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Background: Listeriosis is an orphan disease, which is nevertheless fatal in immunocompromised people. CRS0540 is a novel PolC DNA polymerase inhibitor that has demonstrated good in vitro and in vivo activity against Listeria monocytogenes., Methods: Rodent-to-human allometry projection-based human population pharmacokinetics of CRS0540 were used for all studies. CRS0540 pharmacokinetics/pharmacodynamics studies in an intracellular hollow-fibre system model of disseminated listeriosis (HFS-Lister) examined the effect of eight treatment doses, administered daily over 7 days, in duplicate units. Total bacterial burden versus AUC/MIC exposures on each day were modelled using the inhibitory sigmoid Emax model, while CRS0540-resistant bacterial burden was modelled using a quadratic function. Ten thousand-subject Monte Carlo simulations were used to predict an optimal clinical dose for treatment., Results: The mean CRS0540 intracellular/extracellular AUC0-24 ratio was 34.07 (standard error: 15.70) as measured in the HFS-Lister. CRS0540 demonstrated exposure-dependent bactericidal activity in the HFS-Lister, with the highest exposure killing approximately 5.0 log10 cfu/mL. The free drug AUC0-24/MIC associated with 80% of maximal kill (EC80) was 36.4. Resistance emergence versus AUC/MIC was described by a quadratic function, with resistance amplification at an AUC/MIC of 54.8 and resistance suppression at an AUC/MIC of 119. Monte Carlo simulations demonstrated that for the EC80 target, IV CRS0540 doses of 100 mg/kg achieved PTAs of >90% at MICs up to 1.0 mg/L., Conclusions: CRS0540 is a promising orphan drug candidate for listeriosis. Future PK/PD studies comparing it with penicillin, the standard of care, could lead to this drug as a new treatment in immunocompromised patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Objectives: The standard of care (SOC) for the treatment of pulmonary Mycobacterium avium complex (MAC) disease (clarithromycin, rifabutin, and ethambutol) achieves sustained sputum conversion rates of only 54%. Thus, new treatments should be prioritized., Methods: We identified the omadacycline MIC against one laboratory MAC strain and calculated drug half life in solution, which we compared with measured MAC doubling times. Next, we performed an omadacycline hollow fibre system model of intracellular MAC (HFS-MAC) exposure-effect study, as well as the three-drug SOC, using pharmacokinetics achieved in patient lung lesions. Data was analysed using bacterial kill slopes (γ-slopes) and inhibitory sigmoid Emax bacterial burden versus exposure analyses. Monte Carlo experiments (MCE) were used to identify the optimal omadacycline clinical dose., Results: Omadacycline concentration declined in solution with a half-life of 27.7 h versus a MAC doubling time of 16.3 h, leading to artefactually high MICs. Exposures mediating 80% of maximal effect changed up to 8-fold depending on sampling day with bacterial burden versus exposure analyses, while γ-slope-based analyses gave a single robust estimate. The highest omadacycline monotherapy γ-slope was -0.114 (95% CI: -0.141 to -0.087) (r2 = 0.98) versus -0.114 (95% CI: -0.133 to -0.094) (r2 = 0.99) with the SOC. MCEs demonstrated that 450 mg of omadacycline given orally on the first 2 days followed by 300 mg daily would achieve the AUC0-24 target of 39.67 mg·h/L., Conclusions: Omadacycline may be a potential treatment option for pulmonary MAC, possibly as a back-bone treatment for a new MAC regimen and warrants future study in treatment of this disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Objective: To investigate the role of PF-06650833, a highly potent and selective small-molecule inhibitor of interleukin-1-associated kinase 4 (IRAK4), in autoimmune pathophysiology in vitro, in vivo, and in the clinical setting., Methods: Rheumatoid arthritis (RA) inflammatory pathophysiology was modeled in vitro through 1) stimulation of primary human macrophages with anti-citrullinated protein antibody immune complexes (ICs), 2) RA fibroblast-like synoviocyte (FLS) cultures stimulated with Toll-like receptor (TLR) ligands, as well as 3) additional human primary cell cocultures exposed to inflammatory stimuli. Systemic lupus erythematosus (SLE) pathophysiology was simulated in human neutrophils, dendritic cells, B cells, and peripheral blood mononuclear cells stimulated with TLR ligands and SLE patient ICs. PF-06650833 was evaluated in vivo in the rat collagen-induced arthritis (CIA) model and the mouse pristane-induced and MRL/lpr models of lupus. Finally, RNA sequencing data generated with whole blood samples from a phase I multiple-ascending-dose clinical trial of PF-06650833 were used to test in vivo human pharmacology., Results: In vitro, PF-06650833 inhibited human primary cell inflammatory responses to physiologically relevant stimuli generated with RA and SLE patient plasma. In vivo, PF-06650833 reduced circulating autoantibody levels in the pristane-induced and MRL/lpr murine models of lupus and protected against CIA in rats. In a phase I clinical trial (NCT02485769), PF-06650833 demonstrated in vivo pharmacologic action pertinent to SLE by reducing whole blood interferon gene signature expression in healthy volunteers., Conclusion: These data demonstrate that inhibition of IRAK4 kinase activity can reduce levels of inflammation markers in humans and provide confidence in the rationale for clinical development of IRAK4 inhibitors for rheumatologic indications., (© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: Respiratory system involvement and fever are considered as a cardinal manifestation of Covid-19 infection for the screening of case detection. We (India) are into the fourth month of Covid-19 and cases are still rising, this could mean that fever and respiratory symptoms may not be the only initial symptoms. Therefore, we intend to investigate whether neurological symptoms can precede the cardinal symptoms., Methods: Totally, 391 Covid-19 RTPCR positive hospitalized patients were enrolled. All included subjects were presented with a questionnaire pertaining to systemic symptoms. For analysis of the chronology of symptoms, the study population was sub-grouped according to onset of their systemic involvement e.g., (1) Fever (2) Respiratory symptoms (3) Neurological symptoms (4) Gastrointestinal symptoms., Results: New-onset neurological symptoms were found in 106 (27.1%) out of 391 patients irrespective of their chronology to the onset of other symptoms. Of these 106 patients, altered taste (33.1%), altered smell (24.5%), and headache (22.6%) were the most common neurological symptoms. However, 38 (9.7%) subjects recognized neurological symptoms, as the initial manifestation of their illness. Mean duration of neurological symptoms before the onset of respiratory symptoms or fever was 2 ± 1.57 days., Conclusion: New-onset headache, altered taste, and smell were the most common neurological symptoms. In the context of the current pandemic, a high index of suspicion should be kept in patients presenting with these symptoms even in the absence of fever and respiratory symptoms. To the best of our knowledge, this is the first study from India comparing chronology of neurological symptoms with cardinal symptoms., Competing Interests: There are no conflicts of interest., (Copyright: © 2006 - 2020 Annals of Indian Academy of Neurology.)

Drug-resistant tuberculosis represents a global emergency, requiring new drugs. We found that minocycline was highly potent in laboratory strains of Mycobacterium tuberculosis and that 30 drug-susceptible and multidrug/extensively drug-resistant clinical strains were susceptible to clinically achievable concentrations. In the hollow fiber system model, lung concentration-time profiles of 7 mg/kg/day human-equivalent minocycline dose achieved bacterial kill rates equivalent to those of first-line antituberculosis agents. Minocycline killed extracellular bacilli directly. Minocycline also killed intracellular bacilli indirectly, via concentration-dependent granzyme A-driven apoptosis. Moreover, minocycline demonstrated dose-dependent antiinflammatory activity and downregulation of extracellular matrix-based remodeling pathways and, thus, could protect patients from tuberculosis immunopathology. In RNA sequencing of repetitive samples from the hollow fiber system and in independent protein abundance experiments, minocycline demonstrated dose-dependent inhibition of sonic hedgehog-patched-gli signaling. These findings have implications for improved lung remodeling and for dual immunomodulation and direct microbial kill-based treatment shortening regimens for drug-susceptible and drug-resistant latent and active M. tuberculosis infection., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Understanding the mechanisms underlying autoantibody development will accelerate therapeutic target identification in autoimmune diseases such as systemic lupus erythematosus (SLE) 1 . Follicular helper T cells (T FH cells) have long been implicated in SLE pathogenesis. Yet a fraction of autoantibodies in individuals with SLE are unmutated, supporting that autoreactive B cells also differentiate outside germinal centers 2 . Here, we describe a CXCR5 - CXCR3 + programmed death 1 (PD1) hi CD4 + helper T cell population distinct from T FH cells and expanded in both SLE blood and the tubulointerstitial areas of individuals with proliferative lupus nephritis. These cells produce interleukin-10 (IL-10) and accumulate mitochondrial reactive oxygen species as the result of reverse electron transport fueled by succinate. Furthermore, they provide B cell help, independently of IL-21, through IL-10 and succinate. Similar cells are generated in vitro upon priming naive CD4 + T cells with plasmacytoid dendritic cells activated with oxidized mitochondrial DNA, a distinct class of interferogenic toll-like receptor 9 ligand 3 . Targeting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE.

Background: The factors associated with the spontaneous remission (SR) of symptoms in carpal tunnel syndrome (CTS) are not well known., Objectives: To look for determinants of SR in medically treated, electrophysiologically proven patients of CTS., Methods: We revisited the medical records and nerve conduction study data of 130 hands with CTS and divided them into two groups as per the absence or persistence of the symptoms when contacted after a median time lapse of 3 years following the diagnosis., Results: SR occurred in 46.1% of the hands. Higher odds of SR were linked with female gender, symptoms restriction to lateral fingers, symptom duration <10 months, mildly delayed median motor and sensory distal latencies, and median sensory amplitude >20 μV. We developed a seven-point scale, on which a score of ≥4 had a strong association (odds ratio 4.31) with SR., Discussion and Conclusion: No single risk factor, standalone, can predict SR in patients with CTS, which could lead to an invasive treatment (Surgery or local injection) to them. We propose that patients scoring ≥4 on our 7 point scale should be treated medically for the initial 10 months after the symptom onset., Competing Interests: There are no conflicts of interest.

Human dendritic cells (DCs) play a fundamental role in the initiation of long-term adaptive immunity during vaccination against influenza. Understanding the early response of human DCs to vaccine exposure is thus essential to determine the nature and magnitude of maturation signals that have been shown to strongly correlate with vaccine effectiveness. In 2009, the H1N1 influenza epidemics fostered the commercialization of the nonadjuvanted monovalent H1N1 California vaccine (MIV-09) to complement the existing nonadjuvanted trivalent Fluzone 2009-2010 vaccine (TIV-09). In retrospective studies, MIV-09 displayed lower effectiveness than TIV-09. We show that TIV-09 induces monocyte-derived DCs (moDCs), blood conventional DCs (cDCs), and plasmacytoid DCs (pDCs) to express CD80, CD83, and CD86 and secrete cytokines. TIV-09 stimulated the secretion of type I interferons (IFNs) IFN-α and IFN-β and type III IFN interleukin-29 (IL-29) by moDC and cDC subsets. The vaccine also induced the production of IL-6, tumor necrosis factor, and the chemokines IFN-γ-inducible protein 10 (IP-10) and macrophage inflammatory protein-1β (MIP-1β). Conversely, MIV-09 did not induce the production of type I IFNs in moDCs and blood cDCs. Furthermore, it inhibited the TIV-09-induced secretion of type I IFNs by these DCs. However, both vaccines induced pDCs to secrete type I IFNs, indicating that different influenza vaccines activate distinct molecular signaling pathways in DC subsets. These results suggest that subtypes of nonadjuvanted influenza vaccines trigger immunity through different mechanisms and that the ability of a vaccine to induce an IFN response in DCs may offset the absence of adjuvant and increase vaccine efficacy., (Copyright © 2017, American Association for the Advancement of Science.)

Autoantibodies against nucleic acids and excessive type I interferon (IFN) are hallmarks of human systemic lupus erythematosus (SLE). We previously reported that SLE neutrophils exposed to TLR7 agonist autoantibodies release interferogenic DNA, which we now demonstrate to be of mitochondrial origin. We further show that healthy human neutrophils do not complete mitophagy upon induction of mitochondrial damage. Rather, they extrude mitochondrial components, including DNA (mtDNA), devoid of oxidized (Ox) residues. When mtDNA undergoes oxidation, it is directly routed to lysosomes for degradation. This rerouting requires dissociation from the transcription factor A mitochondria (TFAM), a dual high-mobility group (HMG) protein involved in maintenance and compaction of the mitochondrial genome into nucleoids. Exposure of SLE neutrophils, or healthy IFN-primed neutrophils, to antiribonucleotide protein autoantibodies blocks TFAM phosphorylation, a necessary step for nucleoid dissociation. Consequently, Ox nucleoids accumulate within mitochondria and are eventually extruded as potent interferogenic complexes. In support of the in vivo relevance of this phenomenon, mitochondrial retention of Ox nucleoids is a feature of SLE blood neutrophils, and autoantibodies against Ox mtDNA are present in a fraction of patients. This pathway represents a novel therapeutic target in human SLE., (© 2016 Caielli et al.)

The mechanisms by which microbial vaccines interact with human APCs remain elusive. Herein, we describe the transcriptional programs induced in human DCs by pathogens, innate receptor ligands and vaccines. Exposure of DCs to influenza, Salmonella enterica and Staphylococcus aureus allows us to build a modular framework containing 204 transcript clusters. We use this framework to characterize the responses of human monocytes, monocyte-derived DCs and blood DC subsets to 13 vaccines. Different vaccines induce distinct transcriptional programs based on pathogen type, adjuvant formulation and APC targeted. Fluzone, Pneumovax and Gardasil, respectively, activate monocyte-derived DCs, monocytes and CD1c+ blood DCs, highlighting APC specialization in response to vaccines. Finally, the blood signatures from individuals vaccinated with Fluzone or infected with influenza reveal a signature of adaptive immunity activation following vaccination and symptomatic infections, but not asymptomatic infections. These data, offered with a web interface, may guide the development of improved vaccines.

The aim of the study was to find out the prevalence of fungal meningitis among AIDS cases and to assess the prognosis of fungal meningitis among HIV positive & negative subjects. The study comprised of 15 & 10 cases of fungal meningitis among HIV positive & negative subjects respectively during the study period 1992-2001. India ink preparation and Gram's staining procedures were carried out on the centrifuged CSF deposits. The CSF deposits were also used for bacterial and fungal culture. In the present study the prevalence of fungal meningitis was noted among 15 (3.1%) of 483 AIDS cases. Twelve of them had cryptococcal meningitis while 3 were infected with Candida albicans. Four AIDS cases presented fungal meningitis as a primary opportunistic infection and HIV status was confirmed in 4 of them after the diagnosis of fungal meningitis. 13 of the 15 cases were in the age group 26-40 yrs while one was 55 yrs old and the other 16 month old child; these two cases had blood transfusion transmitted and vertically transmitted mode of HIV transmission respectively. Further, only two of 15 cases were females and both acquired HIV infection through blood transfusion. Overall prognosis of fungal meningitis was poor among HIV positives and 7 of the 15 cases died in hospital within 2-3 weeks after diagnosis of cryptococcal meningitis. Among HIV negative subjects, ten cases of fungal meningitis (3 with Candida albicans and 7 with Cryptococcous neoformans) were noted at our end and nine of them had immunocompromised status (3 cases of renal transplant on immunosuppressives, 3 cases neonates/infant and 2 diabetic subjects. The fungal meningitis is one of the important causes of morbidity & mortality among immunocompromised among HIV positive subjects.

Fungal infections of the central nervous system (CNS) are fortunately rare but remain challenging problems occurring mostly in immunocompromised individuals, with protean manifestations, unpredictable course and unfavorable outcome in many cases despite aggressive neurosurgical intervention and recent antifungal drugs. Rhino-orbito-cerebral mucormycosis is a potentially lethal opportunistic fungal infection with rapid progression and high mortality. Its pathogenic nature becomes evident when the patient's general resistance is compromised. We present a case of an invasive rhino-orbito-cerebral mucormycosis in an apparently normal adult who initially developed mild paranasal sinusitis and later developed status epilepticus and despite an aggressive management died. Interesting clinical, neuroimaging and histological findings are described, and the possibility of fatal mucormycosis in an apparently normal host is highlighted., (Copyright 2001 Harcourt Publishers Ltd.)

Diffuse idiopathic skeletal hyperostosis (DISH) has long been regarded as a benign asymptomatic clinical entity with an innocuous clinical course. Precise information is lacking in the world literature. Authors report the results of a retrospective analysis of 74 cases of DISH. Eleven patients presented with progressive spinal cord or cauda equina compression. In nine cases ossified posterior longitudinal ligament (OPLL) and in two cases ossified ligamentum flavum (OLF) were primarily responsible. Surgically treated patients (eight) had far better outcome as compared to the patients managed conservatively, as they had refused surgery. 'DISH' is neither a benign condition, nor it always runs a innocuous clinical course. In fact, in about 15% of the cases, serious neurological manifestations occur, which may require a major neurosurgical intervention.

Two unique cases of chronic calcified subdural hematomas are reported in children as a long-term complication of a ventriculoperitoneal shunt. Both the patients had undergone shunt procedures in infancy for congenital hydrocephalus. In one patient, the cause of the hydrocephalus was aqueduct stenosis, while in the second patient, a lumbar meningomyelocele was associated with hydrocephalus. In both these patients, a ventriculoperitoneal shunt was done in infancy. In one of them, following the shunt surgery, a bilateral subdural collection was noticed which required burr hole evacuation. Both the patients remained asymptomatic for 9 years, when they presented to our center with acute raised intracranial pressure and contralateral hemiparesis. Both the patients had a relatively short history and had altered sensorium at admission. Surprisingly, in both the patients, the CT scan showed significant mass effect producing calcified subdural hematomas. The shunt systems were found to be working well at surgery. Craniotomy and excision of the calcified subdural hematomas was undertaken. Postoperatively, the patients showed satisfactory recovery, and at discharge the patients were doing well. At the follow-up at the outpatient clinic, the patients were asymptomatic.

Objective: To describe the classic appearance of persistent trigeminal artery on MR imaging with the typical MR appearance of the hypoplastic precommunal basilar artery. This finding may be used as an ancillary sign of this anomaly in subtle cases of persistent fetal carotid-basilar artery anastomoses., Materials and Methods: Two women (46 and 19 years of age) with persistent trigeminal artery were examined. An MR imaging study using spin-echo sequences was performed. The findings were confirmed on conventional angiography., Results: Two cases showed a hypoplastic basilar trunk flow void in the caudal posterior fossa that enlarged to a more normal caliber rostrally above the persistent trigeminal artery anastomosis. The actual anastomosis was also demonstrated in both cases, and in one of the cases the persistent trigeminal artery was shown to form a groove in the dorsum sellae., Conclusion: A proximal hypoplastic basilar trunk below the anastomosis that enlarges to a more normal caliber above the aberrant communication is an important ancillary sign of persistent trigeminal artery and should be searched for on routine MR studies in cases with suspected carotid-basilar anastomoses.