Journal of negative results in biomedicine最新文献

Background: Osteoporosis, characterized by low bone mineral density (BMD) and high bone fracture risk, is prevalent in Thai menopausal women. Genetic factors are known to play a key role in BMD. Low density lipoprotein receptor-related protein 5 (LRP5), a co-receptor in the Wnt/beta-catenin pathway, is involved in many aspects of bone biology. As coding single nucleotide polymorphisms (cSNPs) of LRP5, including A1330V (rs3736228), and Asian-related Q89R (rs41494349) and N740N (rs2306862), are associated with lowered BMD, this study aimed to determine the relationship between these LRP5 polymorphisms and BMD in 277 Thai menopausal women.

Results: Only rs3736228 deviated from the Hardy-Weinberg equilibrium of allele frequency (p = 0.022). The median, range and p value for the BMD related to each SNP parameter were compared (Mann-Whitney U test). Significant differences were observed between wild-type and risk alleles for both rs3736228 (total radial, p = 0.011; and radial 33, p = 0.001) and rs2306862 (radial 33: p = 0.015) SNPs, with no significant difference for rs41494349 SNP. Linkage disequilibrium was strong for both rs3736228 and rs2306862 SNPs. Haplotype analysis identified high CC frequency in both normal and osteopenia/osteoporosis groups, with a significant odds ratio for carrying the TT haplotype; however, this was non-significant after adjusting for age. Multivariate binary logistic regression analysis performed for rs3736228 showed that individuals with a body mass index <25 kg/m(2) had an increased risk of osteoporosis for each decade, but the polymorphism had no effect.

Conclusions: This study did not identify LRP5 polymorphisms as a risk factor for osteoporosis in Thai menopausal women. Further studies with larger sample sizes are needed to further clarify the role of LRP5 as a genetic determinant of osteoporosis.

Virtual screening is used in biomedical research to predict the binding affinity of a large set of small organic molecules to protein receptor targets. This report shows the development and evaluation of a novel yet straightforward attempt to improve this ranking in receptor-based molecular docking using a receptor-decoy strategy. This strategy includes defining a decoy binding site on the receptor and adjusting the ranking of the true binding-site virtual screen based on the decoy-site screen. The results show that by docking against a receptor-decoy site with Autodock Vina, improved Receiver Operator Characteristic Enrichment (ROCE) was achieved for 5 out of fifteen receptor targets investigated, when up to 15 % of a decoy site rank list was considered. No improved enrichment was seen for 7 targets, while for 3 targets the ROCE was reduced. The extent to which this strategy can effectively improve ligand prediction is dependent on the target receptor investigated.

Background: We aimed to ascertain if Gastrokine 1 mRNA in the sera of patients with gastric cancer might be an informative biomarker for the disease.

Results: Analysis of GKN1 mRNA in serum samples from healthy individuals (n = 23) and from patients with diagnosis of gastric cancer (n = 16), performed by using absolute quantification based on standard curve method, did not show any significative statistical difference between the two unpaired group of individuals.

Conclusions: Our preliminary results did not confirm GKN1 as a potential biomarker for gastric cancer.

Background: It has been suggested that mindfulness is a protective factor that buffers individuals from experiencing severe posttraumatic stress following exposure to a trauma. We aimed to examine the association between dispositional (trait) mindfulness and posttraumatic stress in individuals who had been exposed to the trauma of a natural disaster.

Method: A disaster group (n = 25) consisting of Norwegian tourists who survived the 2004 South East Asian tsunami at a location with high mortality rates was recruited. Dispositional mindfulness and posttraumatic stress were measured with the Five-Facet Mindfulness Questionnaire and the Impact of Event Scale-Revised Version, respectively.

Results: There was no significant association between mindfulness and posttraumatic stress. Moreover, there were no significant associations between posttraumatic stress and the mindfulness sub-facets of observing, acting with awareness, non-judging, and non-reacting. However, there was a significant positive correlation between the descriptive factor of mindfulness and IES-R total. There were no significant linear correlations between the five sub-facets of mindfulness and the three categories of posttraumatic symptoms, intrusion, avoidance and hyper-arousal.

Conclusions: Our findings do not indicate a relationship between dispositional mindfulness and posttraumatic stress levels after exposure to a trauma, except for the descriptive sub-facet of mindfulness and here the correlation is positive and not negative as would be expected if mindfulness is a protective factor for posttraumatic stress. Future studies should investigate the relationship between mindfulness and posttraumatic stress while accounting for factors such as trauma history, type of trauma, and individual differences in traumatic stress reactions.

Background: Patients admitted to emergency departments with traumatic brain injury (TBI) are commonly being treated with oral anticoagulants. In contrast to patients without anticoagulant medication, no guidelines, scores or recommendations exist for the management of mild traumatic brain injury in these patients. We therefore tested whether age as one of the high risk factors of the Canadian head CT rule is applicable to a patient population on oral anticoagulants.

Methods: This cross-sectional analysis included all patients with mild TBI and concomitant oral anticoagulant therapy admitted to the Emergency Department, Inselspital Bern, Switzerland, from November 2009 to October 2014 (n = 200). Using a logistic regression model, two groups of patients with mild TBI on oral anticoagulant therapy were compared - those with and those without intracranial haemorrhage.

Results: There was no significant difference in age between the patient groups with (n = 86) and without (n = 114) intracranial haemorrhage (p = 0.078). In univariate logistic regression, GCS (OR = 0.419 (0.258; 0.680)) and thromboembolic event as reason for anticoagulant therapy (OR = 0.486 (0.257; 0.918)) were significantly associated with intracranial haemorrhage in patients with mild TBI and anticoagulation (all p < 0.05). However, there was no association with age (p = 0.078, OR = 1.024 (0.997; 1.051)), the type of accident or additional medication with acetylsalicylic acid or clopidogrel ((both p > 0.05; 0.552 (0.139; 2.202) and 0.256 (0.029; 2.237), respectively).

Conclusion: Our study found no association between age and intracranial bleeding. Therefore, until further risk factors are identified, diagnostic imaging with CCT remains necessary for mild TBI patients on oral anticoagulation of all ages, especially those with therapeutic anticoagulation because of thromboembolic events.

SLC4A3 has been shown to cause retinal degeneration in a genetically engineered knockout mouse, and in a naturally occurring form of canine progressive retinal atrophy considered to be the equivalent of retinitis pigmentosa in humans (RP). This study was undertaken to investigate if SLC4A3 coding variants were implicated in human retinal degeneration. SLC4A3 exons were amplified and sequenced in 200 patients with autosomal recessive retinal degeneration who had no known molecular diagnosis for their condition, which included 197 unrelated individuals with suspected RP and three individuals with other forms of retinal disease. Three rare variants were identified that were predicted to be potentially pathogenic, however each variant was heterozygous in a single patient and therefore not considered disease-causing in isolation. Of these three variants, SNP-3 was the rarest, with an allele frequency of 7.06 x 10(-5) (>46,000 exomes from the ExAC database). In conclusion, no compound heterozygous or homozygous potentially pathogenic variants were identified that would account for recessive RP or retinal degeneration in this cohort, however the possibility remains that the rare variants identified could be acting with as yet undiscovered mutations in introns or regulatory regions. SLC4A3 remains an excellent candidate gene for human retinal degeneration, and with the advent of whole exome and whole genome sequencing of cohorts of molecularly unsolved patients with syndromic and non-syndromic forms of retinal degeneration, SLC4A3 may yet be implicated in human disease.

Background: Selective glucocorticoid receptor modulators (SEGRMs) comprise a novel class of drugs promising both reduced side effects and similar pharmacological potency relative to glucocorticoids, which presently serve as the only clinical treatment for many otologic disorders. In the first otologic SEGRM experiment in an animal model of noise trauma, we compare the effects of Compound A (a SEGRM) and dexamethasone (potent glucocorticoid).

Methods: Forty adult guinea pigs received experimental treatment once daily for ten days. The animals were divided into four cohorts based on the treatment received: Compound A (1 mg/kg or 3 mg/kg), dexamethasone (1 mg/kg) as gold standard, or water as negative control. After five applications, animals were exposed to broadband noise (8-16 kHz) at 115 dB for three hours. Hearing thresholds were determined by recording auditory brainstem responses to clicks and noise bursts (1-32 kHz) and were assessed a week prior to and immediately after exposure, as well as on days 1, 3, 7, 14, 21, and 28. Cochleae were prepared as whole-mounts or embedded and sectioned for histological analysis.

Results: Relative to the control treatments, Compound A failed to preserve auditory thresholds post-noise exposure with statistical significance. Histological analyses confirm the physiological result.

Conclusion: The present findings suggest that Compound A does not have substantial otoprotective capacities in a noise trauma model.

Background: Evidence suggests that vagal nerve activity may play a role in sleep apnea induction. In anesthetized rats, dronabinol, a cannabinoid (CB) receptor agonist, injected into the nodose ganglia attenuates reflex apnea and increases genioglossus activity, and reflex apnea attenuation is blocked by systemic pre-treatment with cannabinoid type 1 and/or type 2 receptor antagonists. However, it is unclear whether dronabinol has similar effects in the central nervous system; CB receptors are widely distributed in the brain, especially on neuronal circuitry important for respiration and upper airway activation. Here, we examine the effects of intracerebroventricular (ICV) injection of dronabinol on serotonin (5-HT)-induced apnea.

Methods: Adult male Sprague-Dawley rats were anesthetized and instrumented with bilateral electrodes to monitor genioglossi EMG and with a piezoelectric strain gauge to monitor respiratory pattern. Serotonin was intravenously infused into a femoral vein to induce reflex apnea. After baseline recordings, rats were placed in a stereotaxic apparatus. A unilateral osteotomy was made to allow access for injection to the right lateral ventricle, and the dura were carefully removed. Dronabinol (100, 10, 1, or 0.1 μg/3 μl DMSO) or control (3 μl DMSO) was injected into the right lateral ventricle and 5-HT infusion was repeated. Data (mean ± SEM) were analyzed using a mixed model analysis with a repeated/fixed measure.

Results: There was no main effect in 5-HT-induced apnea or breath duration, or in breath instability, between ICV dronabinol injected and ICV vehicle control injected groups. Moreover, there was no main effect in phasic or tonic genioglossus activity between ICV dronabinol injected and ICV vehicle control injected groups.

Conclusion: Our data show that ICV injection of dronabinol did not decrease 5-HT-induced apneas, and did not increase genioglossus activity. This in contrast to published results of dronabinol's effect on apnea via the vagus nerve. Our results suggest that the effects of dronabinol on reflex apneas are peripherally mediated via suppression of vagal nerve activity.

Background: Toll-like receptors (TLRs) are involved in a variety of cardiovascular disorders, including septic cardiomyopathy, ischemia/reperfusion, heart failure, and cardiac hypertrophy. Previous research revealed that TLR4 promotes cardiac hypertrophy in vivo. Therefore, we investigated whether TLR2 is also involved in the development of cardiac hypertrophy.

Methods: Tlr2 deficient and wild type mice were subjected to transverse aortic constriction (TAC) or sham operation procedure. Left ventricular, heart and lung weights as well as hemodynamic parameters were determined after 3, 14 or 28 days. Real-time RT PCR was used to evaluate left ventricular gene expression. Protein content was determined via ELISA.

Results: TAC increased systolic left ventricular pressure, contraction and relaxations velocities as well as the heart weight in both genotypes. Tlr2 deficiency significantly enhanced cardiac hypertrophy after 14 and 28 days of TAC. Left ventricular end-diastolic pressure and heart rate increased in Tlr2(-/-) TAC mice only. Fourteen days of TAC led to a significant elevation of ANP, BNP, TGFβ and TLR4 mRNA levels in Tlr2(-/-) left ventricular tissue.

Conclusion: These data suggest that Tlr2 deficiency may promote the development of cardiac hypertrophy and ventricular remodeling after transverse aortic constriction.