Acute effect of high-intensity interval training versus moderate-intensity continuous training on appetite perception: A systematic review and meta-analysis.

Interval training protocols have gained popularity over the years, but their impact on appetite sensation compared to officially recommended training method, moderate intensity continuous training (MICT) is not well understood. Thus, this systematic review and meta-analysis aimed to compare a single session of high intensity interval training (HIIT) including sprint interval training (SIT) with MICT on appetite perception measured by the visual analog scale (VAS). After searching up articles published up to September 2021, 13 randomized controlled studies were included in the meta-analysis. Outcomes of meta-analysis demonstrated that both acute sessions of HIIT/SIT and MICT suppressed appetite compared to no-exercise control groups immediately post exercise but there were no significant effects 30-90 min post exercise or in AUC values, indicating a transient effect of exercise on appetite sensations. Moreover, differences in appetite sensations between HIIT/SIT and MICT were negligible immediately post exercise, but HIIT/SIT suppressed hunger (MD = -6.347 [-12.054, -0.639], p = 0.029) to a greater extent than MICT 30- to 90-min post exercise, while there was a lack of consistency other VAS subscales of appetite. More studies that address the impact of exercising timing, nutrient compositions of energy intake (energy intake (EI)) and differences in participants' characteristics and long-term studies analyzing chronic effects are needed to comprehensively examine the differences between HIIT/SIT and MICT on appetite and EI. SYSTEMATIC REVIEW REGISTRATION: [https://www.crd.york.ac.uk/PROSPERO], Identifier [CRD42021284898].

Comparative Effectiveness of Multiple Exercise Interventions in the Treatment of Mental Health Disorders: A Systematic Review and Network Meta-Analysis.

BACKGROUND: The efficacy of exercise interventions in the treatment of mental health disorders is well known, but research is lacking on the most efficient exercise type for specific mental health disorders. OBJECTIVE: The present study aimed to compare and rank the effectiveness of various exercise types in the treatment of mental health disorders. METHODS: The PubMed, Web of Science, PsycINFO, SPORTDiscus, CINAHL databases, and the Cochrane Central Register of Controlled Trials as well as Google Scholar were searched up to December 2021. We performed pairwise and network meta-analyses as well as meta-regression analyses for mental health disorders in general and each type of mental health disorder, with alterations in symptom severity as the primary outcome. RESULTS: A total of 6456 participants from 117 randomized controlled trials were surveyed. The multimodal exercise (71%) had the highest probability of being the most efficient exercise for relieving depressive symptoms. While resistance exercise (60%) was more likely to be the most effective treatment for anxiety disorder, patients with post-traumatic stress disorder (PTSD) benefited more from mind-body exercise (52%). Furthermore, resistance exercise (31%) and multimodal exercise (37%) had more beneficial effects in the treatment of the positive and negative symptoms of schizophrenia, respectively. The length of intervention and exercise frequency independently moderated the effects of mind-body exercise on depressive (coefficient = 0.14, p = .03) and negative schizophrenia (coefficient = 0.96, p = .04) symptoms. CONCLUSION: Multimodal exercise ranked best for treating depressive and negative schizophrenic symptoms, while resistance exercise seemed to be more beneficial for those with anxiety-related and positive schizophrenic symptoms. Mind-body exercise was recommended as the most promising exercise type in the treatment of PTSD. However, the findings should be treated with caution due to potential risk of bias in at least one dimension of assessment and low-to-moderate certainty of evidence. Trial Registration This systematic review was registered in the PROSPERO international prospective register of systematic reviews (CRD42022310237).

Sprint Interval Exercise Improves Cognitive Performance Unrelated to Postprandial Glucose Fluctuations at Different Levels of Normobaric Hypoxia.

Objective: The aim of our study was to examine cognition response to sprint interval exercise (SIE) against different levels of hypoxia. Research design and methods: 26 recreational active males performed SIE (20 × 6 s of all-out cycling bouts, 15 s of passive recovery) under normoxia (FIO2: 0.209), moderate hypoxia (FIO2: 0.154), and severe hypoxia (FIO2: 0.112) in a single-blinded crossover design. Cognitive function and blood glucose were assessed before and after 0, 10, 30, and 60 min of the SIE. Heart rate (HR), peripheral oxygen saturation (SpO2), and ratings of perceived exertion (RPE, the Borg 6−20-point scale) during each SIE trial were recorded before and immediately after every five cycling bouts, and after 0, 10, 30, and 60 min of the SIE. Results: All the three SIE trials had a significantly faster overall reaction time in the Stroop test at 10 min after exercise as compared to that of the baseline value (p = 0.003, ƞ2 = 0.606), and returned to normal after 60 min. The congruent RT at 10 min after SIE was significantly shorter than that of the baseline (p < 0.05, ƞ2 = 0.633), while the incongruent RT at both 10 min and 30 min were significantly shorter than that measured at baseline (p < 0.05, ƞ2 = 0.633). No significant differences in terms of accuracy were found across the three trials at any time points (p = 0.446, ƞ2 = 0.415). Blood glucose was significantly reduced at 10 min and was sustained for at least 60 min after SIE when compared to pre-exercise in all trials (p < 0.05). Conclusions: Acute SIE improved cognitive function regardless of oxygen conditions, and the sustained improvement following SIE could last for at least 10−30 min and was unaffected by the altered blood glucose level.

The Impact of Sprint Interval Exercise in Acute Severe Hypoxia on Executive Function.

Kong, Zhaowei, Qian Yu, Shengyan Sun, On Kei Lei, Yu Tian, Qingde Shi, Jinlei Nie, and Martin Burtscher. The impact of sprint interval exercise in acute severe hypoxia on executive function. High Alt Med Biol. 23: 135-145, 2022. Objective: The present study evaluated executive performance responses to sprint interval exercise in normoxia and relatively severe hypoxia. Methods: Twenty-five physically active men (age 22 ± 2 years; maximal oxygen uptake 43 ± 2 ml/[kg·min]) performed four trials including two normoxic (FIO2 = 0.209) and two normobaric hypoxic trials (FIO2 = 0.112), at rest (control) and exercise at the same time on different days. The exercise scheme consisted of 20 sets of 6-seconds all-out cycling sprint interspersed with 15-seconds recovery. The Stroop task was conducted before, 10, 30, and 60 minutes after each trial, whereas peripheral oxygen saturation (SpO2), heart rate, ratings of perceived exertion, and feelings of arousal were additionally recorded immediately after the interventions. Results: Despite the low SpO2 levels, both resting and sprint interval exercise in hypoxia had no adverse effects on executive function. Exercise elicited executive improvements in normoxia (-5.3% and -3.4% at 10 and 30 minutes after exercise) and in hypoxia (-7.8% and -4.3%), which is reflected by ameliorating incongruent reaction time and its 30-minutes sustained effects (p = 0.018). Conclusions: The findings demonstrate that sprint interval exercise caused sustained executive benefits, and exercise in relatively severe hypoxia did not impair executive performance.

Effects of Low-Carbohydrate Diet and Exercise Training on Gut Microbiota.

Objective: This study was aimed to evaluate the effects of low-carbohydrate diet (LC) and incorporated high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT) on gut microbiota, and the associations between changes in gut microbiota and cardiometabolic health-related profiles. Methods: Fifty overweight/obese Chinese females (age 22.2 ± 3.3 years, body mass index 25.1 ± 3.1 kg/m-2) were randomized to the groups of LC, LC and HIIT (LC-HIIT, 10 repetitions of 6-s sprints and 9-s rest), and LC and MICT group (LC-MICT, cycling at 50-60% V̇O2peak for 30 min). The LC-HIIT and LC-MICT experienced 20 training sessions over 4 weeks. Results: The 4-week LC intervention with/without additional training failed to change the Shannon, Chao 1, and Simpson indexes (p > 0.05), LC increased Phascolarctobacterium genus, and LC-HIIT reduced Bifidobacterium genus after intervention (p < 0.05). Groups with extra exercise training increased short-chain fatty acid-producing Blautia genus (p < 0.05) and reduced type 2 diabetes-related genus Alistipes (p < 0.05) compared to LC. Sutterella (r = -0.335) and Enterobacter (r = 0.334) were associated with changes in body composition (p < 0.05). Changes in Ruminococcus, Eubacterium, and Roseburia genera were positively associated with blood pressure (BP) changes (r = 0.392-0.445, p < 0.05), whereas the changes in Bacteroides, Faecalibacterium, and Parabacteroides genera were negatively associated with BP changes (r = -0.567 to -0.362, p < 0.05). Conclusion: LC intervention did not change the α-diversity and overall structure of gut microbiota. Combining LC with exercise training may have additional benefits on gut physiology. Specific microbial genera were associated with LC- and exercise-induced regulation of cardiometabolic health.

Hypoxic repeated sprint interval training improves cardiorespiratory fitness in sedentary young women.

OBJECTIVE: The purpose of this study was to investigate the effects of repeated sprint interval training (RSIT) under different hypoxic conditions in comparison with normoxic RSIT on cardiorespiratory fitness (CRF) and metabolic health in sedentary young women. METHODS: Sixty-two sedentary young women (age: 21.9 ± 2.8 years, peak oxygen uptake [V̇O2peak] 25.9 ± 4.5 ml kg-1·min-1) were randomized into one of the four groups, including a normoxic RSIT group (N), RSIT simulating an altitude of 2500 m (H2500), RSIT simulating an incremental altitude of 2500-3400 m (H2500-3400) and a non-exercise control group (C). The training intervention (80 × 6 s all-out cycling sprints with 9 s recovery) was performed three times/week for 4 weeks. Anthropometric measures, V̇O2peak, fasting blood glucose and lipids were assessed during the follicular phase of the menstrual cycle before and after the intervention. RESULTS: Compared with the control group, significant increases in V̇O2peak were found in both hypoxic groups (H2500: +8.2%, p < 0.001, d = 0.52; H2500-3400: +10.9%, p < 0.05, d = 0.99) but not in the N group (+3.6%, p > 0.05, d = 0.21) after the intervention, whereas the two hypoxic groups had no difference in V̇O2peak. Blood glucose and lipids, and body composition remained unchanged in all groups. CONCLUSION: The present study indicates that combining hypoxia with RSIT can enhance the improvement of CRF compared with normoxic RSIT alone in the sedentary young population. Yet, compared with RSIT under stable hypoxia, incremental hypoxia stress in the short-term does not additionally ameliorate CRF.

Carbohydrate Restriction with or without Exercise Training Improves Blood Pressure and Insulin Sensitivity in Overweight Women.

OBJECTIVE: The purpose of this study was to evaluate the effects of a 4-week low-carbohydrate diet (LC) with or without exercise training on cardiometabolic health-related profiles in overweight/obese women. METHODS: Fifty overweight/obese Chinese women (age: 22.2 ± 3.3 years, body mass index (BMI): 25.1 ± 3.1 kg·m-2) were randomized to either a LC control group (LC-CON, n = 16), a LC and high-intensity interval training group (LC-HIIT, n = 17), or a LC and moderate-intensity continuous training group (LC-MICT, n = 17). All groups consumed LC for 4 weeks, while the LC-HIIT and LC-MICT groups followed an additional five sessions of HIIT (10 × 6 s cycling sprints and 9 s rest intervals, 2.5 min in total) or MICT (cycling continuously at 50-60% of peak oxygen uptake (VO2peak) for 30 min) weekly. Blood pressure, fasting glucose, insulin sensitivity, and several metabolic or appetite regulating hormones were measured before and after intervention. RESULTS: Significant reductions in body weight (- ~2.5 kg, p < 0.001, η2 = 0.772) and BMI (- ~1 unit, p < 0.001, η2 = 0.782) were found in all groups. Systolic blood pressure was reduced by 5-6 mmHg (p < 0.001, η2 = 0.370); fasting insulin, leptin, and ghrelin levels were also significantly decreased (p < 0.05), while insulin sensitivity was improved. However, there were no significant changes in fasting glucose, glucagon, and gastric inhibitory peptide levels. Furthermore, no group differences were found among the three groups, suggesting that extra training (i.e., LC-HIIT and LC-MICT) failed to trigger additional effects on these cardiometabolic profiles. CONCLUSIONS: The short-term carbohydrate restriction diet caused significant weight loss and improved blood pressure and insulin sensitivity in the overweight/obese women, although the combination with exercise training had no additional benefits on the examined cardiometabolic profiles. Moreover, the long-term safety and effectiveness of LC needs further study.

Paraganglioma of the Vagina Associated With Germline SDHB Mutation: Report of a Case With Review of the Literature.

Paragangliomas are rare neuroendocrine neoplasms in the vagina, and their molecular pathogenesis has not been documented. We report a case of vaginal paraganglioma in a 15-yr-old adolescent girl who presented with irregular heavy menses and anemic symptoms. Examination under anesthesia revealed a polypoid mass of 3 cm size in the left anterior vaginal wall, which was resected piecemeal. Histology showed a circumscribed nodular tumor with typical nested morphology of paraganglioma and no significant nuclear atypia. Immunohistochemically the tumor cells were diffusely positive for synaptophysin and chromogranin while being negative for cytokeratin, accompanied by S100-positive sustentacular cells. SDHB immunohistochemistry demonstrated the absence of cytoplasmic staining in the tumor cells with preserved staining in sustentacular cells, raising the possibility of a germline mutation in the genes encoding subunits of succinate dehydrogenase. Sanger sequencing for all the exons and exon-flanking intronic regions of the SDHB gene revealed no mutation, but further investigation with multiplex ligation-dependent probe amplification identified a heterozygous deletion of exon 1 of the SDHB gene in the patient and her mother, confirming the diagnosis of SDHB-related hereditary paraganglioma-pheochromocytoma syndrome. The patient had no evidence of disease upon imaging surveillance and follow-up for 56 mo. A review of the published cases of vaginal paraganglioma seems to suggest a relatively young age of presentation, commonly encountered as incidental findings in asymptomatic patients or presenting with abnormal vaginal bleeding. The association between vaginal paraganglioma and germline SDHB mutation has not been reported. We believe this case illustrates the clinical significance of SDHB immunohistochemistry and genetic testing for this rare vaginal neoplasm.

Severe Hypoxia Does Not Offset the Benefits of Exercise on Cognitive Function in Sedentary Young Women.

Purpose: To examine the effect of acute moderate-intensity continuous exercise performed under normobaric severe hypoxia on cognition, compared to sea-level normoxia. Methods: Thirty healthy inactive women randomly performed two experimental trials separated by at least three days but at approximately the same time of day. Executive functions were measured during the follicular stage via an interference control task before (rest) and during exercise with 45% peak power output under normobaric normoxia (PIO2 = 150 mmHg, FIO2 = 0.21), and (2) hypoxia (PIO2 = 87 mmHg, FIO2 = 0.12, simulated at an altitude of 4000 m). Reaction time (RT), accuracy rate (AC), heart rate, ratings of perceived exertion, and peripheral oxygen saturation (SpO2) were collected before and during exercise. Results: RT (p < 0.05, η²p = 0.203) decreased during moderate exercise when compared at rest, while a short bout of severe hypoxia improved RT (p < 0.05, η²p = 0.134). Exercise and hypoxia had no effects on AC (p > 0.05). No significant associations were found between the changes of RT and SpO2 under the conditions of normoxia and hypoxia (p > 0.05). Conclusions: At the same phase of the menstrual cycle, a short bout of severe hypoxia simulated at 4000 m altitude caused no impairment at rest. RT during moderate exercise ameliorated in normoxia and severe hypoxia, suggesting that both exercise and short-term severe hypoxia have benefits on cognitive function in sedentary young women.

A recurrent de novo DYNC1H1 tail domain mutation causes spinal muscular atrophy with lower extremity predominance, learning difficulties and mild brain abnormality.

We describe four unrelated patients with the same de novo heterozygous missense mutation c.751C>T in the DYNC1H1 gene. We found a high phenotype-genotype correlation with all four patients having early childhood-onset predominant lower limb muscle weakness and wasting which was slowly progressing and later-onset mild upper extremities proximal weakness. All four patients presented minor cognitive dysfunction with learning difficulty and developmental behavioural comorbidities with mild abnormalities in the brain MRI. The leg muscle MRI findings are highly consistent in DYN1CH1-related spinal muscular atrophy with lower limb predominance (SMALED) with relative sparing of biceps femoris and semitendinosus, and hypertrophy of adductor longus in the thighs; and sparing the anterior and medial muscles in the calves. This report provides important clinical evidence indicating the de novo heterozygous missense mutation c.751C>T in the DYNC1H1 gene is pathogenic causing SMALED. Muscle MRI is more specific than muscle biopsy in the diagnosis of SMALED.

Spinal Muscular Atrophy With Respiratory Distress Type 1-A Child With Atypical Presentation.

The authors report a child with spinal muscular atrophy with respiratory distress type 1 (SMARD1). She presented atypically with hypothyroidism and heart failure due to septal defects that required early heart surgery and microcephaly in association with cerebral atrophy and thin corpus collosum. The subsequent asymmetrical onset of diaphragmatic paralysis, persistent hypotonia, and generalized muscle weakness led to the suspicion of spinal muscular atrophy with respiratory distress type 1. Sanger sequencing confirmed a compound heterozygous mutation in the Immunoglobulin Mu Binding Protein 2 (IGHMBP2) gene, with a known mutation c.2362C > T (p.Arg788*) and a novel frameshift mutation c.2048delG (p.Gly683A1afs*50). Serial nerve conduction study and electromyography confirmed progressive sensorimotor polyneuropathy and neuronopathy. In summary, this case report describes a child with spinal muscular atrophy with respiratory distress type 1 also with congenital cardiac disease and endocrine dysfunction, expanding the phenotypic spectrum of this condition. A high index of suspicion is needed in diagnosing this rare condition to guide the management and genetic counseling.

Effect of plasmapheresis on serum levels of clobazam, levetiracetam and topiramate.

A 27-year-old man with a diagnosis of new onset refractory status epilepticus (NORSE) was treated with five anti-seizure drugs (ASDs) including clobazam, levetiracetam and topiramate. He received plasma exchange (PE) for presumed autoimmune etiology. Serum ASD levels were serially monitored in two sessions. Levels of clobazam, levetiracetam and topiramate were significant reduced by PE. Serum clobazam level dropped down to at least 85% and 75% of the baseline during and after the procedure respectively; levetiracetam dropped down to 83% and 83%; and topiramate dropped to 86% and 79%. The results may imply a theoretical risk of breakthrough seizure during PE due to low ASD levels.

Significance of Size of Persistent/Recurrent Central Nodal Disease on Surgical Morbidity and Response to Therapy in Reoperative Neck Dissection for Papillary Thyroid Carcinoma.

BACKGROUND: To balance the risk of disease progression, morbidity, and efficacy of reoperative central neck dissection (RCND) in papillary thyroid carcinoma, the latest clinical guidelines recommend early surgery over surveillance when the largest diseased node is >8 mm in its smallest dimension. However, the evidence remains scarce. To determine an appropriate size for first-time RCND, the relationship between size of largest diseased central node, morbidity, and response-to-therapy following RCND was examined. METHODS: A total of 130 patients who underwent RCND following initial surgery for persistent/recurrent nodal disease were reviewed. Patients with largest diseased central node measured preoperatively by ultrasonography were included. Eligible patients were categorized into three groups: largest central node <10 mm (group I), 10-15 mm (group II), and >15 mm (group III). Surgical morbidity and response to therapy at one year after RCND were compared between groups. To evaluate biochemical response, patients with structural incompleteness were excluded. RESULTS: Group III not only had significantly more high-risk tumors (by American Thyroid Association risk stratification) at initial therapy (64.5% vs. 44.4%, respectively; p = 0.038), but this group also a higher risk of extranodal extension (35.5% vs. 16.0%; p = 0.055), recurrent laryngeal nerve involvement (19.4% vs. 0.0%; p < 0.001), incomplete surgical resection (48.4% vs. 7.4%; p < 0.001), new-onset vocal cord paresis (16.7% vs. 2.5%; p = 0.017), overall surgical morbidity (22.6% vs. 7.4%; p = 0.021), and biochemical incompleteness (80.6% vs. 67.9%; p = 0.004) than groups I and II combined did. However, overall morbidity did not differ between groups I and II (5.7% vs. 8.7%; p = 0.694). After adjusting for American Thyroid Association risk stratification, only the size of the largest diseased central node ≥15 mm (odds ratio = 7.256 [confidence interval 1.302-40.434], p = 0.001) was an independent risk factor for biochemical incompleteness following RCND. CONCLUSIONS: Patients with larger diseased central node(s) had a significantly higher risk of local invasion, surgical morbidity, and biochemical incompleteness. Relative to nodal size <10 mm, size >15 mm in the largest disease central node was an independent risk factor for incomplete biochemical response, while nodal size 10-15 mm was not. These findings imply that the recommended threshold of 8 mm might be too stringent and could be raised to 15 mm without increasing the surgical morbidity from RCND.

Novel presenilin 1 mutation (p.F386I) in a Chinese family with early-onset Alzheimer's disease.

Autosomal dominant familial Alzheimer's disease accounts for 0.5% of all Alzheimer's disease. A familial Alzheimer's disease Chinese family, with 7 affected family members, underwent PSEN1 screening in 3 affected family members. A heterozygous novel missense mutation in the PSEN1 gene c.1156T>A, altering phenylalanine to isoleucine at codon 386, was identified. Because the change occurred in conserved domains of this gene and cosegregated with affected family members, this change may have a mutagenic and probably pathogenic effect.

A systematic review of familial Alzheimer's disease: Differences in presentation of clinical features among three mutated genes and potential ethnic differences.

There are great diversities of clinical phenotypes among the various familial Alzheimer's disease (FAD) families. We aimed to systematically review all the previously reported cases of FAD and to perform comparisons between Asian and white patients. In this regard, we collected individual-level data from 658 pedigrees. We found that patients with presenilin 1 (PSEN1) mutations had the earliest age of onset (AOO; 43.3 ± 8.6 years, p < 0.001) and were more commonly affected by seizures, spastic paraparesis, myoclonus, and cerebellar signs (p < 0.001, p < 0.001, p = 0.003, and p = 0.002, respectively). Patients with PSEN2 mutations have a delayed AOO with longest disease duration and presented more frequently with disorientation (p = 0.03). Patients with amyloid precursor protein (APP) mutations presented more frequently with aggression (p = 0.02) and those with APP duplication presented more frequently with apraxia (p = 0.03). PSEN1 mutations before codon 200 had an earlier AOO than those having mutations after codon 200 (41.4 ± 8.0 years vs. 44.7 ± 8.7 years, p < 0.001). Because 42.9% of the mutations reported are novel, the mutation spectrum and clinical features in Asian FAD families could be different from that of whites. Asian patients with PSEN1 mutations presented more frequently with disorientation (p = 0.02) and personality change (p = 0.01) but less frequently with atypical clinical features. Asian patients with APP mutations presented less frequently with aphasia (p = 0.02). Thus, clinical features could be modified by underlying mutations, and Asian FAD patients may have different clinical features when compared with whites.

Diagnosis of 5α-reductase 2 deficiency: is measurement of dihydrotestosterone essential?

BACKGROUND: 5α-Reductase 2 deficiency (5ARD) is a known cause of 46,XY disorders of sex development (DSD). Traditionally, the diagnosis relies on dihydrotestosterone (DHT) measurement, but the results are often equivocal, potentially leading to misdiagnosis. We reviewed alternative approaches for diagnosis of 5ARD. METHODS: We conducted a retrospective review of the results of urinary steroid profiling (USP) by GC-MS and mutational analysis of SRD5A2 [steroid-5-alpha-reductase, alpha polypeptide 2 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 2)] by PCR and direct DNA sequencing of all 46,XY DSD patients referred to our laboratory with biochemical and/or genetic findings compatible with 5ARD. We also performed a literature review on the laboratory findings of all 5ARD cases reported in the past 10 years. RESULTS: Of 16 patients diagnosed with 5ARD between January 2003 and July 2012, 15 underwent USP, and all showed characteristically low 5α- to 5ß-reduced steroid metabolite ratios. Four patients had DHT measured, but 2 did not reach the diagnostic cutoff. In all 12 patients who underwent genetic analysis, 2 mutations of the SRD5A2 gene were detected to confirm the diagnosis. Twenty-four publications involving 149 patients with 5ARD were published in the review period. Fewer than half of these patients had DHT tested. Nearly 95% of them had the diagnosis confirmed genetically. CONCLUSIONS: 5ARD can be confidently diagnosed by USP at 3 months postnatally and confirmed by mutational analysis of SRD5A2. Interpretation of DHT results may be problematic and is not essential in the diagnosis of 5ARD. We propose new diagnostic algorithms for 46,XY DSD.

MicroRNA-21* regulates the prosurvival effect of GM-CSF on human eosinophils.

Eosinophils are the principal effector cells of allergic inflammation, and hematopoietic cytokine granulocyte macrophage colony-stimulating factor (GM-CSF) is the primary cytokine that activates and prolongs the survival of eosinophils in local inflammatory sites by mediating anti-apoptotic activity in allergic inflammation. To investigate the immunopathological role of microRNA (miRNA) in allergic inflammation, we elucidated the regulatory mechanisms of miRNA on the GM-CSF-mediated in vitro survival in eosinophils. Eosinophils were purified from fresh human peripheral blood buffy coat fraction obtained from adult volunteer using microbead magnetic cell sorting. The apoptosis, viability and phosphorylation of extracellular signal-regulated kinase (ERK) were assessed by flow cytometry, and the expression of miRNA was analyzed using Agilent Human miRNA Microarray with Human miRNA Microarray Version 3 and real time RT-PCR. We have confirmed the increased in vitro viability of GM-CSF-treated eosinophils and upregulated expression of miRNA-21* (miR-21*), a complementary miRNA of miR-21, in GM-CSF-treated eosinophils. The transfection of pre-miR miR-21* precursor molecule could up-regulate the miR-21* expression, subsequently enhance the GM-CSF-activated ERK pathway and reverse the apoptosis of eosinophils, while anti-miR-21* inhibitor could down-regulate the miR-21* expression, suppress the GM-CSF-activated ERK pathway and enhance the apoptosis. Our results should shed light on the potential immunopathological role of miRNA-21* regulating the in vitro apoptosis of eosinophils and development of novel molecular treatment of allergic inflammation.

Activation of eosinophils interacting with dermal fibroblasts by pruritogenic cytokine IL-31 and alarmin IL-33: implications in atopic dermatitis.

BACKGROUND: IL-31 is a pruritogenic cytokine, and IL-33 is an alarmin for damaging inflammation. They together relate to the pathogenesis of atopic dermatitis (AD). Eosinophil infiltration into the inner dermal compartment is a predominant pathological feature of AD. We herein investigated the in vitro inflammatory effects of IL-31 and IL-33 on the activation of human eosinophils and dermal fibroblasts. METHODOLOGY/PRINCIPAL FINDINGS: Receptors, adhesion molecules and signaling molecules were assessed by Western blot or flow cytometry. Chemokines and cytokine were quantitated by multiplex assay. Functional IL-31 receptor component IL-31RA, OSMR-ß and IL-33 receptor component ST2 were constitutively expressed on the surface of eosinophils. Co-culture of eosinophils and fibroblasts significantly induced pro-inflammatory cytokine IL-6 and AD-related chemokines CXCL1, CXCL10, CCL2 and CCL5. Such inductions were further enhanced with IL-31 and IL-33 stimulation. IL-31 and IL-33 could significantly provoke the release of CXCL8 from eosinophils and fibroblasts, respectively, which was further enhanced upon co-culture. In co-culture, eosinophils and fibroblasts were the main source for the release of CCL5, and IL-6, CXCL1, CXCL8, CXCL10 and CCL2, respectively. Direct interaction between eosinophils and fibroblasts was required for CXCL1, CXCL10, CXCL8 and CCL5 release. Cell surface expression of intercellular adhesion molecule-1 on eosinophils and fibroblasts was up-regulated in co-culture upon IL-31 and IL-33 stimulation. The interaction between eosinophils and fibroblasts under IL-31 and IL-33 stimulation differentially activated extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, nuclear factor-κB and phosphatidylinositol 3-kinase-Akt pathways. Using specific signaling molecule inhibitors, the differential induction of IL-31 and IL-33-mediated release of cytokines and chemokines such as IL-6 and CXCL8 from co-culture should be related to their distinct activation profile of intracellular signaling pathways. CONCLUSIONS/SIGNIFICANCE: The above findings suggest a crucial immunopathological role of IL-31 and IL-33 in AD through the activation of eosinophils-fibroblasts interaction via differential intracellular signaling mechanisms.

A 12-year-old chinese girl with Cushing syndrome and virilization due to adrenocortical carcinoma.

A Chinese adolescent girl presented with secondary amenorrhea. During follow-up, she gradually developed Cushingoid features and virilization. After a series of endocrine investigations, including urinary steroid profiling, a diagnosis of adrenocortical carcinoma was made. The treatment and prognosis of the disease are discussed.