a radiographically open apex at the time of lateral luxation showed complications. External root resorption was only seen in one tooth. Conclusions: Laterally luxated permanent teeth with incomplete root formation have a good prognosis, with all teeth surviving in this study. The most frequent complication was pulp necrosis that was only seen in teeth with closed apices.