[Effect of RDN on long-term blood pressure in refractory hypertensive patients with different cardiovascular risk stratification].

Objective: To investigate the long-term therapeutic effects and safety of renal denervation (RDN) on hypertensive patients with different cardiovascular risks, as well as its impact on adverse events, cardiovascular death and all-cause mortality. Methods: This was a single-center, single-arm, real-world retrospective study. Patients with refractory hypertension who underwent RDN at Tianjin First Central Hospital from July 6, 2011 to December 23, 2015 were enrolled and divided into either a high or intermediate-low risk group based on baseline cardiovascular risk. The treatment responsiveness of hypertensive patients with different cardiovascular stratification to RDN was assessed by comparing the results of office blood pressure, home blood pressure, and 24-h ambulatory blood pressure monitoring at 1, 5, and 11 years after RDN. Long-term safety of RDN was assessed by creatinine, and estimated glomerular filtration rate (eGFR) at 1 and 11 years after RDN. In addition, the total defined daily dose (DDD) of antihypertensive medications and the incidence of long-term adverse events, cardiovascular deaths, and all-cause deaths after RDN were followed up 11 years after RDN in person or by telephone. Results: A total of 62 patients with refractory hypertension, aged (50.2±15.0) years, of whom 35 (56.5%) were male, were included. There were 35 cases in high-risk group and 27 cases in low and medium risk group. The decrease in clinic systolic blood pressure (high risk vs. low-medium risk: (-38.0±15.1) mmHg vs. (-25.0±16.6) mmHg(1 mmHg=0.133kPa),P=0.002), home self-measured systolic blood pressure ((-28.4±12.7) mmHg vs. (-19.7±13.1) mmHg,P=0.011) and clinic systolic blood pressure 11 years after RDN ((-43.0±18.4) mmHg vs. (-27.8±17.9) mmHg,P=0.003) in the high-risk group was significantly higher than that in the low-medium risk group. The differences in heart rate and the decrease in total DDD number of antihypertensive drugs between the two groups were not statistically significant (all P>0.05). Creatinine and eGFR levels in the two groups at 1 and 11 years after RDN were not statistically significant when compared with the baseline values (all P>0.05). The cumulative cardiovascular mortality rate was 1.6% (1/62) and 8.1% (5/62), and the cumulative all-cause mortality rate was 3.2% (2/62) and 11.3% (7/62) at 5 and 11 years after RDN, respectively. The differences in the incidence rate of adverse events, cardiovascular mortality, and all-cause mortality rate between the two groups were not statistically significant (all P>0.05). Conclusions: RDN has long-term antihypertensive effect and good safety. Hypertensive patients who belong to the high-risk stratification of cardiovascular risk may respond better to RDN treatment.

[Pathological evaluation of endoscopic submucosal dissection for early gastric cancer and precancerous lesion in 411 cases].

OBJECTIVE: To evaluate the pathological characteristics of endoscopic submucosal dissection (ESD) specimens for early gastric cancer and precancerous lesions, accumulating experience for clinical management and pathological analysis. METHODS: A total of 411 cases of early gastric cancer or precancerous lesions underwent ESD. According to the Japanese guidelines for ESD treatment of early gastric cancer and classification of gastric carcinoma, the clinicopathological data, pathologic evaluation, concordance rate of pathological diagnosis between preoperative endoscopic forceps biopsies and their ESD specimens (in 400 cases), as well as the risk factors of non-curative resection of early gastric cancer, were analyzed retrospectively. RESULTS: 23.4% (96/411) of the 411 cases were adenoma/low-grade dysplasia and 76.6% (315/411) were early gastric cancer. The latter included 28.0% (115/411) non-invasive carcinoma/high-grade dysplasia and 48.7% (200/411) invasive carcinoma. The concordance rate of pathological diagnosis between endoscopic forceps biopsies and ESD specimens was 66.0% (264/400), correlating with pathological diagnosis and lesion location (P < 0.01). The rate of upgraded diagnosis and downgraded diagnosis after ESD was 29.8% (119/400) and 4.2% (17/400), respectively. Among the 315 cases of early gastric cancer, there were 277 cases (87.9%) of differentiated type and 38 cases (12.1%) of undifferentiated type. In the study, 262 cases (83.2%) met with absolute indication, while 53 cases (16.8%) met relative indication. En bloc and curative resection rates were 98.1% and 82.9%, respectively. Risk factors for non-curative resection included a long diameter >20 mm (OR=3.631, 95%CI: 1.170-11.270, P=0.026), tumor infiltration into submucosa (OR=69.761, 95%CI: 21.033-231.376, P < 0.001)and undifferentiated tumor histology (OR=16.950, 95%CI: 4.585-62.664, P < 0.001). CONCLUSION: Several subjective and objective factors, such as the limitations of biopsy samples, the characteristics and distribution of the lesions, different pathological understanding, and the endoscopic sampling and observation, can lead to the differences between the preoperative and postoperative pathological diagnosis of ESD. In particular, the pathological upgrade of postoperative diagnosis was more significant and should receive more attention by endoscopists and pathologists. The curative resection rate of early gastric cancer in ESD was high. Non-curative resection was related to the long diameter, the depth of tumor invasion and histological classification. ESD can also be performed in undifferentiated early gastric cancer if meeting the indication criteria. The comprehensive and standardized pathological analysis of ESD specimens is clinically important to evaluate the curative effect of ESD operation and patient outcomes.

[Safety and efficacy analysis of the removal of refractory esophageal self-expandable metal stents by stent-in-stent technique].

To evaluate the safety and efficacy of esophageal stent-in-stent (SIS) in patients with refractory esophageal self-expandable metal stents (SEMS). Case series study. Retrospective analysis was made on the patients with refractory esophageal SEMS treated with SIS technology in Zhongda Hospital Affiliated to Southeast University from June 2015 to June 2021. The success rate of stent removal and the incidence of adverse events were analyzed. A total of 12 patients were included, including 7 males and 5 females, aged 50-73 (62.7±8.5) years. The clinical success rate of the internal stents was 12/12, with the median retention time of [M(Q1, Q3), 64.5 (52.0, 90.8)] days. The postoperative displacement rate and severe stenosis incidence were 1/12 and 3/12, respectively. The esophageal stents were successfully removed in one endoscopic session in all patients. A small amount of mucous membrane extravasation occurred in all patients after SIS, and no patients died after 90 days of follow-up.

[Construction of a prediction model for predicting rebleeding in patients with obscure gastrointestinal bleeding after capsule endoscopy].

Objective: To explore the risk factors of rebleeding in patients with obscure gastrointestinal bleeding (OGIB) after capsule endoscopy (CE), and construct a model to predict rebleeding. Methods: The data of patients with OGIB who underwent CE in Zhongda Hospital Affiliated to Southeast University from July 2018 to September 2021 were retrospectively analyzed. Follow-up data were obtained via electronic medical records or telephone interviews. Univariate and multivariate Cox regression models were performed to figure out the risk factors of rebleeding in OGIB patients. Then the optimal prediction model was determined and presented as a nomogram. The model was evaluated by C statistic, calibration curve and decision curve analysis. Results: One hundred and thirty patients with OGIB were included, including 64 females and 66 males, aged (55.8±17.2) years (18-87 years), and 39 (30.0%) cases developed rebleeding during follow-up. Univariate and multivariate Cox regression model analysis showed the duration of more than 2 weeks OGIB (HR=3.70, 95%CI: 1.85-7.42, P<0.001), a history of previous gastrointestinal bleeding (HR=5.25, 95%CI: 2.00-13.81, P<0.001), positive CE findings (HR=3.72, 95%CI: 1.66-8.33, P=0.001), and the lowest hemoglobin level before CE<80 g/L (HR=2.00, 95%CI: 1.02-3.84, P=0.044) were risk factors for rebleeding, while specific treatment (HR=0.25, 95%CI: 0.11-0.54, P<0.001) was a protective factor. The corresponding scores of the above five predictive factors were: OGIB duration>2 weeks: 79 points; Previous history of gastrointestinal bleeding: 100 points; The result of CE was positive: 79 points; Specific treatment:-85 points; Minimum hemoglobin before CE<80 g/L: 41 points. The prediction model constructed from the above five variables had good discriminative capability (concordance index=0.798, 95%CI: 0.732-0.865). The calibration curves showed high consistency between nomogram-predicted probabilities and actual observations. The decision curves showed that when the threshold probability was above 0.04, the use of the nomogram to predict rebleeding provided a greater net benefit than the assumption of "all patients rebleeding or no patients rebleeding". Conclusion: The prediction model established in this study has a good ability to predic rebleeding in patients with OGIB after CE examination.

[Circulating tumor cells in pancreatic cancer patients: progression in the detection methods and clinical application].

Circulating tumor cells (CTC) disseminate from primary tumors by undergoing epithelial mesenchymal transition that allow their entry into the circulation to drive metastatic formation in pancreatic cancer patients.Technological advances in detection and characterization of CTC are conducive to the early diagnosis, differential diagnosis, monitoring disease progression and predicating the probability of canceration or the chemotherapeutic efficacy. Nowadays, detection methods of CTC can be based on immunomagnetic beads technique, cell filtration or microfluidic chips technology, but there are great differences in the sample throughput, CTC recovery rate, purity, and CTC viability among them.Owing to the dilemma in detection methods, the intrinsic relevance between the biological characteristics of CTC and clinical manifestations is still not exactly elucidated. By the improved methodology, next generation sequencing technology and exploring the technique for culturing CTC in vitro and establishing xenotransplanted tumor model in nude mice, more and more biological information will be revealed, and finally, individualized treatment is achieved.

The nuclear hormone receptor E75A regulates vitellogenin gene (Al-Vg) expression in the mirid bug Apolygus lucorum.

Apolygus lucorum is the predominant pest of Bacillus thuringiensis (Bt) cotton in China. 20-hydroxyecdysone (20E) plays a key role in the reproduction of this insect. To better understand the mechanism underlying 20E-regulated reproduction, the nuclear hormone receptor E75 isoform-A of Ap. lucorum (Al-E75A) was cloned and its expression analysed. A 2241-bp sequence of Al-E75A cDNA encoded an open reading frame of a polypeptide with a predicted molecular mass of 69.04 kDa. Al-E75A mRNA was detected in female adult stages of Ap. lucorum with peak expression in 7-day-old animals. Al-E75A was also expressed in several tissues, particularly in the fat body and ovary. A 3.2 kb Al-E75A mRNA was detected in all tissues by Northern blot. The fecundity and longevity were significantly decreased in female adults treated with Al-E75A small interfering RNA. The rates of egg incubation rates were considerably lower in the RNA interference-treated animals compared to the untreated controls. In order to investigate the molecular mechanism underlying the effects described above, vitellogenin (Al-Vg) was selected for further investigation. The expression pattern of Al-Vg was similar to that of Al-E75A and was up-regulated by 20E. After knockdown of Al-E75A, the expression profile of Al-Vg and the protein levels were down-regulated. These findings suggest that Al-E75A plays a crucial role in the regulation of Al-Vg expression in Ap. lucorum.

Association of EGFR and KRAS mutations with expression of p-AKT, DR5 and DcR1 in non-small cell lung cancer.

The activation of AKT is one of the causes of resistance to epidermal growth factor receptor (EGFR)- tyrosine kinase inhibitors (TKIs). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) combines with related receptors to trigger apoptosis or protect the cells against TRAIL apoptosis. This research focused on the association of EGFR and KRAS mutations with expression of AKT, p-AKT, DR5 and DcR1 in non-small cell lung cancer. 82 NSCLC patients were included in the study. xTAG liquichip techonolgy (xTAG-LCT) was applied to investigate the genetic mutation of EGFR and KRAS, Quantitative Real-time PCR was used to test the mRNA expression of AKT, DR5 and DcR1 and Western Blot was applied to test the protein expression of AKT, p-AKT, DR5, and DcR1. We found that of 82 patients, 31 cases had EGFR-activating mutations, more common in female, adenocarcinoma, and non-smoker patients; 9 cases had KRAS mutations, frequently found in patients with smoking history. The expression of AKT and p-AKT correlated with staging, tumor differentiation, and lymph node metastasis. The expression of DR5 in phase III and low differentiation tumor was significantly higher than that in phase I+II and high and median differentiation tumor; the expression of DcR1 in phase III and low differentiation tumor was significantly lower than that in phase I+II and high and median differentiation tumor. Compared with EGFR and KRAS wild type, in NSCLC tissue with EGFR and KRAS mutations, the expression of AKT and p-AKT was significantly higher. These results suggest that EGFR and KRAS mutation status was associated with the expression of AKT and p-AKT. AKT, p-AKT, DR5, and DcR1 all took part in the occurrence and development of NSCLC, and may become a reference index to evaluate the prognosis of NSCLC.

[Obstetrical complications of thyroid peroxidase antibody positive during pregnancy and effects of intervention: a meta-analysis].

OBJECTIVE: To explore the correlation between thyroid peroxidase antibody(TPOAb)and outcomes during pregnancy and the effects of treatment on outcomes. METHODS: PubMed, Cochrane Library, Science Direct, Embase, Chinese Biomedicine, and Wanfangdata had been searched. Case-control and cohort studies about TPOAb and pregnancy outcomes were searched according to the inclusion and exclusion criteria. Fifty studies were finally recruited(all of cohort-studies, 10 for English and 5 for Chinese). Review Manager 5.3 were used to test the heterogeneity of the results among the different studies and amalgamate the effect size using fixed or random effect models. RESULTS: Meta-analysis showed TPOAb(+)with normal thyroid function increase the risks of miscarriage,and premature delivery, OR calculated were 2.02(95%CI: 1.13-3.62, P=0.001)and 1.39(95%CI: 1.11-1.76, P=0.005), while showed no relative risk to hypertensive disease, placental abruption in pregnancy and fetal growth restriction, OR calculated were 1.29(95%CI: 1.00-1.67, P=0.080), 0.42(95%CI: 0.12-1.43, P=0.210)and 1.61(95%CI: 0.23-11.12, P=0.100). TPOAb(+)with normal thyroid function increase miscarriage in in vitro fertilization and embryo transfer(IVF-ET), OR calculated were 2.14(95%CI: 1.43-3.21, P=0.000). Levothyroxine(LT4)for patients of TPOAb(+)with normal thyroid dysfunction decrease adverse obstetric outcomes, OR calculated were 0.43(95%CI: 0.22-0.85, P=0.020). CONCLUSIONS: TPOAb(+)with normal thyroid function increase the risks of miscarriage,and premature delivery. TPOAb(+)with normal thyroid function increase miscarriage in IVF-ET. LT4 for patients of TPOAb(+)with normal thyroid dysfunction decrease adverse obstetric outcomes.

Effects of Wiskott-Aldrich Syndrome Protein Deficiency on IL-10-Producing Regulatory B Cells in Humans and Mice.

The Wiskott-Aldrich syndrome protein (WASp) is an important regulator of the actin cytoskeleton and is required for immune cell function. WASp deficiency causes a marked reduction in major mature peripheral B cell subsets, particularly marginal zone (MZ) B cells. We hypothesized that WASp deficiency may also lead to a reduction of regulatory B cells (known as B10 cells) belonging to a novel subset of B cells. And in consideration of the key role of B10 cells play in maintaining peripheral tolerance, we conjectured that a deficit of these cells could contribute to the autoimmunity in patients with Wiskott-Aldrich syndrome (WAS). The effects of WASp deficiency on B10 cells have been reported by only one group, which used an antigen-induced arthritis model. To add more information, we measured the percentage of B10 cells, regulatory T cells (Tregs) and Th1 cells in WASp knockout (WASp KO) mice. We also measured the percentage of B10 cells in patients with WAS by flow cytometry. Importantly, we used the non-induced autoimmune WASp KO mouse model to investigate the association between B10 cell frequency and the Treg/Th1 balance. We found that the percentage of B10 cells was reduced in both mice (steady state and inflammatory state) and in humans and that the lower B10 population correlated with an imbalance in the Treg/Th1 ratio in old WASp KO mice with autoimmune colitis. These findings suggest that WASp plays a crucial role in B10 cell development and that WASp-deficient B10 cells may contribute to autoimmunity in WAS.

Relationship between the angle of vertebral screws and spinal lateral angulation after fixation of thoracolumbar fractures via an anterior approach.

This study investigated possible contributors to lateral spinal angulation after surgical fixation of thoracolumbar fractures via an anterior approach. We retrospectively examined lateral angulation in 172 cases of thoracolumbar fractures treated in this manner. The coronal Cobb angle and angles of the screws relative to the endplates were determined from radiographs. The patients completed the Short Form 36, Oswestry Disability Index, Japanese Orthopaedic Association Back Pain Evaluation Questionnaire, and Visual Analogue Scale at the final follow-up visit. The mean coronal Cobb angle was 0.75° ± 3.91° (-14.25° to 14.55°) preoperatively, 3.17° ± 4.07° (-8.18° to 14.01°) immediately postoperatively, and 3.46° ± 4.21° (-1.05° to 17.27°) at the final follow-up visit. The superior posterior and inferior anterior screws were more parallel to their respective endplates when the approach was made ≥2 vs ≤1 vertebral levels above the fracture (P < 0.001). Lateral angulation was more likely when the approach was made ≤1 vs ≥2 levels above the fracture (P < 0.001). The coronal Cobb angle differed significantly (P < 0.01) between patients with lumbar and thoracic fractures. The immediate postoperative coronal Cobb angle correlated tightly with the sum of the screw angles (superior plus inferior posterior and/or inferior plus superior anterior). Lateral angulation may occur after surgical fixation of thoracic and lumbar fractures via an anterior approach. Non-parallelism between the vertebral screws and their corresponding endplates may predict postoperative lateral spinal angulation. Postoperative lateral angulation does not correlate with low back pain, quality of life, or preoperative lateral angulation.

Clinical features, STAT3 gene mutations and Th17 cell analysis in nine children with hyper-IgE syndrome in mainland China.

Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency disease characterized by eczema, recurrent staphylococcal aureus skin abscesses, pneumonia with pneumatocele formation, remarkably high serum IgE levels, eosinophilia and involvement of skeleton and connective tissues. Heterozygous signal transducer and activator of transcription 3 (STAT3) mutations were shown to be the cause of autosomal dominant HIES (AD-HIES). In this study, we diagnosed nine patients with HIES from 9 unrelated families on the basis of a National Institutes of Health (NIH) score of ≥40 points, sequenced the STAT3 gene of all nine patients, and quantified Th17 cells in peripheral blood of seven patients by flow cytometry in mainland China. All nine patients had characteristic manifestation of HIES with the range of NIH scores 45-77 points. STAT3 hot mutations V637M or R382W/Q were identified in five patients. We identified two novel heterozygous missense mutations (T620S and R609G) located in Src homology 2 (SH2) domain in two patients, respectively. In two other patients, no STAT3 mutations were found. Quantified Th17 cell numbers were markedly decreased or absent (0-0.28% of CD4(+) T cells) in six patients with STAT3 mutations and almost normal (0.53% of CD4(+) T cells) in one wild-type STAT3 patient compared with healthy controls (0.40-2.25% of CD4(+) T cells). These results suggest that not all patients with HIES who had NIH scores over 40 points carry STAT3 mutations, those whose Th17 cell numbers strikingly decreased probably had AD-HIES with STAT3 mutations.

Sulforaphane enhances the activity of the Nrf2-ARE pathway and attenuates inflammation in OxyHb-induced rat vascular smooth muscle cells.

AIM: A growing body of evidence indicates that the nuclear factor erythroid 2-related factor 2-antioxidant response element (Nrf2-ARE) pathway plays a protective role in many physiological stress processes such as inflammatory damage, oxidative stress, and the accumulation of toxic metabolites, which are all involved in the cerebral vasospasm following subarachnoid hemorrhage (SAH). We hypothesized that the Nrf2-ARE pathway might have a protective role in cerebral vasospasm following SAH. MATERIALS AND METHODS: In our study, we investigate whether the oxyhemoglobin (OxyHb) can induce the activation of the Nrf2-ARE pathway in vascular smooth muscle cells (VSMCs), and evaluate the modulatory effects of sulforaphane (SUL) on OxyHb-induced inflammation in VSMCs. RESULTS: As a result, both the protein level and the mRNA level of the nuclear Nrf2 were significantly increased, while the mRNA levels of two Nrf2-regulated gene products, both heme oxygenase-1 and NAD(P)H: quinone oxidoreductase-1, were also up-regulated in VSMCs induced with OxyHb. A marked increase of inflammatory cytokines such as IL-1ß, IL-6 and TNF-α release was observed at 48 h after cells were treated with OxyHb. SUL enhanced the activity of the Nrf2-ARE pathway and suppressed cytokine release. CONCLUSIONS: Our results indicate that the Nrf2-ARE pathway was activated in OxyHb-induced VSMCs. SUL suppressed cytokine release via the activation of the Nrf2-ARE pathway in OxyHb-induced VSMCs.

Purine analogues compared with mesalamine or 5-ASA for the prevention of postoperative recurrence in Crohn's disease: a meta-analysis.

Objective: To use a meta-analysis approach to evaluate the efficacy and safety of purine analogues, azathioprine (AZA) and 6-mercaptopurine (6-MP), in the prevention of postoperative recurrence of Crohn's disease (CD), as compared with mesalamine or 5-aminosalicylic acid (5-ASA). Methods: The Pubmed, Cochrane Library, and Embase literature databases were searched for relevant studies with the key words "azathioprine", "6-mercaptopurine", "purine analogue", "mesalamine", or "5-ASA". The efficacy and safety of purine analogues in the retrieved randomized controlled trials (RCTs) were evaluated with RevMan 5.0.25 (The Cochrane Collaboration, Oxford, England) and STATA 12.0 (Stata Corporation, College Station, TX, USA). The outcome measures of AZA and 6-MP, compared to mesalamine and 5-ASA (control arms), were: clinical recurrence, endoscopic recurrence, and adverse event rates. Results: Five RCTs, comprised of 429 patients, were analyzed. The effect of purine analogues for preventing clinical recurrence for year 1 and 2 were similar to controls (year 1: n = 390; recurrence rate: 18.6% vs. 20.9%; RR: 0.88, 95% CI: 0.60-1.30, p = 0.53; year 2: n = 270; recurrence rate: 29.9% vs. 38.2%; RR: 0.76, 95% CI: 0.55-1.05, p = 0.10). In contrast, purine analogues were more effective than controls in preventing severe endoscopic recurrence (i2-4) for year 1 (n = 289; 32.4% vs. 46.1%; RR: 0.71, 95% CI: 0.53-0.94, p = 0.02). However, purine analogues were associated with more adverse events leading to drug withdrawal than the controls (20.1% vs. 7.9%; RR: 2.57, 95% CI: 1.47-4.51, p = 0.0010). Conclusion: Purine analogues are more effective than controls in preventing endoscopic postoperative recurrence in CD, but are associated with more adverse events.

Clinical and molecular characteristics of immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome in China.

Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare X-linked recessive disorder causing life-threatening systemic autoimmunity because of immunodysregulation. The FOXP3 gene had been reported as the responsible gene, which was critical for the functions of CD4(+) CD25(+) FOXP3(+) regulatory T cells (Tregs) and maintenance of peripheral immunologic tolerance. So far, no IPEX patients with definite mutations in the FOXP3 gene had been reported in China. In this study, the genotypes and phenotypes were investigated in three IPEX infants from three unrelated Chinese families. Patient 1 (P1) presented with a classical clinical phenotype, whose mutation was a novel frameshift insertion in exon 11, led to the complete abrogation of Tregs. Patient 2 (P2) showed incomplete IPEX phenotype. He carried a missense mutation in exon 11 with slightly increased frequency of Tregs, whereas Patient 3 (P3) presented with a relatively mild classical phenotype and had a previously reported missense mutation in exon 10 with decreased frequency of Tregs. We firstly report three Chinese IPEX patients with definite mutations of FOXP3 gene. Our study indicated the potential correlation between the genotype and the phenotype of IPEX, which was different from the previous reports.

DUSP22 promotes senescence of HS-1 skin cancer cells through triggering MAPK signaling pathway.

The article "DUSP22 promotes senescence of HS-1 skin cancer cells through triggering MAPK signaling pathway, by X.-D. Zhao, C. Huang, R.-X. Wang, S.-A. Wang, published in Eur Rev Med Pharmacol Sci 2018; 22 (22): 7819-7825-DOI: 10.26355/eurrev_201811_16406-PMID: 30536326" has been withdrawn from the authors due to substantial deficiency in the experimental design. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/16406.

[Intravenous immunoglobulin replacement therapy in 114 cases of congenital agammaglobulinemia].

Objective: To analyze the clinical characteristics of congenital agammaglobulinemia and the efficacy of intravenous immunoglobulin (IVIG) replacement therapy for this disease. Methods: The basic characteristics, clinical manifestations, laboratory examinations, and outcomes of 114 patients with congenital agammaglobulinemia diagnosed in Children's Hospital of Chongqing Medical University from January 1988 to April 2020 were retrospectively analyzed. The efficacy of IVIG in improving the clinical symptoms between regular and irregular treatment groups were compared by χ2 test. To explore the clinical characteristics associated with delayed diagnosis and treatment, the patients were also stratified into following subgroups: non-cough, short-term cough and long-term cough groups, chronic lung disease and non-chronic lung disease groups, and arthritis and non-arthritis groups. The age at onset, age at diagnosis, time consumed for diagnosis, initial time of immunoglobulin replacement, dose of IVIG, IgG trough level between the above groups were compared by t test, F test or non-parametric test. Results: All the 114 patients were male, with the onset age of (22±18) months. The age at diagnosis was (89±54) months, time consumed in diagnosis was (63±46) months, and the initial time of immunoglobulin replacement was (75±45) months. A total of 66 patients had been followed up to April 2020, with a follow-up period of (54±41) months. Among these children, 42 (63.6%) received regular infusion, whose monthly IVIG dose was (538±105) mg/kg and IgG trough level was (5.8±1.5) g/L, whereas 24 patients (36.4%) were treated irregularly. There was no significant difference in the improvement rate of fever, cough, sinusitis, diarrhea, otitis media and arthritis between regular and irregular IVIG replacement groups (all P>0.05). Sixty-one out of the 66 patients (92.4%) had fever before IVIG treatment, whose fever episodes were significantly decreased after IVIG treatment (5 (2,12) vs. 0 (0, 1) per year, Z =-6.436, P<0.01). Sixty patients (90.9%) suffered from wet cough before treatment and 36 (54.5%) after treatment. Initial time of immunoglobulin replacement was significantly delayed in the long-term cough (27 cases) and short-term cough groups (9 cases) compared with non-cough group (18 cases) ((97±51) vs. (64±41) vs. (63±42) months, F=3.554, P=0.035). Twenty-nine patients (43.9%) were diagnosed with chronic lung disease, whose initial time of immunoglobulin replacement (103 (75,144) vs. 46 (26,64) months, Z=-4.330, P<0.01), age at diagnosis (103 (75,142) vs. 47 (31,68) months, Z=-3.486, P<0.01), and time consumed in diagnosis (91 (55,129) vs. 29 (10,41) months, Z =-4.386, P<0.01) were significantly later and longer than those in children without chronic lung disease (37 cases). In addition, thirty-two patients(48.5%) were diagnosed with arthritis, whose initial time of immunoglobulin replacement ((98±51) vs. (58±39) months,t=3.420, P=0.001) and time consumed in diagnosis ((74±49) vs. (44±40) months, t=2.600, P=0.010) were also significantly later and longer than those in children without arthritis (34 cases). Conclusions: After immunoglobulin replacement therapy, the clinical symptoms such as fever, sinusitis, diarrhea, and otitis media can be improved more or less. However, long-term wet cough, chronic lung disease, and arthritis are still prominent clinical problems, which could be controlled by standard immunoglobulin replacement therapy in some patients.

[Clinical characteristics and risk factors of deaths in patients with Wiskott-Aldrich syndrome].

Objective: To explore the clinical characteristics and risk factors of pediatric patients with Wiskott-Aldrich syndrome (WAS). Methods: This was a case-control study. Clinical data of 165 cases of pediatric patients with WAS, who visited the Department of Rheumatology, Children's Hospital of Chongqing Medical University between January 2007 and August 2020 were retrospectively analyzed and divided into death group and survival group (control group) according to the prognosis in the follow-up. Two independent samples t-test, Welch approximate t-test, Mann-Whitney U test, Pearson χ² test, Yates corrected χ² test, or Fisher exact probability test were used for comparison between groups. Risk factors were analyzed by multivariate Logistic regression analysis. Results: A total of 165 patients with Wiskott-Aldrich syndrome were enrolled in this study, including 40 cases in the death group and 125 cases in the survival group. The WAS score was (4.1±0.8) score in the death group and (3.1±1.2) score in the survival group. The age was 19 (9, 28) months in the death group and 60 (36,86) in the survival group. The episode rates of recurrent infection and (or) severe infection, intracranial hemorrhage and eczema in the death group were significantly higher than those in the survival group (95.0% (38/40) vs.32.0% (40/125),25.0% (10/40) vs. 2.4% (3/125), 90.0% (36/40) vs. 72.0% (90/125), χ²=48.253, 18.325, 5.440, all P<0.05). Infection (22 cases, 55.0%) and intracerebral hemorrhage (15 cases, 37.5%) were the main causes of death, 3 cases (7.5%) died of severe graft-versus-host disease after transplantation. The Logistic regression model indicated that repeated infection and (or) severe infection and non-use of intravenous immunoglobulin (IVIG) replacement therapy were risk factors for death in Chinese WAS patients (OR values were 8.999 and 2.860, 95% CI were (2.041-39.667) and (1.375-5.950), respectively, all P<0.05). Conclusions: Recurrent and (or) severe infection is the main risk factor of death for WAS patietns. Regular IVIG treatment can improve the survival rate of patients with WAS.

Clinical characteristics and molecular analysis of 21 Chinese children with congenital agammaglobulinemia.

Congenital agammaglobulinemia is a humoral primary immunodeficiency and affected patients have extremely low levels of peripheral B cells and profound deficiency of all immunoglobulin isotypes. Mutations of the Bruton's tyrosine kinase (BTK) gene are responsible for most of the congenital agammaglobulinemia. In this study, the phenotypes of congenital agammaglobulinemia were investigated in 21 male children from 21 unrelated Chinese families. Sixteen different mutations of BTK gene were identified in 18 patients, and three patients did not have BTK gene mutations. Nine mutations had been reported previously including one gross deletion (c.722_2041del), one missense mutation (c.1764G>T), three non-sense mutations (c.194C>A, c.895C>T and c.1821G>A) and four invariant splice-site mutations (c.971+2T>C, c.1481+2T>A, c.1482-2A>G, c.1699-2A>G). Seven novel mutations were identified (c.373_441del, c. 504delG, c.537delC, c.851delA, c.1637G>A, c.1879T>C and c. 1482_1882 del). Ten of the eighteen mutations of BTK gene were located in the TK domain, four in the PH domain, three in the SH3 domain and one spanned the TH, SH3, SH2 and TK domain. Candidate genes of autosomal-recessive agammaglobulinemia, including IGHM, CD79a, CD79b and IGLL1, were screened in three patients without mutations in the BTK gene. A compound heterozygosity mutation in the IGHM gene (c.1956G>A, c.175_176insC) was identified in one patient. The results of our study further support that molecular genetic testing represents an important tool for early confirmed diagnosis of congenital agammaglobulinemia and may allow accurate carrier detection and prenatal diagnosis.