Effects of maternal food restriction on offspring lung extracellular matrix deposition and long term pulmonary function in an experimental rat model

Intrauterine growth restriction (IUGR) increases the risk of respiratory compromise throughout postnatal life. However, the molecular mechanism(s) underlying the respiratory compromise in offspring following IUGR is not known. We hypothesized that IUGR following maternal food restriction (MFR) would affect extracellular matrix deposition in the lung, explaining the long‐term impairment in pulmonary function in the IUGR offspring. Using a well‐established rat model of MFR during gestation to produce IUGR pups, we found that at postnatal day 21, and at 9 months (9M) of age the expression and abundance of elastin and alpha smooth muscle actin (αSMA), two key extracellular matrix proteins, were increased in IUGR lungs when compared to controls (P < 0.05, n = 6), as determined by both Western and immunohistochemistry analyses. Compared to controls, the MFR group showed no significant change in pulmonary resistance at baseline, but did have significantly decreased pulmonary compliance at 9M (P < 0.05 vs. control, n = 5). In addition, MFR lungs exhibited increased responsiveness to methacholine challenge. Furthermore, exposing cultured fetal rat lung fibroblasts to serum deprivation increased the expression of elastin and elastin‐related genes, which was blocked by serum albumin supplementation, suggesting protein deficiency as the predominant mechanism for increased pulmonary elastin deposition in IUGR lungs. We conclude that accompanying the changes in lung function, consistent with bronchial hyperresponsiveness, expression of the key alveolar extracellular matrix proteins elastin and αSMA increased in the IUGR lung, thus providing a potential explanation for the compromised lung function in IUGR offspring. Pediatr Pulmonol. 2012; 47:162–171. © 2011 Wiley Periodicals, Inc.     

Safety and efficacy of AK0529 in respiratory syncytial virus-infected infant patients: A phase 2 proof-of-concept trial

Background

Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality in young children. There is currently no effective therapy available.

Methods

This was a Phase 2 study of the oral RSV fusion protein inhibitor AK0529 in infants aged 1–24 months, hospitalized with RSV infection. In Part 1, patients (n = 24) were randomized 2:1 to receive a single dose of AK0529 up to 4 mg/kg or placebo. In Part 2, patients (n = 48) were randomized 2:1 to receive AK0529 at 0.5, 1, or 2 mg/kg bid or placebo for 5 days. Sparse pharmacokinetic samples were assessed using population pharmacokinetics modelling. Safety, tolerability, viral load, and respiratory signs and symptoms were assessed daily during treatment.

Results

No safety or tolerability signals were detected for AK0529: grade ≥3 treatment-emergent adverse events occurring in 4.1% of patients in AK0529 and 4.2% in placebo groups, respectively, and none led to death or withdrawal from the study. In Part 2, targeted drug exposure was reached with 2 mg/kg bid. A numerically greater reduction in median viral load with 2 mg/kg bid AK0529 than with placebo at 96 h was observed. A −4.0 (95% CI: −4.51, −2.03) median reduction in Wang Respiratory Score from baseline to 96 h was observed in the 2 mg/kg group compared with −2.0 (95% CI: −3.42, −1.82) in the placebo group.

Conclusions

AK0529 was well tolerated in hospitalized RSV-infected infant patients. Treatment with AK0529 2 mg/kg bid was observed to reduce viral load and Wang Respiratory Score.

Clinical Trials Registration

NCT02654171.     

The validity and reliability of the Turkish version of the bipolar depression rating scale

Introduction

Unipolar depression and bipolar depression differ in their clinical presentations, and the conventional depression rating scales fail to capture these differences. Recently, a new scale to rate the severity of depression in bipolar disorder was developed, and this study aims to evaluate the validity and reliability of this scale in a Turkish clinical sample.

Methods

A total of 81 patients (30 males, 51 females) diagnosed with bipolar depression according to the DSM-IV-TR criteria at three different sites in Turkey were interviewed with the Bipolar Depression Rating Scale (BDRS), the Montgomery Asberg Depression Rating Scale, the Young Mania Rating Scale, and the Positive and Negative Syndrome Scale Depression and Excitement subscales. Internal consistency, interrater reliability and concurrent validity of the BDRS were evaluated.

Results

The Turkish version of the BDRS had an acceptable internal consistency (Cronbach’s alpha = 0.786). Moderate to strong correlations between the BDRS, and the MADRS (r = 0.808), and the PANSS-D (r = 0.426) were observed, and the BDRS correlated weakly to moderately with the PANSS-E (r = 0.297), and the YMRS (r = 0.368). The mixed symptom cluster score of the BDRS significantly correlated with the YMRS (r = 0.755), and the PANSS-E (r = 0.712). Exploratory factor analysis showed a three-factor solution. These factors corresponded to somatic depression, psychological depression, and mixed symptoms.

Conclusions

This study shows that the Turkish version of the BDRS is a valid and reliable instrument to measure depressive symptomatology in bipolar disorder. The scale has good internal validity, strong interrater reliability, and moderate to strong correlations with other depression rating scales.     

Comparison of accelerated and rapid schedules for monovalent hepatitis B and combined hepatitis A/B vaccines in children with cancer

The aim of this study was to determine the efficacy of immunization against hepatitis A and B infections with "rapid" or "accelerated" schedules in children with cancer receiving chemotherapy. Fifty-one children were recruited to receive either vaccination schedule, in the "rapid vaccination schedule"; hepatitis B (group I) or combined hepatitis A/B vaccines (group III) were administered at months 0, 1, 2, and 12; in the "accelerated vaccination schedule," hepatitis B (group II) or combined hepatitis A/B (group IV) vaccines were administered on days 0, 7, 21, and 365 intramuscularly. The seroconversion rates at months 1 and 3 were 35.7 and 57.1% in group I and 25 and 18.8% in group II, respectively. Group I developed higher seroconversion rates at month 3. In group III the seroconversion rates for hepatitis B at months 1 and 3 were 54.5 and 60% and in group IV 50 and 70%, respectively. For hepatitis A, the seroconversion rates at months 1 and 3 were 81.8 and 90% in group III and 80 and 88.9% in group IV, respectively. The accelerated vaccination schedule seems to have no advantage in children receiving cancer chemotherapy except for high antibody levels at month 1. In conclusion, the accelerated vaccination schedules are not good choices for cancer patients. The combined hepatitis A/B vaccine is more effective than monovalent vaccine in cancer patients, which probably can be explained by an adjuvant effect of the antigens. The seroconversion of hepatitis A by the combined hepatitis A/B vaccination is very good in cancer patients.     

Maternal serum glycodelin levels in preeclampsia and its relationship with the severity of the disease

Purpose: Preeclampsia, in which insufficient trophoblastic invasion is thought to be one of the underlying mechanisms, is a common pregnancy disorder. Glycodelin is a regulator of immunosuppression, fertilization, implantation, and placentation. Because of its inhibitory effects on trophoblastic activity, trophoblast invasion is disturbed when its levels alter. We aimed to analyze serum glycodelin levels in preeclampsia and evaluate whether it correlates with the severity of disease.

Methods: This is a prospective case–control study conducted in a research and training hospital between March and September 2016. In this study, a total of 55 preeclamptic and 65 healthy pregnants were included. Preeclamptic patients were divided into two subgroups: 25 severe and 30 mild. Maternal serum glycodelin levels were measured using enzyme-linked immunosorbent assay.

Results: Glycodelin levels were higher in preeclamptic group as compared with controls (71.38?±?22.78 versus 42.32?±?12.28?ng/ml, p?p?r?=?0.637 and r?=?0.714, respectively, p?r?=?0.369, p?=?.006 and r?=?0.377, p?=?.005) and proteinuria (r?=?0.342, p?=?.011). Moreover, it was correlated with birth weights and gestational age at delivery (r?=??0.386, p?=?.004 and r?=??0.394, p?=?.003, respectively). The role of glycodelin to diagnose preeclampsia was evaluated by receiver operating curve (ROC) curve. Area under the curve for glycodelin is 0.897 with p?53.64?ng/ml. Moreover, area under the curve for glycodelin to diagnose severe preeclampsia is 0.788 with p?83.97?ng/ml.

Conclusion: Glycodelin may be a promising marker in predicting the presence and severity of preeclampsia.     

A comparison of the efficacy and safety of a half dose of fluticasone propionate with beclamethasone dipropionate and budesonide in childhood asthma.

This study was carried out in an attempt to compare the efficacy and safety of fluticasone propionate (FP) at the half dose of budesonide (BUD) and beclamethasone dipropionate (BD) in childhood asthma. Ninety-six children with moderate to severe asthma (9.6 +/- 2.17 years) whose asthma was already controlled on BUD (n = 52) or BD (n = 44) were recruited into the study. In the first part of the study (the first 12 weeks) each group was followed with three weekly lung function measurements, daily diary records, and peak expiratory flow (PEF) measurements on the initial medication. At the end of 6 weeks, drugs were switched to a half dose of FP, and the subjects were followed for another 6 weeks. Blood samples were obtained for osteocalcin and plasma cortisol levels after each treatment period. In the second part of the study, 50 patients continued to take FP at the half dose of BUD or BD for another 30 weeks. Clinic visits, including lung function and PEF measurements, were conducted every 10 weeks. After 6 weeks of FP treatment, there was a small but statistically significant decrease in FEV1 and FEF(25-75) in both groups (BUD and BD) without any significant obstruction. These mild changes in lung function measurements continued during long-term follow-up. However, there was no statistically significant further decrease in any lung function parameters while receiving FP (visits 3-8) (coefficient = -0.00751 L/day, p = 0.39 for FEF(25-75) and coefficient = -0.00910 L/sec/day, p = 0.055 for FEV1). There were no significant changes in the morning and evening PEF measurements and diurnal PEF variations after 6 weeks of treatment with FP compared with BUD and BD treatments. There were no significant changes in basal cortisol and osteocalcin levels before or after 6 weeks of FP treatment (p > 0.05). The present study concluded that, although FP at the half dose of BUD or BD seems to maintain reasonable control of the disease symptoms, a mild but significant and persistent decrease in lung function parameters may indicate that FP may not be twice as potent as BUD or BD in childhood asthma by evaluation of lung functions. This conclusion must be further verified with long-term studies.