The influence of inhibitors of apoptosis proteins (IAPs) on chronic rhinosinusitis with nasal polyps.

BACKGROUND: Inhibitors of apoptosis proteins (IAPs) modulate the inflammatory process, and may facilitate the formation of chronic rhinosinusitis with nasal polyps (CRSwNP). This study aimed to observe if IAPs were differently expressed between patients with CRSwNP and controls, and to correlate the expression of IAPs with some inflammatory markers, as with the response to nasal corticosteroids in patients with CRSwNP. METHODOLOGY: We obtained nasal biopsies from patients with CRSwNP (n=27) and controls (n=16). qRT-PCR measured the expression of IAPs and caspases, while Luminex assay measured the concentration of cytokines. Unpaired parametric tests and Principal Component Analysis (PCA) were used for statistical analysis. RESULTS: We observed lower expression of IAP genes (XIAP, BIRC2/IAP1, and BIRC3/IAP2) in CRSwNP patients compared to controls, and we identified that patients with bad response to corticosteroids presented lower levels of BIRC2/IAP1, XIAP, BCL2, CASP9, and IL-17, and higher levels of CASP7 and TGF-B. CONCLUSIONS: IAPs expression was downregulated in CRSwNP, and was associated with poorer response to nasal corticosteroids. The present findings suggest the importance of IAPs as a link between environment and the host inflammatory responses, and this pathway could be explored as a potential new target therapy for patients with CRSwNP.

Smell loss associated with SARS-CoV-2 is not clinically different from other viruses: a multicenter cohort study.

BACKGROUND: Although the COVID-19 pandemic has increased the prevalence of cases with olfactory loss, other respiratory viruses can also cause this condition. We aimed to compare the prevalence of acute SARS-CoV-2 infection and other respiratory viruses in patients with sudden smell loss, and to assess the impact of SARS-CoV-2 viral load and co-infection on olfactory symptoms. METHODS: Patients with sudden smell loss were recruited in a multicenter prospective cohort study in 15 hospitals in Brazil. Clinical questionnaire, Connecticut Chemosensory Clinical Research Center (CCCRC) olfactory test and nasopharyngeal swab to perform a PCR-based respiratory viral panel were collected at first visit (day 0) and 30 and 60 days after recruitment. RESULTS: 188 of 213 patients presented positive test result for SARS-CoV-2, among which 65 were co-infected with other respiratory viruses (e.g., rhinovirus, enterovirus, and parainfluenza). 25 had negative test results for SARS-CoV-2. Patients in both SARSCoV-2 and non-SARS-CoV-2 groups had objective anosmia (less than 2 points according to the psychophysical olfactory CCCRC) at day 0, with no significant difference between them. Both groups had significant smell scores improvement after 30 and 60 days, with no difference between them. Co-infection with other respiratory viruses, and SARS-CoV-2 viral load did not impact olfactory scores. CONCLUSION: Patients with sudden smell loss associated with SARS-CoV-2 and other respiratory viruses had similar presentation, with most participants initiating with anosmia, and total or near total recovery after 60 days. SARS-CoV-2 viral load and co-infections with other respiratory viruses were not associated with poorer olfactory outcomes.

Epispadias and the associated embryopathies: genetic and developmental basis.

The abnormalities in the urogenital organs are frequently observed as human developmental diseases. Among such diseases, the defects in the upper part of external genitalia are rather rare named epispadias. The cleft in the dorsal part of external genitalia often reaches to the urethra. In general, the urogenital abnormalities accompany defects in the adjacent tissues and organs. The ventral body wall and bladder can also be affected in the patients with dorsal defects of the external genitalia. Therefore, such multiple malformations are often classified as bladder exstrophy and epispadias complex (BEEC). Because of the lower frequency of such birth defects and their early embryonic development, animal models are required to analyze the pathogenic mechanisms and the functions of responsible genes. Mutant mouse analyses on various signal cascades for external genitalia and body wall development are increasingly performed. The genetic interactions between growth factors such as bone morphogenetic proteins (Bmp) and transcription factors such as Msx1/2 and Isl1 have been suggested to play roles for such organogenesis. The significance of epithelial-mesenchymal interaction (EMI) is suggested during development. In this review, we describe on such local interactions and developmental regulators. We also introduce some mutant mouse models displaying external genitalia-body wall abnormalities.

Evaluation of phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome: results of an international multicentre study.

Objective A task force of scientists at the International Congress on Antiphospholipid Antibodies recognized that phosphatidylserine-dependent antiprothrombin antibodies (aPS/PT) might contribute to a better identification of antiphospholipid syndrome (APS). Accordingly, initial and replication retrospective, cross-sectional multicentre studies were conducted to ascertain the value of aPS/PT for APS diagnosis. Methods In the initial study (eight centres, seven countries), clinical/laboratory data were retrospectively collected. Serum/plasma samples were tested for IgG aPS/PT at Inova Diagnostics (Inova) using two ELISA kits. A replication study (five centres, five countries) was carried out afterwards. Results In the initial study ( n = 247), a moderate agreement between the IgG aPS/PT Inova and MBL ELISA kits was observed ( k = 0.598). IgG aPS/PT were more prevalent in APS patients (51%) than in those without (9%), OR 10.8, 95% CI (4.0-29.3), p < 0.0001. Sensitivity, specificity, positive (LR+) and negative (LR-) likelihood ratio of IgG aPS/PT for APS diagnosis were 51%, 91%, 5.9 and 0.5, respectively. In the replication study ( n = 214), a moderate/substantial agreement between the IgG aPS/PT results obtained with both ELISA kits was observed ( k = 0.630). IgG aPS/PT were more prevalent in APS patients (47%) than in those without (12%), OR 6.4, 95% CI (2.6-16), p < 0.0001. Sensitivity, specificity, LR + and LR- for APS diagnosis were 47%, 88%, 3.9 and 0.6, respectively. Conclusions IgG aPS/PT detection is an easily performed laboratory parameter that might contribute to a better and more complete identification of patients with APS.

Primary prophylaxis to prevent obstetric complications in asymptomatic women with antiphospholipid antibodies: a systematic review.

OBJECTIVE: Obstetric complications are common in patients with antiphospholipid syndrome. However, the impact of antiphosholipid antibodies (aPL) in the pregnancy outcomes of asymptomatic aPL carriers is uncertain. The aim of this systematic review is to assess whether primary prophylaxis is beneficial to prevent obstetric complications during pregnancy in asymptomatic women positive for aPL who have no history of recurrent pregnancy loss or intrauterine fetal death. METHODS: Studies evaluating the effect of prophylactic treatment versus no treatment in asymptomatic pregnant aPL carriers were identified in an electronic database search. Design, population and outcome homogeneity of studies was assessed and meta-analysis was performed. The pooled Mantel-Haenszel relative risk of specific pregnancy outcomes was obtained using random effects models. Heterogeneity was measured with the I(2) statistic. All analyses were conducted using Review Manager 5.3. RESULTS: Data from five studies involving 154 pregnancies were included and three studies were meta-analysed. The risk ratio and 95% confidence interval (CI) of live birth rates, preterm birth, low birth weight and overall pregnancy complications in treated and untreated pregnancies were 1.14 (0.18-7.31); 1.71 (0.32-8.98); 0.98 (0.07-13.54) and 2.15 (0.63-7.33),respectively. Results from the meta-analysis revealed that prophylactic treatment with aspirin is not superior to placebo to prevent pregnancy complications in asymptomatic aPL carriers. CONCLUSION: This systematic review did not find evidence of the superiority of prophylactic treatment with aspirin compared to placebo or usual care to prevent unfavourable obstetric outcomes in otherwise healthy women with aPL during the first pregnancy.

A case of Raynaud's disease with uterine cancer producing interleukin-6.

A case of cervical cancer of the uterine producing interleukin-6(IL-6) in a patient who suffered from Raynaud's phenomenon is described. Her serum contained anti SS-A antibody. The cancer was removed surgically. High level of IL-6 activity was detected in the culture supernatant of the resected cancer cells. After operation, Raynaud's phenomenon had improved and anti SS-A antibody had disappeared. This case shows us that IL-6 produced by malignant tumour might induce autoimmune connective tissue disease-like symptoms.

Very low-dose cyclosporin treatment of steroid-resistant interstitial pneumonitis associated with Sjögren's syndrome.

Cyclosporin is known to be effective for both transplantation and a spectrum of immune-mediated diseases. Because this agent also causes severe adverse effects, especially nephrotoxicity, careful monitoring is required for the development of such reactions. Here we report the successful treatment with extremely low-dose cyclosporin (1 mg/kg/day) of a patient who had steroid-resistant interstitial pneumonitis and Sjögren's syndrome.

Unusual neurologic manifestations associated with Epstein-Barr virus infection.

We describe two patients who displayed unusual neurologic manifestations associated with reactivation of latent Epstein-Barr virus (EBV) infection. The patients included a 34-year-old woman who suffered from meningoencephalitis presenting with symptoms identical to those of transient global amnesia, and a 57-year-old man with jumbling phenomenon and gait ataxia. The protean neurologic manifestations of EBV infection underscore the need to suspect this infection in any acute neurologic disorders of possible infectious origin irrespective of the age of the patient.

PP104. Pregnancy-induced hypertension is a strong risk factor for hypertension just 5 years after delivery: A double cohort study at the National Center for Child Health and Development and Showa University Hospital, Tokyo.

INTRODUCTION: Pregnancy-induced hypertension (PIH) is associated with increased risk for cardiovascular diseases later in life. OBJECTIVES: To assess the prevalence of subsequent hypertension and other life-style diseases five years after delivery in women who experienced pregnancy- induced hypertension. METHODS: A total of 1527 women who delivered singletons were registered at the National Center for Child Health and Development and Showa University Hospital Mother and child health center of integrated perinatal period between 2003 and 2005. After five years, these women were invited to participate in this study by mail, and 816 women completed the analysis. The women visited our hospital and underwent a medical examination. Women who were pregnant and nursing at the time when the physical examination was conducted were excluded from this survey. The outcomes assessed included the prevalences of hypertension, diabetes, and dyslipidemia. RESULTS: The number of PIH cases was 27 (3.3%: PIH group), whereas 787 women were used as controls subjects. The mean blood pressure five years after delivery was higher in the PIH group than in the control group (91.6±15.5mmHg vs 82.4±8.8mmHg, respectively; p<0.001), and the prevalence of hypertension five years after labor was 18.5% in the PIH group and 2.9% in the controls (odds ratio UOR Y=6.2; 95% confidence interval (CI)=2.2-17.5; p=0.003). Moreover, regarding high-normal blood pressure (>130/85mmHg), the prevalence was 33.4% in the PIH group and 6.1% in the control subjects (OR=7.2; 95% CI=3.1-16.3; p=0.003). No differences in the prevalences of subsequent diabetes or dyslipidemia were observed. CONCLUSION: Five years after the index pregnancy, women who experienced PIH exhibit an increased risk for subsequent hypertension. Therefore, the blood pressure of women with history of PIH should be regularly monitored after delivery.

Vitamin B6 deficiency and anemia in pregnancy.

Iron deficiency is the most common cause of anemia in pregnancy. Pregnant women with anemia are, in general, exclusively treated with iron supplementation. We observed that several pregnant women with anemia who were nonresponsive to iron supplementation also had vitamin B6 deficiency, and that anemia in these cases improved with the administration of vitamin B6. Our prospective study in healthy pregnant women showed that blood levels of iron, ferritin and vitamin B6, in particular, fell to the lower limit of the nonpregnant reference range by the third trimester. We conclude that it is important to take into account the deficiency of vitamin B6 besides iron in the evaluation of anemia during pregnancy.

Relation between soluble interleukin 2 receptor and clinical findings in patients with systemic lupus erythematosus.

The concentration of soluble interleukin 2 receptor (IL-2R) was determined in the serum of 54 patients with systemic lupus erythematosus (SLE) by an enzyme linked immunosorbent assay (ELISA) using two monoclonal antibodies with the IL-2R. Concentrations of soluble IL-2R in the serum of the patients with SLE (study group) were significantly higher than in 20 normal subjects (control group). The relation between concentrations of soluble IL-2R and clinical findings was investigated. The concentration of soluble IL-2R showed no particular relation with the clinical manifestations and did not correlate with the level of anti-DNA antibody or CH50. Significant correlation between the concentration of soluble IL-2R and disease activity did exist, however. Furthermore, the concentration of soluble IL-2R in some cases changed simultaneously with the disease activity. Thus the concentration of soluble IL-2R may serve as a new clinical indicator of disease activity in patients with SLE.

Activated peripheral blood mononuclear cells detected by murine monoclonal antibodies to proliferating cell nuclear antigen in active lupus patients.

Hybridoma producing monoclonal antibody to proliferating cell nuclear antigen (PCNA/cyclin) (TOB7, IgG1 kappa) was newly established. Using TOB7, PCNA was detected in the peripheral blood mononuclear cells (PBMC) in patients with systemic lupus erythematosus (SLE). Forty-four of 58 patients with SLE had PBMC expressing PCNA. The percentage of PCNA-positive PBMC in patients with SLE was 0-20% (mean: 2.63%) which was significantly higher (P less than 0.01) compared with normal controls (mean: 0.18%), patients with rheumatoid arthritis (mean: 0.83%), and patients with mixed connective tissue disease (mean: 0.38%). Patients with high numbers of PCNA positive PBMC tended to complicate pulmonary disorders (P less than 0.005), especially pulmonary fibrosis (P less than 0.005). In addition, the percentage of PCNA-positive cells in SLE patients correlated with the disease activity (r = 0.45, P less than 0.01). The lymphocyte subsets of PCNA-positive PBMC were examined, and most of those cells belonged to CD4- or CD8-positive T-cell populations in three lupus patients. Our findings indicate that PCNA-positive activated PBMC are present in SLE patients and the percentage of PCNA-positive PBMC may be used as an indicator of disease activity.

HLA antigens in Japanese patients with systemic lupus erythematosus.

To determine the association of HLA antigens with SLE and the clinical findings of the disease, HLA antigens were tested in 58 Japanese patients with SLE, who fulfilled the ARA diagnostic criteria, along with 97 normal controls. HLA class I and II antigens were typed serologically using the antisera provided by the 11th HLA Workshop. Among the HLA class II antigens, further DRB, DQ and DP alleles were defined by DNA typing using the PCR/SSOP method. There were significantly more SLE patients with HLA-B39, DRB1*1501, DRB5*0101 and DQB1*0602 than normal controls. This result suggested that the haplotype of HLA-DRB1*1501-DRB5*0101-DQA1*0102-DQB1*0602 consists of the SLE-associated MHC markers in Japan. There were some positive and negative associations between the HLA antigens and clinical or serological findings in SLE. There is a possibility that some HLA alleles might be related to the clinical and/or serological subsets of SLE.

Long term prognosis of children born to lupus patients.

OBJECTIVE: To determine the long term prognosis of children of patients with systemic lupus erythematosus (SLE). METHODS: Children of patients with SLE were invited to attend our clinic for physical examination and laboratory tests. A total of 195 children (aged 4 months to 26 years; male = 82, female = 113) were examined in 1991, 1995, 1997, and 1998. RESULTS: Two cases were diagnosed as SLE at the first visit and were excluded from the second visit. A significantly higher percentage (52/195 (27%)) of patients were positive for antinuclear antibodies (ANA) at a cut off serum dilution of 1/40 compared with controls (4/57 (7%)). ANA were detected more frequently in female subjects than in men (p<0.05). Forty four subjects were examined on more than two occasions. Nine of the 10 patients who were positive for ANA at the second visit were girls aged 4-8 years. The incidence of anti-DNA and antiphospholipid antibodies in children of patients with SLE was similar to that in the controls. CONCLUSIONS: The finding that children, especially girls, born to maternal lupus patients had a high positive rate for ANA suggests that a genetic factor is involved in SLE pathogenesis. Longitudinal observation of these patients may provide important clinical information and clues to the pathogenesis of SLE.

Human B-cell differentiation factor defined by an anti-peptide antibody and its possible role in autoantibody production.

The partial amino acid sequence of the NH2 terminus of a factor named human B-cell differentiation factor or B-cell stimulatory factor 2 (BSF-2) has been determined. Antibodies raised against the synthetic peptide corresponding to residues 1-13 of the NH2-terminal sequence specifically react with BSF-2 generated by a T-cell line and by phytohemagglutinin-stimulated normal T cells. Furthermore, the antipeptide antibodies react with a BSF-2-like factor produced by cardiac myxoma as well as uterine cervical carcinoma cells. The results show that BSF-2 functions in vivo as well and suggest that the constitutive production of BSF-2 may be involved in autoantibody production, since patients with cardiac myxoma and uterine carcinoma showed autoantibody production.