Bronchiectasis is associated with delayed diagnosis and adverse outcomes in the New Zealand Common Variable Immunodeficiency Disorders cohort study.

Common variable immunodeficiency disorders (CVID) are multi-system disorders where target organ damage is mediated by infective, autoimmune and inflammatory processes. Bronchiectasis is probably the most common disabling complication of CVID. The risk factors for bronchiectasis in CVID patients are incompletely understood. The New Zealand CVID study (NZCS) is a nationwide longitudinal observational study of adults, which commenced in 2006. In this analysis, the prevalence and risk factors for bronchiectasis were examined in the NZCS. After informed consent, clinical and demographic data were obtained with an interviewer-assisted questionnaire. Linked electronic clinical records and laboratory results were also reviewed. Statistical methods were applied to determine if variables such as early-onset disease, delay in diagnosis and increased numbers of infections were associated with greater risk of bronchiectasis. One hundred and seven adult patients with a diagnosis of CVID are currently enrolled in the NZCS, comprising approximately 70% of patients known to have CVID in New Zealand. Fifty patients (46·7%) had radiologically proven bronchiectasis. This study has shown that patients with compared to those without bronchiectasis have an increased mortality at a younger age. CVID patients with bronchiectasis had a greater number of severe infections consequent to early-onset disease and delayed diagnosis. Indigenous Maori have a high prevalence of CVID and a much greater burden of bronchiectasis compared to New Zealand Europeans. Diagnostic latency has not improved during the study period. Exposure to large numbers of infections because of early-onset disease and delayed diagnosis was associated with an increased risk of bronchiectasis. Earlier diagnosis and treatment of CVID may reduce the risk of bronchiectasis and premature death in some patients.

Ovarian teratoma-associated anti-NMDAR encephalitis in a 12-year-old girl.

The association of ovarian teratoma and anti-N-Methyl-Daspartate receptor (anti-NMDAR) is one of the most common autoimmune encephalitis syndromes and it is a serious and potentially fatal pathology that occurs in young women. This case report describes of a pediatric patient with anti-NMDAR encephalitis. A-12-year-old girl presented with abnormal behavior for one week came to Emergency Department of Sarawak General Hospital, Malaysia. She had psychotic spectrum symptoms including suicidal tendency. She was diagnosed with anti-NMDAR encephalitis as positive antibody was seen in her cerebrospinal fluid. She was treated with Injection Immunoglobulin. She turned out to have teratoma which was successfully removed later. Her progress was remarkable after the surgery with the Immunoglobulin. A multi-disciplinary team involving a psychiatrist, neurologist and gynaecologist liaised with intensivist to successfully manage the case and achieve the good outcome.

Transient hypogammaglobulinaemia of infancy: many patients recover in adolescence and adulthood.

Transient hypogammaglobulinaemia of infancy (THI) is a relatively rare disorder where there is an exaggeration of the physiological nadir of immunoglobulin (Ig)G between loss of transplacentally acquired maternal IgG and production by the infant. Patients may be vulnerable to infections during the period of hypogammaglobulinaemia. The precise time to recovery in all infants is currently unknown. We sought to determine the clinical features and time-course of recovery for patients with THI. We reviewed our experience with THI over the last three decades in order to describe clinical and laboratory features, as well as the time-course of recovery. Forty-seven patients were identified with THI. Only thirty-seven per cent remitted by 4 years of age, while some patients did not recover until the third or fourth decade. In keeping with previous studies, the majority (25 of 47) presented with recurrent infections, nine had a family history of immunodeficiency and 13 had adverse reactions to food as their dominant clinical manifestation. Chronic tonsillitis developed in 10 patients and symptoms improved following surgery. The group with food allergies recovered sooner than those presenting with infections or with a family history immunodeficiency. Eight patients failed to respond to at least one routine childhood vaccine. Two have IgA deficiency and four individuals recovering in adolescence and adulthood continue to have borderline/low IgG levels. None have progressed to common variable immunodeficiency disorders (CVID). THI is a misnomer, as the majority do not recover in infancy. Recovery from THI can extend into adulthood. THI must be considered in the differential diagnosis of adolescents or young adults presenting with primary hypogammaglobulinemia.

Body image and psychological distress in nipple-sparing mastectomy: the roles of self-compassion and appearance investment.

OBJECTIVE: Women with breast cancer face threats to body image following surgery. Nipple-sparing mastectomy with immediate breast reconstruction (NSM + IBR) may minimise body image disturbance as this preserves the woman's skin and areola complex. We assessed levels of body image disturbance and psychological distress in women undergoing NSM + IBR. To further understand the body image-distress relationship, we investigated the potential moderating effect of self-compassion and appearance investment on this relationship. METHODS: Women diagnosed with breast cancer (N = 75) who had undergone NSM + IBR completed online questionnaires including the Body Image Scale, general (Depression, Anxiety and Stress Scales) and cancer-specific (Impact of Event Scale) psychological distress and Self-Compassion Scale and Appearance Schemas Inventory - Revised. RESULTS: Mean general and cancer-specific psychological distress scores were within normal ranges, and body image disturbance was moderately low. Body image was positively correlated with depression, stress, Impact of Event Scale scores and appearance investment and negatively correlated with self-compassion. MANCOVA analyses indicated a significant moderating effect of self-compassion and appearance investment on the body image disturbance-distress relationship (for depression, stress and intrusion), such that participants with high self-compassion and low appearance investment experienced lower distress than individuals with low self-compassion and high appearance investment. CONCLUSIONS: Moderately low levels of psychological distress and body image disturbance suggest NSM + IBR may minimise adverse psychological impacts of mastectomy. Increased body image disturbance was associated with psychological distress and moderated by self-compassion and appearance investment, suggesting a potential role for these characteristics as the focus of psychological interventions to minimise the negative impacts of mastectomy. Copyright © 2016 John Wiley & Sons, Ltd.

New diagnostic criteria for common variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or subcutaneous immunoglobulin.

Common variable immune deficiency (CVID) is the most frequent symptomatic primary immune deficiency in adults. The standard of care is intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (scIG) therapy. The cause of CVID is currently unknown, and there is no universally accepted definition of CVID. This creates problems in determining which patients will benefit from IVIG/scIG treatment. In this paper, we review the difficulties with the commonly used European Society of Immune Deficiencies (ESID) and the Pan American Group for Immune Deficiency (PAGID) definition of CVID. We propose new criteria for the diagnosis of CVID, which are based on recent scientific discoveries. Improved diagnostic precision will assist with treatment decisions including IVIG/scIG replacement. We suggest that asymptomatic patients with mild hypogammaglobulinaemia are termed hypogammaglobulinaemia of uncertain significance (HGUS). These patients require long-term follow-up, as some will evolve into CVID.

Variability of memory B cell markers in a cohort of common variable immune deficiency patients over 6 months.

Common Variable Immunodeficiency Disorder (CVID) is a complex disorder that predisposes patients to recurrent and severe infections. Immunophenotypic classification schemes were developed to categorize patients with CVID into phenotypic and prognostic groups based on different memory B cell subsets. Whether the B cell subset analysis is stable over time has not been investigated. B cell phenotyping in patients with CVID (n = 15) and sex- and age-matched controls (n = 26) were carried out according to the three B cell classifications. Patients with CVID were evaluated monthly over 6 months. Controls were assessed once during the study. We scored how often each patient was assigned to the same group within each classification. The Freiburg classification assigned patients to the same group at a rate of 73% and the Paris classification at 88%. The EUROclass classification of smB- versus smB+ was at 90%. The two subclassifications [(smB-21low or smB-21norm) and transitional B] were at 87% and 97%, respectively. The level of naïve B cells measured in all patients with CVID during the 6-month evaluation was the most stable B cell subset. We conclude that all classifications systems show considerable variability, but the EUROclass classification was the most reliable scheme for our 15 CVID and 26 healthy cohorts. Our results indicate that phenotypic classifications within CVID will be difficult while there is variability of commonly used assays.

Pre-closure assessment of elevated arsenic and other potential environmental constraints to developing aquaculture and fisheries: The case of the Mae Moh mine and power plant, Lampang, Thailand.

Our assessment of 30 water bodies in the vicinity of the Mae Moh coal mine and power station in northern Thailand does not indicate substantial water quality management challenges to developing fisheries/aquaculture in peripheral reservoirs and streams. Negative water quality issues such as high concentrations of arsenic (2-17 µg/L) and ions including sulfate (868-2605 mg/L), sodium (217-552 mg/L), and total ammonia (<1-5 mg/L) were associated with groundwater and surface water resources on the facility, as well as the stream network draining from it. Total dissolved solids were also very high, ranging from 658 to 3610 mg/L. Six of seven ponds tested had As concentrations in the range of 5-17 µg/L. Although these levels are less than the Thai regulation for industrial effluent, they are elevated over background surface water concentrations. The highest concentration in a contaminated stream was 10.54 µg/L As, which is only slightly above the WHO (2017) regulation of 10 µg/L for drinking water. Ponds, contaminated streams, and deep subsurface water should not be used for fisheries/aquaculture without extensive remediation/treatment. Concentrations of these water parameters in peripheral streams and reservoirs were not of environmental concern. High water hardness (161-397 mg/L CaCO3 and potential ionic imbalances may be the greatest hindrances to developing sustainable fisheries and aquaculture in reservoirs in the study area. Routine monitoring of inorganic As species and other contaminants in water is needed to assess the full extent of arsenic risk at the site following closure.

Follicular lymphoma in a X-linked lymphoproliferative syndrome carrier female.

X-linked lymphoproliferative (XLP) syndrome is a rare primary immune-deficiency disorder caused by mutations of the SH2D1A or XIAP genes. Males with the disorder are usually in good health until contracting Epstein-Barr virus (EBV) whereupon the majority of patients die from fulminant infectious mononucleosis, lymphoma or hypogammaglobulinaemia. This report describes a female carrier with an XLP phenotype who was retrospectively identified after her grandson died from the disorder. Subsequent genetic testing identified the patient's mother and affected maternal grandmother as XLP carriers. The family's medical records were significant. The proband had lymphoma at ages 2 and 8 and made a full recovery following treatment. Both the maternal grandmother and uncle died of non-Hodgkin's lymphoma. We were concerned that the XLP carrier mother may be predisposed to lymphoma if the normal X chromosome is skewed towards inactivation. The human androgen receptor assay detected random X chromosome inactivation in the carrier mother. EBV was not detected in the lymphoma tissues of the proband and his grandmother, confirming previous findings that EBV is not always associated with lymphoma in XLP. More significantly, our study highlights the importance of identifying XLP in families with a high incidence of lymphoma.

Maintenance of CD8+ T-cell anergy by CD4+CD25+ regulatory T cells in chronic graft-versus-host disease.

In a murine model of systemic lupus erythematosus (SLE)-like chronic graft-versus-host disease (cGVHD), donor CD8+ T cells rapidly fall into anergy to host cells, while donor CD4+ T cells hyperactivate B cells and break B-cell tolerance to self-Ags in the recipient mouse. The functional recovery of donor CD8+ T cells can result in the conversion of cGVHD to acute GVHD (aGVHD), indicating that donor CD8+ T-cell anergy is a restriction factor in the development of cGVHD. In this report, we present evidence that donor CD4+CD25+ regulatory T cells (Treg cells) are critical in maintaining the donor CD8+ T-cell anergy and thus suppressing the development of aGVHD in mice that are naturally prone to cGVHD. Our results provide a novel insight into the role of Treg cells in determining cGVHD versus aGVHD.

Three-dimensional transesophageal echocardiography for determination of the mitral valve area after mitral valve repair surgery for mitral stenosis.

BACKGROUND: Pressure half-time (PHT) method is usually unreliable for accurate determination of mitral valve area (MVA) immediately after surgical intervention of mitral stenosis (MS). The planimetry method using three-dimensional (3D) transesophageal echocardiography (3D-planimetery method) could enhance accurate determination of the intraoperative MVA. Authors investigated the efficacy of 3D-planimetry method in determining MVA immediately after mitral valve repair procedure (MVRep) for severe mitral stenosis (MS). METHODS: In severe MS patients undergoing elective MVRep (N.=41), intraoperative MVAs were determined by using PHT-method and 3D-planimetry method before and immediately after cardiopulmonary bypass (pre- and post-MVAPHT, and -MVA3D-planimetry). MVAs were also determined by using multi-detector computed tomographic scan (MDCT) before MVRep and within 7 days after MVRep (pre- and post-MVACT). MVAs determined by using three different methods were analysed. RESULTS: Mitral inflow pressure gradient (median [25th-75th percentile]) was significantly reduced after MVRep (3.0 [2.0-4.0] vs. 7.0 [6.0-9.0] mmHg; P<0.001). Pre-MVAPHT, pre-MVA3D-planimetry and preop-MVACT (mean [95% confidence interval]) did not differ significantly (1.08 [1.00-1.05], 1.08 [0.98-1.08], and 1.14 [1.07-1.22] cm2, respectively), but post-MVA3D-planimetry and post-MVACT (2.22 [2.07-2.36] and 2.31 [2.07-2.36] cm2, respectively) were significantly larger than post-MVAPHT (1.98 [1.83-2.13] cm2; P=0.007 and P<0.001, respectively). The correlation coefficient between post-MVA3D-planimetry and post-MVACT (0.59, P<0.01) was greater than that between post-MVAPHT and post-MVACT (0.39, P=0.01). CONCLUSIONS: These results support the clinical efficacy of 3D-planimetry for accurate evaluation of the MVA immediately after MVRep for severe MS, as a valuable alternative to PHT-method which usually underestimates MVA during this period.

NF-kappa B activation in vivo in both host and tumour cells by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA).

5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a new anticancer agent developed in this centre, has an antivascular action and causes regression of transplantable murine tumours that is mediated partially by the intratumoral production of tumour necrosis factor (TNF). DMXAA activates the nuclear factor-kappaB (NF-kappaB) transcription factor, which is involved in TNF synthesis and has also been suggested to mediate resistance to TNF. We wished to determine whether tumour cell NF-kappaB activation modulated the in vitro and in vivo effects of DMXAA. We compared the response of the 70Z/3 pre-B lymphoma cell line with that of its mutant 1.3E2 sub-line, which has a defective gamma-subunit of IKK, the kinase that phosphorylates IkappaB leading to NF-kappaB activation. As shown by electrophoretic mobility shift assays (EMSAs), DMXAA induced in vitro translocation of NF-kappaB (p50 and p65 subunits) into the nucleus of 70Z/3 cells, but not of 1.3E2 cells. However, when the cell lines were then grown as subcutaneous tumours in mice and treated with DMXAA (25 mg/kg), activation of NF-kappaB was found in nuclear extracts prepared from both 70/Z3 and 1.3E2 tumours, as well as from Colon 38 tumours that were used for comparison. This suggests that DMXAA induces NF-kappaB responses in host components of the tumour. Tumours grown from both 70Z/3 and 1.3E2 cells were found to regress completely following DMXAA treatment. Thus, the antitumour action of DMXAA appears to be independent of the ability of the target tumour cell population to induce NF-kappaB expression. Moreover, activation of NF-kappaB in the tumour cell did not confer resistance to DMXAA-induced therapy.

Antiphospholipid antibodies bind to activated but not resting endothelial cells: is an independent triggering event required to induce antiphospholipid antibody-mediated disease?

INTRODUCTION: Antiphospholipid antibodies (aPL) cause thrombotic disease and recurrent pregnancy loss. Despite their name it is now clear that the antigen for most antiphospholipid antibodies is the phospholipid-binding protein beta(2) glycoprotein I (beta(2)GPI). However, beta(2) glycoprotein I is only antigenic for antiphospholipid antibodies when the protein is immobilised on a suitable surface such as phosphatidyl serine. It has been suggested that antiphospholipid antibodies bind to beta(2) glycoprotein I on the surface of resting endothelial cells and this in turn leads to endothelial activation and the initiation of thrombosis. However, as phosphatidyl serine is absent from resting endothelial cell membranes, we questioned this hypothesis. MATERIALS AND METHODS: The ability of human antiphospholipid antibody-containing sera and monoclonal antiphospholipid antibodies to interact with endothelial cells was examined using cell-based ELISAs employing human umbilical vein endothelial cells (HUVECs) as the antigen. The expression of adhesion molecules in response to treatment with antiphospholipid antibodies was also measured by a cell-based ELISA. Activation of NF kappa beta was examined using electrophoretic mobility shift assays (EMSAs). RESULTS: Neither monoclonal antiphospholipid antibodies nor human sera containing antiphospholipid antibodies bound to resting endothelial cells. In contrast, one monoclonal antiphospholipid antibody did bind to both activated and apoptotic endothelial cells. CONCLUSIONS: Antiphospholipid antibodies do not bind to resting endothelial cells nor do antiphospholipid antibodies activate resting endothelial cells. Rather, an independent triggering event is required to activate endothelial cells and subsequently some antiphospholipid antibodies may then bind to the activated endothelial cells and initiate a thrombogenic process.

Conversion of alloantigen-specific CD8+ T cell anergy to CD8+ T cell priming through in vivo ligation of glucocorticoid-induced TNF receptor.

In this study, we investigated the effect of an agonistic mAb (DTA-1) against glucocorticoid-induced TNF receptor (GITR) in a murine model of systemic lupus erythematosus-like chronic graft-vs-host disease (cGVHD). A single dose of DTA-1 inhibited the production of anti-DNA IgG1 autoantibody and the development of glomerulonephritis, typical symptoms of cGVHD. DTA-1-treated mice showed clinical and pathological signs of acute GVHD (aGVHD), such as lymphopenia, loss of body weight, increase of donor cell engraftment, and intestinal damage, indicating that DTA-1 shifted cGVHD toward aGVHD. The conversion of cGVHD to aGVHD occurred because DTA-1 prevented donor CD8+ T cell anergy. Functionally active donor CD8+ T cells produced high levels of IFN-gamma and had an elevated CTL activity against host Ags. In in vitro MLR, anergic responder CD8+ T cells were generated, and DTA-1 stimulated the activation of these anergic CD8+ T cells. We further confirmed in vivo that donor CD8+ T cells, but not donor CD4+ T cells, were responsible for the DTA-1-mediated conversion of cGVHD to aGVHD. These results indicate that donor CD8+ T cell anergy is a restriction factor in the development of aGVHD and that in vivo ligation of GITR prevents CD8+ T cell anergy by activating donor CD8+ T cells that otherwise become anergic. In sum, our data suggest GITR as an important costimulatory molecule regulating cGVHD vs aGVHD and as a target for therapeutic intervention in a variety of related diseases.

Stimulation with 4-1BB (CD137) inhibits chronic graft-versus-host disease by inducing activation-induced cell death of donor CD4+ T cells.

4-1BB, a member of the tumor necrosis factor (TNF) receptor superfamily, is a costimulator for activated T cells. Previous studies have established that treatment with agonistic anti-4-BB monoclonal antibody (3H3) is effective in reversing the progression of spontaneous systemic lupus erythematosus. Its therapeutic effect is mediated by suppression of autoantibody production. In this report, we show that a single injection of 3H3 blocks chronic graft-versus-host disease (cGVHD) in the parent-into-F1 model. In particular, donor CD4+ T cells are rapidly eliminated from host spleens by activation-induced cell death after 4-1BB triggering. Since donor CD4+ T cells are required for the development of cGVHD, and 3H3-mediated inhibition of autoantibody production occurs without donor CD8+ T cells, 3H3 blocks cGVHD by preventing alloreactive donor CD4+ T cells from activating host B cells. Importantly, 3H3 treatment can reverse the progression of advanced cGVHD. Our findings indicate that agonistic anti-4-1BB monoclonal antibody has potential as an immunotherapeutic agent for preventing and treating cGVHD.

Amount of air infused to patient increases as fluid flow rates decrease when using the Hotline HL-90 fluid warmer.

OBJECTIVE: The intraoperative use of fluid warming devices has been recommended to avoid perioperative hypothermia and related adverse outcomes. To evaluate whether these devices might introduce risks of their own, we measured the volume of air escaping from a warmed intravenous solution that might be delivered to a patient. METHODS: In an operating room maintained at 19-19.5 degrees C, we tested an HL-90 Hotline fluid warmer with the L-70 fluid-warming set. One liter of lactated Ringer's solution was infused at flow rates of 150, 300, 500 and 3400 ml/h. The air that formed within the L-70 tubing during infusion was collected in a bubble trap placed at the end of the L-70 tubing. The volume of air in the bubble trap was measured. Twelve separate measurements were obtained at each flow rate. One additional study (n = 8) was performed using the L-10 Gas Vent to determine whether this equipment might reduce the volume of air infused when fluid flow rate was 300 mL/h. The volume of air collected at each flow rate was compared using ANOVA. RESULTS: Volume of air increased significantly from 1.0 +/- 0.2 mL to 2.9 +/- 0.4 ml as flow rate decreased from 3400 ml/h to 150 ml/h (p < 0.0001). The L-10 gas eliminator was ineffective in reducing the amount of air infused. CONCLUSIONS: We conclude that the use of the Hotline fluid warmer can result in infusion of air into the patient, introducing possible risk of air embolism.

Efectos de la Cisteína (Cys) y Metionina (Met) en la intoxicación agudacon plomo (Pb) en ratas Wistar / Effects of Cysteine (Cys) and Methionine (Met) in acute poisoning with lead

El plomo es un metal ubicuo y un contaminante ambiental con efectos sobre varios sistemas biológicos, siendo los sistemas hematopoyético, renal y hepático, los primeros en afectarse en una intoxicación aguda por este metal. El tratamiento de la intoxicación aguda por plomo se fundamenta en su eliminación del torrente sanguíneo y de los sitios de acumulación. El propósito del trabajo fue evaluar los efectos de la Metionina y Cisteína en ratas Wistar con intoxicación aguda por plomo. Metodología: Estudio prospectivo, experimental, tipo ensayo clínico, de corte longitudinal, de muestreo probabilístico estratificado. Se utilizaron quince ratas de la especie Wistar de sexo femenino, de 3 meses de nacidas con un peso promedio de 345 g. Se los distribuyó aleatoriamente en tres grupos de cinco ratas, denominados “placebo”, “intoxicación” y “experimentación”, de acuerdo a la administración de alimento y agua estándar, acetato de plomo y acetato de plomo más Metionina y Cisteína, respectivamente. Resultados: Los datos obtenidos demostraron que los niveles de plomo en sangre aumentó, con respecto al grupo placebo, 42 veces más (p<0,05) en animales intoxicados con 100 mg/kg de acetato de Plomo. La administración de Metionina y Cisteína de 200 mg/Kg redujo los niveles séricos de Pb en un 58% (p< 0,05) cuando se compara con el grupo de intoxicación. Conclusión: Al evaluar la acción combinada de la Metionina y la Cisteína se comprobó que estas inducen la disminución de los niveles de Plomo en sangre si se lo compara con el grupo intoxicación, dando un resultado estadísticamente significativo.