In this issue of the
Journal,
there are reports describing in detail three patients in whom progressive multifocal leukoencephalopathy (PML) developed during treatment with natalizumab, a humanized ...monoclonal antibody against α
4
integrins.
1
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3
These patients were among 3000 who had participated in clinical trials of natalizumab for the treatment of multiple sclerosis or Crohn's disease. PML is a deadly opportunistic infection of the central nervous system (CNS) for which there is no specific treatment. It is caused by reactivation of a clinically latent JC polyomavirus infection. This virus infects and destroys oligodendrocytes, leading to multifocal areas of demyelination and . . .
BACKGROUND:Approximately 1 million new cases of herpes zoster (HZ) occur in the United States annually, including 10%–20% with herpes zoster ophthalmicus (HZO). Postherpetic neuralgia, a debilitating ...pain syndrome occurs in 30% HZ, whereas 50% HZO develop ophthalmic complications. Diplopia from cranial nerve palsy occurs in less than 30% HZO, whereas optic neuropathy is seen in less than 1% HZO. We reviewed recent developments in the diagnosis, treatment, and prevention of HZ as well as neurological and ophthalmological complications of relevance to the neuro-ophthalmologist.
EVIDENCE ACQUISITION:We searched the English language literature on Pubmed and Google scholar for articles relevant to the various sections of this review.
RESULTS:Antiviral treatment should be initiated within 48–72 hours of onset of HZ and HZO to decrease pain and reduce complications. We recommend neuroimaging in all patients with neuro-ophthalmic manifestations such as diplopia and acute vision loss. Diagnostic confirmation using polymerase chain reaction and serology on paired serum and cerebrospinal fluid samples should be obtained in those with neurological signs and symptoms or abnormal imaging. Patients with neurological and/or retinal varicella zoster virus (VZV) infection should be treated promptly with intravenous acyclovir. Patients with isolated optic neuropathy or cranial nerve palsy can be managed with oral antivirals. The prognosis for visual recovery is good for patients with isolated optic neuropathy and excellent for patients with isolated ocular motor cranial nerve palsy.
CONCLUSIONS:HZ produces a spectrum of potentially blinding and life-threatening complications that adversely affect quality of life and increase health care costs. Individuals at risk for HZ, such as the elderly and immunocompromised, should be encouraged to receive the highly effective VZV vaccine to prevent HZ and its complications.
Progressive multifocal leukoencephalopathy (PML) is a rare, but serious, complication encountered in patients treated with a select number of disease-modifying therapies (DMTs) utilized in treating ...multiple sclerosis (MS). PML results from a viral infection in the brain for which the only demonstrated effective therapy is restoring the perturbed immune system—typically achieved in the patient with MS by removing the offending therapeutic agent or, in the case of HIV-associated PML, treatment with highly active antiretroviral therapies. Other therapies for PML remain either ineffective or experimental. Significant work to understand the virus and host interaction has been undertaken, but lack of an animal model for the disorder has significantly hindered progress, especially with respect to development of treatments. Strategies to limit risk of PML with natalizumab, a drug that carries a uniquely high risk for the development of the disorder, have been developed. Identifying factors such as positive JC virus antibody status that increase PML risk, at least in theory, should decrease the incidence rate of the disease. Whether other risk factors for PML can be identified and validated or unique strategies should be employed in association with other DMTs that predispose to PML and whether this has a salutary effect on outcome remains to be demonstrated. Identifying PML early, then promptly eliminating drug in the case of natalizumab-associated PML has demonstrated better outcomes, but the complication of PML continues to carry significant morbidity and mortality. While the scientific community has yet to identify targeted therapy with proven efficacy against JCV or PML there are several candidates being studied.
Ongoing research on martian meteorites and a new set of observations of carbonate minerals provided by an unprecedented series of robotic missions to Mars in the past 15 years help define new ...constraints on the history of martian climate with important crosscutting themes including: the CO
2
budget of Mars, the role of Mg-, Fe-rich fluids on Mars, and the interplay between carbonate formation and acidity.
Carbonate minerals have now been identified in a wide range of localities on Mars as well as in several martian meteorites. The martian meteorites contain carbonates in low abundances (<1 vol.%) and with a wide range of chemistries. Carbonates have also been identified by remote sensing instruments on orbiting spacecraft in several surface locations as well as in low concentrations (2–5 wt.%) in the martian dust. The Spirit rover also identified an outcrop with 16 to 34 wt.% carbonate material in the Columbia Hills of Gusev Crater that strongly resembled the composition of carbonate found in martian meteorite ALH 84001. Finally, the Phoenix lander identified concentrations of 3–6 wt.% carbonate in the soils of the northern plains.
The carbonates discovered to date do not clearly indicate the past presence of a dense Noachian atmosphere, but instead suggest localized hydrothermal aqueous environments with limited water availability that existed primarily in the early to mid-Noachian followed by low levels of carbonate formation from thin films of transient water from the late Noachian to the present. The prevalence of carbonate along with evidence for active carbonate precipitation suggests that a global acidic chemistry is unlikely and a more complex relationship between acidity and carbonate formation is present.
Relativistic effects are known to alter the chemical bonds and spectroscopic properties of heavy‐element compounds. In this work, we introduce the concept of spin–orbit (SO) electronegativity of a ...heavy atom, as reflected by an SO‐induced change in the interatomic distance between the heavy atom (HA) and a neighboring light atom (LA). We provide a transparent interpretation of these SO effects by using the concept of spin–orbit electron deformation density (SO‐EDD). Spin–orbit coupling at the HA induces rearrangement of the electron density for the scalar‐relativistically optimized geometry that, in turn, exerts a new force on the LA. The resulting expansion or contraction of the HA−LA bond depends on the nature and electron configuration of the HA. In addition, we quantify the change in atomic electronegativity induced by SO coupling for a series of hydrides, thereby complementing the SO‐EDD picture. The trends in the SO‐induced electronegativity and the HA−LA bond length across the periodic table of elements are demonstrated and interpreted, and also linked, intuitively, with the SO‐induced NMR shielding at the LA.
Relativistic spin–orbit electronegativity and the periodic table. The relativistic spin–orbit coupling associated with the presence of a heavy atom in a molecule is shown to have a significant effect on the electron charge density, HA−LA bond distance, and NMR shielding at a neighboring light atom. This phenomenon is transparently interpreted across the periodic table of elements by the SO‐induced rearrangement of the electron density and electronegativity of the HA.
The risk algorithm for natalizumab-associated PML was first established in 2012 using the observations that JC virus antibody status, prolonged duration of natalizumab therapy (>2 years), and prior ...exposure to immunosuppressive therapy increased the risk for the disease. Prior to the publication of Biogen’s algorithm, a risk algorithm was created by Fox and Rudick using an Excel spreadsheet in order to address the concerns of their patients. Applying the most recently available data regarding natalizumab-associated PML, the risk assessments for PML were recalculated. The current numbers indicate substantially higher risks for PML in 2015 than in 2012. Our calculations suggest that an individual having all three risk factors has an approximately 1 in 44 chance of developing PML.
Radek Marek and his co‐workers at Masaryk University, Brno, Czechia have been invited to prepare the cover of this issue. The image depicts the relativistic spin–orbit coupling that is associated ...with the presence of a heavy atom in a molecule influencing the electron density around a light atom and modulating the chemical bond between these two atoms. Read the full text of the article at 10.1002/chem.202200277.
“The effects of spin–orbit coupling on the HA–LA bond… could have significant consequences for the molecular sciences and the design of new materials.” This and more about the story behind the front cover can be found in the article at 10.1002/chem.202200277).
CNS fungal infections: A review Nathan, Cody L.; Emmert, Brian E.; Nelson, Ernest ...
Journal of the neurological sciences,
03/2021, Letnik:
422
Journal Article
Recenzirano
•CNS fungal diseases have become increasingly common due to immunosuppressive therapies, transplantation, and HIV/AIDS.•Several therapies increasingly employed for neurological conditions may ...predispose to fungal disease.•CNS fungal disorders may present in variegate fashion and are often difficult to diagnosis and treat.•Clinical, laboratory and radiographic features of these infections are valuable in establishing their diagnosis.
Post-translational modification of proteins is a strategy widely used in biological systems. It expands the diversity of the proteome and allows for tailoring of both the function and localization of ...proteins within cells as well as the material properties of structural proteins and matrices. Despite their ubiquity in biology, with a few exceptions, the potential of post-translational modifications in biomaterials synthesis has remained largely untapped. As a proof of concept to demonstrate the feasibility of creating a genetically encoded biohybrid material through post-translational modification, we report here the generation of a family of three stimulus-responsive hybrid materials-fatty-acid-modified elastin-like polypeptides-using a one-pot recombinant expression and post-translational lipidation methodology. These hybrid biomaterials contain an amphiphilic domain, composed of a β-sheet-forming peptide that is post-translationally functionalized with a C
alkyl chain, fused to a thermally responsive elastin-like polypeptide. They exhibit temperature-triggered hierarchical self-assembly across multiple length scales with varied structure and material properties that can be controlled at the sequence level.
Progressive multifocal leukoencephalopathy (PML) is a rare, complex opportunistic infection of the central nervous system caused by the JC virus. This past decade, PML was increasingly recognized to ...be associated with the use of immunosuppressive and biologic agents. The risk for PML differs among these agents and remains difficult to quantify because of the complex pathogenesis of PML and the presence of confounding factors. This paper explores and updates the association of PML with different biologic and immunosuppressive agents and proposes an expanded classification system for the risk of PML. We identify three classes of drug that vary by PML risk, latency to infection, and underlying illness. We also review some of the most common agents with known associations to PML and explore risk mitigation strategies that aim to inform the decision-making process for clinicians and patients in the face of the changing incidence of PML and the growing landscape of immunologic agents.
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