Incidence and Treatment of Developmental Hip Dysplasia in Mongolia: A Prospective Cohort Study

Background

In Mongolia, adequate early diagnosis and treatment of developmental hip dysplasia (DDH) have been unavailable and its incidence was unknown. We determined the incidence of ultrasonographic DDH in newborns and established adequate procedures for diagnosis and treatment of DDH at the largest maternity hospital in Ulaanbaatar, Mongolia.

Methodology/Principal Findings

During one year (Sept 2010 – Aug 2011) we assessed the hips newborns using ultrasound and Graf’s classification of DDH. 8,356 newborns were screened; median age at screening was 1 day. We identified 14,873 Type 1 (89.0%), 1715 Type 2a (10.3%), 36 Type 2c (0.2%), 70 Type D (0.4%), 14 Type 3 (0.08%), and 4 Type 4 hips (0.02%). Children with Type 1 hips (normal) were discharged. Children with Type 2a hips (physiologically immature) received follow-up ultrasounds at monthly intervals. Children with Type 2c to 4 (DDH; deformed or misaligned hip joint) hips were treated with a Tubingen hip flexion splint and also followed up. The hip abnormalities resolved to mature hips in all children who were followed up. There was no evidence for severe treatment related complications.

Conclusion/Significance

This study suggests that the incidence of DDH in Mongolian neonates is comparable to that in neonates in Europe. Early ultrasound-based assessment and splinting treatment of DDH led to mature hips in all children followed up. Procedures are feasible and will be continued.     

Epidemiological and serological survey of brucellosis in Mongolia by ELISA using sarcosine extracts

Brucellosis is an important zoonosis, and serological surveillance is essential to its control. However, cross-reactions of attenuated live cells of Brucella abortus strain S-19 and B. melitensis strain Rev-1 with Yersinia enterocolitica O9 or vaccinated animal sera interfere with accurate serological diagnosis by the Rose Bengal test (RBT). Therefore, we used ELISA with sarcosine extracts from the virulent B. abortus strain 544 to eliminate false-positives among RBT positive-sera. A total of 697 serum samples were collected in Mongolia from humans and animals in 23 nomadic herds. The herds were classified into three groups as brucellosis-endemic (BE), brucellosis-suspected (BS), or Brucella-vaccinated (BV). The number of 295 animals (43.0%) was positive by RBT, but 206 (69.8%) of these were positive according to ELISA; therefore, 30.2% of the RBT-positive sera were found to be false positives. The false positive samples for RTB represent 4.1%, 27.4%, and 68.2% of the animals from the BE, BS, and BV herds, respectively. In addition, 32% of RBT-positive human sera were also false positives. Thus, our ELISA would be more specific than RTB and useful for epidemiological surveillance for brucellosis.     

Regulation of N-cadherin-based cell-cell interaction by JSAP1 scaffold in PC12h cells

We previously reported that the level of c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1), a scaffold protein for JNK signaling, increases dramatically during nerve growth factor (NGF)-induced differentiation of PC12h cells. In the present study, we investigated the function of JSAP1 during PC12h cell differentiation by knocking down the level of JSAP1. The depletion of JSAP1 caused NGF-treated PC12h cells to form aggregates and impaired their differentiation. The aggregation was not observed in JSAP1-depleted cells that were untreated or treated with epidermal growth factor. Immunocytochemical studies indicated that N-cadherin, but not E-cadherin, was localized to sites of cell-cell contact in the aggregated cells. Furthermore, an inhibitory anti-N-cadherin antibody completely blocked the aggregation. Taken together, these results suggest that JSAP1 regulates cell-cell interactions in PC12h cells specifically in the NGF-induced signaling pathway, and does so by modulating N-cadherin.     

Induction of neuronal death by microglial AGE-albumin: implications for Alzheimer's disease

Advanced glycation end products (AGEs) have long been considered as potent molecules promoting neuronal cell death and contributing to neurodegenerative disorders such as Alzheimer's disease (AD). In this study, we demonstrate that AGE-albumin, the most abundant AGE product in human AD brains, is synthesized in activated microglial cells and secreted into the extracellular space. The rate of AGE-albumin synthesis in human microglial cells is markedly increased by amyloid-β exposure and oxidative stress. Exogenous AGE-albumin upregulates the receptor protein for AGE (RAGE) and augments calcium influx, leading to apoptosis of human primary neurons. In animal experiments, soluble RAGE (sRAGE), pyridoxamine or ALT-711 prevented Aβ-induced neuronal death in rat brains. Collectively, these results provide evidence for a new mechanism by which microglial cells promote death of neuronal cells through synthesis and secretion of AGE-albumin, thereby likely contributing to neurodegenerative diseases such as AD.     

Microglial AGE-Albumin Is Critical in Promoting Alcohol-Induced Neurodegeneration in Rats and Humans

Alcohol is a neurotoxic agent, since long-term heavy ingestion of alcohol can cause various neural diseases including fetal alcohol syndrome, cerebellar degeneracy and alcoholic dementia. However, the molecular mechanisms of alcohol-induced neurotoxicity are still poorly understood despite numerous studies. Thus, we hypothesized that activated microglial cells with elevated AGE-albumin levels play an important role in promoting alcohol-induced neurodegeneration. Our results revealed that microglial activation and neuronal damage were found in the hippocampus and entorhinal cortex following alcohol treatment in a rat model. Increased AGE-albumin synthesis and secretion were also observed in activated microglial cells after alcohol exposure. The expressed levels of receptor for AGE (RAGE)-positive neurons and RAGE-dependent neuronal death were markedly elevated by AGE-albumin through the mitogen activated protein kinase pathway. Treatment with soluble RAGE or AGE inhibitors significantly diminished neuronal damage in the animal model. Furthermore, the levels of activated microglial cells, AGE-albumin and neuronal loss were significantly elevated in human brains from alcoholic indivisuals compared to normal controls. Taken together, our data suggest that increased AGE-albumin from activated microglial cells induces neuronal death, and that efficient regulation of its synthesis and secretion is a therapeutic target for preventing alcohol-induced neurodegeneration.