33 research outputs found
Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification.
Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification
A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease
Purpose: The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families. Methods: To investigate the genetic cause of the disease, exome or genome sequencing were performed in 5 unrelated families identified via different research networks and Matchmaker Exchange. Deep clinical and brain imaging evaluations were performed by clinical pediatric neurologists and neuroradiologists. The functional effect of the candidate variant on both MED11 RNA and protein was assessed using reverse transcriptase polymerase chain reaction and western blotting using fibroblast cell lines derived from 1 affected individual and controls and through computational approaches. Knockouts in zebrafish were generated using clustered regularly interspaced short palindromic repeats/Cas9. Results: The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death. Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits. A zebrafish knockout model recapitulates key clinical phenotypes. Conclusion: Loss of the C-terminal of MED subunit 11 may affect its binding efficiency to other MED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration
PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation.
OBJECTIVE: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. METHODS: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. RESULTS: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5'-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. INTERPRETATION: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225-240
Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome
Background: Pathogenic variants of GNB5 encoding the β5 subunit of the guanine nucleotide-binding protein cause IDDCA syndrome, an autosomal recessive neurodevelopmental disorder associated with cognitive disability and cardiac arrhythmia, particularly severe bradycardia. Methods: We used echocardiography and telemetric ECG recordings to investigate consequences of Gnb5 loss in mouse. Results: We delineated a key role of Gnb5 in heart sinus conduction and showed that Gnb5-inhibitory signalling is essential for parasympathetic control of heart rate (HR) and maintenance of the sympathovagal balance. Gnb5-/- mice were smaller and had a smaller heart than Gnb5+/+ and Gnb5+/-, but exhibited better cardiac function. Lower autonomic nervous system modulation through diminished parasympathetic control and greater sympathetic regulation resulted in a higher baseline HR in Gnb5-/- mice. In contrast, Gnb5-/- mice exhibited profound bradycardia on treatment with carbachol, while sympathetic modulation of the cardiac stimulation was not altered. Concordantly, transcriptome study pinpointed altered expression of genes involved in cardiac muscle contractility in atria and ventricles of knocked-out mice. Homozygous Gnb5 loss resulted in significantly higher frequencies of sinus arrhythmias. Moreover, we described 13 affected individuals, increasing the IDDCA cohort to 44 patients. Conclusions: Our data demonstrate that loss of negative regulation of the inhibitory G-protein signalling causes HR perturbations in Gnb5-/- mice, an effect mainly driven by impaired parasympathetic activity. We anticipate that unravelling the mechanism of Gnb5 signalling in the autonomic control of the heart will pave the way for future drug screening
Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study
Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised
THE LANGUAGE OF OCCUPATION IN PALESTINE
The analysis of political discourse under occupation reflects the spirit of new orientaliism in the Middle East. The objective of orientalism is to create two contrastive pictures of two types of people , a powerful brilliant and civilized nation hungry for control and sovereignty against a powerless uncivilized nation whose aspiration does not go beyond struggle by all means for survival including terrorism and obsequiousness.
This is the case of the Israeli occupation in Palestine. The realization of power through language is evident in the quotes of hate speech of the Israelis. The aspects of hate speech project the ideology of occupation. Such aspects will be analyzed to explore the linguistic features of such language. In analyzing the linguistic means to spread hatred in the interest of power, speech acts by the authorities in power (statement, question, command, promise, threat, etc.) are important, because they enforce their interests. Some speech acts are associated with special supporting conventions that enforce one’s power and serve one’s interests such as insult and slander, condemnation, and so forth (Brekle, 1989). It has been noticed that such speech conventions of insults and slander are abundant in the Israeli quotes.
Applying Grice’s maxims to Israeli quotes, it is found that, by motivation of power, such quotes meet, to a large extenct, clarity, brevity, relation and truthfulness; however, the quotes of Palestinians, motivated by lack of power, barely meet Grice’s maxims. The main arguments in the Israeli ideology are supported by prejudice keywwords supporting the main arguments like use of imagery and metaphor in particular, i.e., images of hated creatures, killing, arrogance, deception and lies.The focus here is on: 1- the Israeli discursive position as power; 2- discursive position of the Palestiniians lacking power; and 3- the asymmetrical discursive relation between the Israelis and Palestinians
Enhancing intrusion detection in IoT networks using machine learning-based feature selection and ensemble models
Internet of Things (IoT) technology has evolved significantly, transitioning from personal devices to powering smart cities and global deployments across diverse industries. However, security challenges arise due to diverse devices using various protocols and having limited computational capabilities, leading to vulnerabilities and potential intrusions in IoT networks. This paper addresses the challenge of intrusion detection in IoT by introducing a heterogeneous machine learning-based stack classifier model for IoT data. The model employs feature selection and ensemble modelling to investigate and enhance key classification metrics for intrusion detection of IoT data. This approach comprises two core components: the utilization of the K-Best algorithm for feature selection, extracting the top 15 critical features and the construction of an ensemble model incorporating various traditional machine learning models. The integration of these components harnesses information from selected features and leverages the collective strength of individual models to enhance classification performance. Using the ‘Ton IoT dataset,’ our experiments compare the ensemble model with individual ones. This research aims to improve key classification metrics for IoT intrusion detection, focusing on accuracy, precision, recall and F1 score. Through rigorous experimentation and comparisons, the proposed ensemble approach showcases exceptional performance, providing a robust solution to fortify IoT network security
The cross-talk between lateral sheet dimensions of pristine graphene oxide nanoparticles and Ni2+ adsorption
This study investigated the removal of nickel(II) ions by using two sizes of graphene oxide nanoparticles (GO – 450 nm and GO – 200 nm). The thickness and lateral sheet dimensions of GO are considered to be an important adsorbent and promising method for sufficient removal of metals like nickel, lead, copper, etc. The graphite oxide was prepared by oxidation–reduction reaction (Hummers method), and the final product was labelled as GO – 450 nm. A tip sonicator was used to reduce the size of particles to 200 nm under controlled conditions (time and power of sonication). FTIR spectroscopy shows that both sizes of GO particles contain several types of oxygen groups distributed onto the surface of GO particles. Scanning electron microscopy (SEM) and the statistical analysis confirmed the formation of these two sizes of GO particles. The GO – 200 nm performed better removal of Ni(II) compared with GO – 450 nm, due to more surfaces being available. The adsorption capacity of GO particles increased drastically from 45 mg g−1 to 75 mg g−1 for GO – 450 nm and GO – 200 nm respectively, these values were carried out after 2 h of incubation. The kinetics of adsorption and several parameters like initial concentration at equilibrium, pH, temperature, and adsorbent dose are controlled and studied by using UV-visible spectroscopy. The results indicated a significant potential of GO – 200 nm as an adsorbent for Ni(II) ion removal. An additional experiment was performed to estimate the surface area of GO – 450 nm and GO – 200 nm, the results show that the surface areas of GO – 450 nm and GO – 200 nm are 747.8 m2 g−1 and 1052.2 m2 g−1 respectively
Nurses' attitude towards patients with mental illness in a general hospital in Kuwait
Introduction: Stigma and discrimination have been reported to cause unnecessary delay in mentally-ill patients seeking help, which adversely affects a patient's outcome. The attitude of health care professionals has been described as being, even more, negative than that of the general public, which worsens the prognosis for patients with a mental illness.
Aims: The aim of this study was to describe the attitude of nurses toward mentally-ill patients in a general hospital.
Methods: All the nurses in the hospital were administered a 40-item Community Attitudes Toward the Mentally-Ill (CAMI) questionnaire which determines whether the mentally-ill are viewed as “inferior;” deserve “sympathy;” perceived as a “threat” to society or “acceptable” if residing in community dwellings. The analysis of variance was performed to determine association of the four subscales with the individual characteristics, including age, gender, education, qualification type, position held, contact and contact type.
Results: Out of a total of 990 nurses, 308 (31%) completed the CAMI questionnaire. The mean scores for the authoritarian (2.85), benevolent (3.66), social restrictiveness (2.97) and community mental health ideology (3.48) subscales reflected a negative attitude of nurses toward mentally-ill patients. The direct or indirect utilization of the mental health facilities resulted in significantly higher authoritarian and lower benevolence scores, indicating a positive attitude change in this group of nurses.
Conclusion: Despite the small size and selective nature of the sample, the nurses' negative attitude toward the mentally-ill patients provides useful baseline data for further large-scale studies and underscores the need for psychoeducation of different health care professionals, including nurses
Calcium Phosphate Spacers for the Local Delivery of Sitafloxacin and Rifampin to Treat Orthopedic Infections: Efficacy and Proof of Concept in a Mouse Model of Single-Stage Revision of Device-Associated Osteomyelitis
Osteomyelitis is a chronic bone infection that is often treated with adjuvant antibiotic-impregnated poly(methyl methacrylate) (PMMA) cement spacers in multi-staged revisions. However, failure rates remain substantial due to recurrence of infection, which is attributed to the poor performance of the PMMA cement as a drug release device. Hence, the objective of this study was to design and evaluate a bioresorbable calcium phosphate scaffold (CaPS) for sustained antimicrobial drug release and investigate its efficacy in a murine model of femoral implant-associated osteomyelitis. Incorporating rifampin and sitafloxacin, which are effective against bacterial phenotypes responsible for bacterial persistence, into 3D-printed CaPS coated with poly(lactic co-glycolic) acid, achieved controlled release for up to two weeks. Implantation into the murine infection model resulted in decreased bacterial colonization rates at 3- and 10-weeks post-revision for the 3D printed CaPS in comparison to gentamicin-laden PMMA. Furthermore, a significant increase in bone formation was observed for 3D printed CaPS incorporated with rifampin at 3 and 10 weeks. The results of this study demonstrate that osteoconductive 3D printed CaPS incorporated with antimicrobials demonstrate more efficacious bacterial colonization outcomes and bone growth in a single-stage revision in comparison to gentamicin-laden PMMA requiring a two-stage revision