The COL6A5-p.Glu2272* mutation induces chronic itch in mice.

Pruritus is a common irritating sensation that provokes the desire to scratch. Environmental and genetic factors contribute to the onset of pruritus. Moreover, itch can become a major burden when it becomes chronic. Interestingly, the rare Collagen VI alpha 5 (COL6A5) gene variant p.Glu2272* has been identified in two families and an independent patient with chronic neuropathic itch. These patients showed reduced COL6A5 expression in skin and normal skin morphology. However, little progress has been made until now toward understanding the relationships between this mutation and chronic itch. Therefore, we developed the first mouse model that recapitulates COL6A5-p.Glu2272* mutation using the CRISPR-Cas technology and characterized this new mouse model. The mutant mRNA, measured by RT-ddPCR, was expressed at normal levels in dorsal root ganglia and was decreased in skin. The functional exploration showed effects of the mutation with some sex dysmorphology. Mutant mice had increased skin permeability. Elevated spontaneous scratching and grooming was detected in male and female mutants, with increased anxiety-like behavior in female mutants. These results suggest that the COL6A5-p.Glu2272* mutation found in patients contributes to chronic itch and induces in mice additional behavioral changes. The COL6A5-p.Glu2272* mouse model could elucidate the pathophysiological mechanisms underlying COL6A5 role in itch and help identify potential new therapeutic targets.

Mechanisms and management of cough in interstitial lung disease.

INTRODUCTION: Many patients with interstitial lung diseases (ILDs), especially fibrotic ILDs, experience chronic cough. It negatively impacts both physical and psychological well-being. Effective treatment options are limited. AREAS COVERED: The pathophysiology of chronic cough in IPF is complex and involves multiple mechanisms, including mechanical distortion of airways, parenchyma, and nerve fibers. The pathophysiology of cough in other fibrosing ILDs is poorly understood and involves various pathways. The purpose of this review is to highlight mechanisms of chronic cough and to present therapeutic evidence for its management in the most commonly occurring diffuse fibrosing lung diseases including idiopathic pulmonary fibrosis (IPF), connective tissue disease-related interstitial lung disease (CTD-ILD), sarcoidosis-related ILD (Sc-ILD), chronic hypersensitivity pneumonitis-related ILD (CHP-ILD), and post-COVID-19-related interstitial lung disease (PC-ILD). EXPERT OPINION: This review guides the management of chronic cough in fibrosing ILDs. In this era of precision medicine, chronic cough management should be individualized in each interstitial lung disease.

The Human SCN10AG1662S Point Mutation Established in Mice Impacts on Mechanical, Heat, and Cool Sensitivity.

The voltage-gated sodium channel NAV1.8 is expressed in primary nociceptive neurons and is involved in pain transmission. Mutations in the SCN10A gene (encoding NAV1.8 channel) have been identified in patients with idiopathic painful small fiber neuropathy (SFN) including the SCN10AG1662S gain-of-function mutation. However, the role of this mutation in pain sensation remains unknown. We have generated the first mouse model for the G1662S mutation by using homologous recombination in embryonic stem cells. The corresponding Scn10aG1663S mouse line has been analyzed for Scn10a expression, intraepidermal nerve fiber density (IENFD), and nociception using behavioral tests for thermal and mechanical sensitivity. The Scn10aG1663S mutants had a similar Scn10a expression level in dorsal root ganglia (DRG) to their wild-type littermates and showed normal IENFD in hindpaw skin. Mutant mice were more sensitive to touch than wild types in the von Frey test. In addition, sexual dimorphism was observed for several pain tests, pointing to the relevance of performing the phenotypical assessment in both sexes. Female homozygous mutants tended to be more sensitive to cooling stimuli in the acetone test. For heat sensitivity, male homozygous mutants showed shorter latencies to radiant heat in the Hargreaves test while homozygous females had longer latencies in the tail flick test. In addition, mutant males displayed a shorter reaction latency on the 54°C hot plate. Collectively, Scn10aG1663S mutant mice show a moderate but consistent increased sensitivity in behavioral tests of nociception. This altered nociception found in Scn10aG1663S mice demonstrates that the corresponding G1662 mutation of SCN10A found in SFN patients with pain contributes to their pain symptoms.

Region-specific amyloid-ß accumulation in the olfactory system influences olfactory sensory neuronal dysfunction in 5xFAD mice.

BACKGROUND: Hyposmia in Alzheimer's disease (AD) is a typical early symptom according to numerous previous clinical studies. Although amyloid-ß (Aß), which is one of the toxic factors upregulated early in AD, has been identified in many studies, even in the peripheral areas of the olfactory system, the pathology involving olfactory sensory neurons (OSNs) remains poorly understood. METHODS: Here, we focused on peripheral olfactory sensory neurons (OSNs) and delved deeper into the direct relationship between pathophysiological and behavioral results using odorants. We also confirmed histologically the pathological changes in 3-month-old 5xFAD mouse models, which recapitulates AD pathology. We introduced a numeric scale histologically to compare physiological phenomenon and local tissue lesions regardless of the anatomical plane. RESULTS: We observed the odorant group that the 5xFAD mice showed reduced responses to odorants. These also did not physiologically activate OSNs that propagate their axons to the ventral olfactory bulb. Interestingly, the amount of accumulated amyloid-ß (Aß) was high in the OSNs located in the olfactory epithelial ectoturbinate and the ventral olfactory bulb glomeruli. We also observed irreversible damage to the ectoturbinate of the olfactory epithelium by measuring the impaired neuronal turnover ratio from the basal cells to the matured OSNs. CONCLUSIONS: Our results showed that partial and asymmetrical accumulation of Aß coincided with physiologically and structurally damaged areas in the peripheral olfactory system, which evoked hyporeactivity to some odorants. Taken together, partial olfactory dysfunction closely associated with peripheral OSN's loss could be a leading cause of AD-related hyposmia, a characteristic of early AD.

Hypothermia-Related Acute Pancreatitis.

Acute pancreatitis (AP) is an inflammatory disease presenting from mild localized inflammation to severe infected necrotic pancreatic tissue. In the literature, there are a few cases of hypothermia-induced AP. However, the association between hypothermia and AP is still a myth. Generally, mortality from acute pancreatitis is nearly 3-6%. Here, we present a 40-year-old chronic alcoholic female who presented with acute pancreatitis induced by transient hypothermia. A 40-year-old chronic alcoholic female was hypothermic at 81°F on arrival which was improved to 91.7°F with warming blanket and then around 97°F in 8 h. Laboratory tests including complete blood count, lipid panel, and comprehensive metabolic panels were within the normal limit. Serum alcohol level was 0.01, amylase 498, lipase 1,200, ammonia 26, serum carboxyhemoglobin level 2.4, and ß-HCG was negative. The entire sepsis workup was negative. During rewarming period, she had one episode of witnessed generalized tonic-clonic seizure. It was followed by transient hypotension. Fluid challenge was successful with 2 L of normal saline. Sonogram (abdomen) showed fatty liver and trace ascites. CAT scan (abdomen and pelvis) showed evidence of acute pancreatitis without necrosis, peripancreatic abscess, pancreatic mass, or radiopaque gallstones. The patient was managed medically and later discharged from the hospital on the 4th day as she tolerated a normal low-fat diet. In our patient, transient hypothermia from chronic alcohol abuse and her social circumstances might predispose to microcirculatory disturbance resulting in acute pancreatitis. Early and aggressive fluid resuscitation prevents complications.

Catamenial anaphylaxis: a woman under monthly progesterone curse.

Catamenial or cyclical anaphylaxis is a complex clinical syndrome with poorly reported incidence and prevalence in the literature review. The underlying mechanism is still a myth although a few proposed hypotheses are stated. Early recognition of these symptoms will bring optimal treatment and prevent unnecessary intubation and complications. Here, we present a 48-year-old woman without significant medical and family history with recurrent angioedema in the setting of catamenial anaphylaxis or cyclical anaphylaxis in the setting of progesterone hypersensitivity.

Distinct amyloid precursor protein processing machineries of the olfactory system.

Processing of amyloid precursor protein (APP) occurs through sequential cleavages first by ß-secretase and then by the γ-secretase complex. However, abnormal processing of APP leads to excessive production of ß-amyloid (Aß) in the central nervous system (CNS), an event which is regarded as a primary cause of Alzheimer's disease (AD). In particular, gene mutations of the γ-secretase complex-which contains presenilin 1 or 2 as the catalytic core-could trigger marked Aß accumulation. Olfactory dysfunction usually occurs before the onset of typical AD-related symptoms (eg, memory loss or muscle retardation), suggesting that the olfactory system may be one of the most vulnerable regions to AD. To date however, little is known about why the olfactory system is affected so early by AD prior to other regions. Thus, we examined the distribution of secretases and levels of APP processing in the olfactory system under either healthy or pathological conditions. Here, we show that the olfactory system has distinct APP processing machineries. In particular, we identified higher expressions levels and activity of γ-secretase in the olfactory epithelium (OE) than other regions of the brain. Moreover, APP c-terminal fragments (CTF) are markedly detected. During AD progression, we note increased expression of presenilin2 of γ-secretases in the OE, not in the OB, and show that neurotoxic Aß*56 accumulates more quickly in the OE. Taken together, these results suggest that the olfactory system has distinct APP processing machineries under healthy and pathological conditions. This finding may provide a crucial understanding of the unique APP-processing mechanisms in the olfactory system, and further highlights the correlation between olfactory deficits and AD symptoms.

Knowledge attitude and practices of undergraduate students regarding first aid measures.

OBJECTIVES: To assess knowledge, attitude and practices of first aid measures in undergraduate students of Karachi. METHODS: A cross-sectional study was carried out at six colleges of Karachi, three of which were medical colleges and three non-medical colleges. Knowledge was assessed regarding various emergency situations with the help of a questionnaire. The target population size was 460, based on 50% prevalence and 95% confidence interval. The eventual sample size achieved was 446. RESULTS: A total of 446 students were interviewed. Seventy eight students (17.5%) had formal First Aid (FA) training. The mean number of correct answers of students with FA training was 10.3 (+/- 3.5) as opposed to 8.58 (+/- 4.0) in those without FA training (p < 0.001, 95% CI) with a mean difference of 7.84%. The mean number of correct answers by medical students with FA training was 11.2 (+/- 2.9) as opposed to 7.2 (+/- 3.43) by non-medical students (p < 0.001, 95% CI) with a mean difference of 18.14%. Students having received formal first aid training scored better than those who had not (p < 0.001). CONCLUSION: First aid training programmes should be introduced at school and college level in developing countries to decrease the early mortality and morbidity of accidents and emergencies.