A preliminary evaluation of limb salvage surgery for osteosarcoma around knee joint

Objective

To evaluate the effectiveness and drawbacks of diversified procedures of limb salvage surgery (LSS), providing a reference of rational surgical criterion of LSS.

Methods

Fifty eight patients with stage IIB extremity osteosarcoma around knee joint area between 1992 and 2002 were studied retrospectively. Among them, 43 patients were treated by LSS followed by reconstruction. Reconstruction approaches included re-implantation of irradiation-devitalized tumor bone (n = 12), autoclaving-devitalized tumor bone (n = 8), prosthetic replacement (n = 11), allograft transplantation (n = 8) and vascularized fibula autograft implantation (n = 4). Amputations were performed in 15 patients. Patients were followed up for 6–16 years.

Results

There were no significant difference between LSS and amputation groups regarding disease free survival and local recurrence rates. The actuarial 5-year continuous disease free survival and local recurrence rate were 30.0% and 25.0% in patients of devitalized LSS group, whereas those were 56.5% and 8.7% in patients of non-devitalized reconstruction group. The complication rate was significantly higher in LSS group compared to amputation group (P = 0.003).

Conclusion

LSS with non-devitalized procedures is the optimal treatment for osteosarcoma around knee joint area. Prosthesis implantation is the preferred option for bone reconstruction following LSS. Prevention and treatment of post-operative complications should be paid more attention to get good long-term outcomes of surgery.     

Intrapulmonary Vascular Dilatation Evaluated by 99mTc-MAA Scintigraphy and Its Association with Portal Hypertension in Schistosomiasis

Background

Portal hypertension is responsible for various complications in patients with schistosomiasis, among them intrapulmonary vascular dilations (IPVD). In cirrhotic patients the presence of IPVD is a sign of poor prognosis, but in patients with hepatosplenic schistosomiasis (HSS) there are no studies assessing the significance of this change. The aim of this study was to evaluate the occurrence of IPVD through ^99mTc-MAA scintigraphy in patients with HSS and its relationship with clinical, laboratory, endoscopic and ultrasound parameters.

Methods

Cross-sectional study evaluating 51 patients with HSS. Patients were diagnosed with IPVD when the brain uptake of ^99mTc-MAA was higher than 6%. Subsequently, they were divided according to presence (G1) or absence (G2) of IPVD and variables were compared between groups.

Results

Overall, 51 patients with mean age of 56±12 years were assessed. IPVD was observed in 31 patients (60%). There was no statistically significant differences between groups when clinical, laboratory and endoscopic parameters were compared. Regarding ultrasound parameters, the splenic vein diameter was smaller in G1 (0.9±0.3 cm) compared to G2 (1.2±0.4 cm), p = 0.029.

Conclusion

In patients with HSS, the occurrence of IPVD by ^99mTc-MAA scintigraphy was high and was associated with lower splenic vein diameter, which can be a mechanism of vascular protection against portal hypertension. However, more studies are needed to determine the clinical significance of the early diagnosis and natural evolution of IPVD in this population.     

Expression of Neuron-Specific Enolase in Multiple Myeloma and Implications for Clinical Diagnosis and Treatment

Objective

To determine the expression of neuron-specific enolase (NSE) in patients with multiple myeloma (MM) and to evaluate its clinical value as a tumor marker and, an indicator of disease progression and treatment efficacy.

Methods

Using electrochemiluminescence immunoassay (ECLIA), we measured the serum levels of NSE in 47 healthy subjects (control group), 25 patients with small cell lung cancer (lung cancer group), and 52 patients with MM (MM group). For the MM group, serum NSE levels were measured and other disease indicators and related symptoms were monitored before and after chemotherapy. The relationship between NSE expression and other MM-related factors was analyzed. In addition, immunohistochemical staining was performed on bone marrow biopsy specimens from patients with MM.

Results

In the control group, serum NSE levels were within the normal range as previously reported, while the lung cancer group and the untreated MM group exhibited NSE levels that were significantly higher relative to the control group (P<0.05). The difference in NSE expression between the lung cancer group and untreated MM group was statistically significant (P<0.05). NSE levels were significantly decreased in MM patients after chemotherapy and were positively correlated with an MM disease index [beta-2 microglobulin (β₂-MG)]. Changes in NSE were not related to the response rate to chemotherapy but rather were correlated with progression-free survival.

Conclusions

Patients with MM may have increased serum NSE levels, and changes in NSE may provide insight into treatment efficacy of chemotherapy and disease progression. Perhaps NSE expression is a viable biomarker for MM and can be a useful reference for the design and adjustment of clinical MM treatment programs.     

Renal Function in Hepatosplenic Schistosomiasis – An Assessment of Renal Tubular Disorders

Background

Renal involvement in Schistosoma mansoni infection is not well studied. The aim of this study is to investigate the occurrence of renal abnormalities in patients with hepatosplenic schistosomiasis (HSS), especially renal tubular disorders.

Methods

This is a cross-sectional study with 20 consecutive patients with HSS followed in a medical center in Maceió, Alagoas, Brazil. Urinary acidification and concentration tests were performed using calcium chloride (CaCl₂) after a 12-h period of water and food deprivation. The biomarker monocyte chemoattractant protein 1 (MCP-1) was quantified in urine. Fractional excretion of sodium (FE_Na+), transtubular potassium gradient (TTKG) and solute-free water reabsorption (TcH₂O) were calculated. The HSS group was compared to a group of 17 healthy volunteers.

Results

Patients'' mean age and gender were similar to controls. Urinary acidification deficit was found in 45% of HSS patients. Urinary osmolality was significantly lower in HSS patients (588±112 vs. 764±165 mOsm/kg, p = 0,001) after a 12-h period of water deprivation. TcH₂O was lower in HSS patients (0.72±0.5 vs. 1.1±0.3, p = 0.04). Urinary concentration deficit was found in 85% of HSS patients. The values of MCP-1 were higher in HSS group than in control group (122±134 vs. 40±28 pg/mg-Cr, p = 0.01) and positively correlated with the values of microalbuminuria and proteinuria.

Conclusions

HSS is associated with important kidney dysfunction. The main abnormalities found were urinary concentrating ability and incomplete distal acidification defect, demonstrating the occurrence of tubular dysfunction. There was also an increase in urinary MCP-1, which appears to be a more sensitive marker of renal damage than urinary albumin excretion rate.     

Increased T Regulatory Cells Are Associated with Adverse Clinical Features and Predict Progression in Multiple Myeloma

Background

Regulatory T (Treg) cells play an important role in the maintenance of immune system homeostasis. Multiple myeloma (MM) is a plasma cell disorder frequently associated with impaired immune cell numbers and functions.

Methods

We analyzed Treg cells in peripheral blood (n = 207) and bone marrow (n = 202) of pre-malignant and malignant MM patients using flow cytometry. Treg cells and their subsets from MM patients and healthy volunteers were functionally evaluated for their suppressive property. A cohort of 25 patients was analyzed for lymphocytes, CD4 T cells and Treg cells before and after treatment with cyclophosphamide, thalidomide plus dexamethasone (CTD).

Results

We found elevated frequencies of Treg cells in newly diagnosed (P<0.01) and relapsed MM patients (P<0.0001) compared to healthy volunteers. Also, Treg subsets including naïve (P = 0.015) and activated (P = 0.036) Treg cells were significantly increased in MM patients compared to healthy volunteers. Functional studies showed that Treg cells and their subsets from both MM and healthy volunteers were similar in their inhibitory function. Significantly increased frequencies of Treg cells were found in MM patients with adverse clinical features such as hypercalcemia (>10 mg/dL), decreased normal plasma cell (≤5%) count and IgA myeloma subtype. We also showed that MM patients with ≥5% of Treg cells had inferior time to progression (TTP) (13 months vs. median not reached; P = 0.013). Furthermore, we demonstrated the prognostic value of Treg cells in prediction of TTP by Cox regression analysis (P = 0.045). CTD treatment significantly reduced frequencies of CD4 T cells (P = 0.001) and Treg cells (P = 0.018) but not Treg cells/CD4 T cells ratio compared to pre-treatment.

Conclusions

Our study showed immune deregulation in MM patients which is evidenced by elevated level of functionally active Treg cells and patients with increased Treg cells have higher risk of progression.     

Abnormal Anatomical Connectivity between the Amygdala and Orbitofrontal Cortex in Conduct Disorder

Objective

Previous research suggested that structural and functional abnormalities within the amygdala and orbitofrontal cortex contribute to the pathophysiology of Conduct Disorder (CD). Here, we investigated whether the integrity of the white-matter pathways connecting these regions is abnormal and thus may represent a putative neurobiological marker for CD.

Methods

Diffusion Tensor Imaging (DTI) was used to investigate white-matter microstructural integrity in male adolescents with childhood-onset CD, compared with healthy controls matched in age, sex, intelligence, and socioeconomic status. Two approaches were employed to analyze DTI data: voxel-based morphometry of fractional anisotropy (FA), an index of white-matter integrity, and virtual dissection of white-matter pathways using tractography.

Results

Adolescents with CD displayed higher FA within the right external capsule relative to controls (T = 6.08, P<0.05, Family-Wise Error, whole-brain correction). Tractography analyses showed that FA values within the uncinate fascicle (connecting the amygdala and orbitofrontal cortex) were abnormally increased in individuals with CD relative to controls. This was in contrast with the inferior frontal-occipital fascicle, which showed no significant group differences in FA. The finding of increased FA in the uncinate fascicle remained significant when factoring out the contribution of attention-deficit/hyperactivity disorder symptoms. There were no group differences in the number of streamlines in either of these anatomical tracts.

Conclusions

These results provide evidence that CD is associated with white-matter microstructural abnormalities in the anatomical tract that connects the amygdala and orbitofrontal cortex, the uncinate fascicle. These results implicate abnormal maturation of white-matter pathways which are fundamental in the regulation of emotional behavior in CD.     

Preoperative MRI Findings Predict Two-Year Postoperative Clinical Outcome in Lumbar Spinal Stenosis

Purpose

To study the predictive value of preoperative magnetic resonance imaging (MRI) findings for the two-year postoperative clinical outcome in lumbar spinal stenosis (LSS).

Methods

84 patients (mean age 63±11 years, male 43%) with symptoms severe enough to indicate LSS surgery were included in this prospective observational single-center study. Preoperative MRI of the lumbar spine was performed with a 1.5-T unit. The imaging protocol conformed to the requirements of the American College of Radiology for the performance of MRI of the adult spine. Visual and quantitative assessment of MRI was performed by one experienced neuroradiologist. At the two-year postoperative follow-up, functional ability was assessed with the Oswestry Disability Index (ODI 0–100%) and treadmill test (0–1000 m), pain symptoms with the overall Visual Analogue Scale (VAS 0–100 mm), and specific low back pain (LBP) and specific leg pain (LP) separately with a numeric rating scale from 0–10 (NRS-11). Satisfaction with the surgical outcome was also assessed.

Results

Preoperative severe central stenosis predicted postoperatively lower LP, LBP, and VAS when compared in patients with moderate central stenosis (p<0.05). Moreover, severe stenosis predicted higher postoperative satisfaction (p = 0.029). Preoperative scoliosis predicted an impaired outcome in the ODI (p = 0.031) and lowered the walking distance in the treadmill test (p = 0.001). The preoperative finding of only one stenotic level in visual assessment predicted less postoperative LBP when compared with patients having 2 or more stenotic levels (p = 0.026). No significant differences were detected between quantitative measurements and the patient outcome.

Conclusions

Routine preoperative lumbar spine MRI can predict the patient outcome in a two-year follow up in patients with LSS surgery. Severe central stenosis and one-level central stenosis are predictors of good outcome. Preoperative finding of scoliosis may indicate worse functional ability.     

Effect of Hypotensive Resuscitation with a Novel Combination of Fluids in a Rabbit Model of Uncontrolled Hemorrhagic Shock

Objective

The aim of this study was to compare the effects of hypotensive and normotensive resuscitation with a novel combination of fluids via lactate Ringer’s solution (LRS), 6% hydroxyethyl starch 130/0.4 solution (HES), and 7.5% hypertonic saline solution (HSS) at early stage of uncontrolled hemorrhagic shock (UHS) before hemostasis.

Methods

New Zealand white rabbits (n = 32) underwent UHS by transecting the splenic parenchyma, followed by blood withdrawal via the femoral artery to target mean arterial pressure (MAP) of 40–45 mmHg. Animals were distributed randomly into 4 groups (n = 8): in group Sham, sham operation was performed; in group HS, UHS was untreated; in group HS-HR, UHS was treated by hypotensive resuscitation with HSS and LRS+HES (ratio of 2∶1) to MAP of 50–55 mmHg; in group HS-NR, UHS was treated by normotensive resuscitation with HSS and LRS+HES (ratio of 2∶1) to MAP of 75–80 mmHg. Outcomes of hemodynamics, inflammatory and oxidative response, and other metabolic variables were measured and the histopathological studies of heart, lung and kidney were performed at the end of resusucitation.

Results

Hypotensive resuscitation with the novel combination of fluids for UHS rabbits decreased blood loss, maintained better stabilization of hemodynamics, and resulted in relatively higher hematocrit and platelet count, superior outcomes of blood gas, and lower plasma lactate concentration. Besides, hypotensive resuscitation attenuated the inflammatory and oxidative response significantly in UHS rabbits.

Conclusion

Hypotensive resuscitation with the novel combination of fluids via HSS and LRS+HES (ratio of 2∶1) has an effective treatment at early stage of UHS before hemostasis.     

The Associations of Uric Acid,Cardiovascular and All-Cause Mortality in Peritoneal Dialysis Patients

Aims

To investigate whether uric acid (UA) is an independent predictor of cardiovascular (CV) and all-cause mortality in peritoneal dialysis (PD) patients after controlling for recognized CV risk factors.

Methods

A total of 2264 patients on chronic PD were collected from seven centers affiliated with the Socioeconomic Status on the Outcome of Peritoneal Dialysis (SSOP) Study. All demographic and laboratory data were recorded at baseline. Multivariate Cox regression was used to calculate the hazard ratio (HR) of CV and all-cause mortality with adjustments for recognized traditional and uremia-related CV factors.

Results

There were no significant differences in baseline characteristics between patients with (n = 2193) and without (n = 71) UA measured. Each 1 mg/dL of increase in UA was associated with higher all-cause mortality with 1.05(1.00∼1.10) of HR and higher CV mortality with 1.12 (1.05∼1.20) of HR after adjusting for age, gender and center size. The highest gender-specific tertile of UA predicted higher all-cause mortality with 1.23(1.00∼1.52) of HR and higher CV mortality with 1.69 (1.21∼2.38) of HR after adjusting for age, gender and center size. The predictive value of UA was stronger in patients younger than 65 years without CV disease or diabetes at baseline. The prognostic value of UA as both continuous and categorical variable weakened or disappeared after further adjusted for uremia-related and traditional CV risk factors.

Conclusions

The prognostic value of UA in CV and all-cause mortality was weak in PD patients generally, which was confounded by uremia-related and traditional CV risk factors.     

Anterior Segment Optical Coherence Tomography for the Quantitative Evaluation of the Anterior Segment Following Boston Keratoprosthesis

Objective

To quantitatively evaluate the anterior segment using anterior segment optical coherence tomography (AS-OCT) following Boston keratoprosthesis type 1.

Methods

A retrospective study consisted of AS-OCT imaging at a single time point postoperatively in 52 eyes. Main outcomes measures include anatomical and functional anterior chamber depth (ACD), angle (ACA) and peripheral and proximal synechiae.

Results

The mean time point of imaging was 19.3 months postoperatively. Average anatomical and functional ACD was 2.0 and 0.21 mm respectively, and mean ACA ranged from 2.5° to 6.14° in representative meridians. An average of 8.7 clock hours of angle closure was observed in the 25 eyes in which all meridians were imaged. The majority of eyes showed peripheral (86.5%) and proximal (67.3%) synechiae.

Conclusions

AS-OCT is a useful tool for quantitative evaluation of anterior segment and angle after keratoprosthesis, which is otherwise poorly visible. The majority of eyes showed shallow ACD, extensive angle closure and synechiae formation.     

Increased Levels of C-C Chemokine RANTES in Asbestos Exposed Workers and in Malignant Mesothelioma Patients from an Hyperendemic Area

Background

Asbestos-induced mesothelial inflammatory processes are thought to be the basic mechanisms underlying Malignant Mesothelioma (MM) development. Detection of MM often occurs at late stage due to the long and unpredictable latent period and the low incidence in asbestos exposed individuals. The aim of this study was to investigate early immunological biomarkers to characterize the prognostic profile of a possible asbestos-induced disease, in subjects from a MM hyperendemic area.

Methods

The Luminex Multiplex Panel Technology was used for the simultaneous measurement of serum levels of a large panel of 47 analytes, including cytokines and growth factors, from workers previously exposed to asbestos (Asb-workers), asbestos-induced MM patients and healthy subjects. In addition, to explore the influence on serum cytokines profile exerted by SV40 infection, a cofactor in MM development, a quantitative real time PCR was performed for sequences detection in the N-terminal and intronic regions of the SV40 Tag gene. Statistical analysis was done by means of the Mann-Whitney test and the Kruskall-Wallis test for variance analysis.

Results

A variety of 25 cytokines linked to pulmonary inflammation and tumor development were found significantly associated with Asb-workers and MM patients compared with healthy controls. A specific pattern of cytokines were found highly expressed in Asb-workers: IFN-alpha (p<0.05), EOTAXIN (p<0.01), RANTES (p<0.001), and in MM patients: IL-12(p40), IL-3, IL-1 alpha, MCP-3, beta-NGF, TNF-beta, RANTES (p<0.001). Notably, the chemokine RANTES measured the highest serum level showing an increased gradient of concentration from healthy subjects to Asb-workers and MM patients (p<0.001), independently of SV40 infection.

Conclusion

This study shows that, in subjects from an hyperendemic area for MM, the C-C chemokine RANTES is associated with the exposure to asbestos fibres. If validated in larger samples, this factor could have the potential to be a critical biomarker for MM prognosis as recently reported for breast tumor.     

Maintenance Therapy with Immunomodulatory Drugs after Autologous Stem Cell Transplantation in Patients with Multiple Myeloma: A Meta-Analysis of Randomized Controlled Trials

Background

Although high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) has been confirmed to result in longer remission time than conventional chemotherapy, multiple myeloma (MM) remains incurable. Post-ASCT maintenance is considered as a strategy for obtaining durable remissions and preventing tumor progression. Randomized controlled trials (RCTs) studying maintenance therapy with immunomodulatory drugs (IMiDs) after ASCT have shown some valuable survival improvements. This meta-analysis of RCTs therefore assesses the effect of post-ASCT IMiDs maintenance on MM patients.

Methods

We performed a meta-analysis to evaluate the impact of IMiDs (thalidomide or lenalidomide) as post-ASCT maintenance therapy on the survival of newly diagnosed MM patients. The outcomes for this meta-analysis were progression-free survival (PFS) and overall survival (OS).

Results

Eight RCTs enrolling 3514 patients were included for analysis. An obvious improvement in Os (hazard ratio [HR] 0.75) and a significant PFS advantage (HR 0.58) with post-ASCT IMiDs maintenance was revealed. Thalidomide maintenance after ASCT can result in significant benefit in Os (HR 0.72), particularly combined with corticosteroids (HR 0.66).

Conclusions

MM patients after ASCT have a significant overall survival benefit with IMiDs maintenance. IMiDs maintenance was justified for MM patients who received HDT with ASCT.     

Identification of Novel Autoantibodies for Detection of Malignant Mesothelioma

Background

The malignant mesothelioma (MM) survival rate has been hampered by the lack of efficient and accurate early detection methods. The immune system may detect the early changes of tumor progression by responding with tumor-associated autoantibody production. Hence, in this study, we translated the humoral immune response to cancer proteins into a potential blood test for MM.

Methodology/Principal Findings

A T7 phage MM cDNA library was constructed using MM tumor tissues and biopanned for tumor-associated antigens (TAAs) using pooled MM patient and normal serum samples. About 1008 individual phage TAA clones from the biopanned library were subjected to protein microarray construction and tested with 53 MM and 52 control serum samples as a training group. Nine candidate autoantibody markers were selected from the training group using Tclass system and logistic regression statistical analysis, which achieved 94.3% sensitivity and 90.4% specificity with an AUC value of 0.89 in receiver operating characteristic analysis. The classifier was further evaluated with 50 patient and 50 normal serum samples as an independent blind validation, and the sensitivity of 86.0% and the specificity of 86.0% were obtained with an AUC of 0.82. Sequencing and BLASTN analysis of the classifier revealed that five of these nine candidate markers were found to have strong homology to cancer related proteins (PDIA6, MEG3, SDCCAG3, IGHG3, IGHG1).

Conclusions/Significance

Our results indicated that using a panel of 9 autoantibody markers presented a promising accuracy for MM detection. Although the results need further validation in high-risk groups, they provided the potentials in developing a serum-based assay for MM diagnosis.     

Applicability of Preoperative Nuclear Morphometry to Evaluating Risk for Cervical Lymph Node Metastasis in Oral Squamous Cell Carcinoma

Background

We previously reported the utility of preoperative nuclear morphometry for evaluating risk for cervical lymph node metastases in tongue squamous cell carcinoma. The risk for lymph node metastasis in oral squamous cell carcinoma, however, is known to differ depending on the anatomical site of the primary tumor, such as the tongue, gingiva, mouth floor, and buccal mucosa. In this study, we evaluated the applicability of this morphometric technique to evaluating the risk for cervical lymph node metastasis in oral squamous cell carcinoma.

Methods

A digital image system was used to measure the mean nuclear area, mean nuclear perimeter, nuclear circular rate, ratio of nuclear length to width (aspect ratio), and nuclear area coefficient of variation (NACV). Relationships between these parameters and nodal status were evaluated by t-test and logistic regression analysis.

Results

Eighty-eight cases of squamous cell carcinoma (52 of the tongue, 25 of the gingiva, 4 of the buccal mucosa, and 7 of the mouth floor) were included: 46 with positive node classification and 42 with negative node classification. Nuclear area and perimeter were significantly larger in node-positive cases than in node-negative cases; however, there were no significant differences in circular rate, aspect ratio, or NACV. We derived two risk models based on the results of multivariate analysis: Model 1, which identified age and mean nuclear area and Model 2, which identified age and mean nuclear perimeter. It should be noted that primary tumor site was not associated the pN-positive status. There were no significant differences in pathological nodal status by aspect ratio, NACV, or primary tumor site.

Conclusion

Our method of preoperative nuclear morphometry may contribute valuable information to evaluations of the risk for lymph node metastasis in oral squamous cell carcinoma.     

Extreme phenotypic variation in Cetraria aculeata (lichenized Ascomycota): adaptation or incidental modification?

Background and Aims

Phenotypic variability is a successful strategy in lichens for colonizing different habitats. Vagrancy has been reported as a specific adaptation for lichens living in steppe habitats around the world. Among the facultatively vagrant species, the cosmopolitan Cetraria aculeata apparently forms extremely modified vagrant thalli in steppe habitats of Central Spain. The aim of this study was to investigate whether these changes are phenotypic plasticity (a single genotype producing different phenotypes), by characterizing the anatomical and ultrastructural changes observed in vagrant morphs, and measuring differences in ecophysiological performance.

Methods

Specimens of vagrant and attached populations of C. aculeata were collected on the steppes of Central Spain. The fungal internal transcribed spacer (ITS), glyceraldehyde-3-phosphate dehydrogenase (GPD) and the large sub-unit of the mitochondrial ribosomal DNA (mtLSUm), and the algal ITS and actin were studied within a population genetics framework. Semi-thin and ultrathin sections were analysed by means of optical, scanning electron and transmission electron microscopy. Gas exchange and chlorophyll fluorescence were used to compare the physiological performance of both morphs.

Key Results and Conclusions

Vagrant and attached morphs share multilocus haplotypes which may indicate that they belong to the same species in spite of their completely different anatomy. However, differentiation tests suggested that vagrant specimens do not represent a random sub-set of the surrounding population. The morphological differences were related to anatomical and ultrastructural differences. Large intercalary growth rates of thalli after the loss of the basal–apical thallus polarity may be the cause of the increased growth shown by vagrant specimens. The anatomical and morphological changes lead to greater duration of ecophysiological activity in vagrant specimens. Although the anatomical and physiological changes could be chance effects, the genetic differentiation between vagrant and attached sub-populations and the higher biomass of the former show fitness effects and adaptation to dry environmental conditions in steppe habitats.     

Family and Neighbourhood Socioeconomic Inequalities in Childhood Trajectories of BMI and Overweight: Longitudinal Study of Australian Children

Background

Socioeconomic inequalities in longitudinal patterning of childhood overweight could cause marked differentials in total burden by adulthood. This study aims to determine timing and strength of the association between socioeconomic status (SES) and children’s body mass index (BMI) in the pre- and primary school years, and to examine socioeconomic differences in overweight trajectories across childhood.

Methods

Participants were 4949 children from the Longitudinal Study of Australian Children. BMI was measured at four biennial waves starting at age 4–5 years in 2004. Developmental trajectories of childhood overweight were identified with latent class analyses. Composite variables of family and neighbourhood SES were used.

Results

Socioeconomic differences in mean BMI z-scores already present at age 4–5 more than doubled by age 10–11 years, reflecting decreasing mean BMI among advantaged rather than increasing means among disadvantaged children. Latent class analysis identified children with ‘stable normal weight’ (68%), and with ‘persistent’ (15%), ‘late-onset’ (14%), and ‘resolving’ overweight (3%). Risks of persistent and late-onset childhood overweight were highest among low SES families (e.g. most disadvantaged quintile: OR_persistent = 2.51, 95%CI: 1.83–3.43), and only partly explained by birth weight and parental overweight. Relationships with neighbourhood SES were weaker and attenuated fully on adjustment for family SES. No socioeconomic gradient was observed for resolving overweight.

Conclusions

Childhood has become the critical period when socioeconomic inequalities in overweight emerge and strengthen. Although targeting disadvantaged children with early overweight must be a top priority, the presence of childhood overweight even among less-disadvantaged families suggests only whole-society approaches will eliminate overweight-associated morbidity.     

The Burden of Eclampsia: Results from a Multicenter Study on Surveillance of Severe Maternal Morbidity in Brazil

Objective

Maternal mortality (MM) is a core indicator of disparities in women’s rights. The study of Near Miss cases is strategic to identifying the breakdowns in obstetrical care. In absolute numbers, both MM and occurrence of eclampsia are rare events. We aim to assess the obstetric care indicators and main predictors for severe maternal outcome from eclampsia (SMO: maternal death plus maternal near miss).

Methods

Secondary analysis of a multicenter, cross-sectional study, including 27 centers from all geographic regions of Brazil, from 2009 to 2010. 426 cases of eclampsia were identified and classified according to the outcomes: SMO and non-SMO. We classified facilities as coming from low- and high-income regions and calculated the WHO’s obstetric health indicators. SPSS and Stata softwares were used to calculate the prevalence ratios (PR) and respective 95% confidence interval (CI) to assess maternal characteristics, clinical and obstetrical history, and access to health services as predictors for SMO, subsequently correlating them with the corresponding perinatal outcomes, also applying multiple regression analysis (adjusted for cluster effect).

Results

Prevalence of and mortality indexes for eclampsia in higher and lower income regions were 0.2%/0.8% and 8.1%/22%, respectively. Difficulties in access to health care showed that ICU admission (_adjPR 3.61; 95% CI 1.77–7.35) and inadequate monitoring (_adjPR 2.31; 95% CI 1.48–3.59) were associated with SMO.

Conclusions

Morbidity and mortality associated with eclampsia were high in Brazil, especially in lower income regions. Promoting quality maternal health care and improving the availability of obstetric emergency care are essential actions to relieve the burden of eclampsia.     

TGF-β Inhibition Restores Terminal Osteoblast Differentiation to Suppress Myeloma Growth

Background

Multiple myeloma (MM) expands almost exclusively in the bone marrow and generates devastating bone lesions, in which bone formation is impaired and osteoclastic bone resorption is enhanced. TGF-β, a potent inhibitor of terminal osteoblast (OB) differentiation, is abundantly deposited in the bone matrix, and released and activated by the enhanced bone resorption in MM. The present study was therefore undertaken to clarify the role of TGF-β and its inhibition in bone formation and tumor growth in MM.

Methodology/Principal Findings

TGF-β suppressed OB differentiation from bone marrow stromal cells and MC3T3-E1 preosteoblastic cells, and also inhibited adipogenesis from C3H10T1/2 immature mesenchymal cells, suggesting differentiation arrest by TGF-β. Inhibitors for a TGF-β type I receptor kinase, SB431542 and Ki26894, potently enhanced OB differentiation from bone marrow stromal cells as well as MC3T3-E1 cells. The TGF-β inhibition was able to restore OB differentiation suppressed by MM cell conditioned medium as well as bone marrow plasma from MM patients. Interestingly, TGF-β inhibition expedited OB differentiation in parallel with suppression of MM cell growth. The anti-MM activity was elaborated exclusively by terminally differentiated OBs, which potentiated the cytotoxic effects of melphalan and dexamethasone on MM cells. Furthermore, TGF-β inhibition was able to suppress MM cell growth within the bone marrow while preventing bone destruction in MM-bearing animal models.

Conclusions/Significance

The present study demonstrates that TGF-β inhibition releases stromal cells from their differentiation arrest by MM and facilitates the formation of terminally differentiated OBs, and that terminally differentiated OBs inhibit MM cell growth and survival and enhance the susceptibility of MM cells to anti-MM agents to overcome the drug resistance mediated by stromal cells. Therefore, TGF-β appears to be an important therapeutic target in MM bone lesions.