Expression of Eya1 and Six1 is decreased in distal airways of rats with experimental pulmonary hypoplasia

Background/Purpose

Pulmonary hypoplasia (PH) associated with congenital diaphragmatic hernia (CDH) represents one of the major challenges in neonatal intensive care. Eyes absent 1 (Eya1) and sine oculis homebox 1 (Six1) have been identified as essential components of the gene network that regulates foetal lung development. Eya1 and Six1 are expressed in distal epithelial tips of branching airways as well as in surrounding mesenchymal cells, highlighting their important role during branching morphogenesis. Lungs of Eya1^−/− and Six1^−/− knockouts display PH with reduced epithelial branching, appearing to be arrested in the pseudoglandular stage. We hypothesized that Eya1 and Six1 expression is decreased in branching airways of nitrofen-induced PH.

Methods

Time-mated rats received either nitrofen or vehicle on E9.5. Foetal lungs were dissected on E15.5 and divided into control and nitrofen groups, whereas lungs harvested on E18.5 were divided into controls, PH without CDH [PH(−)], and PH with CDH [PH(+)]. Pulmonary gene expression levels of Eya1 and Six1 were analyzed by quantitative real-time PCR. Immunofluorescence staining was performed to investigate Eya1 and Six1 protein expression and localization by confocal laser scanning microscopy (CLSM).

Results

Relative mRNA expression of Eya1 and Six1 was significantly decreased in PH(−) and PH(+) on E18.5 compared to controls. CLSM confirmed markedly diminished immunofluorescence of Eya1 and Six1 in distal airway epithelium as well as in surrounding mesenchymal cells of nitrofen-induced PH on E18.5 compared to controls.

Conclusions

Downregulation of Eya1 and Six1 gene expression in nitrofen-induced PH suggests that decreased Eya1 and Six1 expression during the late pseudoglandular stage may interfere with epithelial branching and distal airway maturation, thus resulting in PH.     

Prenatal retinoic acid increases lipofibroblast expression in hypoplastic rat lungs with experimental congenital diaphragmatic hernia

Background/purpose

Prenatal administration of all-trans retinoic acid (ATRA) has been shown to stimulate alveolarization in nitrofen-induced pulmonary hypoplasia (PH) associated with congenital diaphragmatic hernia (CDH). Lipid-containing interstitial lipofibroblasts (LIFs), characterized by adipocyte differentiation-related protein (ADRP), play a critical role in alveolar development by coordinating lipid homeostasis. Previous studies have demonstrated that ATRA positively affects LIF expression in developing lungs. We hypothesized that pulmonary LIF expression is increased after prenatal ATRA treatment in the nitrofen model of CDH-associated PH.

Methods

Timed-pregnant rats were treated with nitrofen or vehicle on E9.5, followed by injection of ATRA or placebo on E18.5, E19.5, and E20.5. Fetal lungs were dissected on E21.5 and divided into Control + Placebo, Control + ATRA, Nitrofen + Placebo, and Nitrofen + ATRA. Pulmonary gene expression levels of ADRP were analyzed by quantitative real-time polymerase chain reaction, and LIF expression was investigated by ADRP immunohistochemistry, oil-red-O-, and immunofluorescence-double-staining.

Results

Relative mRNA expression of pulmonary ADRP was significantly increased in Nitrofen + ATRA compared to Nitrofen + Placebo (0.31 ± 0.02 vs. 0.08 ± 0.01; P < 0.0001). ADRP immunoreactivity and oil-red-O-staining were markedly increased in alveolar interstitium of Nitrofen + ATRA compared to Nitrofen + Placebo. Immunofluorescence-double-staining confirmed markedly increased LIF expression in alveolar walls of Nitrofen + ATRA compared to Nitrofen + Placebo.

Conclusions

Increased LIF expression after prenatal treatment with ATRA in nitrofen-induced PH suggests that ATRA may have a therapeutic potential in attenuating CDH-associated PH by stimulating alveolar development.     

Fear-avoidance beliefs—a moderator of treatment efficacy in patients with low back pain: a systematic review

Background contextPsychological factors are believed to influence the development of chronic low back pain. To date, it is not known how fear-avoidance beliefs (FABs) influence the treatment efficacy in low back pain.PurposeTo summarize the evidence examining the influence of FABs measured with the Fear-Avoidance Belief Questionnaire or the Tampa Scale of Kinesiophobia on treatment outcomes in patients with low back pain.Study design/settingThis is a systematic review.Patient samplePatients with low back pain.Outcome measuresWork-related outcomes and perceived measures including return to work, pain, and disability.MethodsIn January 2013, the following databases were searched: BIOSIS, CINAHL, Cochrane Library, Embase, OTSeeker, PeDRO, PsycInfo, PubMed/Medline, Scopus, and Web of Science. A hand search of the six most often retrieved journals and a bibliography search completed the search. Study eligibility criteria, participants, and interventions: research studies that included patients with low back pain who participated in randomized controlled trials (RCTs) investigating nonoperative treatment efficacy. Out of 646 records, 78 articles were assessed in full text and 17 RCTs were included. Study quality was high in five studies and moderate in 12 studies.ResultsIn patients with low back pain of up to 6 months duration, high FABs were associated with more pain and/or disability (4 RCTs) and less return to work (3 RCTs) (GRADE high-quality evidence, 831 patients vs. 322 in nonpredictive studies). A decrease in FAB values during treatment was associated with less pain and disability at follow-up (GRADE moderate evidence, 2 RCTs with moderate quality, 242 patients). Interventions that addressed FABs were more effective than control groups based on biomedical concepts (GRADE moderate evidence, 1,051 vs. 227 patients in studies without moderating effects). In chronic patients with LBP, the findings were less consistent. Two studies found baseline FABs to be associated with more pain and disability and less return to work (339 patients), whereas 3 others (832 patients) found none (GRADE low evidence). Heterogeneity of the studies impeded a pooling of the results.ConclusionsEvidence suggests that FABs are associated with poor treatment outcome in patients with LBP of less than 6 months, and thus early treatment, including interventions to reduce FABs, may avoid delayed recovery and chronicity. Patients with high FABs are more likely to improve when FABs are addressed in treatments than when these beliefs are ignored, and treatment strategies should be modified if FABs are present.     

Spondylodiscitis by drug-multiresistant bacteria: a single-center experience of 25 cases

Background contextAlthough the incidence of pyogenic spinal infections is increasing, the ideal treatment of spondylodiscitis is still a controversially discussed issue. Furthermore, the proportion of multiresistant bacteria in spondylodiscitis is increasing, and treatment recommendations or reported results are missing for this especially difficult subset of patients.PurposeThe aim of this study is to evaluate the surgical outcome and the postoperative antibacterial treatment regime.Study designRetrospective case series.Patient samplePatients treated for a spondylodiscitis from multiresistant bacteria at our department between 2006 and 2011.MethodsData were gathered through review of patients' case notes, relevant imaging, and electronic records. Magnetic resonance imaging of the whole spine including gadolinium (Gd)-enhanced T1 sequences and computed tomography scans of the affected regions were obtained in all cases.Outcome measuresC-reactive protein (CRP) and complete blood cell count were analyzed in all cases using routine laboratory techniques. Neurologic deficits were classified according to the American Spinal Injury Association (ASIA) impairment scale.ResultsTwenty-five patients were identified (15 gram-positive and 10 gram-negative drug-multiresistant bacteria). The mean age at presentation was 66 years, and 14 patients were male (56%). All patients presented with pain, and a neurologic deficit was present in 11 (44%) cases. An epidural abscess was found in 11 (44%) cases. At admission, CRP was elevated in all cases with a mean of 13±9.2 mg/dL. The main source of infection was previous spine surgery (36%). All patients in this series underwent surgical debridement of the infection and instrumentation of the spine. Postoperative intravenous antibiotics were administered for 19±8.6 days followed by 3±0.3 months of oral antibiotic therapy. Eradication of the infection was achieved ultimately in all surviving patients. Out of 11 patients with neurologic deficits, 4 had a full recovery, 4 improved incompletely, and 3 remained unchanged after surgery.ConclusionsStaged surgical immobilization and instrumentation and optimal debridement at the interdiscal space and spinal canal is a reliable approach to achieve complete healing of spinal infection with multiresistant bacteria. A period of intravenous antibiotic therapy of 2 to 3 weeks followed by a 3-month oral antibiotic therapy seems appropriate for most cases.     

Mental health outcomes in elderly men with prostate cancer

ObjectiveTo examine the burden of mental health issues (MHI), namely anxiety, depressive disorders, and suicide, in a population-based cohort of older men with localized prostate cancer and to evaluate associations with primary treatment modality.Patients and methodsA total of 50,856 men, who were 65 years of age or older with clinically localized prostate cancer diagnosed between 1992 and 2005 and without a diagnosis of mental illness at baseline, were abstracted from the Surveillance, Epidemiology, and End Results–Medicare database. The primary outcome of interest was the development of MHI (anxiety, major depressive disorder, depressive disorder not elsewhere classified, neurotic depression, adjustment disorder with depressed mood, and suicide) after the diagnosis of prostate cancer.ResultsA total of 10,389 men (20.4%) developed MHI during the study period. Independent risk factors for MHI included age≥75 years (hazard ratio [HR] = 1.29); higher comorbidity (Charlson comorbidity index≥3, HR = 1.63); rural hospital location (HR = 1.14); being single, divorced, or widowed (HR = 1.12); later year of diagnosis (HR = 1.05); and urinary incontinence (HR = 1.47). Black race (HR = 0.79), very high-income status (HR = 0.87), and definitive treatment (radical prostatectomy [RP], HR = 0.79; radiotherapy [RT], HR= 0.85, all P<0.001) predicted a lower risk of MHI. The rates of MHI at 10 years were 29.7%, 29.0%, and 22.6% in men undergoing watchful waiting (WW), RT, and RP, respectively.ConclusionOlder men with localized prostate cancer had a significant burden of MHI. Men treated with RP or RT were at a lower risk of developing MHI, compared with those undergoing WW, with median time to development of MHI being significantly greater in those undergoing RP compared with those undergoing RT or WW.     

Anatomical conditions of the posterior pelvic ring regarding bisegmental transverse sacroiliac screw fixation: a 3D morphometric study of 125 pelvic CT datasets

Introduction

Sacroiliac (SI) screws are used for osteosynthesis in unstable posterior pelvic ring injuries. In the cases of “sacral dysplasia”, in which the elevated upper sacrum does not allow a secure SI screw insertion into the S1 level, the S2 segment must be used to achieve stable fixation. The bone quality of the S2 segment is thinner compared to that of the S1 vertebra and may cause biomechanical weakness. An additional SI screw insertion into the S3 level may improve stability. With respect to the anatomical conditions of the posterior pelvic ring, there have been no anatomical investigations to date regarding SI screw placement into the third sacral segment.

Materials and methods

CT raw datasets from 125 patients (ø59 years, ø172 cm, ø76 kg) were post-processed using Amira 5.2 software to generate 3D pelvic models. A program code implemented in C++ computed a transverse bone corridor for the first, second and third sacral segments for a typical SI screw diameter of 7.3 mm. Volume, sagittal cross-section, iliac entrance area and length of the determined screw corridors were measured. A confidence interval of 95 % was assumed (p < 0.05).

Results

The fully automatic computation revealed a possible transverse insertion for one 7.3-mm screw in the third sacral segment in 30 cases (24 %). The rate (60 %) of feasible S3 screw placements in the cases of sacral dysplasia (n = 25) is significantly higher compared to that (15 %) of “normal” sacra (n = 100). With regard to the existence of transverse iliosacroiliac corridors as a function of sacral position in between the adjacent iliac bone bilaterally, a new classification of three different shape conditions can be made: caudad, intermediate minor, intermediate major, and cephalad sacrum. Gender, age, body height and body weight had no statistically significant influence on either possible screw insertion or on the calculated data of the corridors (p > 0.05).

Conclusion

SI screw insertion into the third sacral level deserves discussion in the cases of sacral dysplasia. Biomechanical and practical utility must be verified.