Presence of Epstein-Barr virus in cerebrospinal fluid is associated with increased mortality in HIV-negative cryptococcal meningitis.

Cryptococcus neoformans is the most common cause of fungal meningitis and is associated with a high mortality. The clinical significance of concurrent Epstein-Barr virus (EBV) in the cerebrospinal fluid (CSF) of human immunodeficiency virus (HIV)-negative patients with cryptococcal meningitis (CM) remains unclear. A retrospective cohort study was performed by analyzing CSF samples from 79 HIV-negative Chinese Han patients with confirmed CM. We identified CSF viral DNA in these patients by metagenomic next-generation sequencing (mNGS) and compared 10-week survival rates among those with and without EBV DNA in CSF. Of the 79 CSF samples tested, 44.3% (35/79) had detectable viral DNA in CSF, while 55.7% (44/79) were virus-negative. The most frequent viral pathogen was EBV, which was detected in 22.8% (18/79) patients. The median number of CSF-EBV DNA reads was 4 reads with a range from 1 to 149 reads. The 10-week mortality rates were 22.2% (4/18) in those with positive CSF-EBV and 2.3% (1/44) in those with negative CSF-virus (hazard ratio 8.20, 95% confidence interval [CI] 1.52-81.80; P = 0.014), which remained significant after a multivariate adjustment for the known risk factors of mortality (adjusted hazard ratio 8.15, 95% CI 1.14-92.87; P = 0.037). mNGS can identify viruses that coexist in CSF of HIV-negative patients with CM. EBV DNA is most commonly found together with C. neoformans in CSF and its presence is associated with increased mortality in HIV-negative CM patients.

We retrospectively analyzed CSF samples from 79 HIV-negative Chinese Han patients with confirmed CM. We identified CSF viral DNA by mNGS and compared 10-week survival rates among those with and without EBV DNA. Positive CSF-EBV DNA is associated with the increased mortality in HIV-negative CM patients.

Exploring Shared Genetic Signatures of Alzheimer's Disease and Multiple Sclerosis: A Bioinformatic Analysis Study.

INTRODUCTION: Many clinical studies reported the coexistence of Alzheimer's disease (AD) and multiple sclerosis (MS), but the common molecular signature between AD and MS remains elusive. The purpose of our study was to explore the genetic linkage between AD and MS through bioinformatic analysis, providing new insights into the shared signatures and possible pathogenesis of two diseases. METHODS: The common differentially expressed genes (DEGs) were determined between AD and MS from datasets obtained from Gene Expression Omnibus (GEO) database. Further, functional and pathway enrichment analysis, protein-protein interaction network construction, and identification of hub genes were carried out. The expression level of hub genes was validated in two other external AD and MS datasets. Transcription factor (TF)-gene interactions and gene-miRNA interactions were performed in NetworkAnalyst. Finally, receiver operating characteristic (ROC) curve analysis was applied to evaluate the predictive value of hub genes. RESULTS: A total of 75 common DEGs were identified between AD and MS. Functional and pathway enrichment analysis emphasized the importance of exocytosis and synaptic vesicle cycle, respectively. Six significant hub genes, including CCL2, CD44, GFAP, NEFM, STXBP1, and TCEAL6, were identified and verified as common hub genes shared by AD and MS. FOXC1 and hsa-mir-16-5p are the most common TF and miRNA in regulating hub genes, respectively. In the ROC curve analysis, all hub genes showed good efficiency in helping distinguish patients from controls. CONCLUSION: Our study first identified a common genetic signature between AD and MS, paving the road for investigating shared mechanism of AD and MS.

Seasonality and meteorological factors of HIV-negative cryptococcal meningitis in Guangdong Province, China.

OBJECTIVE: Information about the seasonal characteristics of human immunodeficiency virus (HIV)-negative cryptococcal meningitis (CM) is quite limited. The aim of this study was to explore the seasonality and meteorological factors of HIV-negative patients with CM. METHODS: We performed a retrospective study of 469 HIV-negative CM patients admitted to the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China. Their initial onset symptoms of CM occurred from January 2011 to December 2020. The temperature, precipitation, sunlight, humidity and wind speed for the corresponding period and the associated topographic, ecological type and soil type parameters data were collected. The Poisson regression model was used to determine the meteorological factors associated with CM onset. The geographical detector method was used to detect other environmental factors associated with CM onset. RESULTS: CM onset did not showed a seasonal fluctuation, but was strongly associated with mean temperature (ß = .010, p = .028) and mean relative humidity (ß = -.011, p = .006). In the rainy season, only mean wind speed remained significantly associated with CM onset (ß = -.108, p = .041). In the dry season, mean temperature (ß = .014, p = .016), mean relative humidity (ß = -.016, p = .006) and hours of sunlight (ß = -.002, p = .016) were significantly associated with CM onset. Topographic, ecological type and soil type factors did not add explanatory power. CONCLUSIONS: Our findings add the knowledge about the environmental factors of HIV-negative CM. Meteorological factors, especially temperature and humidity, may be the main environmental factors affecting the onset of HIV-negative CM.

The effect on brain volume in HIV-negative and non-transplant cryptococcal meningitis.

To explore the brain volume (BV) changes of HIV-negative and non-transplant cryptococcal meningitis (CM) in 1 year after initial therapy. Case data were collected from 78 CM patients who underwent magnetic resonance imaging (MRI) scanning at least 3 times in 1-year interval after initial therapy. The assessment of BV was measured by a non-commercial software, uAI Research Portal. Linear mixed model was used to investigate the association between clinical characteristics and the changes in BV. Longitudinal study showed a decrease in total brain volume (-4.65 cm3, P = .005), regional brain volume including white matter (-2.86 cm3, P = .031) and basal ganglia (-0.25 cm3, P = .007), and increase in cerebrospinal fluid (CSF) volume (3.58 cm3, P = .013) in CM patients in 1 year after initial therapy. Ventricular volume in patients with ventriculoperitoneal shunts (VPS) was lower than that in patients without VPS (-7.5 cm3, P < .05). Ventricular volume in patients with post-infectious inflammatory response syndrome (PIIRS) was larger than that in patients without PIIRS (7.1 cm3, P < .01). In addition, temporal lobe atrophy was associated with corticosteroid therapy (-6.8 cm3, P < .01). The present study suggested that brain atrophy, especially regional BV decrease, could happen in HIV-negative and non-transplant CM patients over a 1-year interval.

We investigated the evolution of brain volume changes in different regions among HIV-negative and non-transplant cryptococcal meningitis (CM) patients within 1 year after initial therapy. To assess whether brain atrophy occurs among HIV-negative and non-transplant CM patients.

Review: The application of corticosteroids in cryptococcal meningitis.

Cryptococcal meningitis (CM) is a serious disease with high morbidity and mortality. Although the patients who received corticosteroids were at high risk of having CM, corticosteroids also have been used as an adjunct to antifungal drugs for treating people with CM in some situations (such as immune reconstitution inflammatory syndrome, cerebral cyptococcoma, et al.). Here, we summarize the current knowledge on the application of the corticosteroids in CM, aiming to help clinicians to reasonably use corticosteroids in patients with CM.

Neurological worsening during treatment of HIV-negative cryptococcal meningitis in a patient with Evans syndrome.

A 49-year-old woman with a rare autoimmune hematological disease, Evans syndrome, was admitted to the authors' hospital with immune reconstitution inflammatory syndrome-like reconstitution syndrome after effective antifungal therapy for cryptococcal meningitis. She initially improved after receiving corticosteroid treatment; after prednisone was tapered, her clinical presentation and brain imaging deteriorated but finally improved with the addition of thalidomide. Immune reconstitution inflammatory syndrome-like reconstitution syndrome is a rare complication in cryptococcal meningitis patients receiving immunosuppressive therapy. Thalidomide can be given in addition to corticosteroid therapy to effectively control the paradoxical inflammatory response and improve clinical outcomes.

Failure of Early Mycological Clearance in HIV-Negative Cryptococcal Meningitis.

Background: Negative cerebrospinal fluid (CSF) cultures at 2 weeks after antifungal treatment (early mycological clearance [EMC]) should be a treatment goal of cryptococcal meningitis (CM). However, EMC in human immunodeficiency virus (HIV)-negative patients with CM is poorly understood. Methods: We conducted a retrospective review of medical records and 1-year follow-up of 141 HIV-negative patients with CM with an initial positive CSF culture for Cryptococcus neoformans. Multivariate logistic regression was performed to analyze clinical features and laboratory and CSF findings of patients with CM with different EMC statuses. Random forest models were used to predict failure of EMC. All-cause mortality and clinical functional status were analyzed. Results: Of 141 patients, 28 (19.9%) had EMC failure. The 1-year mortality rate was 5.7% (8/141). Multivariate analysis showed that non-amphotericin B (AmB)-based regimens, baseline log10 Cryptococcus count/mL, baseline CSF opening pressure (CSF-OP) >30 cm H2O, and baseline serum creatinine were significantly associated with EMC failure. A parsimonious predictive rule given by the decision tree identified patients with CM with non-AmB-based therapy and baseline CSF-OP >30 cm H2O as being at high risk of EMC failure. Incidence of all-cause mortality, the follow-up modified Rankin Scale, and Karnofsky performance status scores were not significantly related to EMC. Conclusions: EMC failure in HIV-negative CM is attributed to non-AmB-based therapy and is associated with log10 Cryptococcus count/mL and CSF-OP >30 cm H2O at baseline. Because of the small number of deaths, we are not able to comment on whether or not EMC is associated with mortality.

Reversible deafness and blindness in Cryptococcus gattii meningitis with a ventriculoperitoneal shunt: A case report and literature review.

Cryptococcus gattii (C. gattii) has been considered a leading cause of meningitis in immunocompetent hosts in tropical and subtropical regions. Visual loss is common but hearing impairment is relatively infrequent in C. gattii meningitis. Notably, there have been limited studies on the etiology, and especially therapy of auditory and ocular complications associated with C. gattii meningitis. Here we report a case of reversible deafness and blindness treated with a ventriculoperitoneal shunt (VPS) surgery in C. gattii meningitis. This case indicated that elevated intracranial pressure (ICP) may play a role in the concurrent hearing and vision impairments associated with C. gattii meningitis and the early VPS surgery after the initiation of the antifungal therapy may effectively improve both hearing and vision in this condition.

Central nervous system nocardiosis diagnosed by metagenomic next-generation sequencing: A case series and literature review.

BACKGROUND: Central nervous system (CNS) nocardiosis is a rare suppurative disease caused by the genus Nocardia. It is found most frequently in immunocompromised individuals. OBJECTIVES: In this study, we retrospectively reviewed the clinical presentations, laboratory examination, therapy and outcomes of 9 patients with CNS nocardiosis diagnosed using metagenomic next-generation sequencing (mNGS) in our hospital. MATERIAL AND METHODS: We reviewed 9 patients with confirmed diagnosis of CNS Nocardia infection from January 2017 to December 2021 in the Department of Neurology at The Third Affiliated Hospital, Sun Yat-sen University (Guangzhou, China). In addition, we searched literature related to CNS Nocardia infection on PubMed and included all case reports with proven CNS nocardiosis since 2016. RESULTS: The metagenomic next-generation sequencing (mNGS) of CSF can be used for the rapid diagnosis of nocardiosis in CNS and N. farcinica are the most commonly isolated species. Underlying autoimmune diseases, immunosuppressive agents including corticosteroids and organ transplantation are predisposing factors of developing CNS nocardiosis. Single or multiple hyper-enhanced ring lesions indicative of cerebral abscesses are commonly presented in brain imaging. Trimethoprim-sulfamethoxazole (TMP-SMX) is used as the primary agent for the antibacterial therapy and in combination with other antibacterial agents. CONCLUSION: Our study demonstrated that mNGS of CSF can be conducted for definitive and rapid diagnosis for CNS nocardiosis.

Venous flow dynamics during spinal block in normotensive and hypertensive elderly patients: a duplex ultrasonographic study.

BACKGROUND: Spinal block induces hyperkinetic change in lower extremity blood flow. We compared the venous flow dynamic responses to spinal block in normotensive and hypertensive elderly patients. METHODS: Following spinal block using 10 mg 0.5% (w/v) bupivacaine, we measured changes in blood pressure, heart rate, and venous flow dynamics of the popliteal vein by duplex ultrasonography in 20 normotensive (NBP group) and 18 hypertensive (HIBP group) patients. RESULTS: Spinal block caused significant decreases in blood pressure in both groups; similar rates of hypotension were observed. At baseline, peak velocity, time-averaged maximum velocity, and time-averaged mean velocity were higher in the HIBP than in the NBP group. During spinal block, peak velocity increased in both groups, and the between-group differences were no longer significant. At baseline, volume flow in the two groups was similar and increased by 141.5% in the NBP and 131.7% in the HIBP group during spinal block. CONCLUSIONS: Blood pressure and flow dynamics in the popliteal vein showed similar changes during spinal anaesthesia in elderly patients taking antihypertensive medication and normotensive patients, despite differences in baseline values.

Post-Infectious Inflammatory Response Syndrome in an HIV-Negative Immunocompetent Elderly Patient With Cryptococcal Meningitis: A Case Report and Literature Review.

We report a previously healthy 82-year-old male with cryptococcal meningitis (CM) who represented neurological deterioration due to post-infectious inflammatory response syndrome (PIIRS) occurring in 4 months after initial antifungal therapy. He was treated with corticosteroids for 2 months and recovered clinically. However, the clinical manifestation, cerebrospinal fluid (CSF), and brain magnetic resonance imaging (MRI) results got worse again on the next day after corticosteroid withdrawal. The analysis of inflammatory cytokines and culture on CSF, as well as brain MRI, still suggested a diagnosis of PIIRS. Therefore, corticosteroid therapy was used again and he subsequently obtained a complete resolution of symptoms.

Coherence properties of individual femtosecond pulses of an x-ray free-electron laser.

Measurements of the spatial and temporal coherence of single, femtosecond x-ray pulses generated by the first hard x-ray free-electron laser, the Linac Coherent Light Source, are presented. Single-shot measurements were performed at 780 eV x-ray photon energy using apertures containing double pinholes in "diffract-and-destroy" mode. We determined a coherence length of 17 µm in the vertical direction, which is approximately the size of the focused Linac Coherent Light Source beam in the same direction. The analysis of the diffraction patterns produced by the pinholes with the largest separation yields an estimate of the temporal coherence time of 0.55 fs. We find that the total degree of transverse coherence is 56% and that the x-ray pulses are adequately described by two transverse coherent modes in each direction. This leads us to the conclusion that 78% of the total power is contained in the dominant mode.

A survey of urban and rural participants in the Otago-Southland pilot breast cancer screening programme.

AIMS: By surveying participants in a pilot breast cancer screening programme, to measure satisfaction with the screening service, to provide feedback for programme staff, to obtain an indication of future participation, and to collect information about costs to women. METHODS: A self administered questionnaire was posted to representative samples of urban and rural women (total 474) who had participated in the Otago-Southland pilot breast cancer screening programme in its first year of operation. RESULTS: There was a 93% response rate to the survey, after one reminder letter. Although some demographic characteristics of urban and rural women differed, their opinions about the screening programme were similar. Satisfaction with the service is extremely high, with 94% of respondents planning to participate again in two years. CONCLUSIONS: The Otago-Southland pilot programme provides a service which is regarded as satisfactory by the great majority of participants.

Onset of labor epidural analgesia with ropivacaine and a varying dose of fentanyl: a randomized controlled trial.

BACKGROUND: This study was conducted to investigate the onset of labor epidural analgesia using 0.17% ropivacaine with a varying dose of fentanyl. We hypothesized that the onset of analgesia would be shortened in proportion to an increase in fentanyl dose. METHODS: Women requesting labor epidural analgesia were enrolled in this randomized controlled clinical trial. Each woman was randomly assigned to receive fentanyl 0, 50, 75, or 100 µg with 0.17% ropivacaine 12 mL. The onset and duration of analgesia, the incidence of side effects and patient satisfaction were measured. RESULTS: Data from 102 women were analyzed. The onset of analgesia (mean ± SD) was shortened with an increasing dose of fentanyl (14.3 ± 5.4, 14.2 ± 6.5, 12.1 ± 5.1, and 8.7 ± 3.8 min with fentanyl 0, 50, 75, or 100 µg, respectively, P=0.001). The duration of analgesia was prolonged with an increasing dose of fentanyl (87.4 ± 20.8, 112.3 ± 19.5, 140.8 ± 18.8, and 143.6 ± 18.6 min with fentanyl 0, 50, 75, or 100 µg, respectively, P<0.001). The incidence of pruritus increased with an increasing dose of fentanyl (P=0.027) but there were no differences for other maternal side effects. There was a significant difference in satisfaction score among groups (P=0.009). CONCLUSION: The addition of increasing doses of fentanyl to 0.17% ropivacaine contributed to shortened onset as well as prolonged duration of labor epidural analgesia and improved patient satisfaction.

Etiologic aspects and orthodontic treatment of unilateral localized arrested tooth-development combined with hearing loss.

In this study a case has been presented involving localized, arrested maxillary tooth development, asymmetric maxillary development, and unilateral loss of hearing. No similar case seems to have been described before. The orthodontic treatment comprised extraction of four permanent tooth germs in the maxilla and autotransplantation of mandibular teeth, followed by the use of fixed orthodontic appliances and a one-unit bridge restoration. Etiologic aspects are discussed. It is suggested that a severe attack of mumps that involved massive swelling of the parotid glands immediately after chicken pox and measles at the age of 4 to 5 years, may have resulted in a neurologic reduction of hearing and arrested tooth development. The teeth in which root development in relation to mumps does not appear to have been reported previously, whereas hearing loss after mumps has been reported. In the search for verification of this possible connection, children with arrested tooth development should be examined for reduction of hearing, and children with hearing loss after mumps ought to have their dental development checked.

Solution structures of the N-terminal domain of histone H4.

Histones, nuclear proteins that interact with DNA to form nucleosomes, are essential for both the regulation of transcription and the packaging of DNA within chromosomes. The N-terminal domain of histone H4 contains four acetylation sites at lysine residues and may play a separate role in chromatin structure from the remainder of the H4 chain. We performed circular dichroism and NMR characterization of both native (H4NTP) and acetylated (Ace-H4NTP) peptides containing N-terminal acetylation domain of histone H4 for various pH environments. Data from CD and NMR suggested that H4NTP exhibited a pH-dependent conformational change, whereas the Ace-H4NTP is insensitive to pH change. However, both peptides showed a defined structural form at acidic pH environments. The solution structure for Ace-H4NTP shows two structurally independent regions comprising residues of Leu10-Gly13 and Arg19-Leu22, demonstrating relatively well-defined turn-type structures. Our results suggest that N-terminal acetylated region of H4 prefers an extended backbone conformation at neutral pH, however, upon acetylation, the regions containing lysine residues induce structural transition, having defined structural form for its optimum function.

Solution structure of a new hypothalamic neuropeptide, human hypocretin-2/orexin-B.

Orexin-A and orexin-B (also called hypocretin-1 and hypocretin-2, respectively) are novel hypothalamic neuropeptides encoded by a single mRNA transcript; they stimulate food intake. We have determined the three-dimensional solution structure of human hypocretin-2/orexin-B using two-dimensional 1H-NMR data and dynamical simulated annealing calculations. On the basis of NOEs, 3JHNalpha coupling constants and hydrogen-deuterium exchange rates together with chemical shift indices, human hypocretin-2/orexin-B was deduced to consist of two alpha-helices connected with a short linker in both H2O and 30% trifluoroethanol solutions. The helical axis of helix I is oriented about 60-80 degrees relative to helix II. Hybrid distance geometry and simulated-annealing protocols were used to generate an ensemble of 30 structures with no constraint violations greater than 0.03 nm for distances and 3 degrees for angles. In addition, human hypocretin-2/orexin-B shares a similar secondary-structural motif with human neuropeptide Y. This result can form the basis for further study on ligand-receptor recognition of human orexin receptors.

Transcriptional regulation of PDGF-A and TGF-beta by +KTS WT1 deletion mutants and a mutant mimicking Denys-Drash syndrome.

Denys-Drash syndrome (DDS) and Frasier syndrome (FS) are rare diseases caused by the mutations of Wilms tumor gene, WT1. The common denominator in these syndromes is a nephropathy which is manifested by early-onset proteinuria, nephrotic syndrome and end stage renal failure. Although these syndromes are genetic models of nephropathy and the mutations of WT1 gene are characterized in these patients the mechanism how mutations of WT1 gene affect the embryonic kidney adversely has not been elucidated. Recently, there was a report that FS is caused by mutations in the donor splice site of WT1. These mutations predicted loss of +KTS isoform, which is one of the four splicing variants of WT1. In this study, two +KTS deletion mutants of WT1 were made as well as a WT1 mutant mimicking a mutation found in a patient who had diffuse mesangial sclerosis, end stage renal failure and Wilms tumor. Mutant embryonic kidney cell lines were established by transfection of 293 embryonic kidney cells with WT1 mutants. We investigated the transcription regulation of mutant WT1 among these cell lines using the reporter vectors containing PDGF-A and TGF-beta promoter sequence. Our results showed that the promoter activity of PDGF-A and TGF-beta, which are related to the progression of glomerular diseases, was modestly increased in the mutant cell mimicking the patent, while those activities were markedly increased in other two deletion mutant cell lines. This study demonstrated that +KTS WT1 mutation found in DDS affected the cytokine expression adversely in vitro. From these results, we suggest that the alteration of +KTS WT1 expression be responsible for the rapid progression of renal diseases in DDS and FS.