Study Design. Rat annulus fibrosus (AF) cells were activated with IL-1 with or without ERK inhibition. Factors associated with the anabolic/catabolic balance of the disc were determined.

Objective.

To clarify the role of ERK pathway in AF cells response to IL-1.Summary of Background Data. IL-1 plays an important role in intervertebral disc degeneration (IDD). ERK is an important inflammatory pathway that plays a crucial role in the expression of inflammatory and catabolic genes induced by IL-1 in chondrocytes. However, the role of the ERK pathway in AF cells response to IL-1 has not been fully investigated.Methods. Rat AF cells in monolayer culture were exposed to IL-1, with or without ERK inhibition; RNA was isolated for Real time polymerase chain reaction (RT-PCR) analysis of gene expression, conditioned media analyzed for nitrite, PGE-2 and IL-6, western blot was performed to detect the changes of protein expression.

Results.

ERK specific inhibitor U0126 significantly inhibited IL-1 induced ERK activation. IL-1-dependent upregulation of iNOS, IL-6, Cox-2, MMP-3 and MMP-13 was significantly reduced by ERK inhibition. The decreased gene expression of collagen І, collagen II, collagen IX and IGF-1induced by IL-1was also reversed by U0126. Gene expression of ADAMTS-4, ADAMTS-5 and TGF-β were not affected by IL-1 or ERK inhibition. IL-1 moderately upregulated aggrecan and TIMP-1expression, ERK inhibition had no significant effect on aggrecan expression but decreased TIMP-1 expression in the presence of IL-1. ERK inhibition reversed the changes of protein expression of MMP-3, MMP-13, TIMP-1, Aggrecan and collagen II induced by IL-1. IL-1 induced NO, PGE-2 and IL-6 accumulation were also reduced by ERK inhibition.

Conclusions.

These results suggest that IL-1 induces an imbalance between anabolic and catabolic events in AF cells, ERK inhibition could provide some protection against the adverse effects of IL-1.

PURPOSE OF REVIEW:

Dry eye syndrome (DES) prevalence is large and its relationship with hormonal diseases is becoming clearer, although more complex. This review provides insight to this association as well as clarifying what remains unanswered about how to interpret and treat findings common to both DES and hormonal diseases.

RECENT FINDINGS:

Several sex hormone-related diseases are associated with DES. Hormone replacement therapy to correct such conditions has conflicting outcomes based on epidemiologic studies and clinical trials. Thyroid-associated diseases are frequently involved in DES and must be investigated in cases where the cause of the ocular disease is undetermined. Diabetes mellitus is one of the major causes of DES, whereas correcting the metabolic imbalance minimizes its ocular symptomology. Gene therapy to treat DES-related hormonal diseases is a promising option based on animal studies.

SUMMARY:

Diagnosis and management of hormonal diseases can minimize the ocular surface damage and severity of DES. Clinical care of DES includes patient evaluation of hormonal status. Future research requires clarification of the underlying disease mechanisms and identifying novel strategies to reprogram the endocrine system rather than chronic medication usage.

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a neurodegenerative disorder caused by mutations in the tau gene. Many mutations identified in FTDP-17 have been shown to affect tau exon 10 splicing in vitro, which presumably causes pathologic imbalances in exon 10(-) [3-repeat (3R)] and exon 10(+) [4-repeat (4R)] tau expression and leads to intracellular inclusions of hyperphosphorylated tau in patient brains. However, no reports have investigated this theory using model mice with a tau intronic mutation. Herein, we generated new transgenic mice harboring the tau intron 10 + 16C→T mutation. We prepared a transgene construct containing intronic sequences required for exon 10 splicing in the longest tau isoform cDNA. Although mice bearing the construct without the intronic mutation showed normal developmental changes of the tau isoform from 3R tau to equal amounts of 3R and 4R tau, mice with the mutation showed much higher levels of 4R tau at the adult stage. 4R tau was selectively recovered in insoluble brain fractions in their old age. Furthermore, these mice displayed abnormal tau phosphorylation, synapse loss and dysfunction, memory impairment, glial activation, pretangle formation, and neuronal loss in an age-dependent manner. These findings provide the first evidence in a mouse model that a tau intronic mutation-induced imbalance of 3R and 4R tau could be a cause of tauopathy.

Hypothalamic glutamate (Glu) and gamma-aminobutyric acid (GABA) neurotransmission are involved in the ovarian hormone-induced gonadotropin-releasing hormone (GnRH) / luteinizing hormone (LH) surge in rodents. Studies have shown that reduced Glu and increased γ-GABA in the rostral preoptic area (rPOA) of the hypothalamus, where most activated GnRH neurons are located, play a key role in decreasing the reproductive function of female rats. However, the mechanism underlying the altered balance of these neurotransmitters is poorly understood. In this study we observed a decline in the function of GnRH neurons in the rPOA at the time of GnRH/LH surge in middle-aged intact female mice with regular estrous cycles. In young mice there is an increase of VGLUT2 on proestrus afternoon, which is not observed in middle-aged mice. On the contrary, VGAT levels in young mice decrease at the time of LH surge while increase in the middle-aged mice. Of note, we found that in middle-aged mice at the time of GnRH/LH surge, the phosphorylation of synapsin I at Ser-603 and CaMKIIα was significantly lower than in young mice. These data suggest that in middle-aged mice higher levels of pre-synaptic stores of GABA, lack of the increase of Glu and decreased ability of synaptic vesicle mobilization could account for the imbalance of Glu and GABA in the rPOA, which decrease the activation of GnRH neurons. This article is protected by copyright. All rights reserved.

The healthy intestine is characterized by a low level of oxygen and by the presence of large bacterial communities of obligate anaerobes. Dysbiosis of the gut microbiota has been reported in patients suffering from inflammatory bowel diseases (IBDs), but the mechanisms causing this imbalance remain unknown. Observations have included a decrease in obligate anaerobes of the phylum Firmicutes and an increase in facultative anaerobes, including members of the family Enterobacteriaceae. The shift of bacterial communities from obligate to facultative anaerobes strongly suggests a disruption in anaerobiosis and points to a role for oxygen in intestinal dysbiosis. Proposals to evaluate this hypothesis of a role for oxygen in IBD dysbiosis are provided. If this hypothesis is confirmed, decreasing oxygen in the intestine could open novel means to rebalance the microbiota and could provide novel preventative or therapeutic strategies for IBD patients in whom current treatments are ineffective.

To investigate pathological changes in the epileptogenic foci of children with intractable epilepsy and their clinical significance.Thirty children with intractable epilepsy were included in the study. The epileptogenic foci were surgically resected and pathological changes in the obtained specimens were observed under a light microscope (LM) and a transmission electron microscope (TEM).Under the LM, cortical dysplasia was found in 14 cases (47%), hippocampal sclerosis in 11 cases (37%), dysembryoplastic neuroepithelial tumor in 1 case (3%), ganglioglioma in 1 case (3%), and encephalomalacia in 3 cases (10%). The TEM observation revealed pathological changes in the ultrastructure of the hippocampus and extra-hippocampal cortex, such as changes in the number of synapses and synaptic structure, decrease in neurons and karyopyknosis, swelling and degeneration of astrocytes, and changes in mitochondrial structures.Pathological changes in the hippocampus and extra-hippocampal cortex, especially synaptic remodeling, may be the morphological basis for spontaneous recurrent seizures in children with intractable epilepsy. The pathological changes and epileptiform activity are related to an imbalance between excitatory and inhibitory neurotransmission.

Background:

 After reports of cardiac impairment caused by mitral annuloplasty with rigid rings, several prosthetic rings with semi-rigidity were introduced. The influence of semi-rigid rings on postoperative cardiac function remains unknown. This study compared postoperative cardiac function between patients receiving a semi-rigid prosthetic ring and those receiving a flexible ring or band.

Methods and Results:

 Transthoracic echocardiographic data of 305 patients who underwent mitral valve repair for degenerative mitral regurgitation (227 patients receiving a semi-rigid ring and 78 receiving a flexible ring or band) were retrospectively reviewed. The imbalance in the preoperative characteristics between groups was adjusted with propensity score matching. Left ventricular ejection fraction, end-diastolic dimension, and end-systolic dimension were compared at 1 week, 6 months, and 1 year after surgery. Propensity score matching yielded 68 matched pairs of patients for whom there were few group differences in preoperative covariates. Between patients receiving a semi-rigid ring and those receiving a flexible ring or band in the propensity-matched cohorts, there were no significant differences in ejection fraction (P=0.322), end-diastolic dimension (P=0.576), or end-systolic dimension (P=0.567).

Conclusions:

 There was little difference in the influence on postoperative cardiac function between semi-rigid rings and flexible rings or bands.

OBJECTIVE:

To investigate factors associated with work ability among nursing professionals.

PARTICIPANTS:

They comprised 514 nursing professionals (83.8% of the total number of workers) from a hospital in São Paulo, Brazil.

METHODS:

In 2009, we conducted a cross-sectional study that was a part of a 5-year planned cohort study initiated in 2008. We administered a comprehensive questionnaire to the participants in order to obtain data on their sociodemographic characteristics, lifestyles, and working conditions. The questionnaire also contained the Brazilian versions of the following: the Job Stress Scale (JSS), Effort-Reward Imbalance (ERI) Questionnaire, Work-Related Activities That May Contribute To Job-Related Pain and/or Injury (WRAPI), and Work Ability Index (WAI). The results were analyzed using descriptive, bivariate, and multivariate linear regression analyses.

RESULTS:

On the WAI, 74.9% of the workers obtained a score of over 40 points (score range 7-49); the mean score was 42.3 points (SD=4.5). The final multivariate model showed that lower WAI scores were related to the work-related outcome, which was work injury, and the following individual characteristics and working conditions: body mass index (p=0.001), sex (female; p=0.002), sedentariness (p < 0.001), time in the profession (p=0.005), social support at work (p=0.003), effort-reward ratio (p=0.001), violence at work (p=0.005), WRAPI score (p < 0.001), and work injuries (yes; p=0.001).

CONCLUSIONS:

Various factors were associated with work ability. The results showed that a number of variables should be considered when planning and implementing actions to maintain or improve work ability among nursing professionals.

Schizophrenia is a multi-factorial genetic disease, and it is caused by a combination of different gene polymorphisms and not individual ones, however, its pathogenesis is still unclear. The purpose of this study was explored the association between the -1082G/A, -819T/C, and -592C/A polymorphisms of interleukin-10 (IL-10) in schizophrenia. A total of 659 schizophrenics were recruited from a teaching hospital, whereas 411 healthy non-schizophrenic individuals were recruited from community in the same geographical area. The -1082G/A, -819T/C and -592C/A polymorphisms were genotyped by using PCR-RFLP, direct sequencing and TaqMan(®) SNP assay. Both maximum likelihood method of UNPHASED program and Bayesian method of PHASE software were utilized for haplotypic analysis. An allelic frequency difference was found between the schizophrenics and community controls at -1082G/A polymorphism of IL-10 promoter (χ(2) =4.678, P=0.031). A haplotype of ACA was observed to be associated with schizophrenia after performing UNPHASED, PHASE and multivariate logistic regression analysis (P<0.001; P=0.001). In addition, the persons who carry haplotype ACA of IL-10 promoter SNPs were estimated for 5.789 fold higher risk to develop schizophrenia than controls. We postulated this haplotype association might due to variant-specific effect on IL-10 gene regulation, which leads to imbalance secretion of Th1/Th2 cytokines. Nevertheless, more detailed mechanism needs to be elucidated in further investigations in order to confirm this hypothesis.

The immune balance controlled by T helper 1 (Th1) and T helper 2 (Th2) is crucial for immunoregulation and its imbalance causes various immune diseases including allergic asthma. Therefore, diagnosis of Th1/Th2 balance in autoimmune diseases including asthma is essential for the application of immune balance regulating drugs. Th1/Th2 balance is not only controlled by Th1 cells and Th2 cells, but also by various regulatory factors including regulatory T cells, sexual factor, chemokines, transcription factors, signal transduction pathway (STAT6) etc. From that point of view, conception of "Th1/Th2 balance" resembles the balance of yin and yang which is main concept of Korean traditional medicine for treatment diseases. This article discusses various regulatory factors that influence Th1/Th2. Current research strategies seek to exploit these observations to improve the generation of novel targets for regulating Th1/Th2 balance. The Th1/Th2 balance could be influenced by imunomodulatory drugs (including herbs, prescription and its main components) but this way of therapy needs further evaluation focused on this various factors and synergistic effect.