An unusual cause of headache: Expanding your differential.

Giant cell arteritis (GCA) is an inflammatory vasculitis that affects larger blood vessels, like the temporal arteries and the aorta. It is systemic and tends to affect individuals over 50. Common symptoms include headache, jaw pain provoked by chewing, and fever. We present an interesting case of a GCA variant.

NOTCH3 p.Arg1231Cys is markedly enriched in South Asians and associated with stroke.

The genetic factors of stroke in South Asians are largely unexplored. Exome-wide sequencing and association analysis (ExWAS) in 75 K Pakistanis identified NM_000435.3(NOTCH3):c.3691 C > T, encoding the missense amino acid substitution p.Arg1231Cys, enriched in South Asians (alternate allele frequency = 0.58% compared to 0.019% in Western Europeans), and associated with subcortical hemorrhagic stroke [odds ratio (OR) = 3.39, 95% confidence interval (CI) = [2.26, 5.10], p = 3.87 × 10-9), and all strokes (OR [CI] = 2.30 [1.77, 3.01], p = 7.79 × 10-10). NOTCH3 p.Arg231Cys was strongly associated with white matter hyperintensity on MRI in United Kingdom Biobank (UKB) participants (effect [95% CI] in SD units = 1.1 [0.61, 1.5], p = 3.0 × 10-6). The variant is attributable for approximately 2.0% of hemorrhagic strokes and 1.1% of all strokes in South Asians. These findings highlight the value of diversity in genetic studies and have major implications for genomic medicine and therapeutic development in South Asian populations.

Genetic risk factors for COVID-19 and influenza are largely distinct.

Coronavirus disease 2019 (COVID-19) and influenza are respiratory illnesses caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses, respectively. Both diseases share symptoms and clinical risk factors1, but the extent to which these conditions have a common genetic etiology is unknown. This is partly because host genetic risk factors are well characterized for COVID-19 but not for influenza, with the largest published genome-wide association studies for these conditions including >2 million individuals2 and about 1,000 individuals3-6, respectively. Shared genetic risk factors could point to targets to prevent or treat both infections. Through a genetic study of 18,334 cases with a positive test for influenza and 276,295 controls, we show that published COVID-19 risk variants are not associated with influenza. Furthermore, we discovered and replicated an association between influenza infection and noncoding variants in B3GALT5 and ST6GAL1, neither of which was associated with COVID-19. In vitro small interfering RNA knockdown of ST6GAL1-an enzyme that adds sialic acid to the cell surface, which is used for viral entry-reduced influenza infectivity by 57%. These results mirror the observation that variants that downregulate ACE2, the SARS-CoV-2 receptor, protect against COVID-19 (ref. 7). Collectively, these findings highlight downregulation of key cell surface receptors used for viral entry as treatment opportunities to prevent COVID-19 and influenza.

Early Diversification of Membrane Intrinsic Proteins (MIPs) in Eukaryotes.

Membrane intrinsic proteins (MIPs), including aquaporins (AQPs) and aquaglyceroporins (GLPs), form an ancient family of transporters for water and small solutes across biological membranes. The evolutionary history and functions of MIPs have been extensively studied in vertebrates and land plants, but their widespread presence across the eukaryotic tree of life suggests both a more complex evolutionary history and a broader set of functions than previously thought. That said, the early evolution of MIPs remains obscure. The presence of one GLP and four AQP clades across both bacteria and archaea suggests that the first eukaryotes could have possessed up to five MIPs. Here, we report on a previously unknown richness in MIP diversity across all major eukaryotic lineages, including unicellular eukaryotes, which make up the bulk of eukaryotic diversity. Three MIP clades have likely deep evolutionary origins, dating back to the last eukaryotic common ancestor (LECA), and support the presence of a complex MIP repertoire in early eukaryotes. Overall, our findings highlight the growing complexity of the reconstructed LECA genome: the dynamic evolutionary history of MIPs was set in motion when eukaryotes were in their infancy followed by radiative bursts across all main eukaryotic lineages.

The potential anti-arrhythmic effect of SGLT2 inhibitors.

Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) were initially recommended as oral anti-diabetic drugs to treat type 2 diabetes (T2D), by inhibiting SGLT2 in proximal tubule and reduce renal reabsorption of sodium and glucose. While many clinical trials demonstrated the tremendous potential of SGLT2i for cardiovascular diseases. 2022 AHA/ACC/HFSA guideline first emphasized that SGLT2i were the only drug class that can cover the entire management of heart failure (HF) from prevention to treatment. Subsequently, the antiarrhythmic properties of SGLT2i have also attracted attention. Although there are currently no prospective studies specifically on the anti-arrhythmic effects of SGLT2i. We provide clues from clinical and fundamental researches to identify its antiarrhythmic effects, reviewing the evidences and mechanism for the SGLT2i antiarrhythmic effects and establishing a novel paradigm involving intracellular sodium, metabolism and autophagy to investigate the potential mechanisms of SGLT2i in mitigating arrhythmias.

Backup Frontal Drainage System for Urgent Tension Pneumocephalus Management After Chronic Subdural Hematoma Surgery: A Retrospective Cohort Study.

OBJECTIVE: To describe a simple variation of burr hole craniostomy for the management of chronic subdural hematoma (CSDH) that uses a frontal drainage system to facilitate timely decompression in the event of tension pneumocephalus and spares the need for additional surgery. METHODS: We conducted a retrospective analysis of 20 patients with CSDH who underwent burr hole craniostomy and 20 patients who underwent the same procedure alongside the placement of a 5 Fr neonatal feeding tube as a backup drainage for the anterior craniostomy. Depending on the situation, the secondary drain stayed for a maximum of 72 hours to be opened and used in emergency settings for drainage, aspiration, or as a 1-way valve with a water seal. RESULTS: The outcomes of 20 patients who underwent this procedure and 20 controls are described. One patient from each group presented tension pneumocephalus. One was promptly resolved by opening the backup drain under a water seal to evacuate pneumocephalus and the other patient had to undergo a reopening of the craniostomy. CONCLUSIONS: The described variation of burr hole craniostomy represents a low-cost and easy-to-implement technique that can be used for emergency decompression of tension pneumocephalus. It also has the potential to reduce reoperation rates and CSDH recurrence. Prospective controlled research is needed to validate this approach further.

Microwave Imaging System Based on Signal Analysis in a Planar Environment for Detection of Abdominal Aortic Aneurysms.

A proof-of-concept of a microwave imaging system for the fast detection of abdominal aortic aneurysms is shown. This experimental technology seeks to overcome the factors hampering the fast screening for these aneurysms with the usual equipment, such as high cost, long-time operation or hazardous exposure to chemical substances. The hardware system is composed of 16 twin antennas mastered by a microcontroller through a switching network, which connects the antennas to the measurement instrument for sequential measurement. The software system is run by a computer, mastering the whole system, automatizing the measurement process and running the signal processing and medical image generation algorithms. Two image generation algorithms are tested: Delay-and-Sum (DAS) and Improved Delay-and-Sum (IDAS). Own-modified versions of these algorithms adapted to the requirements of our system are proposed. The system is carefully calibrated and fine-tuned with known objects placed at known distances. An experimental proof-of-concept is shown with a human torso phantom, including an aorta phantom and an aneurysm phantom placed in different positions. The results show good imaging capabilities with the potential for detecting and locating possible abdominal aortic aneurysms and reporting acceptable errors.

Diversity and Molecular Evolution of Antimicrobial Peptides in Caecilian Amphibians.

Antimicrobial peptides (AMPs) are key molecules in the innate immune defence of vertebrates with rapid action, broad antimicrobial spectrum, and ability to evade pathogen resistance mechanisms. To date, amphibians are the major group of vertebrates from which most AMPs have been characterised, but most studies have focused on the bioactive skin secretions of anurans (frogs and toads). In this study, we have analysed the complete genomes and/or transcriptomes of eight species of caecilian amphibians (order Gymnophiona) and characterised the diversity, molecular evolution, and antimicrobial potential of the AMP repertoire of this order of amphibians. We have identified 477 candidate AMPs within the studied caecilian genome and transcriptome datasets. These candidates are grouped into 29 AMP families, with four corresponding to peptides primarily exhibiting antimicrobial activity and 25 potentially serving as AMPs in a secondary function, either in their entirety or after cleavage. In silico prediction methods were used to identify 62 of those AMPs as peptides with promising antimicrobial activity potential. Signatures of directional selection were detected for five candidate AMPs, which may indicate adaptation to the different selective pressures imposed by evolutionary arms races with specific pathogens. These findings provide encouraging support for the expectation that caecilians, being one of the least-studied groups of vertebrates, and with ~300 million years of separate evolution, are an underexplored resource of great pharmaceutical potential that could help to contest antibiotic resistance and contribute to biomedical advance.

Soluble and insoluble lysates from the human A53T mutant α-synuclein transgenic mouse model induces α-synucleinopathy independent of injection site.

Pathological aggregation of a-synuclein (aS) is implicated in the pathogenesis of Parkinson's disease (PD) and other a-synucleinopathies. The current view is that neuron-to-neuron spreading of aS pathology contributes to the progression of a-synucleinopathy. We used an A53T mutant human aS transgenic mouse model (TgA53T) to examine whether the site of pathogenic aS inoculation affects the pattern of neuropathology and whether soluble and insoluble fractions derived from crude pathogenic tissue lysates exhibit differential capacities to initiate aS pathology. To test whether the inoculation site impacts the ultimate spatial/temporal patterns of aS pathology, aS preformed fibrils (PFF), or brain homogenates from TgA53T mice with a-synucleinopathy, were injected into the cortex/striatum, brain stem, or skeletal muscle. In all cases, inoculation of pathogenic aS induced end-stage motor dysfunction within ~100 days post-inoculation (dpi). Significantly, irrespective of the inoculation sites, ultimate distribution of the aS pathology was like that seen in normally aged TgA53T mice at end-stage, indicating that the intrinsic neuronal vulnerability is a significant determinant in the induction of aS pathology, even when initiated by inoculation of pathogenic aS. Temporal analysis of brain stem injected TgA53T mice show that initial aS pathology was seen by 30 days post-inoculation and inflammatory changes occur at later stages. To determine if the aS species with differential solubility are differentially pathogenic, brain lysates from end-stage TgA53Tmice were fractionated into highly soluble (S150) and insoluble (P150) fractions, as well as the endoplasmic reticulum (ER)-enriched fraction (P100). Significantly, all fractions were able to seed de novo aS pathology in vivo, when injected unilaterally into TgA53Tmice with the ER fractions being most pathogenic. Our results suggest that multiple aS species from brain can initiate the development of progressive aS pathology.