Safety, tolerability, and acceptability of Lactobacillus crispatus CTV-05 (LACTIN-V) in pregnant women at high-risk of preterm birth.

The vaginal microbiota is a determinant for the risk of preterm birth (PTB). Dominance of the vaginal niche by Lactobacillus crispatus associates with term delivery. This is the first observational clinical study of live vaginal biotherapeutics (Lactobacillus crispatus CTV-05 (LACTIN-V)) in pregnant women at high-risk of PTB. The primary aim was to explore safety, tolerability and acceptability of LACTIN-V in pregnancy. Women were offered a course of LACTIN-V at 14 weeks gestation for five consecutive days followed by weekly administration for six weeks. Participants were followed up at 15, 18-, 20-, 28- and 36-weeks' gestation and at delivery for assessment of adverse events, compliance and tolerability. Participants completed a questionnaire to gauge experience and acceptability. In total, 73 women were recruited, of whom eight withdrew, leaving a final cohort size of 61. Self-reported compliance to the course was high (56/60, 93%). Solicited adverse events were reported in 13 women (19%) including changes in vaginal discharge, odour, colour or consistency of urine, itching and vaginal bleeding. One unsolicited adverse event was reported as haematuria at 38 weeks gestation, but was judged to be unrelated to LACTIN-V. No serious adverse events occurred. One mild adverse event led to study withdrawal. Thirty-one women completed an experience and acceptability questionnaire. Women found LACTIN-V easy and comfortable to use and the majority (30/31, 97%) would use LACTIN-V in future pregnancies. Eight women (8/31, 26%) found the schedule of use difficult to remember. The rate of PTB <34 weeks in this cohort was 3.3% compared to 7% in a historical cohort of 2,190 women at similar background PTB risk. With satisfactory uptake and good compliance, we demonstrate that LACTIN-V is safe and accepted in pregnancy, with high tolerability. Further studies are needed to assess colonisation of Lactobacillus crispatus CTV-05 and clinical efficacy.

A dynamical model of oncotripsy by mechanical cell fatigue: selective cancer cell ablation by low-intensity pulsed ultrasound.

The method of oncotripsy, first proposed in Heyden & Ortiz (Heyden & Ortiz 2016 J. Mech. Phys. Solids 92, 164-175 (doi:10.1016/j.jmps.2016.04.016)), exploits aberrations in the material properties and morphology of cancerous cells in order to ablate them selectively by means of tuned low-intensity pulsed ultrasound. We propose the dynamical model of oncotripsy that follows as an application of cell dynamics, statistical mechanical theory of network elasticity and 'birth-death' kinetics to describe the processes of damage and repair of the cytoskeleton. We also develop a reduced dynamical model that approximates the three-dimensional dynamics of the cell and facilitates parametric studies, including sensitivity analysis and process optimization. We show that the dynamical model predicts-and provides a conceptual basis for understanding-the oncotripsy effect and other trends in the data of Mittelstein et al. (Mittelstein et al. 2019 Appl. Phys. Lett. 116, 013701 (doi:10.1063/1.5128627)), for cells in suspension, including the dependence of cell-death curves on cell and process parameters.

Paediatric case series of drug reaction with eosinophilia and systemic symptoms (DRESS): 12-year experience at a single referral centre in Hong Kong and the first reported use of infliximab.

Summary: DRESS (drug reaction with eosinophilia and systemic symptoms) is a rare but potentially life-threatening disorder characterized by fever, skin eruption, haematological abnormalities and multi-organ dysfunction after drug exposure. The pathophysiology is thought to be related to interactions between culprit drugs, viral reactivation and T-lymphocytes activation. We report 4 paediatric patients with DRESS who were treated at our centre over the past 12 years. Most cases improved after corticosteroids. Other immunosuppressive medications were attempted in refractory cases with varied outcomes. Patient 3 was the first reported case that involved the use of infliximab, a TNF-α inhibitor, for DRESS. Although clinical efficacy was not observed for this one patient, a previous study demonstrated that patients with DRESS, disease progression and HHV-6 reactivation had elevated pre-treatment TNF- α and IL-6 levels. Further research is needed to explore the role of these cytokines in DRESS.

TSG-6 Downregulates IFN-Alpha and TNF-Alpha Expression by Suppressing IRF7 Phosphorylation in Human Plasmacytoid Dendritic Cells.

Proinflammatory cytokines such as TNF-α and type I interferons (IFN) are pathogenic signatures of systemic lupus erythematosus, and plasmacytoid dendritic cells (pDCs) play a major role by predominantly producing IFN-α. Given the rise of importance in identifying tumor necrosis stimulated gene 6 (TSG-6) as a key anti-inflammatory regulator, we investigate its function and its ability to counteract proinflammatory cytokine secretion by pDCs in vitro. CpG-A and R837 induced significant endogenous TSG-6 expression in the pDC cell-line GEN2.2. Following recombinant human TSG-6 treatment and CpG-A or R837 stimulation, significant reduction in IFN-α and TNF-α was observed in healthy donors' pDCs, and the same phenomenon was confirmed in GEN2.2. By CD44 blocking assay, we deduced that the suppressive effect of TSG-6 is mediated by CD44, by reducing IRF-7 phosphorylation. Our findings suggest that TSG-6 and its downstream signalling pathway could potentially be targeted to modulate proinflammatory cytokine expression in pDCs.

Remission With Donor Lymphocyte Infusion in a Child With Marrow Relapse After Haploidentical Stem Cell Transplantation for Relapsed Stage 4 Neuroblastoma.

A 7-year-old male with Stage 4 neuroblastoma was treated with chemotherapy and autologous hematopoietic stem cell transplantation (HSCT), resulting in partial response with residual bone and marrow disease. He proceeded to haploidentical-HSCT with his mother as donor and achieved remission. The patient developed marrow relapse 2 years after haploidentical-HSCT with cytopenia and dropping donor chimerism. Donor lymphocyte infusion (DLI) using mother's whole blood was given resulting in clearance of marrow disease, resolution of cytopenia, and full donor chimerism. This is the first report of successful treatment for neuroblastoma relapse after haploidentical-HSCT using DLI alone, supporting the role of adoptive cell therapy post-HSCT in neuroblastoma.

Compound heterozygous mutations in TTC7A cause familial multiple intestinal atresias and severe combined immunodeficiency.

Familial multiple intestinal atresias is an autosomal recessive disease with or without combined immunodeficiency. In the last year, several reports have described mutations in the gene TTC7A as causal to the disease in different populations. However, exact correlation between different genotypes and various phenotypes are not clear. In this study, we report identification of novel compound heterozygous mutations in TTC7A gene in a Malay girl with familial multiple intestinal atresias and severe combined immunodeficiency (MIA-SCID) by whole exome sequencing. We found two mutations in TTC7A: one that destroyed a putative splicing acceptor at the junction of intron 17/exon 18 and one that introduced a stop codon that would truncate the last two amino acids of the encoded protein. Reviewing the recent reports on TTC7A mutations reveals correlation between the position and nature of the mutations with patient survival and clinical manifestations. Examination of public databases also suggests carrier status for healthy individuals, making a case for population screening on this gene, especially in populations with suspected frequent founder mutations.

Exome sequencing identifies novel compound heterozygous mutations of IL-10 receptor 1 in neonatal-onset Crohn's disease.

Inflammatory bowel disease is well recognized for a strong genetic involvement in its pathogenesis. Homozygous mutations in interleukin-10 receptor 1 (IL-10R1) identified by linkage analysis were shown to be involved in this disorder. However, the underlying molecular mechanism and the causal nature of the mutations in the disease process remain to be clarified. In this study, using whole exome sequencing, we identified novel compound heterozygous missense mutations in the extracellular domain of IL-10R1 in a Crohn's disease patient from a non-consanguineous family. These mutations did not affect IL-10R1 expression, nor IL-10 binding. However, they abrogated IL-10R1 phosphorylation induced by IL-10, therefore leading to impaired STAT3 activation and suppression of inflammatory responses. After reconstitution with wild-type IL-10R1, the patient cells showed fully restored IL-10R function including IL-10-induced STAT3 activation and expression of suppressor of cytokine signaling 3. Thus, our results demonstrated that the mutations in IL-10R1 extracellular domain impair IL-10R1 activation rather than IL-10 binding, indicating these residues are important in IL-10 signal transduction through IL-10R1. The reconstitution data also confirmed the causality of the IL-10R1 mutations.

NK cells are dysfunctional in human chronic myelogenous leukemia before and on imatinib treatment and in BCR-ABL-positive mice.

Although BCR-ABL+ stem cells in chronic myeloid leukemia (CML) resist elimination by targeted pharmacotherapy in most patients, immunological graft-versus-leukemia effects can cure the disease. Besides cytotoxic T cells, natural killer (NK) cells may have a role in immune control of CML. Here, we explored the functionality of NK cells in CML patients and in a transgenic inducible BCR-ABL mouse model. Compared with controls, NK-cell proportions among lymphocytes were decreased at diagnosis of CML and did not recover during imatinib-induced remission for 10-34 months. Functional experiments revealed limited in vitro expansion of NK cells from CML patients and a reduced degranulation response to K562 target cells both at diagnosis and during imatinib therapy. Consistent with the results in human CML, relative numbers of NK1.1+ NK cells were reduced following induction of BCR-ABL expression in mice, and the defects persisted after BCR-ABL reversion. Moreover, target-induced degranulation by expanded BCR-ABL+ NK cells was compromised. We conclude that CML is associated with quantitative and functional defects within the NK-cell compartment, which is reproduced by induced BCR-ABL expression in mice. Further work will aim at identifying the mechanisms of NK-cell deficiency in CML and at developing strategies to exploit NK cells for immunotherapy.

Association of CD247 with systemic lupus erythematosus in Asian populations.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. CD247 (CD3Z, TCRZ) plays a vital role in antigen recognition and signal transduction in antigen-specific immune responses, and is known to be involved in SLE pathogenesis. Weak disease association was reported for genetic variants in this gene in Caucasian studies for SLE, Crohn's disease and systemic sclerosis, but its role as a genetic risk factor was never firmly established. METHODS: In this study, using a collection of 612 SLE patients and 2193 controls of Chinese ethnicity living in Hong Kong in a genome-wide study, single nucleotide polymorphisms (SNPs) in and around CD247 were identified as being associated with SLE. The two most significant SNPs in this locus were selected for further replication using TaqMan genotyping assay in 3339 Asian patients from Hong Kong, Mainland China, and Thailand, as well as 4737 ethnically and geographically matched controls. RESULTS: The association of CD247 with SLE in Asian populations was confirmed (rs704853: odds ratio [OR] = 0. 81, p = 2.47 × 10(-7); rs858543: OR = 1.10, p = 0.0048). Patient-only analysis suggested that rs704853 is also linked to oral ulcers, hematologic disorders and anti-double-stranded DNA (dsDNA) antibody production. CONCLUSION: A significant association between variants in CD247 and SLE was demonstrated in Asian populations. Understanding the involvement of CD247 in SLE may shed new light on disease mechanisms and development of new treatment paradigms.

Fractal dimension evaluation of cone beam computed tomography in patients with bisphosphonate-associated osteonecrosis.

OBJECTIVES: The aim of this study was to (1) evaluate the fractal dimension (FD) in regions of the mandible on cone beam CT (CBCT) images of patients with bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ) and (2) to select the most suitable region of interest (ROI) for further study on detection of bone alterations associated with bisphosphonates. METHODS: CBCT images of patients with BP-ONJ were included with matched controls. Values of FD were compared between groups. Selected ROIs were: ROI-1 - below the mandibular foramen; ROI-2 - above the mandibular foramen; ROI-3 - anterior to the mental foramen; ROI-4 - above the mandibular canal. The area of bone exposure was included as ROI-5. The results were analysed using generalized estimating equations and conditional logistic regression. RESULTS: There were 36 patients (67% female) with a mean age of 60.7 years. The mean FDs were: ROI-1 - 1.678 for controls and 1.673 for patients (P = 0.81); ROI-2 - 1.657 for controls and 1.653 for patients (P = 0.78); ROI-3 - 1.661 for controls and 1.684 for patients (P = 0.17); and ROI-4 - 1.670 for controls and 1.698 for patients (P = 0.03). The value of the FD in the area of exposed bone was the highest (1.729). The odds of being a BP-ONJ patient vs being a control was six times as high for individuals with a higher FD score at ROI-4, although the confidence interval was quite wide owing to the small sample size. CONCLUSION: In this preliminary study, BP-ONJ patients had higher FD values than controls at regions close to the alveolar process. The results suggest that FD is a promising tool for detection of bone alterations associated with BP-ONJ.

Prevention of vaginal SHIV transmission in macaques by a live recombinant Lactobacillus.

Most human immunodeficiency virus (HIV) transmissions in women occur through the cervicovaginal mucosa, which is coated by a bacterial biofilm including Lactobacillus. This commensal bacterium has a role in maintaining a healthy mucosa and can be genetically engineered to produce antiviral peptides. Here, we report a 63% reduction in transmission of a chimeric simian/HIV (SHIV(SF162P3)) after repeated vaginal challenges of macaques treated with Lactobacillus jensenii expressing the HIV-1 entry inhibitor cyanovirin-N. Furthermore, peak viral loads in colonized macaques with breakthrough infection were reduced sixfold. Colonization and prolonged antiviral protein secretion by the genetically engineered lactobacilli did not cause any increase in proinflammatory markers. These findings lay the foundation for an accessible and durable approach to reduce heterosexual transmission of HIV in women, which is coitally independent, inexpensive, and enhances the natural protective effects of the vaginal microflora.

Insulin resistance impairs nigrostriatal dopamine function.

Clinical studies have indicated a link between Parkinson's disease (PD) and Type 2 Diabetes. Although preclinical studies have examined the effect of high-fat feeding on dopamine function in brain reward pathways, the effect of diet on neurotransmission in the nigrostriatal pathway, which is affected in PD and parkinsonism, is less clear. We hypothesized that a high-fat diet, which models early-stage Type 2 Diabetes, would disrupt nigrostriatal dopamine function in young adult Fischer 344 rats. Rats were fed a high fat diet (60% calories from fat) or a normal chow diet for 12 weeks. High fat-fed animals were insulin resistant compared to chow-fed controls. Potassium-evoked dopamine release and dopamine clearance were measured in the striatum using in vivo electrochemistry. Dopamine release was attenuated and dopamine clearance was diminished in the high-fat diet group compared to chow-fed rats. Magnetic resonance imaging indicated increased iron deposition in the substantia nigra of the high fat group. This finding was supported by alterations in the expression of several proteins involved in iron metabolism in the substantia nigra in this group compared to chow-fed animals. The diet-induced systemic and basal ganglia-specific changes may play a role in the observed impairment of nigrostriatal dopamine function.

Two missense variants in UHRF1BP1 are independently associated with systemic lupus erythematosus in Hong Kong Chinese.

UHRF1BP1 encodes a highly conserved protein with unknown function. Previously, a coding variant in this gene was found to be associated with systemic lupus erythematosus (SLE) in populations of European ancestry (rs11755393, R454Q, P=2.22 x 10⁻8, odds ratio=1.17). In this study, by a combination of genome-wide study and replication involving a total of 1230 patients and 3144 controls, we confirmed the association of this coding variant to SLE in Hong Kong Chinese. We also identified another coding variant in this gene that independently contributes to SLE susceptibility (rs13205210, M1098T, P=4.44 x 10⁻9, odds ratio=1.49). Cross-population confirmation establishes the involvement of this locus in SLE and indicates that distinct alleles are contributing to disease susceptibility.

Association of BANK1 and TNFSF4 with systemic lupus erythematosus in Hong Kong Chinese.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. Recently, single nucleotide polymorphisms (SNPs) in BANK1 and TNFSF4 have been shown to be associated with SLE in Caucasian populations, but it is not known whether they are also involved in the disease in other ethnic groups. Recent data from our genome-wide association study (GWAS) for 314 SLE cases and 920 controls collected in Hong Kong identified SNPs in and around BANK1 and TNFSF4 to be associated with SLE risk. On the basis of the results of the reported studies and our GWAS, SNPs were selected for further genotyping in 949 SLE patients (overlapping with the 314 cases in our GWAS) and non-overlapping 1042 healthy controls. We confirmed the associations of BANK1 and TNFSF4 with SLE in Chinese (BANK1, rs3733197, odds ratio (OR)=0.84, P=0.021; BANK1, rs17266594, OR=0.61, P=4.67 x 10(-9); TNFSF4, rs844648, OR=1.22, P=2.47 x 10(-3); TNFSF4, rs2205960, OR=1.30, P=2.41 x 10(-4)). Another SNP located in intron 1 of BANK1, rs4522865, was separately replicated by Sequenom in 360 cases and 360 controls and was also confirmed to be associated with SLE (OR=0.725, P=2.93 x 10(-3)). Logistic regression analysis showed that rs3733197 (A383T in ankyrin domain) and rs17266594 (a branch point-site SNP) from BANK1 had independent contributions towards the disease association (P=0.037 and 6.63 x 10(-8), respectively). In TNFSF4, rs2205960 was associated with SLE independently from the effect of rs844648 (P=6.26 x 10(-3)), but not vice versa (P=0.55). These findings suggest that multiple independent genetic variants may be present within the gene locus, which exert their effects on SLE pathogenesis through different mechanisms.

Pedestrian injuries in school-attending children: a comparison of injury data sources in a low-income setting.

OBJECTIVE: To estimate and compare the rate of pedestrian injuries in primary school-attending children of urban Uganda using different data sources. DESIGN: Data collection from a hospital-based trauma registry, police data, teacher reports, and a cross-sectional community-based survey. SETTING: Kawempe, the largest urban district in the capital Kampala, Uganda. Patients or SUBJECTS: Primary school-attending children aged 4-12 from 39 randomly selected schools were included in the trauma registry, police data, and teacher reports. 1828 households randomly selected from the 39 schools were interviewed for the community survey. MAIN OUTCOME MEASURE: A pedestrian injury. For the trauma registry-defined as a pedestrian injury resulting in a visit to the hospital. For the police data-defined as a pedestrian injury reported to the police. For the teacher reports and survey-defined as a pedestrian injury resulting in at least a day off school. RESULTS: The estimated pedestrian injury rates per 100 000 person-years were 54.0 (95% CI 25.3 to 117.4), <53.97 (95% CI 23.8 to 125.9), 1878.8 (95% CI 1513.1 to 2322.4), and 764.0 (95% CI 523.3 to 1117.2) from the trauma registry, police data, teacher reports, and community survey, respectively. CONCLUSIONS: Pedestrian injury rates differed significantly between different data sources. Users must be aware of the different target populations, definitions, and limitations of the data sources before direct comparisons are made. Injury reports by volunteer teachers may be a feasible source of injury data in other low/middle-income countries.

Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese.

In this study, we compared the association of several newly discovered susceptibility genes for systemic lupus erythematosus (SLE) between populations of European origin and two Asian populations. Using 910 SLE patients and 1440 healthy controls from Chinese living in Hong Kong, and 278 SLE patients and 383 controls in Thailand, we studied association of STAT4, BLK and PXK with the disease. Our data confirmed association of STAT4 (rs7574865, odds ratio (OR) =1.71, P=3.55 x 10(-23)) and BLK (rs13277113, OR=0.77, P=1.34 x 10(-5)) with SLE. It was showed that rs7574865 of STAT4 is also linked to hematologic disorders and potentially some other subphenotypes of the disease. More than one genetic variant in STAT4 were found to be associated with the disease independently in our populations (rs7601754, OR=0.59, P=1.39 x 10(-9), and P=0.00034 when controlling the effect of rs7574865). With the same set of samples, however, our study did not detect any significant disease association for PXK, a risk factor for populations of European origin (rs6445975, joint P=0.36, OR=1.06, 95% confidence interval: 0.93-1.21). Our study indicates that some of the susceptibility genes for this disease may be population specific.

Risk-stratified seroprevalence of SARS coronavirus in children residing in a district with point-source outbreak compared to a low-risk area.

1. SARS coronavirus has low transmissibility at the community level. 2. Subclinical SARS coronavirus infection is rare in children.

Health literacy and vision-related quality of life.

BACKGROUND: Non-visual factors influence a person's vision-related quality of life (VRQoL). The purpose of this study was to assess the relationship between health literacy and VRQoL in glaucoma patients. METHODS: One hundred and ninety-five subjects with open-angle glaucoma participated in a cross-sectional patient survey and chart review. Subjects were administered a test of health literacy, an assessment of physical and mental well-being, and an assessment of VRQoL, the National Eye Institute 25-Item Visual Function Questionnaire (VFQ-25). Charts were reviewed for visual acuity and visual field results. RESULTS: In univariate analyses, older age (p<0.001), non-White race (p<0.001), worse visual acuity (p<0.001), worse visual field scores (p<0.001), lower level of education (p<0.001), worse health literacy (p<0.001) and worse score on the mental health component of the SF-12 (p = 0.005) were associated with worse VFQ-25 scores. In multivariate analyses, only older age was associated with worse total VFQ-25 scores (p<0.001), although the association between health literacy and the VFQ subscale of dependency remained significant (p = 0.04). CONCLUSIONS: Individuals with a lower health literacy do not appear to have a worse overall VRQoL compared with those with a higher literacy, but worse health literacy is associated with increased dependency.

Recurrent major infections in juvenile-onset systemic lupus erythematosus--a close link with long-term disease damage.

OBJECTIVES: We postulate that patients with systemic lupus erythematosus (SLE) having recurrent infections are more likely to have poorer disease outcome. The aim of this study is to describe the pattern of infections and disease damage that occurred in a cohort of patients with juvenile-onset SLE, and to find out whether cumulative disease damage was associated with recurrent infections in these patients. METHOD: We retrospectively reviewed (1988-2004) the clinical characteristics, infective complications, and disease damage as measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI) in 47 juvenile-onset SLE patients. Potential risk factors for disease damage were evaluated by univariate analysis and logistic regression. The correlation between number of major infections and disease damage was determined. RESULTS: Thirty-two (68.1%) patients had lupus nephropathy and 16 patients (34%) had neuropsychiatric lupus. Sixty-one episodes of major infections, defined as infections requiring more than 1 week of antimicrobial agents, occurred in 27 patients (57.4%), and 18 patients (31.4%) had recurrent major infections (>/= 2 episodes). Organ damage (SDI >/= 1) was documented in 21 subjects (44.7%). By logistic regression, occurrence of major infections (P < 0.001) was the only significant risk factor for disease damage. There was a positive correlation between SDI score with the number of recurrent major infections (Spearman's correlation coefficient = 0.50, P < 0.001). CONCLUSION: Infections and disease damage are common co-morbidities in juvenile-onset SLE. Recurrent infections could predict poorer disease outcome and associated organ damage in SLE.