Nervous System Response to Neurotrauma: A Narrative Review of Cerebrovascular and Cellular Changes After Neurotrauma.

Neurotrauma is a significant cause of morbidity and mortality worldwide. For instance, traumatic brain injury (TBI) causes more than 30% of all injury-related deaths in the USA annually. The underlying cause and clinical sequela vary among cases. Patients are liable to both acute and chronic changes in the nervous system after such a type of injury. Cerebrovascular disruption has the most common and serious effect in such cases because cerebrovascular autoregulation, which is one of the main determinants of cerebral perfusion pressure, can be effaced in brain injuries even in the absence of evident vascular injury. Disruption of the blood-brain barrier regulatory function may also ensue whether due to direct injury to its structure or metabolic changes. Furthermore, the autonomic nervous system (ANS) can be affected leading to sympathetic hyperactivity in many patients. On a cellular scale, the neuroinflammatory cascade medicated by the glial cells gets triggered in response to TBI. Nevertheless, cellular and molecular reactions involved in cerebrovascular repair are not fully understood yet. Most studies were done on animals with many drawbacks in interpreting results. Therefore, future studies including human subjects are necessarily needed. This review will be of relevance to clinicians and researchers interested in understanding the underlying mechanisms in neurotrauma cases and the development of proper therapies as well as those with a general interest in the neurotrauma field.

Painful Small Fiber Neuropathy Associated With Teriflunomide: A Case Series and Literature Review Related to Teriflunomide and Leflunomide.

Teriflunomide and its prodrug, leflunomide, are disease-modifying medications used to treat relapsing-remitting multiple sclerosis (RRMS) and rheumatoid arthritis (RA), respectively. Peripheral neuropathy is a rare side effect associated with both medications, although the incidence rate and exact pathological mechanism remain unknown. We present a retrospective case series of three patients with RRMS, who developed painful small fiber neuropathy at various timeframes (<6 months, one year, and four years, respectively) while on teriflunomide treatment (14 mg/day); we also engage in a literature review of small and large fiber neuropathy associated with teriflunomide and leflunomide use. All three patients developed small fiber neuropathy following teriflunomide exposure. Laboratory workup was negative for metabolic, infectious, vitamin deficiency-related, and autoimmune etiologies, except for one patient who had chronic metabolic syndromes (impaired glucose, hyperlipidemia) before medication intake. However, the patient developed neuropathy following teriflunomide treatment. Electrophysiological findings were negative for large fiber neuropathy in all three patients with positive skin biopsy, with reduced epidermal nerve fiber density (ENFD) in two of the three patients. Teriflunomide was discontinued in all cases, after which symptoms stabilized. Current literature on leflunomide supports a direct neurotoxic effect or buildup of toxic intermediates from uridine synthesis inhibition. Cessation of teriflunomide use in the described cases resulted in symptom stabilization. Early recognition and treatment may lead to good clinical outcomes in these patients.

Somatosensory Auras in Epilepsy: A Narrative Review of the Literature.

An aura is a subjective experience felt in the initial phase of a seizure. Studying auras is relevant as they can be warning signs for people with epilepsy. The incidence of aura tends to be underestimated due to misdiagnosis or underrecognition by patients unless it progresses to motor features. Also, auras are associated with seizure remission after epilepsy surgery and are an important prognostic factor, guiding the resection site and improving surgical outcomes. Somatosensory auras (SSAs) are characterized by abnormal sensations on one or more body parts that may spread to other parts following a somatotopic pattern. The occurrence of SSAs among individuals with epilepsy can range from 1.42% to 80%. The upper extremities are more commonly affected in SSAs, followed by the lower extremities and the face. The most common type of somatosensory aura is paresthetic, followed by painful and thermal auras. In the primary somatosensory auras, sensations occur more commonly contralaterally, while the secondary somatosensory auras can be ipsilateral or bilateral. Despite the high localizing features of somatosensory areas, cortical stimulation studies have shown overlapping sensations originating in the insula and the supplementary sensorimotor area.

Post-infectious Painful Sensory Neuronopathy Following Giardia Infection Responsive to Intravenous Immunoglobulin Treatment.

Sensory neuronopathy is a rare pure sensory disorder with characteristic clinical features of early-onset ataxia and a multifocal distribution of non-length-dependent sensory deficits. Diabetes is the most common cause of length-dependent peripheral neuropathy. However, in acute to subacute presentations, conditions such as autoimmune diseases, paraneoplastic syndrome, exposure to toxins, and viral infection could be common etiologies. This report presents a patient with sensory neuronopathy following a Giardia infection. Gait disturbance, neuropathic pain, ataxia, and pseudoathetosis improved by varying degrees following the monthly maintenance of intravenous immunoglobulin (IVIG). An immune-mediated or direct pathogenic attack can explain the underlying pathogenesis behind this patient's peripheral nerve dysfunction.

Neutralizing antibody activity against 21 SARS-CoV-2 variants in older adults vaccinated with BNT162b2.

SARS-CoV-2 variants may threaten the effectiveness of vaccines and antivirals to mitigate serious COVID-19 disease. This is of most concern in clinically vulnerable groups such as older adults. We analysed 72 sera samples from 37 individuals, aged 70-89 years, vaccinated with two doses of BNT162b2 (Pfizer-BioNTech) 3 weeks apart, for neutralizing antibody responses to wildtype SARS-CoV-2. Between 3 and 20 weeks after the second vaccine dose, neutralizing antibody titres fell 4.9-fold to a median titre of 21.3 (neutralization dose 80%), with 21.6% of individuals having no detectable neutralizing antibodies at the later time point. Next, we examined neutralization of 21 distinct SARS-CoV-2 variant spike proteins with these sera, and confirmed substantial antigenic escape, especially for the Omicron (B.1.1.529, BA.1/BA.2), Beta (B.1.351), Delta (B.1.617.2), Theta (P.3), C.1.2 and B.1.638 spike variants. By combining pseudotype neutralization with specific receptor-binding domain (RBD) enzyme-linked immunosorbent assays, we showed that changes to position 484 in the spike RBD were mainly responsible for SARS-CoV-2 neutralizing antibody escape. Nineteen sera from the same individuals boosted with a third dose of BNT162b2 contained higher neutralizing antibody titres, providing cross-protection against Omicron BA.1 and BA.2. Despite SARS-CoV-2 immunity waning over time in older adults, booster vaccines can elicit broad neutralizing antibodies against a large number of SARS-CoV-2 variants in this clinically vulnerable cohort.

Pseudotyped Bat Coronavirus RaTG13 is efficiently neutralised by convalescent sera from SARS-CoV-2 infected patients.

RaTG13 is a close relative of SARS-CoV-2, the virus responsible for the COVID-19 pandemic, sharing 96% sequence similarity at the genome-wide level. The spike receptor binding domain (RBD) of RaTG13 contains a number of amino acid substitutions when compared to SARS-CoV-2, likely impacting affinity for the ACE2 receptor. Antigenic differences between the viruses are less well understood, especially whether RaTG13 spike can be efficiently neutralised by antibodies generated from infection with, or vaccination against, SARS-CoV-2. Using RaTG13 and SARS-CoV-2 pseudotypes we compared neutralisation using convalescent sera from previously infected patients or vaccinated healthcare workers. Surprisingly, our results revealed that RaTG13 was more efficiently neutralised than SARS-CoV-2. In addition, neutralisation assays using spike mutants harbouring single and combinatorial amino acid substitutions within the RBD demonstrated that both spike proteins can tolerate multiple changes without dramatically reducing neutralisation. Moreover, introducing the 484 K mutation into RaTG13 resulted in increased neutralisation, in contrast to the same mutation in SARS-CoV-2 (E484K). This is despite E484K having a well-documented role in immune evasion in variants of concern (VOC) such as B.1.351 (Beta). These results indicate that the future spill-over of RaTG13 and/or related sarbecoviruses could be mitigated using current SARS-CoV-2-based vaccination strategies.

Mutations that adapt SARS-CoV-2 to mink or ferret do not increase fitness in the human airway.

SARS-CoV-2 has a broad mammalian species tropism infecting humans, cats, dogs, and farmed mink. Since the start of the 2019 pandemic, several reverse zoonotic outbreaks of SARS-CoV-2 have occurred in mink, one of which reinfected humans and caused a cluster of infections in Denmark. Here we investigate the molecular basis of mink and ferret adaptation and demonstrate the spike mutations Y453F, F486L, and N501T all specifically adapt SARS-CoV-2 to use mustelid ACE2. Furthermore, we risk assess these mutations and conclude mink-adapted viruses are unlikely to pose an increased threat to humans, as Y453F attenuates the virus replication in human cells and all three mink adaptations have minimal antigenic impact. Finally, we show that certain SARS-CoV-2 variants emerging from circulation in humans may naturally have a greater propensity to infect mustelid hosts and therefore these species should continue to be surveyed for reverse zoonotic infections.

Innate Immune Antagonism of Mosquito-Borne Flaviviruses in Humans and Mosquitoes.

Mosquito-borne viruses of the Flavivirus genus (Flaviviridae family) pose an ongoing threat to global public health. For example, dengue, Japanese encephalitis, West Nile, yellow fever, and Zika viruses are transmitted by infected mosquitoes and cause severe and fatal diseases in humans. The means by which mosquito-borne flaviviruses establish persistent infection in mosquitoes and cause disease in humans are complex and depend upon a myriad of virus-host interactions, such as those of the innate immune system, which are the main focus of our review. This review also covers the different strategies utilized by mosquito-borne flaviviruses to antagonize the innate immune response in humans and mosquitoes. Given the lack of antiviral therapeutics for mosquito-borne flaviviruses, improving our understanding of these virus-immune interactions could lead to new antiviral therapies and strategies for developing refractory vectors incapable of transmitting these viruses, and can also provide insights into determinants of viral tropism that influence virus emergence into new species.

Understanding the Mechanisms Underlying Host Restriction of Insect-Specific Viruses.

Arthropod-borne viruses contribute significantly to global mortality and morbidity in humans and animals. These viruses are mainly transmitted between susceptible vertebrate hosts by hematophagous arthropod vectors, especially mosquitoes. Recently, there has been substantial attention for a novel group of viruses, referred to as insect-specific viruses (ISVs) which are exclusively maintained in mosquito populations. Recent discoveries of novel insect-specific viruses over the past years generated a great interest not only in their potential use as vaccine and diagnostic platforms but also as novel biological control agents due to their ability to modulate arbovirus transmission. While arboviruses infect both vertebrate and invertebrate hosts, the replication of insect-specific viruses is restricted in vertebrates at multiple stages of virus replication. The vertebrate restriction factors include the genetic elements of ISVs (structural and non-structural genes and the untranslated terminal regions), vertebrate host factors (agonists and antagonists), and the temperature-dependent microenvironment. A better understanding of these bottlenecks is thus warranted. In this review, we explore these factors and the complex interplay between ISVs and their hosts contributing to this host restriction phenomenon.

Presentations, Causes and Outcomes of Drug-Induced Liver Injury in Egypt.

Drug-induced liver injury (DILI) is a frequent cause of liver injury and acute liver failure. We aimed to review all hospitalized DILI cases in a tertiary Egyptian center from January 2015 through January 2016. Cases with elevated alanine aminotransferase more than 3-fold and/or alkaline phosphatase more than 2-fold the upper limit of normal value were prospectively recruited and followed for one year. Drug history, liver biopsy whenever feasible and application of Roussel Uclaf Causality Assessment Method (RUCAM) were the diagnostic prerequisites after exclusion of other etiologies of acute liver injury. In order of frequency, the incriminated drugs were: Diclofenac (31 cases, 41.3%), amoxicillin-clavulanate (14 cases, 18.7%), halothane toxicity (8 cases, 10.7%), ibuprofen (4 cases, 5.3%), Khat (3 cases, 4%), tramadol (3 cases, 4%), Sofosbuvir with ribavirin (2 cases, 2.7%), and acetylsalicylic acid (2 cases, 2.7%) with one offending drug in 93.3% of cases. Forty-four cases (58.7%) were males; while 56 cases (74.7%) had HCV related chronic liver disease. Thirty-two cases (42.7%) presented with pattern of hepatocellular injury, while 23 cases (30.7%) were with cholestasis, and 20 cases (20.7%) with a mixed hepatocellular/cholestatic injury. One case received a transplant (0.75%), 7 cases died (9.3%), 23 cases (30.6%) developed liver decompensation (hepatic encephalopathy and ascites), and 44 cases completely resolved (58.7%). In conclusion, Diclofenac is the commonest offender in DILI occurrence in an Egyptian cohort. Age and prothrombin concentration were the only predictors of unfavorable outcomes of DILI.

Ultrasound-guided spinal anesthesia for cesarean section in a parturient with spinal metastases.

Preprocedural spinal ultrasound appears to decrease the failure rate and complications of neuraxial anesthesia compared to the conventional landmark technique. It is especially beneficial in difficult cases where conventional palpation technique may fail. We recently encountered a parturient with multiple lumbar and cervical spinal metastatic lesions presenting for cesarean section in the third trimester. We used spinal ultrasound to define the appropriate intervertebral space and measure the distance to the ligamentum flavum-dura mater complex. This greatly helped in administering a safe spinal anesthetic and avoiding general anesthesia which might have been hazardous in this patient.