Introduction

To systematically review the relationship between low pH in intervertebral discs and low back pain.

Material and methods

Electronic database (PubMed, ISI Web of Science, Cochrane Library, CINAHL, AMED, and China National Knowledge Infrastructure) searches and hand searching of conference proceedings were conducted. Two authors independently evaluated the methodological quality and abstracted relevant data according to standard criteria. Then the experimental methods and samples employed in the finally retrieved articles were assessed.

Results

We first retrieved 136 articles regarding pain and pH, and only 16 of them were mainly about low back pain and pH. Finally, 7 articles met our expectation to focus on the pathogenesis of low back pain caused by pH. In these 7 studies the authors held three opinions to explain the pathogenesis of low back pain in relation to low pH. First, low pH caused by lactate stimulates the muscle and increases the muscle tension, which causes low back pain. Second, low pH stimulates the nerve roots and produces the feeling of pain. Third, low pH changes the matrix metabolism, leading to neuronal death and low back pain.

Conclusions

In this systematic review we propose a new hypothesis that low back pain may be caused by low pH based on the previous literature. Further experimental studies are necessary to verify our hypothesis. This hypothesis will promote our understanding of the pathogenesis of low back pain and the development of novel diagnostic and therapeutic approaches for low back pain.

Vanadium compounds were studied during recent years to be considered as a representative of a new class of nonplatinum metal anticancer agents in combination to its low toxicity. Here, we found a vanadium compound Van-7 as an inhibitor of Topo I other than Topo II using topoisomerase-mediated supercoiled DNA relaxation assay. Agarose gel electrophoresis and comet assay showed that Van-7 treatment did not produce cleavable complexes like HCPT, thereby suggesting that Topo I inhibition occurred upstream of the relegation step. Further studies revealed that Van-7 inhibited Topo I DNA binding involved in its intercalating DNA. Van-7 did not affect the catalytic activity of DNase I even up to100 μM. Van-7 significantly suppressed the growth of cancer cell lines with IC50 at nanomolar concentrations and arrested cell cycle of A549 cells at G2/M phase. All these results indicate that Van-7 is a potential selective Topo I inhibitor with anticancer activities as a kind of Topo I suppressor, not Topo I poison.

Climate change is affecting and will increasingly influence human health and wellbeing. Children are particularly vulnerable to the impact of climate change. An extensive literature review regarding the impact of climate change on children’s health was conducted in April 2012 by searching electronic databases PubMed, Scopus, ProQuest, ScienceDirect, and Web of Science, as well as relevant websites, such as IPCC and WHO. Climate change affects children’s health through increased air pollution, more weather-related disasters, more frequent and intense heat waves, decreased water quality and quantity, food shortage and greater exposure to toxicants. As a result, children experience greater risk of mental disorders, malnutrition, infectious diseases, allergic diseases and respiratory diseases. Mitigation measures like reducing carbon pollution emissions, and adaptation measures such as early warning systems and post-disaster counseling are strongly needed. Future health research directions should focus on: (1) identifying whether climate change impacts on children will be modified by gender, age and socioeconomic status; (2) refining outcome measures of children’s vulnerability to climate change; (3) projecting children’s disease burden under climate change scenarios; (4) exploring children’s disease burden related to climate change in low-income countries; and (5) identifying the most cost-effective mitigation and adaptation actions from a children’s health perspective.

A new species of the genus Microtendipes Kieffer, 1915, Microtendipes zhejiangensis sp.n., is described, and its morphological description and illustrations are given. A catalogue of the genus in Oriental Region is provided and a key to the males of Microtendipes in the Oriental Region is given.

Background

Understanding the spatial distribution of suicide can inform the planning, implementation and evaluation of suicide prevention activity. This study explored spatial clusters of suicide in Australia, and investigated likely socio-demographic determinants of these clusters.

Methods

National suicide and population data at a statistical local area (SLA) level were obtained from the Australian Bureau of Statistics for the period of 1999 to 2003. Standardised mortality ratios (SMR) were calculated at the SLA level, and Geographic Information System (GIS) techniques were applied to investigate the geographical distribution of suicides and detect clusters of high risk in Australia.

Results

Male suicide incidence was relatively high in the northeast of Australia, and parts of the east coast, central and southeast inland, compared with the national average. Among the total male population and males aged 15 to 34, Mornington Shire had the whole or a part of primary high risk cluster for suicide, followed by the Bathurst-Melville area, one of the secondary clusters in the north coastal area of the Northern Territory. Other secondary clusters changed with the selection of cluster radius and age group. For males aged 35 to 54 years, only one cluster in the east of the country was identified. There was only one significant female suicide cluster near Melbourne while other SLAs had very few female suicide cases and were not identified as clusters. Male suicide clusters had a higher proportion of Indigenous population and lower median socio-economic index for area (SEIFA) than the national average, but their shapes changed with selection of maximum cluster radii setting.

Conclusion

This study found high suicide risk clusters at the SLA level in Australia, which appeared to be associated with lower median socio-economic status and higher proportion of Indigenous population. Future suicide prevention programs should focus on these high risk areas.

Two new species of Bryophaenocladius Thienemann, 1934, Bryophaenocladius mucronatus sp. n. and Bryophaenocladius parictericus sp. n. are described and illustrated as males. A key to male imagines of the genus from China is presented.

Chemical investigation of the ethanol extract of soft coral Sinularia sp. collected from the South China Sea led to the isolation of three new polyoxygenated sterols, (3S,23R,24S)-ergost-5-ene-3β,23α,25-triol (1), (24S)-ergostane-6-acetate-3β,5α,6β,25-tetraol (2), (24S)-ergostane-6-acetate-3β,6β,12β,25-tetraol (3) together with three known ones (4–6). The structures, including relative configurations of the new compounds (1–3), were elucidated by detailed analysis of spectroscopic data (IR, UV, NMR, MS) and by comparison with related reported compounds. The absolute configuration of 1 was further determined by modified Mosher’s method. Compound 5 exhibited moderate cytotoxicity against K562 cell line with an IC50 value of 3.18 μM, but also displayed strong lethality toward the brine shrimp Artemia salina with a LC50 value of 0.96 μM.

We report here a simple and rapid method by which to screen one bead one compound libraries for highly specific ligands to cell surface proteins such as G protein-coupled receptors. This protocol, which harvests “hits” in a cell-based binding screen magnetically, eliminates the most tedious aspects of previously published bead screening techniques and allows millions of different compounds to be screened rapidly and cheaply. The method is demonstrated using the Orexin Receptor 1, which resulted in the isolation of moderate potency antagonists.

The genus Dicrotendipes Kieffer from China, including 8 species, is reviewed. Two new species, Dicrotendipes nudus sp. n. and Dicrotendipes saetanumerosus sp. n. are described and the male imagines are illustrated; the record of Dicrotendipes fusconotatus (Kieffer) is the first for China. A key to the males of Dicrotendipes in China is given.

Bone morphogenetic protein (BMP) signaling pathway plays important roles in urinary tract development although the detailed regulation of its activity in this process remains unclear. Here we report that follistatin-like 1 (Fstl1), encoding a secreted extracellular glycoprotein, is expressed in developing ureter and antagonizes BMP signaling activity. Mouse embryos carrying disrupted Fstl1 gene displayed prominent hydroureter arising from proximal segment and ureterovesical junction defects. These defects were associated with significant reduction in ureteric epithelial cell proliferation at E15.5 and E16.5 as well as absence of subepithelial ureteral mesenchymal cells in the urinary tract at E16.5 and E18.5. At the molecular level, increased BMP signaling was found in Fstl1 deficient ureters, indicated by elevated pSmad1/5/8 activity. In vitro study also indicated that Fstl1 can directly bind to ALK6 which is specifically expressed in ureteric epithelial cells in developing ureter. Furthermore, Sonic hedgehog (SHH) signaling, which is crucial for differentiation of ureteral subepithelial cell proliferation, was also impaired in Fstl1-/- ureter. Altogether, our data suggest that Fstl1 is essential in maintaining normal ureter development by antagonizing BMP signaling.

Principal component analysis (PCA) is one of the key techniques in functional data analysis. One important feature of functional PCA is that there is a need for smoothing or regularizing of the estimated principal component curves. Silverman's method for smoothed functional principal component analysis is an important approach in situation where the sample curves are fully observed due to its theoretical and practical advantages. However, lack of knowledge about the theoretical properties of this method makes it difficult to generalize it to the situation where the sample curves are only observed at discrete time points. In this paper, we first establish the existence of the solutions of the successive optimization problems in this method. We then provide upper bounds for the bias parts of the estimation errors for both eigenvalues and eigenfunctions. We also prove functional central limit theorems for the variation parts of the estimation errors. As a corollary, we give the convergence rates of the estimations for eigenvalues and eigenfunctions, where these rates depend on both the sample size and the smoothing parameters. Under some conditions on the convergence rates of the smoothing parameters, we can prove the asymptotic normalities of the estimations.

The robustness of image features is a very important consideration in quantitative image analysis. The objective of this paper is to investigate the robustness of a range of image texture features using hematoxylin stained breast tissue microarray slides which are assessed while simulating different imaging challenges including out of focus, changes in magnification and variations in illumination, noise, compression, distortion, and rotation. We employed five texture analysis methods and tested them while introducing all of the challenges listed above. The texture features that were evaluated include co-occurrence matrix, center-symmetric auto-correlation, texture feature coding method, local binary pattern, and texton. Due to the independence of each transformation and texture descriptor, a network structured combination was proposed and deployed on the Rutgers private cloud. The experiments utilized 20 randomly selected tissue microarray cores. All the combinations of the image transformations and deformations are calculated, and the whole feature extraction procedure was completed in 70 minutes using a cloud equipped with 20 nodes. Center-symmetric auto-correlation outperforms all the other four texture descriptors but also requires the longest computational time. It is roughly 10 times slower than local binary pattern and texton. From a speed perspective, both the local binary pattern and texton features provided excellent performance for classification and content-based image retrieval.

Background

Cancer stem cells (CSCs) play an important role in cancer initiation, relapse and metastasis. To date, no specific medicine has been found to target CSCs as they are resistant to most conventional therapies and proliferate indefinitely. Compound Kushen Injection (CKI) has been widely used for cancer patients with remarkable therapeutic effects in Chinese clinical settings for many years. This study focused on whether CKI could inhibit MCF-7 SP cells in vitro and in vivo.

Methods

The analysis of CKI on SP population and the main genes of Wnt signaling pathway were studied first. Then we studied the tumorigenicity of SP cells and the effects of CKI on SP cells in vivo. The mice inoculated with 10,000 SP cells were randomly divided into three groups (6 in each group) and treated with CKI, cisplatin and saline (as a control) respectively for 7 weeks. The tumor formation rates of each group were compared. The main genes and proteins of the Wnt signaling pathway were analyzed by RT-PCR and western blot.

Results

CKI suppressed the size of SP population (approximately 90%), and down-regulated the main genes of Wnt signaling pathway. We also determined that MCF-7 SP cells were more tumorigenic than non-SP and unsorted cells. The Wnt signaling pathway was up-regulated in tumors derived from SP cells compared with that in tumors from non-SP cells. The tumor formation rate of the CKI Group was 33% (2/6, P < 0.05), and that of Cisplatin Group was 50%(3/6, P < 0.05), whereas that of the Control Group was 100% (6/6).The RT-PCR and western blot results indicated that CKI suppressed tumor growth by down-regulating the Wnt/β-catenin pathway, while cisplatin activated the Wnt/β-catenin pathway and might spare SP cells.

Conclusions

It suggested that CKI may serve as a novel drug targeting cancer stem-like cells, though further studies are recommended.

Arginine-rich peptides and small-molecule intercalating agents utilize distinct molecular mechanisms for RNA recognition. Here, we combined these distinct binding modules in an effort to create conjugate ligands with enhanced affinity and specificity using the bacteriophage λ N peptide/boxB interaction as a model system. We first designed and synthesized a series of peptide-acridine conjugates using portions of the RNA-binding domain of N protein (11- and 22- residue peptide segments), then compared the binding affinity, specificity, salt dependence, and structural properties of the RNA-peptide and RNA-peptide-acridine conjugate complexes using steady-state fluorescence, CD spectroscopy, NMR, and native gel mobility shift assays (GMSA). These analyses revealed that the full-length peptide-acridine conjugate displayed substantially improved RNA-binding affinity (~80-fold; Kd ~ 15 pM) relative to the peptide alone (Kd ~ 1.2 nM). In accordance, we also observed specificity enhancement (~25-fold) as determined by comparing binding of the best conjugate to a cognate λ boxB RNA with that to a noncognate P22 RNA hairpin (80-fold vs. 3.2-fold enhancement). Furthermore, the observed binding enhancement was unique to the full length conjugate with a flexible linker, implying that the structural context of acridine presentation was critical. Taken together, our observations support the idea that peptide- and intercalation-based binding can be combined to create a new class of high-affinity, high-specificity RNA-binding ligands.

Cardiac mitochondria, the main source of energy as well as free radicals, are vital organelles for normal functioning of the heart. Mitochondrial number, structure, turnover and function are regulated by processes such as mitochondrial protein quality control, mitochondrial fusion and fission and mitophagy. Recent studies suggest that abnormal changes in these mitochondrial regulatory processes may contribute to the pathology of heart failure (HF). Here we discuss these processes and their potential as therapeutic targets.

Impaired mitochondrial fusion/fission plays a causal role in neuronal death. This study delineated a PKCδ-related signaling cascade in which excessive mitochondrial fission is induced during oxidative stress. Moreover, a selective peptide inhibitor of PKCδ inhibits impaired mitochondrial fission under these pathological conditions.

Neuronal cell death in a number of neurological disorders is associated with aberrant mitochondrial dynamics and mitochondrial degeneration. However, the triggers for this mitochondrial dysregulation are not known. Here we show excessive mitochondrial fission and mitochondrial structural disarray in brains of hypertensive rats with hypertension-induced brain injury (encephalopathy). We found that activation of protein kinase Cδ (PKCδ) induced aberrant mitochondrial fragmentation and impaired mitochondrial function in cultured SH-SY5Y neuronal cells and in this rat model of hypertension-induced encephalopathy. Immunoprecipitation studies indicate that PKCδ binds Drp1, a major mitochondrial fission protein, and phosphorylates Drp1 at Ser 579, thus increasing mitochondrial fragmentation. Further, we found that Drp1 Ser 579 phosphorylation by PKCδ is associated with Drp1 translocation to the mitochondria under oxidative stress. Importantly, inhibition of PKCδ, using a selective PKCδ peptide inhibitor (δV1-1), reduced mitochondrial fission and fragmentation and conferred neuronal protection in vivo and in culture. Our study suggests that PKCδ activation dysregulates the mitochondrial fission machinery and induces aberrant mitochondrial fission, thus contributing to neurological pathology.

Structurally diverse small molecules, including 5–(2–Benzofuryl)-4-phenyl-1,2,4-triazole-3-thiol (BETT), have been identified via high-throughput screening as activators of caspase-3 in HeLa cell extracts. However, little is known about their mechanism of action. In this study, we investigate how BETT regulates Prothymosin α (ProT), a nuclear protein previously shown to play essential roles in apoptosis. We first showed that Apaf-1 is the direct target protein of BETT. We further demonstrated that BETT relieved ProT-mediated inhibition of apoptosome formation by blocking the interaction between Apaf-1 and ProT. Using Two-dimensional 1H/15N-Heteronuclear Single Quantum Correlation (HSQC) experiments, we were also able to examine the interaction between Apaf-1 and 15N-labeled ProT α. Furthermore, we are able to reconstitute the entire caspase-3 activation pathway using purified ProT, Apaf-1, procaspase-9, procaspase-3, Hsp70, cytochrome c, PHAPI, CAS, and regulatory compounds to mimic stress induced apoptosis in vitro. Together, these studies would lead to novel and specific methods for the prevention, diagnosis and treatment of human cancer.

Background

There has been a lack of investigation into the spatial distribution and clustering of suicide in Australia, where the population density is lower than many countries and varies dramatically among urban, rural and remote areas. This study aims to examine the spatial distribution of suicide at a Local Governmental Area (LGA) level and identify the LGAs with a high relative risk of suicide in Queensland, Australia, using geographical information system (GIS) techniques.

Methods

Data on suicide and demographic variables in each LGA between 1999 and 2003 were acquired from the Australian Bureau of Statistics. An age standardised mortality (ASM) rate for suicide was calculated at the LGA level. GIS techniques were used to examine the geographical difference of suicide across different areas.

Results

Far north and north-eastern Queensland (i.e., Cook and Mornington Shires) had the highest suicide incidence in both genders, while the south-western areas (i.e., Barcoo and Bauhinia Shires) had the lowest incidence in both genders. In different age groups (≤24 years, 25 to 44 years, 45 to 64 years, and ≥65 years), ASM rates of suicide varied with gender at the LGA level. Mornington and six other LGAs with low socioeconomic status in the upper Southeast had significant spatial clusters of high suicide risk.

Conclusions

There was a notable difference in ASM rates of suicide at the LGA level in Queensland. Some LGAs had significant spatial clusters of high suicide risk. The determinants of the geographical difference of suicide should be addressed in future research.

Barrett’s esophagus (BE) and associated adenocarcinoma have emerged as a major health care problem. Endoscopic optical coherence tomography is a microscopic sub-surface imaging technology that has been shown to differentiate tissue layers of the gastrointestinal wall and identify dysplasia in the mucosa, and is proposed as a surveillance tool to aid in management of BE. In this work a computer-aided diagnosis (CAD) system has been demonstrated for classification of dysplasia in Barrett’s esophagus using EOCT. The system is composed of four modules: region of interest segmentation, dysplasia-related image feature extraction, feature selection, and site classification and validation. Multiple feature extraction and classification methods were evaluated and the process of developing the CAD system is described in detail. Use of multiple EOCT images to classify a single site was also investigated. A total of 96 EOCT image-biopsy pairs (63 non-dysplastic, 26 low-grade and 7 high-grade dysplastic biopsy sites) from a previously described clinical study were analyzed using the CAD system, yielding an accuracy of 84% for classification of non-dysplastic vs. dysplastic BE tissue. The results motivate continued development of CAD to potentially enable EOCT surveillance of large surface areas of Barrett’s mucosa to identify dysplasia.

A multispectral camera is capable of imaging a histologic slide at narrow bandwidths over the range of the visible spectrum. While several uses for multispectral imaging (MSI) have been demonstrated in pathology [1, 2], there is no unified consensus over when and how MSI might benefit automated analysis [3, 4]. In this work, we use a linear-algebra framework to investigate the relationship between the spectral image and its standard-image counterpart. The multispectral “cube” is treated as an extension of a traditional image in a high-dimensional color space. The concept of metamers is introduced and used to derive regions of the visible spectrum where MSI may provide an advantage. Furthermore, histological stains which are amenable to analysis by MSI are reported. We show the Commission internationale de l’éclairage (CIE) 1931 transformation from spectrum to color is non-neighborhood preserving. Empirical results are demonstrated on multispectral images of peripheral blood smears.

Background

The seasonality of suicide has long been recognised. However, little is known about the relative importance of socio-environmental factors in the occurrence of suicide in different geographical areas. This study examined the association of climate, socioeconomic and demographic factors with suicide in Queensland, Australia, using a spatiotemporal approach.

Methods

Seasonal data on suicide, demographic variables and socioeconomic indexes for areas in each Local Government Area (LGA) between 1999 and 2003 were acquired from the Australian Bureau of Statistics. Climate data were supplied by the Australian Bureau of Meteorology. A multivariable generalized estimating equation model was used to examine the impact of socio-environmental factors on suicide.

Results

The preliminary data analyses show that far north Queensland had the highest suicide incidence (e.g., Cook and Mornington Shires), while the south-western areas had the lowest incidence (e.g., Barcoo and Bauhinia Shires) in all the seasons. Maximum temperature, unemployment rate, the proportion of Indigenous population and the proportion of population with low individual income were statistically significantly and positively associated with suicide. There were weaker but not significant associations for other variables.

Conclusion

Maximum temperature, the proportion of Indigenous population and unemployment rate appeared to be major determinants of suicide at a LGA level in Queensland.

Objective: To determine whether spinal cord decompression plays a role in neural cell apoptosis after spinal cord injury. Study design: We used an animal model of compressive spinal cord injury with incomplete paraparesis to evaluate neural cell apoptosis after decompression. Apoptosis and cellular damage were assessed by staining with terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate nick-end labelling (TUNEL) and immunostaining for caspase-3, Bcl-2 and Bax. Methods: Experiments were conducted in male Sprague-Dawley rats (n=78) weighing 300~400 g. The spinal cord was compressed posteriorly at T10 level using a custom-made screw for 6 h, 24 h or continuously, followed by decompression by removal of the screw. The rats were sacrificed on Day 1 or 3 or in Week 1 or 4 post-decompression. The spinal cord was removed en bloc and examined at lesion site, rostral site and caudal site (7.5 mm away from the lesion). Results: The numbers of TUNEL-positive cells were significantly lower at the site of decompression on Day 1, and also at the rostral and caudal sites between Day 3 and Week 4 post-decompression, compared with the persistently compressed group. The numbers of cells between Day 1 and Week 4 were immunoreactive to caspase-3 and B-cell lymphoma-2 (Bcl-2)-associated X-protein (Bax), but not to Bcl-2, correlated with those of TUNEL-positive cells. Conclusion: Our results suggest that decompression reduces neural cell apoptosis following spinal cord injury.

MHC class I molecules present a comprehensive mixture of peptides on the cell surface for immune surveillance. The peptides represent the intracellular protein milieu produced by translation of endogenous mRNAs. Unexpectedly, the peptides are encoded not only in conventional AUG initiated translational reading frames but also in alternative cryptic reading frames. Here, we analyzed how ribosomes recognize and use cryptic initiation codons in the mRNA. We find that translation initiation complexes assemble at non-AUG codons but differ from canonical AUG initiation in response to specific inhibitors acting within the peptidyl transferase and decoding centers of the ribosome. Thus, cryptic translation at non-AUG start codons can utilize a distinct initiation mechanism which could be differentially regulated to provide peptides for immune surveillance.

The cellular response to excessive endoplasmic reticulum (ER) stress includes the activation of signaling pathways, which lead to apoptotic cell death. Here we show that treatment of cultured cardiac myocytes with tunicamycin, an agent that induces ER stress, causes the rapid translocation of δPKC to the ER. We further demonstrate that inhibition of δPKC using the δPKC-specific antagonist peptide, δV1-1, reduces tunicamycin-induced apoptotic cell death, and inhibits expression of specific ER stress response markers such as CHOP, GRP78 and phosphorylation of JNK. The physiological importance of δPKC in this event is further supported by our findings that the ER stress response is also induced in hearts subjected to ischemia and reperfusion injury and that this response also involves δPKC translocation to the ER. We found that the levels of the ER chaperone, GRP78, the spliced XBP-1 and the phosphorylation of JNK are all increased following ischemia and reperfusion and that δPKC inhibition by δV1-1 blocks these events. Therefore, ischemia-reperfusion injury induces ER stress in the myocardium in a mechanism that requires δPKC activity. Taken together, our data show for the first time that δPKC activation plays a critical role in the ER stress-mediated response and the resultant cell death.

Hypertensive encephalopathy is a potentially fatal condition associated with cerebral edema and the breakdown of the blood-brain barrier (BBB). The molecular pathways leading to this condition, however, are unknown. We determined the role of δPKC, which is thought to regulate microvascular permeability, in the development of hypertensive encephalopathy using δV1-1 — a selective peptide inhibitor of δPKC. As a model of hypertensive encephalopathy, Dahl salt-sensitive rats were fed an 8% high-salt diet from 6 weeks of age and then were infused s.c. with saline, control TAT peptide, or δV1-1 using osmotic minipumps. The mortality rate and the behavioral symptoms of hypertensive encephalopathy decreased significantly in the δV1-1–treated group relative to the control-treated group, and BBB permeability was reduced by more than 60%. Treatment with δV1-1 was also associated with decreased δPKC accumulation in capillary endothelial cells and in the endfeet of capillary astrocytes, which suggests decreased microvasculature disruption. Treatment with δV1-1 prevented hypertension-induced tight junction disruption associated with BBB breakdown, which suggests that δPKC may specifically act to dysregulate tight junction components. Together, these results suggest that δPKC plays a role in the development of hypertension-induced encephalopathy and may be a therapeutic target for the prevention of BBB disruption.