To ASLO or Not to ASLO: Utility of the ASLO Test in Dermatology.

BACKGROUND: Group A Streptococcus (GAS) causes a wide spectrum of acute infections and immune-related diseases, most of which include a dermatological presentation. However, dermatological findings have a wide range of other possible etiologies. The diagnosis of GAS-related disease requires an indication of preceding GAS infection by direct culture or by measuring antistreptolysin O (ASLO) titer. OBJECTIVES: To explore the correlation between ASLO positivity and dermatological diseases. METHODS: We analyzed clinical data from all cases of patients over 18 years of age who underwent ASLO testing between the years 2016 and 2020 in the Department of Dermatology at Rambam Health Care Campus. RESULTS: Of 152 adult patients with ASLO tests, 100 had diagnoses that were potentially related to streptococcal infection. Vasculitis and psoriasis were the most suspected diagnoses. Positive ASLO test was found in 44 (29%) patients. The diagnoses showing the highest ratio of positive ASLO were psoriasis (60%), erythema nodosum (46%), skin infections (43%), Sweet syndrome (33%), and vasculitis (15%). Psoriasis types included plaque psoriasis (8 patients), guttate psoriasis (3 patients), and palmoplantar pustulosis and erythroderma (2 patients each). CONCLUSIONS: Although the applicability of ASLO for the spectrum of dermatological diseases remains unclear, our results enhance the practical relevance of the test. We showed a higher prevalence of positive ASLO tests in psoriasis and erythema nodosum cases and a lower prevalence in vasculitis. Notably, ASLO was positive in all psoriasis subtypes, suggesting high utility of the test for psoriasis.

Revising the value of Antistreptolysin O titre in childhood and its interpretation in the diagnostic approach of rheumatic diseases.

The burden of group A streptococcus (GAS) infection and its rheumatic sequelae remains dramatically high, especially in low-income countries. Recently, an increased number of Acute Rheumatic Fever (ARF) cases was documented in many regions of Italy. The diagnosis of rheumatic sequelae relies on clinical signs and on the evaluation of the Antistreptolysin O titre (ASO), whose variations are globally reported. To re-examine the standard reference value of ASO titre, by measuring either its upper limit of normal (ULN) in a population of healthy children (HC) or comparing these values with streptococcal antibodies registered in a cohort of patients affected by the rheumatic sequelae of GAS infection. We performed a multicenter retrospective study. We enrolled 125 HC, aged 2-17 years, and a total of 181 patients affected by ARF, acute streptococcal pharyngitis, post-streptococcal arthritis, Henoch-Schönlein purpura and erythema nodosum, divided into four groups. The levels of ASO and anti-deoxyribonuclease B (anti-DNase B) titres were analyzed and compared among the various groups. Moreover, the 80th percentile value was calculated and established as the ULN for ASO titre in HC group. The ULN for ASO titre in overall HC group was 515 IU/mL, resulting in higher than used in the routine investigation. The ASO titre was significantly higher in patients with rheumatic sequelae compared with HC group, with a peak in the age between 5 and 15 years.    Conclusion: Our study established a new ULN normal value of streptococcal serology in a childhood and adolescent population of Italy, suggesting the need to extend this revaluation to the critical areas, in order to avoid underestimating ARF diagnosis. The correct interpretation of ASO and anti-DNase B values in the context of rheumatic diseases has been discussed. What is Known: • The global burden of disease caused by group A streptococcus is not known and remains an important cause of morbidity and mortality. Acute rheumatic fever continues to be a serious worldwide public health problem and a recent recurrence of group A streptococcus infection cases is observed. • The streptococcal sequelae requires evidence of preceding streptococcal infection, commonly elevated streptococcal antibody titre, but the upper limit for these titres varies considerably based on age group, region, and origin. What is New: • This study provides population-specific values for streptococcal antibody titres in Italy. • Interpret the results of group A streptococcal antibody tests within the clinical context.

A Longitudinal Study of Group A Streptococcal Colonization and Pharyngitis in US Children.

BACKGROUND: Group A streptococci (GAS) are a major cause of pharyngitis in children. Recently, there were severe GAS outbreaks. The aims of this study were to assess pharyngeal colonization prevalence in healthy children, to assess different diagnostic definitions for GAS pharyngitis and to estimate incidence rates for these infections. METHODS: A 2-year longitudinal study was conducted in healthy children in the United States. Pharyngeal swabs were cultured every 3 months for GAS colonization. Serum antistreptolysin O, antideoxyribonuclease B (DNaseB) and antistreptococcal C5a peptidase (SCP) antibody titers were assessed at baseline. When participants developed a sore throat, pharyngeal swabs were collected for rapid antigen detection test (RADT) and culture, and antibody titers were determined in serum samples. A range of case definitions were used for GAS pharyngitis. RESULTS: A total of 422 children 3-12 years old were enrolled (140, 141 and 141 were 3-5, 6-9 and 10-12 years of age, respectively). The overall prevalence of GAS colonization during the study was 48%. Baseline antistreptolysin O, anti-DNaseB and anti-SCP antibody titers were higher for children older than 5 years. The incidence of GAS pharyngitis per 100 person-years was 15.9 for RADT/culture-proven and 4.6 for serologically confirmed pharyngitis. CONCLUSIONS: GAS throat colonization and pharyngitis were frequent in children 3-12 years old. The case definition employed impacted the measured incidence of GAS pharyngitis, with higher rates detected using RADT/culture-based definitions. These data suggest that case definition is important and that young children are exposed to GAS, which may inform plans for vaccine development and implementation.

Concomitant rapidly progressive glomerulonephritis and acute rheumatic fever after streptococcus infection: a case report.

Acute post-streptococcal glomerulonephritis (APSGN) and acute rheumatic fever (ARF) are common immune-mediated complications after group A streptococcus (GAS) infection. The causative antigenic epitopes on GAS are different for APSGN and ARF, and their simultaneous occurrence is uncommon. A 12-year-old boy presented with fever and gross haematuria. He had subcutaneous nodules on the dorsum of both feet along with a new holosystolic murmur at the apex, and he developed hypertension and generalised oedema after admission. Investigation confirmed the diagnosis of ARF with APSGN. He received a corticosteroid to control inflammation of both the conditions. His clinical signs gradually improved but he still had rheumatic heart disease. As both diseases can occur in the same patient, treatment should be provided for both conditions.Abbreviations: APSGN: acute post-streptococcal glomerulonephritis; ARF: acute rheumatic fever; ASO: antistreptolysin O; Cr: serum creatinine; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; GAS: group A streptococcus; RBC: red blood cells; RPGN: rapidly progressive glomerulonephritis; S1: first heart sound; S2: second heart sound; TTE: transthoracic echocardiogram.

Adolescente con corea de inicio agudo: a propósito de una entidad olvidada / Adolescent with acute-onset chorea: on the subject of a forgotten entity

La corea de Sydenham es como se denomina el cuadro de origen neurológico consistente en agitación y movimientos anormales que ocurre en contexto de una fiebre reumática, secundariamente a la infección por estreptococo del grupo A. Dado que la incidencia de fiebre reumática ha disminuido significativamente en los últimos años, las complicaciones asociadas pueden considerarse actualmente excepcionales. No obstante, dado que presenta un pronóstico excelente si se instaura precozmente el tratamiento, es muy importante saber reconocer el cuadro clínico (AU)

Sydenham’s chorea, with a documented relationship with group A streptococcal infections, is the one of the most common acquired movement disorder of adolescence. However, rheumatic fever´s incidence is significantly lower than years ago. The clinical picture is very characteristic, and its recognition is essential in order to improve the prognostic starting an specific treatment as soon as possible (AU)

Rheumatic pericarditis: a rare cause of constrictive pericarditis.

Constrictive pericarditis is a relatively uncommon form of cardiac failure and presents due to scarring and consequent loss of the normal elasticity of the pericardial sac. This results in abnormal/limited ventricular filling and symptoms of heart failure. The aetiology is varied, from infective causes to idiopathic causes, or can manifest after cardiothoracic surgery. This case involves a 46-year-old man presenting with acute group A beta haemolytic streptococcus infection, and over the subsequent 6 months develops constrictive pericarditis due to what is believed to be a rheumatic aetiology. The patient subsequently underwent pericardiectomy and had restoration of normal filling dynamics confirmed on follow-up echocardiography. This case provides a subject matter for the review of the features of constrictive pericarditis and its investigation and management. This case is that it highlights the fact that pericarditis is not a benign condition. Emerging evidence suggests that pericarditis is due to a failure in inflammatory regulatory mechanisms, and patients suffering this condition have a preponderance to 'autoinflammation'. Pericarditis should be recognised early and treated fully with anti-inflammatory agents.

Refractory Urticaria with Raised Antistreptolysin O (ASO) Titer: An Intriguing Case of Adult-Onset Still's Disease.

BACKGROUND Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disease with a myriad of clinical presentations. The diagnosis is often challenging because there is no specific confirmatory test. Uncommon presentations can delay the proper diagnosis and management. CASE REPORT A 26-year-old woman presented with a history of urticaria for 2 years that had failed to respond to many types of treatment. Cutaneous biopsy showed neutrophilic urticaria. A diagnosis of AOSD was made after infectious, drug-related, neoplastic, and rheumatic etiologies had been excluded and based on the triad of fever, evanescent rash, and joint pain. Besides leukocytosis and increased levels of inflammatory markers, the patient's laboratory results showed an extremely high D-dimer concentration and an increased antistreptolysin O (ASO) titer. Treatment with prednisolone and methotrexate resulted in resolution of the woman's symptoms. Once clinical remission had been achieved, all laboratory markers returned to normal, yet the patient's ASO titer remained elevated during 18 months of follow-up. CONCLUSIONS Urticaria is a rare cutaneous manifestation of AOSD. Histopathology typically shows predominant neutrophilic infiltrates, which is a unique entity called neutrophilic urticarial dermatosis (NUD). Identifying diseases associated with NUD will facilitate prompt diagnosis and treatment of AOSD, as therapies for it largely differ depending on the underlying cause. Known etiologies of AOS include systemic lupus erythematosus (SLE), Schnitzler syndrome, hereditary autoinflammatory periodic syndromes, and serum sickness-like drug eruption. An elevated ASO titer is unusual, and in our case, it did not seem to follow the patient's clinical course. An elevated D-dimer concentration can be an indicator of disease activity and testing might be beneficial in a subset of patients with normal ferritin levels.

Effects of peripheral and different inspiratory muscle training methods in coronary artery disease patients with metabolic syndrome: A randomized-controlled trial.

Background OBJECTIVE: To investigate the effects of peripheral muscle training (PMT) and different inspiratory muscle training (IMT) methods on respiratory functions, exercise capacity, and biochemistry parameters in coronary artery disease patients with metabolic syndrome. METHODS: This prospective, single-blind, randomized-controlled study included 60 patients of stable coronary artery disease with metabolic syndrome (New York Heart Association [NYHA] Class I-II, left ventricular ejection fraction >40%). Patients were randomly divided into three groups: neuromuscular electrical stimulation (NMES) plus PMT group (NMES + PMT group, n = 20), IMT plus PMT group (IMT + PMT group, n = 20) and PMT group (PMT group, n = 20). Treatment continued for six weeks for all groups. The NMES was applied to rectus abdominis, IMT was applied with 30% of maximal inspiratory pressures, and PMT was applied at home. Spirometry, maximal inspiratory and expiratory pressure, dyspnea scores, exercise stress test, and biochemistry parameters were measured before and after training. RESULTS: There were significant improvements in spirometric tests, respiratory muscle strength, dyspnea scores, exercise capacity, fasting blood glucose, and antistreptolysin O after treatment in all groups (p < 0.05). Significant improvements in C-reactive protein and erythrocyte sedimentation rate were observed in NMES + PMT and IMT + PMT groups (p < 0.05). Among the groups, there was a significant difference in maximal inspiratory pressure (p = 0.02) and erythrocyte sedimentation rate (p = 0.037) in favor of NMES + PMT group (p < 0.05). CONCLUSION: Our study results showed significant improvements in respiratory functions, exercise capacity, and biochemistry markers in all groups. Different IMT methods can be used in cardiopulmonary rehabilitation to improve exercise intolerance in coronary artery disease patients with metabolic syndrome. CLINICAL TRIAL REGISTRATION NUMBER: NCT03523026.

Unusual presentation of rheumatic fever in a 3-year-old child in the UK.

In the developed world, acute rheumatic fever (ARF) is rare. When it does arise, symptoms commonly include fever, arthralgia and rash. We describe a presentation of a 3-year-old child with ARF in a UK District General Hospital. The patient had a 6-week history of diarrhoea, rash and intermittent right hip arthralgia. This was initially thought to be a viral illness until she re-presented with shortness of breath and fever with a pan-systolic murmur. A throat-culture was negative, but an anti-streptolysin titre was elevated, with a bedside echocardiogram demonstrating moderate to severe mitral regurgitation. The young child was transferred to the local tertiary centre for further management; however, she went on to develop acute left ventricular failure. This case illustrates the need to be vigilant for the presentation of a rare illness, such as rheumatic fever, as there can be significant impacts on the quality of life of young patients.

Cross-sectional study of population-specific streptococcal antibody titres in Uganda.

OBJECTIVE: Despite substantial variation of streptococcal antibody titres among global populations, there is no data on normal values in sub-Saharan Africa. The objective of this study was to establish normal values for antistreptolysin O (ASO) and antideoxyribonuclease B (ADB) antibodies in Uganda. DESIGN: This was an observational cross-sectional study. SETTING: This study was conducted at Mulago National Referral Hospital, which is located in the capital city, Kampala, and includes the Uganda Heart Institute. PATIENTS: Participants (aged 0-50 years) were recruited. Of 428 participants, 22 were excluded from analysis, and 183 (44.4%) of the remaining were children aged 5-15 years. MAIN OUTCOME MEASURES: ASO was measured in-country by nephelometric technique. ADB samples were sent to Australia (PathWest) for analysis by enzyme inhibition assay: 80% upper limit values were established. RESULTS: The median ASO titre in this age group was 220 IU/mL, with the 80th percentile value of 389 IU/mL. The median ADB titre in this age group was 375 IU/mL, with the 80th percentile value of 568 IU/mL. CONCLUSIONS: The estimated Ugandan paediatric population standardised 80% upper-limit-of-normal ASO and ADB titres is higher than many global populations. Appropriateness of using population-specific antibody cutoffs is yet to be determined and has important implications for the sensitivity and specificity of rheumatic fever diagnosis.

Poststreptococcal acute glomerulonephritis can be a risk factor for accelerating kidney dysfunction in Alport syndrome: a case experience.

Alport syndrome (AS) is a progressive kidney disease. Male cases with X-linked AS (XLAS) are reported to develop end-stage kidney disease (ESKD) at the age of around 20-30 years. One risk factor for developing ESKD at a young age is a genotype of having truncating variants in the COL4A5 gene. However, to date, other such factors have remained unclear. Here, we describe a 15-year-old Japanese boy with XLAS who had a missense variant in the COL4A5 gene. He presented with gross hematuria, severe proteinuria, oliguria, systemic edema, body weight gain, and hypertension after pharyngitis. Blood examination showed kidney dysfunction, hypocomplementemia, and elevated antistreptolysin-O level. We diagnosed him with poststreptococcal acute glomerulonephritis (PSAGN) and he was stopped treatment by lisinopril, and received supportive treatment. However, he showed an unusual clinical course for PSAGN and, consequently, developed ESKD 15 months after the onset of PSAGN without recovery from the kidney dysfunction. This case showed that the onset of PSAGN can be a risk factor for AS patients to develop ESKD at a young age.

Características de pacientes con diagnóstico de patologías de ATM: una serie de casos / Characteristics of patients with diagnosis of TMJ pathologies: case series

Los tejidos que conforman la articulación temporomandibular (ATM) pueden verse afectados como cualquier otra articulación del cuerpo. Entre los factores etiológicos, podemos nombrar los traumáticos, infecciosos, autoinmunes y oclusales. El diagnóstico de las patologías de la ATM debe incluir una completa historia clínica, estudios de laboratorios y de imágenes. El objetivo del siguiente trabajo es describir características de una serie de pacientes que concurrieron a la consulta con signos y síntomas de patologías de la ATM a un consultorio particular en el sur de la provincia de Buenos Aires. Se estudió a 30 pacientes que concurrieron a la consulta con signos y síntomas de patología de la ATM; se completaron historias clínicas, se solicitaron estudios de laboratorio para la detección de anticuerpos específicos contra bacterias y resonancia nuclear magnética. La edad promedio de la población fue de 35 años, 26 eran mujeres y 25 tuvieron resultados de estudios bacteriológicos positivos. Sobre un total de 60 articulaciones, 54 presentaron alteración en la forma y de la posición del disco articular. Se verificó la importancia en la solicitud y asociación de estudios para el diagnóstico diferencial(AU)

Síndrome de shock tóxico estreptocócico / Streptococcal toxic-shock syndrome

El síndrome de shock tóxico estreptocócico (SSTS) es un cuadro grave e infrecuente en Pediatría. Sin embargo, en las últimas décadas está aumentando la incidencia de infecciones invasivas por Streptococcus pyogenes o estreptococo del grupo A. Aparece más frecuentemente en niños preescolares, ya que el diagnóstico de enfermedad estreptocócica es más complicado a esta edad. Es fundamental el diagnóstico y tratamiento precoz debido a su potencial gravedad, precisando en algunas ocasiones medidas intensivas de soporte vital y prevención del fallo multiorgánico

Streptococcal toxic shock syndrome (STSS) is a serious and uncommon disease in Pediatrics. However, in the last decades the incidence of invasive infections by Streptococcus pyogenes of group A streptococcus has increased. It appears more frequently in preschool children since the diagnosis of streptococcal disease is more complicated at this age. Early diagnosis and treatment are essential due to its potential severity, sometimes requiring intensive life support measures and prevention of multiorgan failure

Elevated antistreptolysin O titer is closely related to cardiac mitral insufficiency in untreated patients with Takayasu arteritis.

BACKGROUND: The etiology of Takayasu arteritis (TA) is unknown; however, a possible relationship between streptococcal infection and TA has been proposed. This study aimed to identify the clinical features and cardiac valvular involvement in untreated TA patients with an elevated antistreptolysin O (ASO) titer. METHODS: In this retrospective study, the clinical characteristics and features of valvular involvement were compared in TA patients with or without an elevated ASO titer. RESULTS: Of the 74 untreated TA patients, 13 patients were found have elevated ASO titers (17.6%). Mitral insufficiency was the most common in patients with elevated ASO (69.2%, 9/13), followed by aortic valve insufficiency (46.2%, 5/13) and tricuspid insufficiency (46.2%, 5/13), which were no significantly different than that in normal ASO group. The proportions of moderate to severe mitral (30.8% vs 1.6%, p = 0.000) and tricuspid valve (15.4% vs 1.64%, p = 0.023) insufficiency in the ASO positive group were significantly higher than those in the ASO negative group. The odds of mitral regurgitation in patients with elevated ASO titers were 3.9 times higher than those in the group with normal ASO titers (p = 0.053, OR = 3.929, 95% confidence interval [CI]: 0.983-15.694). Furthermore, the risk of moderate to severe mitral insufficiency in patients with elevated ASO titers was 41.6 times higher than that in patients with normal ASO titers (p = 0.002, OR = 41.600, 95% CI: 3.867-447.559). CONCLUSIONS: An increase in ASO titer is related to valvular involvement in TA and is closely linked to mitral insufficiency.

Atypical presentation of acute rheumatic fever (ARF) in a 25-year-old woman in the Caribbean: a challenging diagnosis.

A 25-year-old woman presented a challenging diagnosis of acute rheumatic fever (ARF). Initial symptoms included dry cough and three minor Jones criteria (unabating fever (38.4°C, 0d), elevated acute phase reactants (C-reactive protein, 13d) and joint pain (monoarthralgia) in her neck (0d)). ARF was diagnosed only after presentation of two major Jones criteria (polyarthritis/polyarthralgia (16d) and erythema marginatum (41d)) and positive antistreptolysin O titre (44d). Parotid swelling, peripheral oedema, elevated liver enzymes and diffuse lymphadenopathy complicated the diagnosis. Throat swab, chorea and carditis were negative or absent. Atypical ARF is challenging to recognise. There is no diagnostic test and its presentation is similar to that of other diseases. While the 2015 Jones criteria modification increased specificity of ARF diagnosis, atypical cases may still be missed, especially by physicians in developed countries. Suspicion of atypical ARF, especially after travel to high incidence regions, would allow for earlier treatment and prevention of rheumatic heart disease.

Diagnostic Value of Different Noninvasive Criteria of Latent Myocarditis in Comparison with Myocardial Biopsy.

PURPOSE: The aim of this study was to quantify the value of various clinical, laboratory, and instrumental signs in the diagnosis of myocarditis in comparison with morphological studies of the myocardium. METHODS: In 100 patients (65 men, 44.7 ± 12.5 years old) with "idiopathic" arrhythmias (n = 20) and dilated cardiomyopathy (DCM; n = 80), we performed the following: 71 endomyocardial biopsies (EMB), 13 intraoperative biopsies, 5 studies of explanted hearts, and 11 autopsies with virus investigation (real-time PCR) of the blood and myocardium. Antiheart antibodies (AHA) were also measured as well as cardiac CT (n = 45), MRI (n = 25), and coronary angiography (n = 47). The comparison group included 50 patients (25 men, 53.7 ± 11.7 years old) with noninflammatory heart diseases who underwent open heart surgery. RESULTS: Active/borderline myocarditis was diagnosed in 76.0% of the study group and in 21.6% of patients in the comparison group (p < 0.001). The myocardial viral genome was observed more frequently in patients in the comparison group than in the study group (65.0 and 40.2%; p < 0.01). We evaluated the diagnostic value of noninvasive markers of myocarditis. The panel of AHA had the greatest importance in the identification of myocarditis: sensitivity was 81.5%, and the positive and negative predictive values were 75.0 and 60.5%. This defined the diagnostic value of noninvasive markers of myocarditis and established a diagnostic algorithm providing an individual assessment of the likelihood of myocarditis development. CONCLUSION: AHA have the greatest significance in the diagnosis of latent myocarditis in patients with "idiopathic" arrhythmias and DCM. The use of a complex of noninvasive criteria allows the probability of myocarditis to be estimated and the indications for EMB to be determined.

Clinical-Serological Characterization and Treatment Outcome of a Large Cohort of Italian Children with Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection and Pediatric Acute Neuropsychiatric Syndrome.

Objective: Pediatric autoimmune neuropsychiatric disorder associated with Streptococcus pyogenes infection (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS) are emerging immune-mediated encephalopathies characterized by sudden onset of seemingly inexplicable complex neuropsychiatric symptoms, including obsessions, compulsions, and heterogeneous tics, which occur in children. Main goal of this study was to report our experience in a large cohort of Italian children affected by either PANDAS or PANS and treated long term with an antibiotic regimen similar to that used for acute rheumatic fever. Patients and Methods: The clinical charts of a cohort of 371 consecutive Italian children, 345 with PANDAS (93.0%) and 26 with PANS (7.0%), were retrospectively evaluated. Antistreptococcal, antinuclear antibodies, and serologic evaluation for a group of common autoantibodies and microbial agents were also assessed. A strict differential diagnosis with other autoimmune diseases displaying neuropsychiatric manifestations was performed. Results: Antistreptolysin O and anti-DNase B antibody titers were tested and were positive in all PANDAS subjects, but negative in PANS. Anti-Mycoplasma pneumoniae antibodies and anti-Epstein-Barr virus Nuclear Antigen antibodies were found positive in 11 (42.3%) and 5 (19.2%) patients with PANS, respectively. Among PANDAS cases, a clear streptococcal infection was clinically evident at the onset of neurological symptoms in only 74 patients (21.4%), whereas the relationship with Streptococcus pyogenes was confirmed by serologic tests in the other 271 (78.6%). All patients fulfilling the diagnostic criteria for PANDAS (n = 345) received amoxicillin/clavulanic acid for 10-21 days at diagnosis, while those who were diagnosed with PANS (n = 26) received treatment according to the causative agent. Thereafter, all PANDAS/PANS patients received prophylaxis with benzathine benzylpenicillin for an overall period of at least 5 years to prevent subsequent potential streptococcal infections. To date, 75.0% of PANDAS patients (n = 258) have shown an improvement of neurologic symptoms, mainly observed within 3-5 months of treatment for PANDAS cases, while 88.4% of PANS patients (n = 23) have improved after 6-12 months. Infection-related relapses of neurologic manifestations were observed in both PANDAS and PANS patients (n = 167 out of 371; 45% of the total cohort) in the long term. Conclusions: Our study has confirmed the usefulness of the preliminary diagnostic criteria for PANDAS and PANS, revealing also the importance of early diagnosis to reduce the risk of evolution toward disabling chronic neurologic sequelae. Long-term antibiotic prophylaxis has resulted in a substantial benefit to reduce neurological symptoms for the majority of PANDAS and PANS patients over a 7-year period.

NF-κB-driven miR-34a impairs Treg/Th17 balance via targeting Foxp3.

The subset of regulatory T (Treg) cells, with its specific transcription Foxp3, is a unique cell type for the maintenance of immune homeostasis by controlling effector T (Teff) cell responses. Although it is common that a defect in Treg cells with Treg/Teff disorder causes autoimmune diseases; however, the precise mechanisms are not thoroughly revealed. Here, we report that miR-34a could attenuate human and murine Foxp3 gene expression via targeting their 3' untranslated regions (3' UTR). The human miR-34a, increased in peripheral blood mononuclear cells (PBMCs) and CD4+ T cells from rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) patients, displayed a positive correlation with some serum markers of inflammation including rheumatoid factor (RF), anti-streptolysin antibody (ASO), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as well as Th17 signature gene RORγt, but inversely correlated with the mRNA expression levels of FOXP3. In addition, murine miR-34a levels were downregulated in TGF-ß-induced Treg cells but upregulated in Th17 cells induced in vitro compared to activated CD4+ T cells. It has also been demonstrated that elevated miR-34a disrupting Treg/Th17 balance in vivo contributed to the progress of pathogenesis of collagen induced arthritis (CIA) mice. Furthermore, IL-6 and TNF-α were responsible for the upregulation of miR-34a and downregulation of Foxp3, which was reverted by the addition of NF-κB/p65 inhibitor BAY11-7082, thus indicating that NF-κB/p65 inhibited Foxp3 expression in an miR-34a-dependent manner. Finally, IL-6 or TNF-α-activated p65 could bind to the miR-34a promotor and enhance its activity, resulting in upregulation of its transcription. Taken together, we show that NF-κB activated by inflammatory cytokines, such as IL-6 and TNF-α, ameliorates Foxp3 levels via regulating miR-34a expression, which provides a new mechanistic and therapeutic insight into the ongoing of autoimmune diseases.