[Efficacy of transcatheter pulmonary valve perforation in neonates with pulmonary atresia with intact ventricular septum].

Objective: To explore the efficacy and safety of transcatheter pulmonary valve perforation in the treatment of neonatal pulmonary atresia with intact ventricular septum (PA-IVS). Methods: The clinical data on surgical treatment and follow-up in 16 patients with PA-IVS who underwent transcatheter pulmonary valve perforation in Women and Children's Hospital, Qingdao University from October 2018 to October 2021 were analyzed retrospectively. The right ventricular systolic pressure and percutaneous oxygen saturation (SpO2) were compared before and after operation. In addition, the SpO2 and echocardiographic data at preoperative and the last follow-up were compared. Comparisons between groups were performed using paired-samples t test. Results: Among the 16 patients (10 males and 6 females) with the age at operation of 19 (14, 26) days, 12 cases underwent transcatheter pulmonary valve perforation successfully, 2 cases were transferred to surgery department for open-heart pulmonary valvulotomy, and the remaining 2 cases were transmitted to surgery department for transthoracic pulmonary valve perforation. The age at operation of the 12 patients who underwent transcatheter pulmonary valve perforation was 18 (14, 27) days, and the weight was (3.6±0.4) kg. The immediate postoperative right ventricular systolic pressure decreased significantly ((57±16) vs. (95±19) mmHg (1 mmHg=0.133 kPa), t=7.49, P<0.001), and the postoperative SpO2 was improved effectively (0.90±0.48 vs.0.75±0.09, t=-5.61, P<0.001). The follow-up time was 22 (7, 33) months for 12 patients who underwent transcatheter pulmonary valve perforation successfully. At the last follow-up, the ratio of right to left ventricular transverse diameter was significantly higher than that before operative (0.55±0.05 vs. 0.45±0.05, t=-3.27,P=0.007). Furthermore, the Z-scores of pulmonary valvular diameter (-0.78±0.23 vs. -1.73±0.56, t=-8.52, P<0.001) and the tricuspid valvular diameter (-0.52±0.12 vs. -1.46±0.38, t=-10.40, P<0.001) were all significantly higher than preoperative data. At last, all the patients achieved biventricular circulation without death or major complications. Conclusion: Transcatheter pulmonary valve perforation is a safe and effective therapy for neonatal PA-IVS, and its curative effect has been confirmed by the medium follow-up data.

[Interim follow-up of fetal cardiac intervention in five fetuses with pulmonary atresia with intact ventricular septum].

Objective: To summarize the interim outcome and right heart development of pulmonary atresia with intact ventricular septum (PA-IVS) in children after fetal cardiac intervention (FCI). Methods: The clinical data of 5 live births underwent FCI from October 2018 to April 2019 in Women and Children's Hospital, Qingdao University were analyzed retrospectively. The development of right ventricle (RV) and tricuspid valve (TV) in uterus after FCI, at birth, the age of 6 months, 1 year and 2 years, and the final outcome were assessed. Results: Five PA-IVS fetuses were included in this study. The first evaluation was performed at 24-26 weeks of gestational age, and the FCI was performed at 26-28 weeks of gestational age. During the follow-up of 6 weeks after FCI, the minimum diameter of tricuspid annulus increased from 0.85 cm to 0.92 cm, and the minimum Z-score of tricuspid annulus decreased from -0.03 to -1.62. The minimum values of TV/mitral valve annular diameter and RV/left ventricular length ratios of all fetuses increased from 0.57, 0.52 to 0.88, 0.82, respectively. The maximum tricuspid regurgitation velocity decreased from 4.60 m/s to 3.64 m/s. No severe hemodynamic change was found in any of the fetuses. All 5 fetuses were born alive. Three cases underwent percutaneous balloon pulmonary valvuloplasty (PBPV) and stent implantation for ductus arteriosus. Two cases received PBPV alone. At follow-up (26 to 32 months), obvious development of TV was observed 6 months to 1 year after birth in 5 cases with the growth rate ranging from 19.64% to 40.00%. Meanwhile, the RV development was relatively slow at 6 months with the growth rate ranging from 9.41% to 21.42%. There were individual differences in RV development at 2 years. The growth and development of all children were equal to healthy children of the same age with the body mass index less than 18.4 kg/m2. At the last follow-up, all children had a transcutaneous oxygen saturation of greater than 0.95, three became biventricular circulation and two had circulation approximation to biventricular circulation with almost closed stent. Conclusions: The findings support the potential of development of right ventricular and tricuspid valve for fetuses with PA-IVS underwent FCI. All fetuses underwent FCI received intervention after birth, and biventricular circulation can be realized finally. The development of right ventricular and tricuspid valve is not proportional. In utero, the right ventricle develops rapidly, and the development of tricuspid valve is more advantageous after birth.

[Fetal cardiac intervention and perioperative management of fetus with hypoplastic right heart syndrome].

Objective: To summarize the experience of perioperative management strategy of fetal pulmonary valvuloplasty (FPV) for hypoplastic right heart syndrome (HRHS). Methods: In the retrospective study of perioperative data, 13 fetuses of HRHS were treated with FPV in Qingdao Women and Children's Hospital from July 2018 to June 2019. Results: (1) The evaluation indexes of the right ventricle in 13 fetuses before FPV: the mean ratio of tricuspid/mitral annulus, right/left ventricular length, pulmonary/aortic annulus, and tricuspid inflow time/cardiac cycle were 0.81±0.04, 0.56±0.14, 0.69±0.06, and 0.35±0.03, respectively. (2) All pregnant mothers underwent general anesthesia. The basic fetal heart rate was (156±12) beats per minutes before FPV, and 9 fetuses showed bradycardia during the operation, and recovered to normal after drug resuscitation. On the first day after FPV, two cases had bradycardia and pregnancy was terminated. The fluctuation of systolic blood pressure of pregnant mother was less than 20%, and there was no significant difference between preoperative and intraoperative pulse pressure [(36.0±5.6) vs (35.8±6.9) mmHg (1 mmHg=0.133 kPa); t=8.102, P=0.951]. (3) All cases of HRHS fetus successfully underwent FPV. The average gestational age was (27.3±0.8) weeks. The average operation time was (23.2±1.0) minutes. The ratio of tricuspid to mitral annulus (t=-2.513, P=0.022) and the ratio of right to left ventricular length (t=-3.373, P=0.003) were significantly improved at 6 weeks postoperatively. Ten fetuses were delivered, and there was no death after early intervention. (4) Of 13 pregnant women, 3 cases were nausea and vomiting on the day of FPV operation, the treatment of the symptoms was improved by tropisetron; one case had tolerable abdominal pain and improved without special treatment. Pregnant women had no major complications such as cardiac failure, abortion and death. (5) Chromosome karyotype analysis and microarray analysis of amniotic fluid was retained during the operation. No typical chromosome abnormality or other abnormal genetic diagnosis was found. Conclusions: FPV colud be used as an effective intervention measure to promote the development of right ventricle in HRHS fetuses. The scientific management of multidisciplinary professional technical team in perioperative period is particularly important to ensure the success of FPV and the safety of pregnant women and fetuses.

[Application of arterial duct stent in ductus-dependent hypoplastic right heart syndrome].

Objective: To summarize the experience of arterial duct (AD) stenting in children with ductus-dependent hypoplastic right heart syndrome (HRHS). Methods: Seven children including 4 cases of pulmonary atresia with intact ventricular septum (PA-IVS) with HRHS and 3 cases of critical pulmonary stenosis (CPS)-IVS with HRHS underwent AD stenting in Qingdao Women and Children's Hospital between January 2012 and January 2019. During the same period, 9 patients of PA-IVS with HRHS received Blalock Taussig (B-T) shunt. Two groups of children on the operation time, hospital stay time, intensive care time and mortality were compared.T test or Mann-Whitney U test was used for comparison between the two groups. Results: There was no significant difference in the age (18 (7-100) vs. 17 (1-142) d, U=31.000, P>0.05) and weight ((3.8±1.1) vs. (3.7±1.3) kg, t=0.272, P>0.05) between the AD stenting group and the B-T group.The operation time ((108±7) vs. (160±49) min, t=-4.304), intensive care time ((3.4±1.0) vs. (6.3±4.5) d, t=-8.692) and total hospitalization time ((10.3±1.0) vs. (26.3±1.0) d, t=-7.822) in the AD stenting group were differed significantly compared with the B-T group (all P<0.05). The transcutaneous oxygen saturation improved significantly (0.723±0.125 vs. 0.926±0.005, t=-6.044, P<0.05) after AD stenting. The diameter of AD stent ranged from 3.5 to 4.0 mm, and the length of AD stent was 16-21 mm. There were no complications such as vascular injury, acute thrombus, catheter spasm and death in the AD stenting group. The mortality of children in the B-T group was 3 in 9 cases. Three cases in the AD stenting group received pulmonary valvulotomy and bilateral Glenn operation at 6, 9 and 9 months after AD stenting, respectively. Conclusions: AD stenting is a feasible, effective, safe and minimally invasive procedure for children with ductus-dependent HRHS. It can even be used as an alternative to B-T shunt.

Correction: Role of integrin-linked kinase in regulating the protein stability of the MUC1-C oncoprotein in pancreatic cancer cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Ba3B10O17Br2: a new barium borate halide with B-O layered structure.

A new barium borate halide, Ba3B10O17Br2, has been obtained. A detailed structural comparison with other barium borate halides suggested that Ba3B10O17Br2 is the first barium borate halide with a B-O layered structure. First-principles theoretical studies were conducted to aid understanding of the electronic structure and optical properties.

[Investigation of pregestational diabetes mellitus in 15 hospitals in Guangdong province].

Objective: To investigate the morbidity, diagnostic profile and perinatal outcome of pregestational diabetes mellitus (PGDM) in 15 hospitals in Guangdong province. Methods: A total of 41 338 women delivered in the 15 hospitals during the 6 months, 195 women with PGDM (PGDM group) and 195 women with normal glucose test result (control group) were recruited from these tertiary hospitals in Guangdong province from January 2016 to June 2016. The morbidity and diagnostic profile of PGDM were analyzed. The complications during pregnancy and perinatal outcomes were compared between the two groups. In the PGDM group, pregnancy outcomes were analyzed in women who used insulin treatment (n=91) and women who did not (n=104). Results: (1) The incidence of PGDM was 0.472%(195/41 338). Diabetes mellitus were diagnosed in 59 women (30.3%, 59/195) before pregnancy, and 136 women (69.7%,136/195) were diagnosed as PGDM after conceptions. Forty-six women (33.8%) were diagnosed by fasting glucose and glycohemoglobin (HbA1c) screening. (2) The maternal age, pre-pregnancy body mass index (BMI) , prenatal BMI, percentage of family history of diabetes, incidence of macrosomia, concentration of low density lipoprotein were significantly higher in PGDM group than those in control group (all P<0.05). Women in PGDM group had significantly higher HbA1c concentration ((6.3±1.3)% vs (5.2±0.4)%) , fasting glucose [(6.3±2.3) vs (4.8±1.1) mmol/L], oral glucose tolerance test (OGTT) -1 h glucose ((12.6±2.9) vs (7.1±1.3) mmol/L) and OGTT-2 h glucose [(12.0±3.0) vs (6.4±1.0) mmol/L] than those in control group (P<0.01). (3) The morbidity of preterm births was significantly higher (11.3% vs 1.0%, P<0.01), and the gestational age at delivery in PGDM group was significantly smaller [(37.6±2.3) vs (39.2±1.2) weeks, P<0.01]. Cesarean delivery rate in the PGDM group (70.8% vs 29.7%) was significantly higher than the control group (P<0.01). There was significantly difference between PGDM group and control in the neonatal male/female ratio (98/97 vs 111/84, P=0.033). The neonatal birth weight in PGDM group was significantly higher ((3 159±700) vs (3 451±423) g, P<0.01) . And the incidence of neonatal hypoglycemia in the PGDM group was higher than the control group (7.7% vs 2.6%, P=0.036). (4) In the PGDM group, women who were treated with insulin had a smaller gestational age at delivery [(36.9±2.9) vs (37.9±2.5) weeks, P<0.01], and the neonates had a higher neonatal ICU (NICU) admission rate (24.2% vs 9.6%, P<0.01). Conclusions: The morbidity of PGDM in the 15 hospitals in Guangdong province is 0.472%. The majority of PGDM was diagnosed during pregnancy; HbA1c and fasting glucose are reliable parameters for PGDM screening. Women with PGDM have obvious family history of diabetes and repeated pregnancy may accelerate the process of diabetes mellitus. Women with PGDM have higher risk for preterm delivery and neonatal hypoglycemia. Unsatisfied glucose control followed by insulin treatment may increase the need for NICU admission.

Role of integrin-linked kinase in regulating the protein stability of the MUC1-C oncoprotein in pancreatic cancer cells.

MUC1-C overexpression has been associated with the progression of pancreatic tumors by promoting the aggressive and metastatic phenotypes. As MUC1 is a STAT3 target gene, STAT3 plays a major role in regulating MUC1-C expression. In this study, we report an alternative mechanism by which integrin-linked kinase (ILK) post-transcriptionally modulates the expression of MUC1-C by maintaining its protein stability in pancreatic cancer cells. We found that ILK acts in concert with STAT3 to facilitate IL-6-mediated upregulation of MUC1-C; ILK depletion was equally effective as STAT3 depletion in abolishing IL-6-induced MUC1-C overexpression without disturbing the phosphorylation or cellular distribution of STAT3. Conversely, ectopic expression of constitutively active ILK increased MUC1-C expression, though this increase was not noted with kinase-dead ILK. This finding suggests the requirement of the kinase activity of ILK in regulating MUC1-C stability, which was confirmed by using the ILK kinase inhibitor T315. Furthermore, our data suggest the involvement of protein kinase C (PKC)δ in mediating the suppressive effect of ILK inhibition on MUC1-C repression. For example, co-immunoprecipitation analysis indicated that ILK depletion-mediated MUC1-C phosphorylation was accompanied by increased phosphorylation of PKCδ at the activation loop Thr-507 and increased binding of PKCδ to MUC1-C. Conversely, ILK overexpression resulted in decreased PKCδ phosphorylation. From a mechanistic perspective, the present finding, together with our recent report that ILK controls the expression of oncogenic KRAS through a regulatory loop, underscores the pivotal role of ILK in promoting pancreatic cancer progression.

Spinal cord injury and Parkinson's disease: a population-based, propensity score-matched, longitudinal follow-up study.

OBJECTIVES: To investigate whether patients with spinal cord injury (SCI) are at an increased risk of developing Parkinson's disease (PD). STUDY DESIGN: A population-based, propensity score-matched, longitudinal follow-up cohort study. SETTING: The study was conducted using the National Health Insurance (NHI) Research Database. METHODS: A total of 10 125 patients with at least 2 ambulatory visits with a diagnosis of SCI in 2001 were enrolled in the SCI group. The non-SCI group comprised 10 125 propensity score-matched patients without SCI. The propensity scores were computed using a logistic regression model that included age, sex, comorbidities and socioeconomic status. The PD-free survival rates of the two groups were estimated using the Kaplan-Meier method. Stratified Cox proportional hazard regression was used to estimate the effect of SCI on subsequent occurrence of PD. RESULTS: During the 3-year follow-up period, 99 subjects in the SCI group and 59 in the non-SCI group developed PD. The hazard ratio of PD for the SCI group compared with the non-SCI group was 1.65 (95% confidence interval 1.16-2.33, P=0.0049). The PD-free survival rate for the SCI group was lower than that for the non-SCI group (P=0.0017). CONCLUSIONS: This study shows that SCI is associated with a subsequent increased risk of PD. Further studies are needed to elucidate the mechanism underlying this association.

A pulmonary tuberculosis outbreak in a long-term care facility.

In long-term care facilities (LTCFs), the elderly are apt to be infected because those with latent tuberculosis infections (LTBIs) are at an increased risk for reactivation and post-primary TB disease. We report an outbreak of TB in staff and residents in a LTCF. An outbreak investigation was conducted after two TB cases were reported from the LTCF. A tuberculin skin test (TST), bacteriological examination and chest radiograph were administered to all facility staff and residents. An outbreak is defined as at least two epidemiologically linked cases that have identical Mycobacterium tuberculosis genotype isolates. This outbreak infected eight residents and one staff member, who were confirmed to have TB in a LTCF between September 2011 and October 2012. Based on the Becker method, the latent and infectious periods were estimated at 223·6 and 55·9 days. Two initial TST-negative resident contacts were diagnosed as TB cases through comprehensive TB screening. Observing elderly people who have a negative TST after TB screening appears to be necessary, given the long latent period for controlling a TB outbreak in a LTCF. It is important to consider providing LTBI treatment for elderly contacts.

Orally active microtubule-targeting agent, MPT0B271, for the treatment of human non-small cell lung cancer, alone and in combination with erlotinib.

Microtubule-binding agents, such as taxanes and vinca alkaloids, are used in the treatment of cancer. The limitations of these treatments, such as resistance to therapy and the need for intravenous administration, have encouraged the development of new agents. MPT0B271 (N-[1-(4-Methoxy-benzenesulfonyl)-2,3-dihydro-1H-indol-7-yl]-1-oxy-isonicotinamide), an orally active microtubule-targeting agent, is a completely synthetic compound that possesses potent anticancer effects in vitro and in vivo. Tubulin polymerization assay and immunofluorescence experiment showed that MPT0B271 caused depolymerization of tubulin at both molecular and cellular levels. MPT0B271 reduced cell growth and viability at nanomolar concentrations in numerous cancer cell lines, including a multidrug-resistant cancer cell line NCI/ADR-RES. Further studies indicated that MPT0B271 is not a substrate of P-glycoprotein (P-gp), as determined by flow cytometric analysis of rhodamine-123 (Rh-123) dye efflux and the calcein acetoxymethyl ester (calcein AM) assay. MPT0B271 also caused G2/M cell-cycle arrest, accompanied by the up-regulation of cyclin B1, p-Thr161 Cdc2/p34, serine/threonine kinases polo-like kinase 1, aurora kinase A and B and the downregulation of Cdc25C and p-Tyr15 Cdc2/p34 protein levels. The appearance of MPM2 and the nuclear translocation of cyclin B1 denoted M phase arrest in MPT0B271-treated cells. Moreover, MPT0B271 induced cell apoptosis in a concentration-dependent manner; it also reduced the expression of Bcl-2, Bcl-xL, and Mcl-1 and increased the cleavage of caspase-3 and -7 and poly (ADP-ribose) polymerase (PARP). Finally, this study demonstrated that MPT0B271 in combination with erlotinib significantly inhibits the growth of the human non-small cell lung cancer A549 cells as compared with erlotinib treatment alone, both in vitro and in vivo. These findings identify MPT0B271 as a promising new tubulin-binding compound for the treatment of various cancers.

The HDAC inhibitor, MPT0E028, enhances erlotinib-induced cell death in EGFR-TKI-resistant NSCLC cells.

Epidermal growth factor receptor (EGFR), which promotes cell survival and division, is found at abnormally high levels on the surface of many cancer cell types, including many cases of non-small cell lung cancer. Erlotinib (Tarceva), an oral small-molecule tyrosine kinase inhibitor, is a so-called targeted drug that inhibits the tyrosine kinase domain of EGFR, and thus targets cancer cells with some specificity while doing less damage to normal cells. However, erlotinib resistance can occur, reducing the efficacy of this treatment. To develop more effective therapeutic interventions by overcoming this resistance problem, we combined the histone deacetylase inhibitor, MPT0E028, with erlotinib in an effort to increase their antitumor effects in erlotinib-resistant lung adenocarcinoma cells. This combined treatment yielded significant growth inhibition, induced the expression of apoptotic proteins (PARP, γH2AX, and caspase-3), increased the levels of acetylated histone H3, and showed synergistic effects in vitro and in vivo. These effects were independent of the mutation status of the genes encoding EGFR or K-Ras. MPT0E028 synergistically blocked key regulators of the EGFR/HER2 signaling pathways, attenuating multiple compensatory pathways (e.g., AKT, extracellular signal-regulated kinase, and c-MET). Our results indicate that this combination therapy might be a promising strategy for facilitating the effects of erlotinib monotherapy by activating various networks. Taken together, our data provide compelling evidence that MPT0E028 has the potential to improve the treatment of heterogeneous and drug-resistant tumors that cannot be controlled with single-target agents.

Dermatomyositis is associated with an increased risk of cardiovascular and cerebrovascular events: a Taiwanese population-based longitudinal follow-up study.

BACKGROUND: While the chronic inflammation related to autoimmune diseases is known to be associated with an increased cardiovascular risk, much less is known about cerebrovascular risks. OBJECTIVES: The present population-based, age- and sex-matched follow-up study was undertaken to investigate the risks of acute myocardial infarction (AMI) and ischaemic stroke in patients with dermatomyositis (DMS). METHODS: In total 907 patients with DMS were enrolled and compared with a non-DMS control group consisting of 4535 age- and sex-matched, randomly sampled subjects without DMS. The AMI-free and ischaemic stroke-free survival curves were generated using the Kaplan-Meier method. Cox proportional hazard regression was used to estimate the DMS-associated risks of AMI and ischaemic stroke. RESULTS: During the 2-year follow-up period, 14 patients with DMS (1.5%) and 18 patients in the non-DMS control group (0.4%) suffered AMIs. The crude hazard ratio (HR) for suffering an AMI in patients with DMS compared with subjects in the non-DMS group was 3.96 [95% confidence interval (CI) 1.97-7.96, P = 0.0001], while the adjusted HR was 3.37 (95% CI 1.67-6.80, P = 0.0007), after taking into account demographic characteristics and cardiovascular comorbidities. During the same follow-up period, 46 patients (5.1%) and 133 subjects in the control group (2.9%) developed ischaemic strokes. The crude HR for developing an ischaemic stroke in patients with DMS compared with subjects in the non-DMS group was 1.78 (95% CI 1.27-2.49, P = 0.0007), and the adjusted HR was 1.67 (95% CI, 1.19-2.34, P = 0.0028). CONCLUSIONS: These findings suggest that DMS is associated with an increased risk of cardiovascular and cerebrovascular events.

Increased risk of trigeminal neuralgia after hypertension: a population-based study.

OBJECTIVE: Very few studies have explored the temporal relationship between hypertension and trigeminal neuralgia (TN). The aim of this population-based follow-up study was to investigate whether hypertension is associated with a higher risk of developing TN. METHODS: A total of 138,492 persons with at least 2 ambulatory visits with the principal diagnosis of hypertension in 2001 were enrolled in the hypertension group. The nonhypertension group consisted of 276,984 age- and sex-matched, randomly sampled subjects without hypertension. The 3-year TN-free survival rate and the cumulative incidence of TN were calculated using the Kaplan-Meier method. Cox proportional hazard regression was used to estimate the hazard ratio of TN. RESULTS: In the hypertension group, 121 patients developed TN during follow-up, while, in the nonhypertension group, 167 subjects developed TN. The crude hazard ratio for the hypertension group was 1.52 (95% confidence interval [CI] 1.20-1.92; p = 0.0005), while, after adjustment for demographic characteristics and medical comorbidities, the adjusted hazard ratio was 1.51 (95% CI 1.19-1.90; p = 0.0006). CONCLUSIONS: This study shows a significantly increased risk of developing TN after hypertension. Further studies are needed to elucidate the underlying mechanism of the association between hypertension and TN.

Laetispicine, an amide alkaloid from Piper laetispicum, presents antidepressant and antinociceptive effects in mice.

In the present work, we studied the effect of laetispicine, an amide alkaloid isolated from the stems of Piper laetispicum (Piperaceae), in forced swimming, open field, acetic acid writhing and formalin tests in KM mice to assess antidepressant and antinociceptive effects. A significant and dose-dependent decrease in the immobility time, as evaluated by the forced swimming test, was observed after laetispicine administration (38.18, 39.79, 58.77 and 67.28% decreased at the doses of 5, 10, 20, 40mg/kg, respectively), suggesting an antidepressant effect. Furthermore, in the open field test, laetispicine at the given doses did not alter the number of crossings and rearing, as compared to controls. Results from writhing and formalin tests showed that laetispicine reduced the number of writhing in mice in a dose-dependent manner, attenuated the licking and spiting time of the injected paw in the first phase of formalin test. The antinociceptive effect of laetispicine was not affected by pre-treatment (i.p.) with naloxone (2mg/kg). In conclusion, we showed that laetispicine possessed significant antidepressant and antinociceptive properties, making this drug potentially useful in depression and pain.