Relationship of maternal cytomegalovirus-specific antibody responses and viral load to vertical transmission risk following primary maternal infection in a rhesus macaque model.

Cytomegalovirus (CMV) is the most common congenital infection and cause of birth defects worldwide. Primary CMV infection during pregnancy leads to a higher frequency of congenital CMV (cCMV) than maternal re-infection, suggesting that maternal immunity confers partial protection. However, poorly understood immune correlates of protection against placental transmission contributes to the current lack of an approved vaccine to prevent cCMV. In this study, we characterized the kinetics of maternal plasma rhesus CMV (RhCMV) viral load (VL) and RhCMV-specific antibody binding and functional responses in a group of 12 immunocompetent dams with acute, primary RhCMV infection. We defined cCMV transmission as RhCMV detection in amniotic fluid (AF) by qPCR. We then leveraged a large group of past and current primary RhCMV infection studies in late-first/early-second trimester RhCMV-seronegative rhesus macaque dams, including immunocompetent (n = 15), CD4+ T cell-depleted with (n = 6) and without (n = 6) RhCMV-specific polyclonal IgG infusion before infection to evaluate differences between RhCMV AF-positive and AF-negative dams. During the first 3 weeks after infection, the magnitude of RhCMV VL in maternal plasma was higher in AF-positive dams in the combined cohort, while RhCMV glycoprotein B (gB)- and pentamer-specific binding IgG responses were lower magnitude compared to AF-negative dams. However, these observed differences were driven by the CD4+ T cell-depleted dams, as there were no differences in plasma VL or antibody responses between immunocompetent AF-positive vs AF-negative dams. Overall, these results suggest that levels of neither maternal plasma viremia nor humoral responses are associated with cCMV following primary maternal infection in healthy individuals. We speculate that other factors related to innate immunity are more important in this context as antibody responses to acute infection likely develop too late to influence vertical transmission. Yet, pre-existing CMV glycoprotein-specific and neutralizing IgG may provide protection against cCMV following primary maternal CMV infection even in high-risk, immunocompromised settings.

CXCL9 as a Reliable Biomarker for Discriminating Anti-IFN-γ-Autoantibody-Associated Lymphadenopathy that Mimics Lymphoma.

The diagnosis of adult-onset immunodeficiency syndrome associated with neutralizing anti-interferon γ autoantibodies (AIGA) presents substantial challenges to clinicians and pathologists due to its nonspecific clinical presentation, absence of routine laboratory tests, and resemblance to certain lymphoma types, notably nodal T follicular helper cell lymphoma, angioimmunoblastic type (nTFHL-AI). Some patients undergo lymphadenectomy for histopathological examination to rule out lymphoma, even in the absence of a preceding clinical suspicion of AIGA. This study aimed to identify reliable methods to prevent misdiagnosis of AIGA in this scenario through a retrospective case-control analysis of clinical and pathological data, along with immune gene transcriptomes using the NanoString nCounter platform, to compare AIGA and nTFHL-AI. The investigation revealed a downregulation of the C-X-C motif chemokine ligand 9 (CXCL9) gene in AIGA, prompting an exploration of its diagnostic utility. Immunohistochemistry (IHC) targeting CXCL9 was performed on lymph node specimens to assess its potential as a diagnostic biomarker. The findings exhibited a significantly lower density of CXCL9-positive cells in AIGA compared to nTFHL-AI, displaying a high diagnostic accuracy of 92.3% sensitivity and 100% specificity. Furthermore, CXCL9 IHC demonstrated its ability to differentiate AIGA from various lymphomas sharing similar characteristics. In conclusion, CXCL9 IHC emerges as a robust biomarker for differentiating AIGA from nTFHL-AI and other similar conditions. This reliable diagnostic approach holds the potential to avert misdiagnosis of AIGA as lymphoma, providing timely and accurate diagnosis.

Species distribution and antifungal susceptibility of clinical Aspergillus isolates: A multicentre study in Taiwan, 2016-2020.

BACKGROUND: Epidemiological knowledge is important to guide antifungal therapy. OBJECTIVE: This multicentre study aimed to investigate the species distribution and antifungal susceptibility of Aspergillus isolates in Taiwan. METHOD: Four hundred and ninety-two clinical Aspergillus isolates, collected during 2016-2020, were identified by calmodulin sequencing and tested for antifungal susceptibility using CLSI M38-A3. The Cyp51A sequences of azole-resistant Aspergillus fumigatus and Aspergillus flavus isolates were analysed. RESULTS: This collection comprised 30 species from eight Aspergillus sections-Flavi (33.5%), Nigri (26.0%), Fumigati (24.2%), Terrei (10.0%), Nidulantes (5.1%), Circumdati (0.8%), Restricti (0.2%) and Aspergillus (0.2%). Sections Fumigati, Flavi and Terrei were primarily represented by A. fumigatus (99.2%), A. flavus (95.8%) and A. terreus (100%), respectively. Section Nigri comprised nine species, mostly A. welwitschiae (60.2%), A. niger (12.5%), A. brunneoviolaceus (10.9%) and A. tubingensis (10.2%). A. fumigatus (39.6%) and A. flavus (26.4%) predominated among 53 isolates from lower respiratory samples, whereas section Nigri species (46.2%) and A. terreus (29.2%) predominated among 65 isolates from ear samples. Reduced susceptibility to amphotericin B (minimal inhibitory concentration (MIC) > 1 µg/mL) was noted in A. flavus (7.0%), A. terreus (6.1%), A. nidulans and section Circumdati (A. flocculosus, A. subramanianii and A. westerdijkiae) isolates. Acquired azole resistance was observed in seven A. fumigatus (5.9%), all of which carried TR34 /L98H or TR34 /L98H/S297T/F495I mutation, and three A. flavus (1.9%), one of which carried G441S mutation. Reduced susceptibility to itraconazole (MIC >1 µg/mL) was noted in 55.5% of section Nigri isolates, mainly in A. welwitschiae, A. niger and A. tubingensis, whereas A. brunneoviolaceus, A. aculeatinus and A. japonicus were hypersusceptible to azoles. Anidulafungin was active against all isolates except for one isolate. CONCLUSIONS: This study depicted the molecular epidemiology and species-specific characteristics of Aspergillus in Taiwan, which aids in appropriate antifungal therapy and underlines the need of speciation and susceptibility testing of disease-causing Aspergillus.

Biomechanical analysis of tibial plateau posterolateral fracture fragment fixation and introduction of a lateral tibia plateau hook plate system.

BACKGROUND: Fixing the posterolateral fragments of tibial plateau fractures has been challenging owing to potential neurovascular injuries and fibular head blocks. Several surgical approaches and fixation techniques have been reported, with distinct limitations. We propose a novel lateral tibia plateau hook plate system and compare its biomechanical stability with other fixation methods. METHODS: Twenty-four synthetic tibia models were simulated to present posterolateral tibial plateau fractures. These models were randomly assigned to three groups. Group A models were fixed with the lateral tibia plateau hook plate system, Group B with variable-angle anterolateral locking compression plates, and Group C with direct posterior buttress plates. The models' biomechanical stability was evaluated using static (gradually increased axial compressive loads) and fatigue (cyclically loaded from 100 to 600 N for 2000 cycles each) tests. RESULTS: Groups A and C models exhibited comparable axial stiffness, subsidence load, failure load, and displacement in the static test. Group A model exhibited higher subsidence and failure loads than Group B model. Groups A and C models exhibited comparable displacement at 100 N cyclic loading in the fatigue test. Group C model was more stable at higher loads. Group C model endured the highest subsidence cycle numbers, followed by Groups A and B models. CONCLUSIONS: The lateral tibia plateau hook plate system provided similar static biomechanical stability as the direct posterior buttress plates and comparable dynamic stability under limited axial loading. This system is a potential posterolateral treatment choice owing to its convenience and safety, in treating tibia plateau fractures.

Distinguishing lupus lymphadenitis from Kikuchi disease based on clinicopathological features and C4d immunohistochemistry.

OBJECTIVES: Distinguishing Kikuchi disease (KD) from lupus lymphadenitis (LL) histologically is nearly impossible. We applied C4d immunohistochemical (IHC) stain to develop diagnostic tools. METHODS: We retrospectively investigated clinicopathological features and C4d IHC staining in an LL-enriched development cohort (19 LL and 81 KD specimens), proposed risk stratification criteria and trained machine learning models, and validated them in an external cohort (2 LL and 55 KD specimens). RESULTS: Clinically, we observed that LL was associated with an older average age (33 vs 25 years; P=0.005), higher proportion of biopsy sites other than the neck [4/19 (21%) vs 1/81 (1%); P=0.004], and higher proportion of generalized lymphadenopathy compared with KD [9/16 (56%) vs 7/31 (23%); P=0.028]. Histologically, LL involved a larger tissue area than KD did (P=0.006). LL specimens exhibited more frequent interfollicular pattern [5/19 (26%) vs 3/81 (4%); P=0.001] and plasma cell infiltrates (P=0.002), and less frequent histiocytic infiltrates in the necrotic area (P=0.030). Xanthomatous infiltrates were noted in 6/19 (32%) LL specimens. Immunohistochemically, C4d endothelial staining in the necrotic area [11/17 (65%) vs 2/62 (3%); P<10-7], and capillaries/venules [5/19 (26%) vs 7/81 (9%); P=0.048] and trabecular/hilar vessels [11/18 (61%) vs 8/81 (10%); P<10-4] in the viable area was more common in LL. During validation, both the risk stratification criteria and machine learning models were superior to conventional histological criteria. CONCLUSIONS: Integrating clinicopathological and C4d findings could distinguish LL from KD.

Clinical and epidemiological characteristics of tinea capitis in northern Taiwan during 2014-2019: An unusual bimodal distribution of patients and comparison of paediatric and adult cases.

Tinea capitis (TC) mainly occurs in children, and related studies in adults are rare. We aimed to investigate the current epidemiological, clinical and mycological characteristics of TC and to compare adult and paediatric patients in northern Taiwan. We conducted a retrospective study at Chang Gung Memorial Hospital, Linkou Branch, from 2014 to 2019. The dataset included age, sex, records of underlying diseases, animal contact history, frequent hair salon visits, clinical patterns, treatment and outcome via chart or phone call reviews. The average ages of 72 children and 104 adults recruited were 6.0 and 74.0 years, respectively. A female predominance was noted in both groups, and the ratio of females was significantly higher in adults (94.2% vs 59.7%, P < .0001). Microsporum canis (76.4%) and Trichophyton mentagrophytes (11.1%) in children, and M. canis (49.0%) and T. violaceum (31.7%) in adults were the most common pathogens. Adults were more likely to be infected with T. violaceum (OR = 10.14, 95% CI = 2.04-50.26) than children. In contrast, adults were less likely to be infected with M. canis than children (OR = 0.31, 95% CI = 0.11-0.90). Furthermore, adults visited hair salons more, had less animal contact and were more immunosuppressed than children. TC is not unusual in the adult population. Dermatologists are advised to realise risk factors such as immunosuppression and regular hair salon visit in adult TC.

Risk of HBV infection among male and female first-time blood donors born before and after the July 1986 HBV vaccination program in Taiwan.

BACKGROUND: In July 1984, Taiwan officially began a nationwide hepatitis B virus (HBV) vaccination program where only infants born to HBsAg-positive mothers were vaccinated free of charge until June 1986. However, from July 1986, all infants were vaccinated against HBV. The impact of the July 1986 HBV vaccination program on first-time blood donors has not been exhaustively studied. We, therefore, determined the risk of HBV among male and female first-time blood donors born before and after the July 1986 HBV vaccination program in Taiwan. METHODS: Initially, we recruited 857,310 first-time blood donors whose data were collected between 2013 and 2018 from 5 blood donation centers in Taiwan. However, we excluded donors with incomplete and outlying data (n = 12,213) and those born between July 1984 and June 1986 (n = 21,054). The final study participants comprised 9118 HBV positive and 814,925 HBV negative individuals. We divided the participants into two birth cohorts (born before and after July 1986) and assumed that those born before July 1986 were not vaccinated at birth while those born after July 1986 were vaccinated. RESULTS: The prevalence of HBV among those born before and after July 1986 was 4.53 and 0.25%, respectively. Individuals born after July 1986 had a lower risk of HBV than those born before July 1986. The adjusted odds ratio (OR), 95% confidence interval (CI) was 0.16, 0.13-0.19. Men had a higher risk of HBV than women (OR = 1.40, 95% CI = 1.34-1.47). The interaction between sex and birth date was significant (p-value = 0.0067). Stratification of participants by birth date revealed a higher risk of HBV in men compared to women in both birth cohorts. The OR, 95% CI was 1.47, 1.40-1.55 for those born before July 1986 but declined to 1.15, 1.02-1.29 for those born after July 1986. CONCLUSIONS: The risk of HBV was lower among those born after than those born before the July 1986 vaccination program. In both cohorts, the risk was high in men relative to women. The seemingly protective effect among those born after July 1986 was higher in women than men.

Multicenter Study of Azole-Resistant Aspergillus fumigatus Clinical Isolates, Taiwan1.

In a multicenter study, we determined a prevalence rate of 4% for azole-resistant Aspergillus fumigatus in Taiwan. Resistance emerged mainly from the environment (TR34/L98H, TR34/L98H/S297T/F495I, and TR46/Y121F/T289A mutations) but occasionally during azole treatment. A high mortality rate observed for azole-resistant aspergillosis necessitates diagnostic stewardship in healthcare and antifungal stewardship in the environment.

The National Dental Practice-Based Research Network Adult Anterior Open Bite Study: Patient satisfaction with treatment.

INTRODUCTION: This article evaluates and reports on the satisfaction of adult patients across the United States who received orthodontic treatment for anterior open bite malocclusion. The factors that influence satisfaction are also described. METHODS: Practitioners were recruited from the National Dental Practice-Based Research Network. On joining the Network, practitioner demographics and information on their practices were acquired. Practitioners enrolled their adult patients in active treatment for anterior open bite. Patient demographics, patient dentofacial characteristics, and details regarding previous and current treatment were collected through questionnaires at enrollment (T1). Pretreatment lateral cephalograms and intraoral frontal photographs were submitted. Treatment performed, and details related to treatment outcome were recorded through questionnaires at the end of active treatment (T2). Posttreatment lateral cephalograms and intraoral frontal photographs were submitted. Patient satisfaction at T2 was assessed using a 5-point Likert-type scale and open-ended responses. Predictive univariate models were developed to evaluate the factors that affect patient satisfaction. Open-ended responses were reviewed for general trends. RESULTS: T2 data were received for 260 patients, and 248 of these patients completed and returned the patient satisfaction questionnaires. High levels of satisfaction were found in this sample of adult patients receiving treatment for anterior open bite malocclusion. Specifically, 96% of the sample reported being very or somewhat satisfied. Only 10 patients (4%) were not satisfied with the treatment provided or an element of the final result. Successful open bite closure, treatment modality, and certain patient characteristics may affect patient satisfaction. However, there was insufficient power to demonstrate statistical significance because of the very low number of dissatisfied patients. Open-ended responses directly associated with patient satisfaction were received from 23 patients (9%). They relayed positive, neutral, and negative feelings about the treatment received and final results. Additional responses regarding the orthodontic treatment in general, but not specifically linked to patient satisfaction, were received from 119 patients (48%). These comments depict an overwhelmingly positive experience. CONCLUSIONS: Adult patients who received orthodontic treatment for anterior open bite malocclusion were generally satisfied with the treatment provided, as well as the final esthetic and functional results.

The National Dental Practice-Based Research Network Adult Anterior Open Bite Study: Treatment success.

INTRODUCTION: Anterior open bite (AOB) continues to be a challenging malocclusion for orthodontists to treat and retain long-term. There is no consensus on which treatment modality is most successful. This study reports on the overall success rate of AOB orthodontic treatment in the adult population across the United States, as well as 4 major treatment modalities and other factors that may influence treatment success. METHODS: Practitioners and their adult patients with AOB were recruited through the National Dental Practice-Based Research Network. Patient dentofacial and demographic characteristics, practitioner demographic and practice characteristics, and factors relating to orthodontic treatment were reported. Treatment success was determined from posttreatment (T2) lateral cephalometric films and intraoral frontal photographs. Treatment was categorized into 4 main groups: aligners, fixed appliances, temporary anchorage devices (TADs), and orthognathic surgery. Extractions were also evaluated. Bivariate and multivariable models were used to investigate the association between treatment success and treatment modality, pretreatment (T1) dentofacial characteristics, patient and practitioner demographics, and practice characteristics, adjusting for clustering of patients within practice. RESULTS: A total of 254 patients, enrolled by 84 practitioners, contributed to T2 data for this study. There were 29 patients in the aligner group, 152 in fixed appliances, 20 in TADs, and 53 in surgery. A total of 49 patients underwent extractions of teeth other than third molars. Ninety-three percent finished treatment with a positive overbite on the T2 lateral cephalogram, and 84% finished with a positive vertical overlap of all incisors. The small number of aligners and TAD patients limited the ability to compare success rates in these groups. Patients treated with orthognathic surgery had a higher rate of success compared with those treated with fixed appliances only. Treatment success was also associated with academic practice setting, T1 mandibular plane angle ≤30°, no to mild T1 crowding, and treatment duration <30 months. CONCLUSIONS: The overall success of orthodontic treatment in adult patients with AOB who participated in this study was very high. Orthognathic surgery was the only treatment modality that exhibited a statistically higher odds of successful outcomes. Some T1 dentofacial characteristics and treatment factors were associated with the successful closure of AOB.

Azole resistance in Aspergillus species in Southern Taiwan: An epidemiological surveillance study.

Poor clinical outcomes for invasive aspergillosis are associated with antifungal resistance. Performing antifungal susceptibility tests on clinically relevant Aspergillus isolates from patients and environmental regions with known azole resistance is recommended. The aim of the study was to assess the presence of azole resistance in clinical Aspergillus spp. isolates and those from hospital environments and farmlands within a 40 km radius of the hospital. Clinical Aspergillus spp. isolates were cultured, as well as environmental Aspergillus spp. isolates obtained from air samples. Samples were subcultured in azole-containing agar plates. Isolates with a positive screening test were subjected to YeastOne methods to determine their minimum inhibitory concentrations of antifungals. Resistance mechanisms were investigated in the azole-resistant Aspergillus spp. isolates. No azole-resistant clinical or environmental A flavus, A oryaze, A niger or A terreus isolates were found in the present study. All A fumigatus clinical isolates were azole-susceptible. Seven A fumigatus environmental isolates were associated with cyp51A mutations, including two that harboured TR34 /L98H mutations with S297T/F495I substitutions, two with TR34 /L98H mutations and three with TR46 /Y121F/T289A mutations. One of these isolates was collected from farmland, one was from A ward and five were from B ward. The proportion of azole-resistant A fumigatus was 10.2% (6/59) and 3.2% (1/31) in the hospital environments and the farmlands near the hospital, respectively. The results showed that azole-resistant A fumigatus existed within hospital environments. This emphasises the importance of periodic surveillance in hospital environments and monitoring for the emergence of azole-resistant A fumigatus clinical isolates.

The conserved AU dinucleotide at the 5' end of nascent U1 snRNA is optimized for the interaction with nuclear cap-binding-complex.

Splicing is initiated by a productive interaction between the pre-mRNA and the U1 snRNP, in which a short RNA duplex is established between the 5' splice site of a pre-mRNA and the 5' end of the U1 snRNA. A long-standing puzzle has been why the AU dincucleotide at the 5'-end of the U1 snRNA is highly conserved, despite the absence of an apparent role in the formation of the duplex. To explore this conundrum, we varied this AU dinucleotide into all possible permutations and analyzed the resulting molecular consequences. This led to the unexpected findings that the AU dinucleotide dictates the optimal binding of cap-binding complex (CBC) to the 5' end of the nascent U1 snRNA, which ultimately influences the utilization of U1 snRNP in splicing. Our data also provide a structural interpretation as to why the AU dinucleotide is conserved during evolution.

The National Dental Practice-Based Research Network Adult Anterior Open Bite Study: Treatment recommendations and their association with patient and practitioner characteristics.

INTRODUCTION: This aim of this paper is to describe and identify the practitioner and patient characteristics that are associated with treatment recommendations for adult anterior open bite patients across the United States. METHODS: Practitioners and patients were recruited within the framework of the National Dental Practice-Based Research Network. Practitioners were asked about their demographic characteristics and their treatment recommendations for these patients. The practitioners also reported on their patients' dentofacial characteristics and provided initial cephalometric scans and intraoral photographs. Patients were asked about their demographic characteristics, previous orthodontic treatment, and goals for treatment. Four main treatment groups were evaluated: aligners, fixed appliances, temporary anchorage devices (TADs), and orthognathic surgery. Extractions were also investigated. Predictive multivariable models were created comparing various categories of treatment as well as extraction/nonextraction decisions. RESULTS: Ninety-one practitioners (mostly orthodontists) and 347 patients were recruited from October 2015 to December 2016. Increased aligner recommendations were associated with white and Asian patients, the presence of tongue habits, and female practitioners. TADs were recommended more often in academic settings. Recommendations for orthognathic surgery were associated with demographic factors, such as availability of insurance coverage and practitioner race/ethnicity, and dentofacial characteristics, such as anteroposterior discrepancies, more severe open bites, and steeper mandibular plane angles. Extraction recommendations were largely associated with severe crowding and incisor proclination. CONCLUSIONS: Both doctor and patient demographic factors, as well as dentofacial characteristics, were significantly associated with treatment recommendations for adult anterior open bite patients.

Prevalence, mechanisms and genetic relatedness of the human pathogenic fungus Aspergillus fumigatus exhibiting resistance to medical azoles in the environment of Taiwan.

Emerging azole resistance in Aspergillus fumigatus poses a serious threat to human health. This nationwide surveillance study investigated the prevalence and molecular characteristics of azole-resistant A. fumigatus environmental isolates in Taiwan, an island country with increasing use of azole fungicides. Of the 2760 air and soil samples screened from 2014 to 2016, 451 A. fumigatus isolates were recovered from 266 samples and 34 isolates from 29 samples displayed resistance to medical azoles (itraconazole, voriconazole or posaconazole). The resistance prevalence was 10.9% and 7.5% in A. fumigatus-positive samples and isolates respectively. Most (29, 85.3%) azole-resistant isolates harboured TR34 /L98H mutations, which were widely distributed, clustered genetically with clinical isolates, and had growth rates that were similar to those of the wild-type isolates. Microsatellite genotyping revealed both the global spread of the TR34 /L98H isolates and the occurrence of TR34 /L98H/S297T/F495I isolates belonging to local microsatellite genotypes. AfuMDR3 and atrF, two efflux transporter genes, were constitutively upregulated in two individual resistant isolates without cyp51A mutations, highlighting their potential roles in azole resistance. These results emphasize the need for periodic environmental surveillance at the molecular level in regions in which azole fungicides are applied, and agricultural fungicide management strategies that generate less selective pressure should be investigated.

Comparison of the Sensititre YeastOne and CLSI M38-A2 Microdilution Methods in Determining the Activity of Amphotericin B, Itraconazole, Voriconazole, and Posaconazole against Aspergillus Species.

This study compared the YeastOne and reference CLSI M38-A2 broth microdilution methods for antifungal susceptibility testing of Aspergillus species. The MICs of antifungal agents were determined for 100 Aspergillus isolates, including 54 Aspergillus fumigatus (24 TR34/L98H isolates), 23 A. flavus, 13 A. terreus, and 10 A. niger isolates. The overall agreement (within 2 2-fold dilutions) between the two methods was 100%, 95%, 92%, and 90% for voriconazole, posaconazole, itraconazole, and amphotericin B, respectively. The voriconazole geometric mean (GM) MICs were nearly identical for all isolates using both methods, whereas the itraconazole and posaconazole GM MICs obtained using the YeastOne method were approximately 1 dilution lower than those obtained using the reference method. In contrast, the amphotericin B GM MIC obtained using the YeastOne method was 3.3-fold higher than that observed using the reference method. For the 24 A. fumigatus TR34/L98H isolates assayed, the categorical agreement (classified according to the CLSI epidemiological cutoff values) was 100%, 87.5%, and 83.3% for itraconazole, voriconazole, and posaconazole, respectively. For four A. niger isolates, the itraconazole MICs were >8 µg/ml using the M38-A2 method due to trailing growth, whereas the corresponding itraconazole MICs obtained using the YeastOne method were all ≤0.25 µg/ml without trailing growth. These data suggest that the YeastOne method can be used as an alternative for azole susceptibility testing of Aspergillus species and for detecting the A. fumigatus TR34/L98H isolates but that this method fails to detect A. niger isolates exhibiting trailing growth with itraconazole. Additionally, for isolates with azole MICs that approach or that are at susceptibility breakpoints or with high amphotericin B MICs detected using the YeastOne method, further MIC confirmation using the reference CLSI method is needed.

SP110b Controls Host Immunity and Susceptibility to Tuberculosis.

RATIONALE: How host genetic factors affect Mycobacterium tuberculosis (Mtb) infection outcomes remains largely unknown. SP110b, an IFN-induced nuclear protein, is the nearest human homologue to the mouse Ipr1 protein that has been shown to control host innate immunity to Mtb infection. However, the function(s) of SP110b remains unclear. OBJECTIVES: To elucidate the role of SP110b in controlling host immunity and susceptibility to tuberculosis (TB), as well as to identify the fundamental immunological and molecular mechanisms affected by SP110b. METHODS: Using cell-based approaches and mouse models of Mtb infection, we characterized the function(s) of SP110b/Ipr1. We also performed genetic characterization of patients with TB to investigate the role of SP110 in controlling host susceptibility to TB. MEASUREMENTS AND MAIN RESULTS: SP110b modulates nuclear factor-κB (NF-κB) activity, resulting in downregulation of tumor necrosis factor-α (TNF-α) production and concomitant upregulation of NF-κB-induced antiapoptotic gene expression, thereby suppressing IFN-γ-mediated monocyte and/or macrophage cell death. After Mtb infection, TNF-α is also downregulated in Ipr1-expressing mice that have alleviated cell death, less severe necrotic lung lesions, more efficient Mtb growth control in the lungs, and longer survival. Moreover, genetic studies in patients suggest that SP110 plays a key role in modulating TB susceptibility in concert with NFκB1 and TNFα genes. CONCLUSIONS: These results indicate that SP110b plays a crucial role in shaping the inflammatory milieu that supports host protection during infection by fine-tuning NF-κB activity, suggesting that SP110b may serve as a potential target for host-directed therapy aimed at manipulating host immunity against TB.

Minimal Detectable Change on the Lawton Instrumental Activities of Daily Living Scale in Community-Dwelling Patients With Schizophrenia.

The main purpose of this study was to estimate the minimal detectable change (MDC) on the Lawton Instrumental Activities of Daily Living (LIADL) scale in community-dwelling patients with schizophrenia. Fifty-seven patients completed the LIADL assessment twice, about 14 days apart. Two scoring methods (dichotomous and polytomous) were used to record the patients' performance on the LIADL scale. The MDCs of the LIADL scale were 1.5 (dichotomous) and 4.4 (polytomous) points. The MDC percentages were 22.0% (dichotomous) and 22.5% (polytomous), both of which are within acceptable measurement errors. The test-retest reliabilities of the LIADL scale were both acceptable with two different scoring methods (dichotomous = .75; polytomous = .76). Users can choose the scoring method according to their individual needs.

{Fe(NO)(2)(9) Dinitrosyl Iron Complex Acting as a Vehicle for the NO Radical.

To carry and deliver nitric oxide with a controlled redox state and rate is crucial for its pharmaceutical/medicinal applications. In this study, the capability of cationic {Fe(NO)2}9 dinitrosyl iron complexes (DNICs) [(RDDB)Fe(NO)2]+ (R = Me, Et, Iso; RDDB = N,N'-bis(2,6-dialkylphenyl)-1,4-diaza-2,3-dimethyl-1,3-butadiene) carrying nearly unperturbed nitric oxide radical to form [(RDDB)Fe(NO)2(•NO)]+ was demonstrated and characterized by IR, UV-vis, EPR, NMR, and single-crystal X-ray diffractions. The unique triplet ground state of [(RDDB)Fe(NO)2(•NO)]+ results from the ferromagnetic coupling between two strictly orthogonal orbitals, one from Fe dz2 and the other a π*op orbital of a unique bent axial NO ligand, which is responsible for the growth of a half-field transition (ΔMS = 2) from 70 to 4 K in variable-temperature EPR measurements. Consistent with the NO radical character of coordinated axial NO ligand in complex [(MeDDB)Fe(NO)2(•NO)]+, the simple addition of MeCN/H2O into CH2Cl2 solution of complexes [(RDDB)Fe(NO)2(•NO)]+ at 25 °C released NO as a neutral radical, as demonstrated by the formation of [S5Fe(NO)2]- from [S5Fe(µ-S)2FeS5]2-.

A comparison of the immunological potency of Burkholderia lipopolysaccharides in endotoxemic BALB/c mice.

Lipopolysaccharide is one of the virulence factors of the soil-borne pathogens Burkholderia pseudomallei, B. thailandensis, B. cenocepacia and B. multivorans, which cause septic melioidosis (often in B. pseudomallei infections but rarely in B. thailandensis infections) or cepacia syndromes (commonly in B. cenocepacia infections but rarely in B. multivorans infections). The inflammatory responses in Burkholderia LPS-induced endotoxemia were evaluated in this study. Prior to induction, the conserved structures and functions of each purified LPS were determined using electrophoretic phenotypes, the ratios of 3-hydroxytetradecanoic to 3-hydroxyhexadecanoic acid and endotoxin units. In an in vitro assay, cytokine expression of myeloid differentiation primary response gene 88 and Toll/IL-1 receptor domain containing adapter-inducing INF-ß-dependent signaling-dependent signaling differed when stimulated by different LPS. Endotoxemia was induced in mice by s.c. injection as evidenced by increasing serum concentrations of 3-hydroxytetradecanoic acid and the septic prognostic markers CD62E and ICAM-1. During endotoxemia, splenic CD11b+ I-A+ , CD11b+ CD80+ , CD11b+ CD86+ and CD11b+ CD11c+ subpopulations increased. After induction with B. pseudomallei LPS, there were significant increases in splenic CD49b NK cells and CD14 macrophages. The inflamed CD11b+ CCR2+ , CD11b+ CD31+ , CD11b+ CD14+ , resident CD11b+ CX3 CR1+ and progenitor CD11b+ CD34+ cells showed delayed increases in bone marrow. B. multivorans LPS was the most potent inducer of serum cytokines and chemokines, whereas B. cenocepacia LPS induced relatively low concentrations of the chemokines MIP-1α and MIP-1ß. Endotoxin activities did not correlate with the virulence of Burkholderia strains. Thus factors other than LPS and/or other mechanisms of low activity LPS must mediate the pathogenicity of highly virulent Burkholderia strains.

Validation of a Mandarin Chinese version of the pelvic organ prolapse/urinary incontinence sexual questionnaire IUGA-revised (PISQ-IR).

INTRODUCTION AND HYPOTHESIS: Sexual dysfunction has a high prevalence in women with pelvic organ disorders. Until recently, there has been no single one questionnaire translated or validated that can evaluate the sexual function of patients with a pelvic floor disorder, either for sexually active or inactive women. The Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire IUGA-Revised (PISQ-IR) was developed to fill this gap. The aim of this study was to translate and validate the Mandarin Chinese version of PISQ-IR for global use. METHODS: This study was conducted with a sample of 106 patients. The PISQ-IR was translated and back-translated by two bilingual urogynecological specialists, and the Mandarin Chinese version was approved by the PISQ-IR Working Group of the International Urogynecological Association (IUGA). Its reliability was assessed using test-retest reliability and internal consistency, and its criterion validity was assessed in relation to other currently valid Chinese questionnaires. Both exploratory and confirmatory factor analyses were assessed. RESULTS: The mean age of the participants was 52 ± 10.6 years. The Cronbach alpha value for each subscale ranged from 0.65 to 0.84 and from 0.6 to 0.83 for the sexually active and inactive groups, respectively. The convergent validity test showed that the value of each subscale was positively correlated with those of other questionnaires (P < 0.05). Exploratory and confirmatory factor analysis illustrated both good factor extraction and model fit. CONCLUSION: This study demonstrated the Mandarin Chinese version of PISQ-IR is a valid, reliable and condition-specific instrument to assess sexual function in sexually active or inactive women with a pelvic floor disorder.