Hematological manifestation of Pediatric Systemic Lupus Erythematosus (SLE) - A single centered cross-sectional study.

Introduction: Systemic lupus erythematosus (SLE), the commonest type of lupus, is an autoimmune multisystemic disorder that can affect any organ system of the body, especially blood vessels and connective tissues, causing widespread inflammation. Pediatric onset of SLE is a rare condition with more hematological involvement. Aim: This study was undertaken to observe various hematological abnormalities and their association with various autoantibodies present in pediatric SLE in Eastern India. Methodology: It was a single-centered, cross-sectional, observational, hospital-based study conducted in the Department of Pediatric Medicine in collaboration with the Department of Rheumatology in IPGME and R and SSKM Hospital, Kolkata. The duration of the study was 1.5 years, and a total of 30 children up to 12 years of age of either gender were enrolled. Study participants were evaluated for various parameters like demographic, hematological (anemia, neutropenia, leucopenia, lymphopenia, and thrombocytopenia), biochemical (CRP, Lactate dehydrogenase (LDH), and bilirubin), autoantibodies (anti-dsDNA, anti-Ro 52, and anti-Ribonucleoprotein [RNP]), and SLE related pathologies (Cutaneous, nephritis, serositis). Results: In the present study, most of the participants had arthritis, muscle pain (86.66%), and hematological involvement (80%). Among cytopenias, anemia was the commonest. dsDNA autoantibody was positive in most of the patients (83%), and about one-third suffered from autoimmune hemolytic anemia (AIHA). No association was observed between autoantibodies and various hematological manifestations. Conclusion: It can be concluded from the present study that anemia is the most common cytopenia in pediatric SLE, but there is no association between autoantibodies and these cytopenias. However, study on larger population may give better results.

Anti-factor H autoantibodies in patients with lupus nephritis.

INTRODUCTION: Lupus nephritis (LN) is a disease marked by autoantibodies against complement components. Autoantibodies against negative complement regulator factor H (anti-FH) are prevalent in aHUS, are associated with deletion of factor H-related protein 1 (FHR1) gene, and have overt functional consequences. They are also observed in C3 glomerulopathies. The frequency and relevance of anti-FH in LN are poorly studied. AIM: The aim of our investigation was to screen for the presence of anti-FH and FHR1 gene deletion in a cohort of LN patients and to evaluate their association with LN activity. METHOD: ELISA test and Western blot for detection of anti-FH and FHR1 deletion were used, respectively. Patients' clinical and laboratory parameters regarding anti-FH role were processed by statistical analysis. RESULTS: Anti-FH were found at low level in a small number of LN patients - 11.7% (7/60) and were not associated with deletion of FHR1. Anti-FH did not correlate with ANA titers, anti-dsDNA, C3/C4 hypocomplementemia, eGFR, proteinuria, or active urinary sediment in LN patients. A weak correlation was found between anti-FH and anti-C3 levels. Anti-FH were linked with endocapillary proliferation and histological activity index. Four anti-FH positive patients had severe to moderate LN as per the BILAG renal score. CONCLUSIONS: Anti-FH autoantibodies are an accessory finding in LN and are more likely to manifest during the active phase of the disease. Due to their low frequency and plasma levels, they do not seem suitable for routine laboratory investigation in patients with LN.

UNCovering new causes of monogenic systemic lupus erythematosus.

UNC93B1 is essential for the stability and endosomal trafficking of nucleic-acid sensing Toll-like receptors (TLRs) including TLR7 and TLR8. Increased TLR7 responses are associated with lupus autoimmunity in both mice and humans. In a recent article, Al-Azab et al. demonstrate the role of a variant of UNC93B1 (p.V117L) in the induction of pediatric systemic lupus erythematosus in patients and in mice through TLR7/8 hyperresponsiveness. They also highlight a potential role for the pharmacological inhibition of interleukin-1 receptor-associated kinase (IRAK) 1 and/or 4 in ameliorating disease.

Biochemical study of ZNF76 rs10947540 and SCUBE3 rs1888822 single nucleotide polymorphisms in the Egyptian patients with systemic lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a common autoimmune disease marked by the formation of apoptotic debris and the presence of autoantibodies that target nuclear components. At this moment, the actual cause of SLE is uncertain. Genetic variables have been well proven to have a significant role in the propensity of SLE. This study aimed to investigate the effect of (ZNF76) rs (10947540) and (SCUBE) rs (1888822) gene polymorphism in patients with systemic lupus erythematosus. A case control study has been carried out at Medical Biochemistry & Molecular biology and Rheumatology unit of Internal Medicine Departments, Faculty of Medicine, Menoufia University, Egypt, for 1-year duration between 1 June 2022 and 1 June 2023. Sixty patients were females (75%) and twenty patients were males (25%). Their ages ranged from 19 to 53 years. Their disease durations ranged from 7 months to 20 years. The findings indicated that the TC genotype of the ZNF76 rs10947540 gene increases the risk of SLE by 2.274-fold, while the dominant TC + CC increases the risk by 2.472-fold, and the C allele increases the risk by 2.115-fold. Additionally, the results showed that the TT genotype of the SCUBE3 rs1888822 gene increases the risk of SLE by 3.702-fold, the dominant GT + TT increases the risk by 2.304-fold, and the T allele increases the risk by 2.089-fold, while the GT genotype increases the risk by 1.918-fold. The study revealed significant associations between the genotypes of these polymorphisms and certain clinical parameters in SLE patients. These findings highlight the potential genetic contributions to SLE susceptibility and its clinical manifestations, providing valuable insights for future research and potential personalized approaches to the management of this complex autoimmune disease.

Harnessing cGAS-STING axis for therapeutic benefits in systemic lupus erythematosus.

The cyclic GMP-AMP synthase (cGAS), a prominent intracellular DNA sensor in mammalian cells, controls the innate immune response and the stimulator of interferon genes (STING)-mediated synthesis of pro-inflammatory cytokines, such as type-I interferon (IFN-I). For decades, IFN-I has been hypothesized to be essential in the development of systemic lupus erythematosus (SLE), a chronic multisystem autoimmunity characterized by immune complex (IC) deposition in small vessels. Recent findings revealed that the activation of the cGAS-STING pathway by self-DNA would propagate the autoimmune responses via upregulating IFN-I production in SLE. In this review, we aimed to provide a comprehensive outlook of the role of the cGAS-STING pathway in SLE pathobiology, as well as, a better understanding of current therapeutic opportunities targeting this axis.

Acute-Onset Blindness in a Patient Diagnosed With Myelin Oligodendrocyte Glycoprotein Antibody Disease (MOG-AD): A Case Report.

Myelin oligodendrocyte glycoprotein antibody disease (MOG-AD) poses a diagnostic challenge, often masquerading as other neurological disorders such as multiple sclerosis and aquaporin-4-positive neuromyelitis optica spectrum disorder. The deceptive clinical similarities demand a nuanced approach to differentiate these conditions effectively. This entails an extensive evaluation encompassing a meticulous medical history, advanced magnetic resonance imaging (MRI), cerebrospinal fluid analysis, and serum studies. In this context, we present a compelling case involving a 28-year-old Hispanic female with a history of migraine headache. She sought medical attention due to acute peripheral vision loss, ultimately diagnosed as MOG-AD through a comprehensive clinical assessment coupled with specific diagnostic tests. This case underscores the critical importance of precision in diagnostic procedures to ensure accurate identification and subsequent tailored treatment for MOG-AD, avoiding potential pitfalls associated with its resemblance to other neurological disorders.

Sclerosing Mesenteritis Presenting With Small Bowel Obstruction in a Patient With Systemic Lupus Erythematosus: A Case Report.

Sclerosing mesenteritis (SM) is a rare inflammatory disorder characterized by chronic inflammation and fibrosis of the mesenteric adipose tissue. While SM can manifest with various gastrointestinal symptoms, its association with small bowel obstruction (SBO) is infrequent. We present a case of a 78-year-old male with a history of systemic lupus erythematosus (SLE) who presented with acute abdominal pain and distention. The patient had multiple admissions with the same symptoms. A CT scan showed swirling of the proximal central mesentery, small bowel malrotation with volvulus, and high-grade mechanical obstruction of the proximal jejunum. The patient underwent exploratory laparotomy, with findings significant for multiple inflammatory nodules in the mesentery. These were causing adhesions between the bowel and mesentery, resulting in a volvulus of the bowel. One segment was resected, and subsequent histopathological examination revealed subserosal fibrosis and chronic inflammation. The clinical scenario was consistent with a diagnosis of SM. This case highlights the challenges of diagnosing and managing SBO in the presence of SM and SLE. Further research is needed to understand the underlying pathophysiological mechanisms and improve management techniques for this rare clinical condition.

The role of gut microbiota in different murine models of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by immune system dysfunction that can lead to serious health issues and mortality. Recent investigations highlight the role of gut microbiota alterations in modulating inflammation and disease severity in SLE. This review specifically summaries the variations in gut microbiota composition across various murine models of lupus. By focusing on these differences, we aim to elucidate the intricate relationship between gut microbiota dysbiosis and the development and progression of SLE in preclinical settings.

The dualistic role of Lyn tyrosine kinase in immune cell signaling: implications for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE, lupus) is a debilitating, multisystem autoimmune disease that can affect any organ in the body. The disease is characterized by circulating autoantibodies that accumulate in organs and tissues, which triggers an inflammatory response that can cause permanent damage leading to significant morbidity and mortality. Lyn, a member of the Src family of non-receptor protein tyrosine kinases, is highly implicated in SLE as remarkably both mice lacking Lyn or expressing a gain-of-function mutation in Lyn develop spontaneous lupus-like disease due to altered signaling in B lymphocytes and myeloid cells, suggesting its expression or activation state plays a critical role in maintaining tolerance. The past 30 years of research has begun to elucidate the role of Lyn in a duplicitous signaling network of activating and inhibitory immunoreceptors and related targets, including interactions with the interferon regulatory factor family in the toll-like receptor pathway. Gain-of-function mutations in Lyn have now been identified in human cases and like mouse models, cause severe systemic autoinflammation. Studies of Lyn in SLE patients have presented mixed findings, which may reflect the heterogeneity of disease processes in SLE, with impairment or enhancement in Lyn function affecting subsets of SLE patients that may be a means of stratification. In this review, we present an overview of the phosphorylation and protein-binding targets of Lyn in B lymphocytes and myeloid cells, highlighting the structural domains of the protein that are involved in its function, and provide an update on studies of Lyn in SLE patients.

Gene-Based Predictive Modelling for Enhanced Detection of Systemic Lupus Erythematosus Using CNN-Based DL Algorithm.

Systemic Lupus Erythematosus (SLE) is a multifaceted autoimmune disease that presents with a diverse array of clinical signs and unpredictable disease progression. Conventional diagnostic methods frequently fall short in terms of sensitivity and specificity, which can result in delayed diagnosis and less-than-optimal management. In this study, we introduce a novel approach for improving the identification of SLE through the use of gene-based predictive modelling and Stacked deep learning classifiers. The study proposes a new method for diagnosing SLE using Stacked Deep Learning Classifiers (SDLC) trained on Gene Expression Omnibus (GEO) database data. By combining transcriptomic data from GEO with clinical features and laboratory results, the SDLC model achieves a remarkable accuracy value of 0.996, outperforming traditional methods. Individual models within the SDLC, such as SBi-LSTM and ACNN, achieved accuracies of 92% and 95%, respectively. The SDLC's ensemble learning approach allows for identifying complex patterns in multi-modal data, enhancing accuracy in diagnosing SLE. This study emphasises the potential of deep learning methods, in conjunction with open repositories like GEO, to advance the diagnosis and management of SLE. Overall, this research shows strong performance and potential for improving precision medicine in managing SLE.

A Comprehensive and Practical Approach to the Management of Lupus Nephritis in the Current Era.

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) and is one of the leading causes of morbidity and mortality in patients with SLE. It is estimated that up to 60% of individuals with SLE will develop LN, which can manifest at any stage of a patient's life; however, it commonly emerges early in the course of SLE and tends to exhibit a more aggressive phenotype in men compared to women. Black and Hispanic patients are more likely to progress to kidney failure than white patients. LN is characterized by kidney inflammation and chronic parenchymal damage, leading to impaired kidney function and potential progression to kidney failure. This article provides a comprehensive overview of the epidemiology, pathogenesis, clinical presentation, diagnosis, and management of LN, highlighting the importance of early recognition and treatment of LN to prevent progressive, irreversible kidney damage and improve patient outcomes. Additionally, the article discusses current and emerging therapies for LN, including traditional immunosuppressive agents, biological agents, and novel therapies targeting specific pathways involved in LN pathogenesis, to provide a practical guide for clinicians in properly diagnosing LN and determining a patient-centered treatment plan.

Sex-specific differences in SLE - Significance in the experimental setting of inflammation and kidney damage in MRL-Faslpr mice.

Animal models are an important tool in the research of chronic autoimmune diseases, like systemic lupus erythematosus (SLE). MRL-Faslpr mice are one of different lupus models that develop spontaneously an SLE-like disease with autoantibodies and immune complex deposition that leads into damage of different organs. In contrast to human SLE, both sexes of MRL-Faslpr mice develop a similar autoimmune disease. Due to the sex bias in human and the delayed disease progression in male MRL-Faslpr mice, the majority of studies have been performed in female mice. To determine the suitability of male MRL-Faslpr mice for SLE research, especially with regard to the 3 R-principle and animal welfare, analyses of phenotype, inflammation and damage with focus on kidney and spleen were performed in mice of both sexes. Female mice developed lymphadenopathy and skin lesions earlier as males. At an age of 3.5 month, more immune cells infiltrated kidney and spleen in females compared to males. At the age of 5 months, however, substantially less sex-specific differences were detected. Since other studies have shown differences between both sexes on other manifestations like autoimmune pancreatitis and Sjögren syndrome in MRL-Faslpr mice, the use of male mice as part of 3 R-principle and animal welfare must be carefully considered.

Clinical disease activity in autoimmune rheumatic patients receiving COVID-19 vaccines.

BACKGROUND: Vaccines are a crucial component of the global efforts to control the spread of COVID-19. Very little is known about COVID-19 vaccine responses in patients living with autoimmune rheumatic conditions in Africa. We examined the clinical reaction to COVID-19 vaccinations in Ghanaians diagnosed with autoimmune rheumatic disease. METHODS: This was a hospital-based interventional cohort study of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients recruited via regular face-to-face clinic visits. The systemic lupus erythematosus disease activity index Selena modification (SELENA-SLEDAI) and the disease activity score 28-joint count-erythrocyte sedimentation rate (DAS28-ESR) were used to measure changes in disease activity levels. RESULTS: Thirty-eight (38) patients of which 21 (55.3%) were diagnosed with SLE and 17 (44.7%) with RA contributed data for analyses. Most (89.5%) of the patients were females, with a mean age of 37.4 years. The SLE patients experienced a notable increase in severe flares during weeks three and six, as well as the third and sixth months, followed by subsequent decreases in the twelfth month, while remission levels increased throughout the same period. Among RA patients, high disease activity decreased during weeks three and six, as well as the third, sixth, and twelfth months, with remission levels increasing during the same time. A low dose (≥ 50 < 75 mg) dose of azathioprine was at some point associated with having a severe flare among SLE patients. After both vaccine doses, SLE patients were the majority having experienced both local and systemic reactions, all resolving within 24 h. Approximately 73.7% of the patients were COVID-19 negative at baseline. During post-vaccination visits, this increased to 100% by week six, with no positives thereafter. CONCLUSION: This study explores COVID-19 vaccine responses in Ghanaian autoimmune rheumatic disease patients, revealing disease activity levels in RA patients improved after vaccination compared to SLE patients. Our findings identify a potential link between low-dose azathioprine and severe flares in SLE patients, particularly evident in the third-week post-vaccination. Further research is warranted to clarify these findings and guide tailored treatment approaches in this medically significant population during pandemics and vaccination efforts.

Transcobalamin 2 orchestrates monocyte proliferation and TLR4-driven inflammation in systemic lupus erythematosus via folate one-carbon metabolism.

Background: SLE is a complex autoimmune disease with deleterious effects on various organs. Accumulating evidence has shown abnormal vitamin B12 and one-carbon flux contribute to immune dysfunction. Transcobalamin II (TCN2) belongs to the vitamin B12-binding protein family responsible for the cellular uptake of vitamin B12. The role of TCN2 in SLE is still unclear. Methods: We collected clinical information and blood from 51 patients with SLE and 28 healthy controls. RNA sequencing analysis, qPCR, and western blot confirmed the alteration of TCN2 in disease monocytes. The correlation between TCN2 expression and clinical features and serological abnormalities was analyzed. TCN2 heterozygous knockout THP1 cells were used to explore the effects of TCN2 dysfunction on monocytes. CCK-8 assay and EdU staining were used to detect cell proliferation. ELISA was conducted to assess vitamin B12, glutathione, and cytokines changes. UHPLC-MRM-MS/MS was used to detect changes in the intermediates of the one-carbon cycle. Flow cytometry is used to detect cell cycle, ROS, mitoROS, and CD14 changes. Results: Elevated TCN2 in monocytes was correlated positively with disease progression and specific tissue injuries. Using CD14+ monocytes and TCN2 genetically modified THP1 cell lines, we found that the TCN2 was induced by LPS in serum from SLE patients. TCN2 heterozygous knockout inhibited cellular vitamin B12 uptake and one-carbon metabolism, leading to cell proliferation arrest and decreased Toll-like receptor 4 (TLR4)-mediated CCL2 release. Methionine cycle metabolites, s-adenosylmethionine and homocysteine, rescued these effects, whereas folate treatment proved to be ineffective. Folate deficiency also failed to replicate the impact of TCN2 downregulation on THP1 inflammatory response. Conclusion: Our study elucidated the unique involvement of TCN2-driven one-carbon flux on SLE-associated monocyte behavior. Increased TCN2 may promote disease progression and tissue damage by enhancing one-carbon flux, fostering monocyte proliferation, and exacerbating TLR4 mediated inflammatory responses. The inhibition of TCN2 may be a promising therapeutic approach to ameliorate SLE.

Predicting role of Myc-induced nuclear antigen 53 in determining the development and severity of systemic lupus erythematosus.

Introduction: Systemic lupus erythematosus (SLE) as an autoimmune disease can relate to an imbalance between regulatory T cells (Tregs) and Th17 cells. Previous reports have shown that Myc-induced nuclear antigen (Mina) 53 protein is involved in the developments of Tregs and Th17 cells. Therefore, the current study focused on determining whether Mina53 level is correlated to the severity of SLE. Methods: The blood samples were collected from 60 patients with SLE (30 cases with mild SLE and 30 cases with severe SLE) and 30 healthy subjects. The serum concentration of Mina53 was measured using enzyme-linked immunosorbent assay (ELISA). The expression of Mina53 gene was assessed using real-time PCR method after extracting RNA from isolated peripheral blood mononuclear cells and synthesizing cDNA. Results: Patients with SLE showed significant increases in the serum level and gene expression of Mina53 compared to healthy subjects (P<0.001). Furthermore, serum level and gene expression of Mina53 showed significant effects on SLE disease and its severity (P<0.01). There was the highest sensitivity and maximum specificity in the cut-off point of Mina53 serum level equal to 125.4 (area under the curve (AUC)=0.951) and Mina53 expression level equal to 8.5 (AUC=0.88) for SLE diagnosis. The cut-off point of Mina53 serum level equal to 139.5 (AUC=0.854) and the cut-off point of Mina53 expression level equal to 8.5 (AUC=0.788) had the highest sensitivity and maximum specificity determining severe forms of SLE. Discussion: Our results showed that the changes in serum and expression levels of Mina53 have significant effects on SLE disease and its severity. These levels may be considered as diagnostic and predictive markers for SLE.

Evaluation of immune profiles associated with control of mycobacterial growth in systemic lupus erythematosus (SLE) patients.

Tuberculosis (TB) is an infectious disease with the burden concentrated in low- and middle-income countries. Systemic lupus erythematosus (SLE) is an autoimmune disease associated with widespread inflammation that is prevalent in some TB endemic areas including East Africa and parts of Southeast Asia. SLE patients are known to be at higher risk of becoming infected with M. tb, developing TB disease. However, the immune mechanisms underlying this susceptibility are not well understood, particularly in the absence of immunosuppressive drugs. We present a pilot study in which we have evaluated intracellular cytokine responses and ex vivo ability to control mycobacterial growth using peripheral blood mononuclear cells (PBMC) collected from SLE patients before and during SLE treatment. After six months of treatment, SLE patients had the highest frequencies of CD8+ T cells, NK cells and NKT cells producing IFN-γ and/or TNF-α. This group also showed superior control of mycobacterial growth, and proinflammatory cytokine-producing NK and NKT cells correlated with mycobacterial growth inhibition at the individual patient level. These findings contribute to a better understanding of autoimmune profiles associated with control of mycobacterial growth in SLE patients, which may inform intervention strategies to reduce risk of TB disease in this population.

A Rare Presentation of Systemic Lupus Erythematosus (SLE) With Hemoptysis and Hematuria: A Case Report.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by type II and type III hypersensitivity reactions that affect multiple organs, including the joints, heart, lungs, brain, skin, and kidneys. Patients with SLE can experience a range of symptoms, ranging from fever and joint pain to a distinctive butterfly facial rash. Severe complications may encompass conditions such as diffuse alveolar hemorrhage (DAH), pulmonary hypertension, and lupus nephritis, among others. Among them, DAH, a critical pulmonary complication in SLE, involves bleeding from interstitial capillaries and alveoli due to immune complex damage. This case report describes a patient who was initially misdiagnosed but later confirmed to have SLE. The patient presented with persistent symptoms, including cough, dyspnea, and fever, over two weeks and subsequently developed hematuria and hemoptysis within the last two days. The progression of symptoms led to an acute exacerbation, resulting in her admission to the emergency department. Subsequent evaluations confirmed the diagnosis of lupus nephritis and DAH. This case highlights the importance of considering SLE in the differential diagnosis of unexplained systemic symptoms and underscores the urgent need for medical intervention in DAH to substantially reduce mortality.

Inhibition of GRK2 ameliorates the pristane-induced mouse SLE model by suppressing plasma cells differentiation.

Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by diverse clinical manifestations and organ damage. Despite its elusive etiology, dysregulated subsets and functions of B cells are pivotal in SLE pathogenesis. Peoniflorin-6'-O-benzene sulfonate (CP-25), an esterification modification of Paeoniflorin, exhibits potent anti-inflammatory and immunomodulatory properties in autoimmune diseases (AID). However, the involvement of CP-25 and its target, GRK2, in SLE development has not been explored. In this study, we demonstrate that both genetic deficiency and pharmacological inhibition of GRK2 attenuate autoantibodies production, reduce systemic inflammation, and mitigate histopathological alterations in the spleen and kidney in the pristane-induced mouse SLE model. Importantly, our findings highlight that both genetic deficiency and pharmacological inhibition of GRK2 suppress plasma cells generation and restore dysregulated B-cell subsets by modulating two crucial transcription factors, Blimp1 and IRF4. Collectively, targeting GRK2 with CP-25 emerges as a promising therapeutic approach for SLE.

SLE: a cognitive step forward-a synthesis of rethinking theories, causality, and ignored DNA structures.

Systemic lupus erythematosus (SLE) is classified by instinctual classification criteria. A valid proclamation is that these formally accepted SLE classification criteria legitimate the syndrome as being difficult to explain and therefore enigmatic. SLE involves scientific problems linked to etiological factors and criteria. Our insufficient understanding of the clinical condition uniformly denoted SLE depends on the still open question of whether SLE is, according to classification criteria, a well-defined one disease entity or represents a variety of overlapping indistinct syndromes. Without rational hypotheses, these problems harm clear definition(s) of the syndrome. Why SLE is not anchored in logic, consequent, downstream interdependent and interactive inflammatory networks may rely on ignored predictive causality principles. Authoritative classification criteria do not reflect consequent causality criteria and do not unify characterization principles such as diagnostic criteria. We need now to reconcile legendary scientific achievements to concretize the delimitation of what SLE really is. Not all classified SLE syndromes are "genuine SLE"; many are theoretically "SLE-like non-SLE" syndromes. In this study, progressive theories imply imperative challenges to reconsider the fundamental impact of "the causality principle". This may offer us logic classification and diagnostic criteria aimed at identifying concise SLE syndromes as research objects. Can a systems science approach solve this problem?