Development of EBV Related Diffuse Large B-cell Lymphoma in Deficiency of Adenosine Deaminase 2 with Uncontrolled EBV Infection.

Deficiency of Adenosine Deaminase 2 (DADA2) patients presenting with primary immunodeficiency are at risk of uncontrolled EBV infection and secondary malignancies including EBV-related lymphoproliferative disorders (LPD). This paper describes the first case of EBV related diffuse large B-cell lymphoma in a patient with DADA2 and uncontrolled EBV infection. Consideration should be given to monitoring for EBV viraemia and to preventative EBV specific therapy in DADA2 and patients with at risk primary immunodeficiencies. A type I interferon (IFN) gene signature is associated with DADA2 though its association with immune dysregulation is unclear.

Endothelial Mitochondria Transfer to Melanoma Induces M2-Type Macrophage Polarization and Promotes Tumor Growth by the Nrf2/HO-1-Mediated Pathway.

Gynecologic tract melanoma is a malignant tumor with poor prognosis. Because of the low survival rate and the lack of a standard treatment protocol related to this condition, the investigation of the mechanisms underlying melanoma progression is crucial to achieve advancements in the relevant gynecological surgery and treatment. Mitochondrial transfer between adjacent cells in the tumor microenvironment regulates tumor progression. This study investigated the effects of endothelial mitochondria on the growth of melanoma cells and the activation of specific signal transduction pathways following mitochondrial transplantation. Mitochondria were isolated from endothelial cells (ECs) and transplanted into B16F10 melanoma cells, resulting in the upregulation of proteins associated with tumor growth. Furthermore, enhanced antioxidation and mitochondrial homeostasis mediated by the Sirt1-PGC-1α-Nrf2-HO-1 pathway were observed, along with the inhibition of apoptotic protein caspase-3. Finally, the transplantation of endothelial mitochondria into B16F10 cells promoted tumor growth and increased M2-type macrophages through Nrf2/HO-1-mediated pathways in a xenograft animal model. In summary, the introduction of exogenous mitochondria from ECs into melanoma cells promoted tumor growth, indicating the role of mitochondrial transfer by stromal cells in modulating a tumor's phenotype. These results provide valuable insights into the role of mitochondrial transfer and provide potential targets for gynecological melanoma treatment.

Neuropathic Pain Affects Quality of Life in Breast Cancer Survivors with Chemotherapy-Induced Peripheral Neuropathy.

BACKGROUND: Despite the significant impact of chemotherapy-induced peripheral neuropathy on the quality of life for breast cancer survivors, there is a notable lack of comprehensive research. Therefore, a crucial need exists for further systematic investigation and inquiry into this matter. AIMS: This study examined predictors of quality of life in breast cancer survivors with chemotherapy-induced peripheral neuropathy. DESIGN: A cross-sectional, correlational design. SETTINGS: This study was conducted at a medical center in northern Taiwan and a teaching hospital in northeastern Taiwan. PARTICIPANTS/SUBJECTS: One hundred and thirty adult women with breast cancer, who have undergone chemotherapy and obtained a Total Neuropathy Scale-Clinical Version score>0, were enrolled. METHODS: Neuropathic pain, sleep disturbances, depression, and quality of life were evaluated using multiple regression analysis to identify quality of life predictors. Clinical importance was established using the minimally important difference of Functional Assessment of Cancer Therapy-Breast. RESULTS: The study indicated that improving depression (B = -10.87, p < .001) and neuropathic pain (B = -8.33, p = .004) may enhance the quality of life of breast cancer survivors with chemotherapy-induced peripheral neuropathy. Moreover, the individual's marital status and family history of breast cancer were identified as predictive factors. CONCLUSIONS: This study illuminates quality of life determinants for breast cancer survivors with chemotherapy-induced peripheral neuropathy, advocating comprehensive care and addressing depression and neuropathic pain for better outcomes.

The association between plasma angiopoietin-like protein 4, glucose and lipid metabolism during pregnancy, placental function, and risk of delivering large-for-gestational-age neonates.

BACKGROUND: Large-for-gestational-age (LGA) neonates have increased risk of adverse pregnancy outcomes and adult metabolic diseases. We aimed to investigate the relationship between plasma angiopoietin-like protein 4 (ANGPTL4), a protein involved in lipid and glucose metabolism during pregnancy, placental function, growth factors, and the risk of LGA. METHODS: We conducted a prospective cohort study and recruited women with singleton pregnancies at the National Taiwan University Hospital between 2013 and 2018. First trimester maternal plasma ANGPTL4 concentrations were measured. RESULTS: Among 353 pregnant women recruited, the LGA group had higher first trimester plasma ANGPTL4 concentrations than the appropriate-for-gestational-age group. Plasma ANGPTL4 was associated with hemoglobin A1c, post-load plasma glucose, plasma triglyceride, plasma free fatty acid concentrations, plasma growth hormone variant (GH-V), and birth weight, but was not associated with cord blood growth factors. After adjusting for age, body mass index, hemoglobin A1c, and plasma triglyceride concentrations, plasma ANGPTL4 concentrations were significantly associated with LGA risk, and its predictive performance, as measured by the area under the receiver operating characteristic curve, outperformed traditional risk factors for LGA. CONCLUSIONS: Plasma ANGPTL4 is associated with glucose and lipid metabolism during pregnancy, plasma GH-V, and birth weight, and is an early biomarker for predicting the risk of LGA.

Isoliquiritigenin inhibits apoptosis and ameliorates oxidative stress in rheumatoid arthritis chondrocytes through the Nrf2/HO-1-mediated pathway.

Rheumatoid arthritis (RA) is a chronic inflammatory condition known for its irreversible destructive impact on the joints. Chondrocytes play a pivotal role in the production and maintenance of the cartilage matrix. However, the presence of inflammatory cytokines can hinder chondrocyte proliferation and promote apoptosis. Isoliquiritigenin (ISL), a flavonoid, potentially exerts protective effects against various inflammatory diseases. However, its specific role in regulating the nuclear factor E2-associated factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in chondrocytes in RA remains unclear. To investigate this, this study used human chondrocytes and Sprague-Dawley rats to construct in vitro and in vivo RA models, respectively. The study findings reveal that cytokines markedly induced oxidative stress, the activation of matrix metalloproteinases, and apoptosis both in vitro and in vivo. Notably, ISL treatment significantly mitigated these effects. Moreover, Nrf2 or HO-1 inhibitors reversed the protective effects of ISL, attenuated the expression of Nrf2/HO-1 and peroxisome proliferator-activated receptor gamma-coactivator-1α, and promoted chondrocyte apoptosis. This finding indicates that ISL primarily targets the Nrf2/HO-1 pathway in RA chondrocytes. Moreover, ISL treatment led to improved behavior scores, reduced paw thickness, and mitigated joint damage as well as ameliorated oxidative stress in skeletal muscles in an RA rat model. In conclusion, this study highlights the pivotal role of the Nrf2/HO-1 pathway in the protective effects of ISL and demonstrates the potential of ISL as a treatment option for RA.

Advanced maternal age-related clustering of metabolic abnormalities is associated with risks of adverse pregnancy outcomes.

AIMS: Advanced maternal age (AMA) is correlated with higher risk of adverse pregnancy outcomes while the pathophysiology remains unclear. Our study aimed to investigate whether AMA is linked to the clustering of metabolic abnormalities, which in turn is associated with an increased risk of adverse pregnancy outcomes. METHOD: A total of 857 pregnant woman were recruited in a prospective cohort at National Taiwan University Hospital, from November 2013 to April 2018. Metabolic abnormalities during pregnancy were defined as following: fasting plasma glucose ≥92 mg/dl, body mass index (BMI) ≥24 kg/m2, plasma high-density lipoprotein cholesterol <50 mg/dl, hyper-triglyceridemia (≥140 mg/dl in the first trimester or ≥220 mg/dl in the second trimester), and blood pressure ≥130/85 mmHg. RESULT: Incidence of large for gestational age (LGA), primary caesarean section (CS), and the presence of any adverse pregnancy outcome increased with age. The advanced-age group tended to have more metabolic abnormalities in both the first and the second trimesters. There was a significant association between the number of metabolic abnormalities in the first and the second trimesters and the incidence of LGA, gestational hypertension or preeclampsia, primary CS, preterm birth, and the presence of any adverse pregnancy outcome, adjusted for maternal age. CONCLUSION: AMA is associated with clustering of metabolic abnormalities during pregnancy, and clustering of metabolic abnormalities is correlated with increased risk of adverse pregnancy outcomes.

Symptom clusters and predominant symptoms in lymphoma survivorship: a cross-sectional study using trend analysis.

PURPOSE: This study explored symptom clusters (SCs) and predominant symptoms in lymphoma survivorships at least 1 month after treatment. METHODS: A cross-sectional trend study design was adopted. Inclusion criteria were participants who were over the age of 20, diagnosed with lymphoma, and 1 month after treatment concluded. The symptoms were assessed by the Functional Assessment of Cancer Therapy Scale-Lymphoma Subscale. Data were analyzed using descriptive statistics, latent profile analysis (LPA), and comparisons of means and frequencies of each symptom in each SC. RESULTS: A total of 234 lymphoma survivors completed this study. Three SCs were identified at < 2 and > 5 years and two SCs at 2-5 years. Worrying about getting new symptoms and infections emerged as predominant symptoms across all SCs over time. This study provides insights into the symptom experiences of survivors of lymphoma and highlights the significant role of worry-related symptoms in their survivorship. CONCLUSION: Through the use of LPA and a trend study design, we identified distinct SCs in lymphoma survivors, providing valuable insights into their longitudinal symptom experiences. The findings emphasize the complexity of symptomatology in lymphoma survivorship and underscore the importance of employing advanced statistical methods to explore and understand these clusters comprehensively, informing targeted interventions and improved care strategies.

Risk of placenta accreta spectrum following myomectomy: a nationwide cohort study.

BACKGROUND: Whether myomectomy increases the risk of placenta accreta spectrum in the following pregnancies remains controversial. OBJECTIVE: This study aimed to investigate the effect of myomectomy on the risk of placenta accreta spectrum in the following pregnancies. Moreover, different methods of myomectomy on the risk of placenta accreta spectrum were explored. STUDY DESIGN: A nationwide cohort study was conducted using data from the Taiwan National Health Insurance Research Database, including all pregnant patients in Taiwan who gave birth between January 2008 and December 2017. A 1:1 propensity score estimation matching was performed for the analysis of myomectomy on the risk of placenta accreta spectrum. Among pregnant patients who received myomectomy, different methods of myomectomy on the risk of placenta accreta spectrum were compared with the control group. RESULTS: Among the 1,371,458 pregnant patients in this study, 11,255 pregnant patients had a history of myomectomy. The risk of placenta accreta spectrum was higher in pregnant patients with a history of myomectomy than in pregnant patients without a history of myomectomy (incidence: 0.96% vs 0.20%; adjusted odds ratio, 2.28; 95% confidence interval, 1.85-2.81; P<.01). Among pregnant patients with a history of myomectomy, 5045 (46.87%) received laparotomic myomectomy, 3973 (36.93%) received laparoscopic myomectomy, and 1742 (16.20%) received hysteroscopic myomectomy. The incidence of placenta accreta spectrum was higher in the hysteroscopic group than in the laparotomic group or the laparoscopic group (1.89% [hysteroscopic group] vs 0.71% [laparotomic group] and 0.81% [laparoscopic group]; P<.05). Compared with patients without a history of myomectomy, the adjusted odds ratio for placenta accreta spectrum was 3.88 (95% confidence interval, 2.68-5.63; P<.05) in the hysteroscopic group. CONCLUSION: Myomectomy, especially hysteroscopic myomectomy, is associated with an increased risk of placenta accreta spectrum in the subsequent pregnancy.

Safe delivery planning of patients with moyamoya disease in pregnancy: Case series of a single center.

OBJECTIVE: Moyamoya disease (MMD) is a rare cerebral vascular disease and there is limited clinical experience for pregnant women. Cerebrovascular condition might deteriorated during pregnancy. Management and mode of delivery is challenging for obstetrics specialist. CASE REPORT: Three cases of parturients with moyamoya disease delivered in National Taiwan University Hospital are presented. All were previously diagnosed and one had stroke incidence before current pregnancy course. Two delivered with Cesarean section and one with vaginal delivery, and all delivered at term without maternal or neonatal complication. CONCLUSION: Although delivery method of parturients with MMD has been debating, vaginal delivery may be suitable for certain cases under adequate monitoring and case selection.

Mitochondrial transplantation attenuates traumatic neuropathic pain, neuroinflammation, and apoptosis in rats with nerve root ligation.

Traumatic neuropathic pain (TNP) is caused by traumatic damage to the somatosensory system and induces the presentation of allodynia and hyperalgesia. Mitochondrial dysfunction, neuroinflammation, and apoptosis are hallmarks in the pathogenesis of TNP. Recently, mitochondria-based therapy has emerged as a potential therapeutic intervention for diseases related to mitochondrial dysfunction. However, the therapeutic effectiveness of mitochondrial transplantation (MT) on TNP has rarely been investigated. Here, we validated the efficacy of MT in treating TNP. Both in vivo and in vitro TNP models by conducting an L5 spinal nerve ligation in rats and exposing the primary dorsal root ganglion (DRG) neurons to capsaicin, respectively, were applied in this study. The MT was operated by administrating 100 µg of soleus-derived allogeneic mitochondria into the ipsilateral L5 DRG in vivo and the culture medium in vitro. Results showed that the viable transplanted mitochondria migrated into the rats' spinal cord and sciatic nerve. MT alleviated the nerve ligation-induced mechanical and thermal pain hypersensitivity. The nerve ligation-induced glial activation and the expression of pro-inflammatory cytokines and apoptotic markers in the spinal cord were also repressed by MT. Consistently, exogenous mitochondria reversed the capsaicin-induced reduction of mitochondrial membrane potential and expression of pro-inflammatory cytokines and apoptotic markers in the primary DRG neurons in vitro. Our findings suggest that MT mitigates the spinal nerve ligation-induced apoptosis and neuroinflammation, potentially playing a role in providing neuroprotection against TNP.

Suppression of TGFß-Induced Interleukin-6 Secretion by Sinulariolide from Soft Corals through Attenuation of the p38-NF-kB Pathway in Carcinoma Cells.

Sinulariolide (SC-1) is a natural product extracted from the cultured-type soft coral Sinularia flexibilis and possesses anti-inflammation, anti-proliferative, and anti-migratory in several types of cancer cells. However, the molecular pathway behind its effects on inflammation remains poorly understood. Since inflammatory cytokines such as TGFß, TNFα, IL-1, IL-6, and IL-8 activate transcription factors such as Smads, NF-κB, STAT3, Snail, Twist, and Zeb that drive the epithelial-to-mesenchymal transition (EMT), in this study, we focus on the investigation in effects of SC-1 on TGFß-induced interleukin-6 (IL-6) releases in an in vitro cell culture model. We showed that both intracellular IL-6 expression and secretion were stimulated by TGFß and associated with strong upregulation of IL-6 mRNA and increased transcription in A549 cells. SC-1 blocked TGFß-induced secretion of IL-6 while showing no effect on the induction of fibronectin and plasminogen activator inhibitor-1 genes, indicating that SC-1 interferes with only a subset of TGFß activities. In addition, SC-1 inhibits TGFß-induced IL-6 by suppressing p38 MAPK signaling and subsequently inhibits NF-κB and its nuclear translocation without affecting the canonical Smad pathway and receptor turnover. Overall, these data suggest that p38 may involve in the inhibition of SC-1 in IL-6 release, thus illustrating an inhibitory effect for SC-1 in the suppression of inflammation, EMT phenotype, and tumorigenesis.

Paraneoplastic pemphigus: Diagnostic mimics, confounders and management challenges in a series of five long-term survivors from a single centre.

We present a series of five cases who presented to our institution with treatment-refractory mucosal ulceration, all of whom were subsequently diagnosed with paraneoplastic pemphigus (PNP). This case series highlights the diagnostic and treatment considerations for PNP - in particular, the steroid-dependent, recalcitrant, polymorphic manifestations; the combination of histopathological and clinical findings that may overlap with clinically similar diseases, for example, pemphigus vulgaris and lichen planus; the importance of immunopathological findings for its diagnosis, and the need for surveillance and management of life-threatening bronchiolitis obliterans.

Sub-Millisecond Laser-Irradiation-Mediated Surface Restructure Boosts the CO Production Yield of Cobalt Oxide Supported Pd Nanoparticles.

The catalytic conversion of CO2 into valuable commodities has the potential to balance ongoing energy and environmental issues. To this end, the reverse water-gas shift (RWGS) reaction is a key process that converts CO2 into CO for various industrial processes. However, the competitive CO2 methanation reaction severely limits the CO production yield; therefore, a highly CO-selective catalyst is needed. To address this issue, we have developed a bimetallic nanocatalyst comprising Pd nanoparticles on the cobalt oxide support (denoted as CoPd) via a wet chemical reduction method. Furthermore, the as-prepared CoPd nanocatalyst was exposed to sub-millisecond laser irradiation with per-pulse energies of 1 mJ (denoted as CoPd-1) and 10 mJ (denoted as CoPd-10) for a fixed duration of 10 s to optimize the catalytic activity and selectivity. For the optimum case, the CoPd-10 nanocatalyst exhibited the highest CO production yield of ∼1667 µmol g-1catalyst, with a CO selectivity of ∼88% at a temperature of 573 K, which is a 41% improvement over pristine CoPd (~976 µmol g-1catalyst). The in-depth analysis of structural characterizations along with gas chromatography (GC) and electrochemical analysis suggested that such a high catalytic activity and selectivity of the CoPd-10 nanocatalyst originated from the sub-millisecond laser-irradiation-assisted facile surface restructure of cobalt oxide supported Pd nanoparticles, where atomic CoOx species were observed in the defect sites of the Pd nanoparticles. Such an atomic manipulation led to the formation of heteroatomic reaction sites, where atomic CoOx species and adjacent Pd domains, respectively, promoted the CO2 activation and H2 splitting steps. In addition, the cobalt oxide support helped to donate electrons to Pd, thereby enhancing its ability of H2 splitting. These results provide a strong foundation to use sub-millisecond laser irradiation for catalytic applications.

OPRM1 A118G polymorphism modulating motor pathway for pain adaptability in women with primary dysmenorrhea.

Introduction: Primary dysmenorrhea (PDM) is a common condition among women of reproductive age, characterized by menstrual pain in the absence of any organic causes. Previous research has established a link between the A118G polymorphism in the mu-opioid receptor (OPRM1) gene and pain experience in PDM. Specifically, carriers of the G allele have been found to exhibit maladaptive functional connectivity between the descending pain modulatory system and the motor system in young women with PDM. This study aims to explore the potential relationship between the OPRM1 A118G polymorphism and changes in white matter in young women with PDM. Methods: The study enrolled 43 individuals with PDM, including 13 AA homozygotes and 30 G allele carriers. Diffusion tensor imaging (DTI) scans were performed during both the menstrual and peri-ovulatory phases, and tract-based spatial statistics (TBSS) and probabilistic tractography were used to explore variations in white matter microstructure related to the OPRM1 A118G polymorphism. The short-form McGill Pain Questionnaire (MPQ) was used to access participants' pain experience during the MEN phase. Results: Two-way ANOVA on TBSS analysis revealed a significant main effect of genotype, with no phase effect or phase-gene interaction detected. Planned contrast analysis showed that during the menstrual phase, G allele carriers had higher fractional anisotropy (FA) and lower radial diffusivity in the corpus callosum and the left corona radiata compared to AA homozygotes. Tractographic analysis indicated the involvement of the left internal capsule, left corticospinal tract, and bilateral medial motor cortex. Additionally, the mean FA of the corpus callosum and the corona radiata was negatively correlated with MPQ scales in AA homozygotes, but this correlation was not observed in G allele carriers. No significant genotype difference was found during the pain-free peri-ovulary phase. Discussion: OPRM1 A118G polymorphism may influence the connection between structural integrity and dysmenorrheic pain, where the G allele could impede the pain-regulating effects of the A allele. These novel findings shed light on the underlying mechanisms of both adaptive and maladaptive structural neuroplasticity in PDM, depending on the specific OPRM1 polymorphism.

Serological intermolecular epitope spreading in a patient with primary Sjögren's syndrome.

Sjögren's syndrome (SS) is one of the prototypic systemic autoimmune diseases characterised by autoreactive T and B cells, sicca symptoms and various extraglandular manifestations. SS is characterised by autoantibodies (anti-Ro52/tripartite motif containing-21 [TRIM21], anti-Ro60 and anti-La) that are important diagnostic biomarkers. Patients have typically stable serostatus; that is, patients who are positive for one or more of these autoantibodies tend to remain thus and vice versa. We describe a rare instance where a woman in her 50s was diagnosed with primary SS and developed new autoantibodies subsequently through serological epitope spreading. She demonstrated primarily glandular features only and clinical stability despite serological evolution. In this case report, we discuss the significance of this molecular feature and the clinical implications for our understanding of autoimmunity.

Isolated anti-Ro52 identifies a severe subset of Sjögren's syndrome patients.

Introduction: Serum autoantibodies targeting the SSA/Ro proteins are a key component of the classification criteria for the diagnosis of Sjögren's syndrome (SS). Most patients' serum reacts with both Ro60 and Ro52 proteins. Here we compare the molecular and clinical characteristics of patients diagnosed with SS with anti-Ro52 in the presence or absence of anti-Ro60/La autoantibodies. Methods: A cross-sectional study was performed. Patients in the SS biobank at Westmead Hospital (Sydney, Australia) that were positive for anti-Ro52 were included and stratified based on the absence (isolated) or presence (combined) of anti-Ro60/La, measured by line immunoassay. We examined clinical associations and the serological and molecular characteristics of anti-Ro52 using ELISA and mass spectrometry in serological groups. Results: A total of 123 SS patients were included for study. SS patients with isolated anti-Ro52 (12%) identified a severe serological subset characterised by higher disease activity, vasculitis, pulmonary involvement, rheumatoid factor (RhF) and cryoglobulinaemia. Serum antibodies reacting with Ro52 in the isolated anti-Ro52 subset displayed less isotype switching, less immunoglobulin variable region subfamily usage and a lower degree of somatic hypermutation than the combined anti-Ro52 subset. Conclusions: In our cohort of SS patients, isolated anti-Ro52 represents a severe subset of SS, and is associated with the presence of cryoglobulinaemia. We therefore provide clinical relevance to the stratification of SS patients by their sero-reactivities. It is possible that the autoantibody patterns may be immunological epiphenomena of the underlying disease process, and further work is required to unearth the mechanisms of the differential clinical phenotypes.

The conundrum of neuropsychiatric systemic lupus erythematosus: Current and novel approaches to diagnosis.

Recognising neuropsychiatric involvement by systemic lupus erythematosus (SLE) is of growing importance, however many barriers to this exist at multiple levels of our currently available diagnostic algorithms that may ultimately delay its diagnosis and subsequent treatment. The heterogeneous and non-specific clinical syndromes, serological and cerebrospinal fluid (CSF) markers and neuroimaging findings that often do not mirror disease activity, highlight important research gaps in the diagnosis of neuropsychiatric SLE (NPSLE). Formal neuropsychological assessments or the more accessible screening metrics may also help improve objective recognition of cognitive or mood disorders. Novel serum and CSF markers, including autoantibodies, cytokines and chemokines have also shown increasing utility as part of diagnosis and monitoring, as well as in distinguishing NPSLE from SLE patients without SLE-related neuropsychiatric manifestations. Novel neuroimaging studies also expand upon our existing strategy by quantifying parameters that indicate microarchitectural integrity or provide an assessment of neuronal function. Some of these novel markers have shown associations with specific neuropsychiatric syndromes, suggesting that future research move away from considering NPSLE as a single entity but rather into its individually recognized neuropsychiatric manifestations. Nevertheless, it is likely that a composite panel of these investigations will be needed to better address the gaps impeding recognition of neuropsychiatric involvement by SLE.

Hyper-IgM and acquired C1q complement deficiency in a patient with de novo ATM mutation.

Hyper-IgM syndrome (HIGM) is a rare immunodeficiency phenotype that is usually accompanied by serious infections. We present a curious case of the incidental detection of HIGM in a 45-year-old male with complement C1q deficiency. He had relatively mild sinopulmonary infections, recurrent skin infections and lipomas in his adulthood. Investigations revealed normal enumeration of total peripheral blood B cells and reduced expression of CD40L on his CD4+ T cells. C1q was noted to be absent, due to a peripheral inhibitor such as an autoantibody. Genomic sequencing of the patient and his parents revealed a novel, de novo heterozygous mutation in the ATM (ataxia telangiectasia mutated) gene although he displayed no clinical evidence of ataxia telangiectasia. This is a rare case of HIGM and acquired C1q deficiency. We present full phenotyping data that contributes to the growing understanding to these interesting immunodeficiencies.