Anthropometric and physiologic assessment in sleep apnoea patients regarding body fat distribution

Background: Obstructive sleep apnoea (OSA) is characterised by repeated episodes of pauses in breathing during sleep due to obstruction of the upper airway that result in transient hypoxaemia, sleep fragmentation and long-term cardiovascular disease. The most common risk factors for OSA include: obesity, age over 50 and neck circumference of more than 41 cm for females and more than 43 cm in males. Sleep apnoea is more common in men than in women. The aim of the conducted research was to evaluate relations between the anthropometric features connected with adipose tissue distribution and the severity of OSA. Materials and methods: The study was carried out on 180 patients (144 males and 36 females) diagnosed with OSA syndrome. The standard sleep parameters obtained from night polysomnography as well as skin-fat fold thickness and neck circumference and waist-to-hip ratio were analysed. Statistical analysis was performed using STATISTICA 10. Results: It was stated that anthropometric parameters connected with the accu­mulation of adipose tissue in upper body were significantly related to severity of OSA in males (p ≤ 0.05). Body mass index (BMI) was significantly correlated with severity of OSA in females (p ≤ 0.05). Conclusions: In males, there is a connection between the severity of OSA, BMI and a higher accumulation of adipose tissue in upper part of the body measured by neck circumference and shoulder thickness of skin-fat folds, whereas in females only by BMI

Estimation of age at death: examination of variation in cortical bone histology within the human clavicle

Background: Continuously, numerous human remains of unknown identity are revealed all over the world. One of the elements of the identification process may be a proper assessment of a histological section of bone fragments in order to answer questions related to the age of the subject. The aim of the study was to define an optimum bone fragment to obtain samples for histological examination. Materials and methods: The study material consisted of fragments of shafts of left clavicles taken from 39 males and 25 females (aged 22–86). The clavicles came from autopsies conducted between 2005 and 2011 at the Department of Forensic Medicine of Poznan and the Bialystok Medical University. The following were taken into account while estimating the age of the bone remains: clavicle length (CL), clavicle width (CW), clavicle thickness (CT), number of osteons in the field of vision (ON), number of osteons with the Haversian canal of more than 70 μm (HC > 70 μm), average diameter of the Haversian canals (avg. ØHC), area occupied by interstitial lamellae (ILA %), area occupied by osteons (OA %), area occupied by fragments-remnants of osteons remain as irregular arcs of lamellar fragments (OFA %), average thickness of outer circumferential lamellae (avg. OCL, μm), the relation of osteons with the Haversian canal of more than 70 μm in diameter to the total number of osteons (HC > 70 μm, %), at p < 0.00001. The age of the bone remains was estimated using univariate linear regression function. Results: It was determined that the best place for sampling the osseous tissue for the analysis was the shaft of the clavicle. It was stated than the number of osteons with a large diameter increased with age. The relation of osteons with the Haversian canal of more than 70 μm in diameter to the total number of osteons (HC > 70 μm, %). The level of statistical significant was p < 0.00001. All analysed microscopic features of the osseous tissue showed significant statistical changes occurring with age. Conclusions: The exact method for preparing osseous tissue for a microscopic analysis to determine the age of the remains is the preparation of histological sections, as the structure of the osseous tissue does not change while processing the material and the time of preparations is relatively short (7–8 days). The best predictors of age with the use of the function of univariate linear regression were: the diameter of Haversian canal, the number of osteons with Haversian canal of more than 70 μm in diameter, the relation of osteons with Haversian canal bigger than 70 μm in diameter to the total number of osteons as well as fragments of secondary osteons

Behavioral Effects of Congenital Ventromedial Prefrontal Cortex Malformation

Background: A detailed behavioral profile associated with focal congenital malformation of the ventromedial prefrontal cortex (vmPFC) has not been reported previously. Here we describe a 14 year-old boy, B.W., with neurological and psychiatric sequelae stemming from focal cortical malformation of the left vmPFC. Case Presentation: B.W.'s behavior has been characterized through extensive review Patience of clinical and personal records along with behavioral and neuropsychological testing. A central feature of the behavioral profile is severe antisocial behavior. He is aggressive, manipulative, and callous; features consistent with psychopathy. Other problems include: egocentricity, impulsivity, hyperactivity, lack of empathy, lack of respect for authority, impaired moral judgment, an inability to plan ahead, and poor frustration tolerance. Conclusions: The vmPFC has a profound contribution to the development of human prosocial behavior. B.W. demonstrates how a congenital lesion to this cortical region severely disrupts this process

Magnetic Resonance-Guided Laser Interstitial Thermal Therapy for Management of Low-Grade Gliomas and Radiation Necrosis: A Single-Institution Case Series

Background: Laser interstitial thermal therapy (LITT) has emerged as a minimally invasive treatment modality for ablation of low-grade glioma (LGG) and radiation necrosis (RN). Objective: To evaluate the efficacy, safety, and survival outcomes of patients with radiographically presumed recurrent or newly diagnosed LGG and RN treated with LITT. Methods: The neuro-oncological database of a quaternary center was reviewed for all patients who underwent LITT for management of LGG between 1 January 2013 and 31 December 2020. Clinical data including demographics, lesion characteristics, and clinical and radiographic outcomes were collected. Kaplan-Meier analyses comprised overall survival (OS) and progression-free survival (PFS). Results: Nine patients (7 men, 2 women; mean [SD] age 50 [16] years) were included. Patients underwent LITT at a mean (SD) of 11.6 (8.5) years after diagnosis. Two (22%) patients had new lesions on radiographic imaging without prior treatment. In the other 7 patients, all (78%) had surgical resection, 6 (67%) had intensity-modulated radiation therapy and chemotherapy, respectively, and 4 (44%) had stereotactic radiosurgery. Two (22%) patients had lesions that were wild-type IDH1 status. Volumetric assessment of preoperative T1-weighted contrast-enhancing and T2-weighted fluid-attenuated inversion recovery (FLAIR) sequences yielded mean (SD) lesion volumes of 4.1 (6.5) cm(3) and 26.7 (27.9) cm(3), respectively. Three (33%) patients had evidence of radiographic progression after LITT. The pooled median (IQR) PFS for the cohort was 52 (56) months, median (IQR) OS after diagnosis was 183 (72) months, and median (IQR) OS after LITT was 52 (60) months. At the time of the study, 2 (22%) patients were deceased. Conclusions: LITT is a safe and effective treatment option for management of LGG and RN, however, there may be increased risk of permanent complications with treatment of deep-seated subcortical lesions

DNM1 encephalopathy: A new disease of vesicle fission.

ObjectiveTo evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling.MethodsWe reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function.ResultsWe identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.ConclusionsThe phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention

Multifaceted role of BTLA in the control of CD8+ T cell fate after antigen encounter

Purpose: Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown an overall clinical response rate 40%–50% in metastatic melanoma patients. BTLA (B-and-T lymphocyte associated) expression on transferred CD8+ TILs was associated with better clinical outcome. The suppressive function of the ITIM and ITSM motifs of BTLA is well described. Here, we sought to determine the functional characteristics of the CD8+BTLA+TIL subset and define the contribution of the Grb2 motif of BTLA in T-cell costimulation. Experimental Design: We determined the functional role and downstream signal of BTLA in both human CD8+ TILs and mouse CD8+ T cells. Functional assays were used including single-cell analysis, reverse-phase protein array (RPPA), antigen-specific vaccination models with adoptively transferred TCR-transgenic T cells as well as patient-derived xenograft (PDX) model using immunodeficient NOD-scid IL2Rgammanull (NSG) tumor-bearing mice treated with autologous TILs. Results: CD8+BTLA? TILs could not control tumor growth in vivo as well as their BTLA+ counterpart and antigen-specific CD8+BTLA? T cells had impaired recall response to a vaccine. However, CD8+BTLA+ TILs displayed improved survival following the killing of a tumor target and heightened “serial killing” capacity. Using mutants of BTLA signaling motifs, we uncovered a costimulatory function mediated by Grb2 through enhancing the secretion of IL-2 and the activation of Src after TCR stimulation. Conclusions: Our data portrays BTLA as a molecule with the singular ability to provide both costimulatory and coinhibitory signals to activated CD8+ T cells, resulting in extended survival, improved tumor control, and the development of a functional recall response. Clin Cancer Res; 23(20); 6151–64. ©2017 AACR

Not all SCN1A epileptic encephalopathies are Dravet syndrome: Early profound Thr226Met phenotype.

OBJECTIVE: To define a distinct SCN1A developmental and epileptic encephalopathy with early onset, profound impairment, and movement disorder. METHODS: A case series of 9 children were identified with a profound developmental and epileptic encephalopathy and SCN1A mutation. RESULTS: We identified 9 children 3 to 12 years of age; 7 were male. Seizure onset was at 6 to 12 weeks with hemiclonic seizures, bilateral tonic-clonic seizures, or spasms. All children had profound developmental impairment and were nonverbal and nonambulatory, and 7 of 9 required a gastrostomy. A hyperkinetic movement disorder occurred in all and was characterized by dystonia and choreoathetosis with prominent oral dyskinesia and onset from 2 to 20 months of age. Eight had a recurrent missense SCN1A mutation, p.Thr226Met. The remaining child had the missense mutation p.Pro1345Ser. The mutation arose de novo in 8 of 9; for the remaining case, the mother was negative and the father was unavailable. CONCLUSIONS: Here, we present a phenotype-genotype correlation for SCN1A. We describe a distinct SCN1A phenotype, early infantile SCN1A encephalopathy, which is readily distinguishable from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile seizures plus. This disorder has an earlier age at onset, profound developmental impairment, and a distinctive hyperkinetic movement disorder, setting it apart from Dravet syndrome. Remarkably, 8 of 9 children had the recurrent missense mutation p.Thr226Met

Multiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts

Cerebral arachnoid cysts (ACs) are one of the most common and poorly understood types of developmental brain lesion. To begin to elucidate AC pathogenesis, we performed an integrated analysis of 617 patient-parent (trio) exomes, 152,898 human brain and mouse meningeal single-cell RNA sequencing transcriptomes and natural language processing data of patient medical records. We found that damaging de novo variants (DNVs) were highly enriched in patients with ACs compared with healthy individuals (P = 1.57 × 10-33). Seven genes harbored an exome-wide significant DNV burden. AC-associated genes were enriched for chromatin modifiers and converged in midgestational transcription networks essential for neural and meningeal development. Unsupervised clustering of patient phenotypes identified four AC subtypes and clinical severity correlated with the presence of a damaging DNV. These data provide insights into the coordinated regulation of brain and meningeal development and implicate epigenomic dysregulation due to DNVs in AC pathogenesis. Our results provide a preliminary indication that, in the appropriate clinical context, ACs may be considered radiographic harbingers of neurodevelopmental pathology warranting genetic testing and neurobehavioral follow-up. These data highlight the utility of a systems-level, multiomics approach to elucidate sporadic structural brain disease

Sprouty Proteins Inhibit Receptor-mediated Activation of Phosphatidylinositol-specific Phospholipase C

PLCγ03B3 binds Spry1 and Spry2. Overexpression of Spry decreased PLCγ03B3 activity and IP3 and DAG production, whereas Spry-deficient cells yielded more IP3. Spry overexpression inhibited T-cell receptor signaling and Spry1 null T-cells hyperproliferated with TCR ligation. Through action of PLCγ03B3, Spry may influence signaling through multiple receptors