MicroRNA-Target Identification: A Combinatorial In Silico Approach.

Contemporary computational target prediction tools with their distinctive properties and stringency have been playing a vital role in pursuing putative targets for a solitary miRNA or a subcategory of miRNAs. These tools utilize a defined set of probabilistic algorithms, machine learning techniques, and information of experimentally validated miRNA targets to provide the best selection. However, there are numerous false-positive predictions, and a method to choose an archetypal approach and put the data provided by the prediction tools into context is still lacking. Moreover, sensitivity, specificity, and overall efficiency of a single tool have not yet been achieved. Therefore, a systematic combination of selective online tools combining elementary and advanced factors of miRNA target identification might reinforce the current target prediction regime. The focus of this study was to build a comprehensive workflow by combining six available online tools to facilitate the current understanding of miRNA-target prediction.

Investigation of Effects of Gadolinium-Based Contrast Agents on Uterine Contractility Using Isolated Rat Myometrium.

BACKGROUND: Despite concerns about safety, gadolinium-based contrast agents (GBCAs) are still used for abdominal and pelvic imaging during pregnancy. Researchers have mainly focused on teratogenicity, while very little is known about their possible direct effects on uterine contractility, yet free gadolinium potentially impacts contractility through interaction with calcium channels. PURPOSE: To investigate possible effects of selected GBCAs (namely gadoteridol, gadoversetamide, gadobutrol, gadoterate meglumine, and gadoxetic acid) on the contractility of rat myometrium. STUDY TYPE: In vitro organ bath study. ANIMAL MODEL: Myometria were isolated from adult (10-12 weeks old) Sprague Dawley rats, both pregnant (N = 8) and nonpregnant (N = 36). FIELD STRENGTH/SEQUENCE: NA. ASSESSMENT: Myometrial strips were suspended in tissue bath containing physiological saline and isometric contractions were recorded. GBCAs were added to the tissue bath cumulatively, and their effects on contractility parameters (quantified by amplitude, frequency, and area under contractility curve [AUC]) were evaluated by 10-minute intervals. STATISTICAL TESTS: Normality data, checked by Shapiro-Wilk test, were transformed by arcsine when needed. One- or two-way analysis of variance was performed, where appropriate, followed by Student-Newman-Keuls test. A P value of <0.05 was considered statistically significant. RESULTS: All of the assayed GBCAs elicited some alterations in the myometrial contractility in a concentration-dependent manner. Gadoterate meglumine, gadoxetic acid, and gadoversetamide caused a concentration-dependent significant attenuation in AUC (oxytocin-induced, from 100% during control period to 45.1 ± 9.0% (nonpregnant) and 59.9 ± 8.5% (pregnant), for 90 µM gadoterate meglumine; respectively), and frequency of the spontaneous and oxytocin-induced contractions. Gadobutrol and gadoteridol at highest dose significantly attenuated mean AUC and frequency of oxytocin-induced contractions of nonpregnant myometrium. DATA CONCLUSION: Results from this in vitro study indicate that GBCAs elicit modulation of myometrial contractions at clinically relevant concentrations. These effects may account, at least partially, for the known potential side effects (rare cases of miscarriages and elective abortion) of these agents. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 5.

Genetic Association Analysis Implicates Six MicroRNA-Related SNPs With Increased Risk of Breast Cancer in Australian Caucasian Women.

INTRODUCTION: Breast cancer (BC), a heterogeneous disease, features microRNA-related single nucleotide polymorphisms (miRSNPs) as underlying factors of BC development, thus providing targets for novel diagnostic and therapeutic strategies. This study investigated miRSNPs in BC susceptibility in Australian Caucasian women. PATIENTS AND METHODS: The study population included patients 33 to 80 years of age stratified by molecular subtypes of breast tumors (luminal A, 47.59%), stage (stage I, 36.96%), tumor-type (ductal, 44.95%), grading (intermediate, 35.52%), size (10.1-25 mm, 31.14%), and lymph node (sentinel negative, 38.93%). Sixty-five miRSNPs underwent allelic analysis in two independent case-control cohorts (GU-CCQ-BB, 377 cases and 521 controls; GRC-BC, 267 cases and 201 controls) using a MassARRAY platform. GU-CCQ-BB, GRC-BC, and the combined populations (BC-CA) (644 cases and 722 controls) underwent independent statistical analysis. RESULTS: In the GU-CCQ-BB population, miRSNPs TET2-rs7670522, ESR1-rs2046210, FGFR2-rs1219648, MIR210-rs1062099, HIF1A-rs2057482, and CASC16-rs4784227 were found to be associated with increased BC risk (P ≤ .05). Only ESR1-rs2046210 was also significantly associated (P ≤ .05) when replicated in the GRC-BC and BC-CA populations. No significant association was correlated with BC-clinical features (pathological types and ER/PR/HER2 status); however, MIR210-rs1062099 was found to be significantly associated (P ≤ .05) with age (>50 years) in the GU-CCQ-BB cohort. CONCLUSION: This is the first study to demonstrate the association of MIR210-rs1062099 and TET2-rs7670522 with increased BC risk. Additionally, four previously reported SNPs (ESR1-rs2046210, FGFR2-rs1219648, HIF1A-rs2057482, and CASC16-rs4784227) were confirmed as BC risk variants. Replication and functional studies in larger Caucasian cohorts are necessary to elucidate the role of these miRSNPS in the development of BC.

Regulatory Mechanisms of Epigenetic miRNA Relationships in Human Cancer and Potential as Therapeutic Targets.

Initiation and progression of cancer are under both genetic and epigenetic regulation. Epigenetic modifications including alterations in DNA methylation, RNA and histone modifications can lead to microRNA (miRNA) gene dysregulation and malignant cellular transformation and are hereditary and reversible. miRNAs are small non-coding RNAs which regulate the expression of specific target genes through degradation or inhibition of translation of the target mRNA. miRNAs can target epigenetic modifier enzymes involved in epigenetic modulation, establishing a trilateral regulatory "epi-miR-epi" feedback circuit. The intricate association between miRNAs and the epigenetic architecture is an important feature through which to monitor gene expression profiles in cancer. This review summarises the involvement of epigenetically regulated miRNAs and miRNA-mediated epigenetic modulations in various cancers. In addition, the application of bioinformatics tools to study these networks and the use of therapeutic miRNAs for the treatment of cancer are also reviewed. A comprehensive interpretation of these mechanisms and the interwoven bond between miRNAs and epigenetics is crucial for understanding how the human epigenome is maintained, how aberrant miRNA expression can contribute to tumorigenesis and how knowledge of these factors can be translated into diagnostic and therapeutic tool development.

Are rehabilitation outcomes after severe anoxic brain injury different from severe traumatic brain injury? A matched case-control study.

Many reports have investigated rehabilitation outcomes after a traumatic brain injury (TBI); however, comparably less is known about whether they differ from outcomes of an anoxic brain injury (ABI). Thus, we aimed to compare the rehabilitation outcomes of patients with ABI with control patients who have TBI. Forty participants with ABI and 40 participants with TBI were included in this retrospective study. Participants with ABI were matched with participants with TBI who had similar clinical characteristics such as age, initial Functional Independence Measurement (FIM) score, and duration of coma. FIM and Functional Ambulation Classification (FAC) scores on rehabilitation admission and on rehabilitation discharge were recorded. The FIM score in the ABI group was 41.7±28.5 on rehabilitation admission and increased to 57.1±31.4 on rehabilitation discharge. The FIM score in the TBI group was 40.8±24.0 on rehabilitation admission and increased to 65.9±35.3 on rehabilitation discharge. There was no statistically significant difference in the FIM scores on rehabilitation discharge between groups. Initial FAC was similar in both groups and there was no statistically significant difference in the FAC scores on rehabilitation discharge. The multiple linear regression analysis showed that intensive care unit length of stay had an inverse relationship with the FAC change. We did not find significant differences in the rehabilitation outcomes of participants with ABI compared with participants with TBI. Considering the lack of information in the literature on ABI rehabilitation, this study may be important to guide rehabilitation teams.

Assessment of forearm muscle spasticity with sonoelastography in patients with stroke.

OBJECTIVE: The aim of the study was to investigate the feasibility of sonoelastography to show muscle stiffness in post-stroke spasticity, and the relationship between sonoelastography findings and clinical spasticity scores in the spastic forearm muscles. METHODS: This study was carried out in a university rehabilitation centre. 23 patients with stroke with forearm muscle spasticity (≥1+ using the Modified Ashworth scale score and ≥1 using the Tardieu scale) were included. Sonoelastography parameters (elasticity index and elasticity ratio) were measured from the flexor digitorum superficialis, flexor digitorum profundus, flexor carpi radialis and flexor carpi ulnaris muscles on the affected and unaffected sides. RESULTS: Both elasticity index and elasticity ratio of the wrist and finger flexors on the hemiplegic side were significantly increased compared with those on the healthy side (p < 0.05). The Tardieu angle of finger flexors was negatively correlated with the elasticity index and elasticity ratio measured in the spastic flexor digitorum profundus (r = -0.418 and r = -0.469, respectively). Tardieu angle of finger flexors was negatively correlated with the elasticity index measured in the spastic flexor digitorum superficialis (r = -0.435). There was no correlation between other parameters. CONCLUSION: Sonoelastography may provide objective assessment of spasticity both in diagnosis and follow-up. To strengthen this prediction, further studies are necessary. Advances in knowledge: The results of this study represent that sonoelastography is a promising evaluation method for forearm muscle spasticity.

Pathological Fracture of Calcaneum: A Case Report.

INTRODUCTION: Aneurysmal bone cysts (ABCs) are blood filled fibrous tumor-like cysts that expand the bone giving it a blown out appearance. It is usually seen in the second decade. ABCs were first described by Jaffe and Litchensen in 1942. The exact etiology is unknown. One of the most widely accepted ideas was that aneurysmal bone cyst was a consequence of increased venous pressure and subsequent dilatation and rupture of the local vascular network. However, studies by Panoutsakopoulus et al. and Olivia et al. uncovered the clonal neoplastic nature of ABCs. Here, we report a case of aneurysmal bone cyst of calcaneum, which is one of the rarest sites. CASE REPORT: A 25-year-old male presented with a history of trivial fall from a ladder and landing on the right heel. He complained of pain and swelling. On examination, he had swelling over the medial aspect of the right heel. The skin over the swelling was stretched, and it was soft in consistency and tender. Curettage and bone grafting was done. The patient was pain-free and was bearing weight fully on the operated limb, 12 weeks postoperatively. CONCLUSION: Aneurysmal bone cyst of calcaneum although seen rarely should be considered as one of the differential diagnoses in the cystic lesions in calcaneum. Curettage and bone grafting has stood the test of time as standard treatment.

Bizarre Parosteal Osteochondromatous Proliferation causing angular deformities: A Case Report.

INTRODUCTION: There have been fewer than 150 cases of Bizarre Parosteal Osteochondromatous proliferation (Nora Lesions) reported in the literature to date and no significant reports on angular deformities caused by this lesion. Nora's lesion can easily be misdiagnosed as osteochondroma or chondrosarcoma and therefore inappropriately managed. Although this condition classically appears in the second or third decade, we present to you a three year old boy who presented with multiple bony swellings over the hand and feet that caused an angular deformity of the involved digits. In the case report we have detailed the angular deformities and its treatment outcome. CASE REPORT: A three year old boy presented with valgus deformity of middle finger of right upper limb with an associated ulnar bony swelling at the level of middle phalanx which was noticed two years before and was progressing rapidly since last three months. On physical examination the swellings were found to be bony hard, midly tender and found to have been causing an angulare deformity of the digits. The initial suspicion was of osteochondromatous lesion however the excision biopsy showed the lesion to be of the rare entity of bizarre parosteal osteochondromatous proliferation. 1 year follow up showed no progression of angular deformity of the operated digits. CONCLUSION: Bizarre osteochondromatous proliferation is an entity that can rarely present in children which needs to be identified and tackled early to prevent the onset of deformities. Almost all cases warrant surgical intervention and the type of excision varies with the type of lesion.

Accuracy of ultrasound-guided suprascapular nerve block measured with neurostimulation.

Although the use of ultrasound (US) to perform suprascapular nerve block (SsNB) is rapidly gaining popularity, information about its accuracy is still lacking. The aim of this study was to investigate the proximity of the needle to suprascapular nerve under US guidance by means of neurostimulation current intensity in SsNB. The patients who were referred for SSnB due to shoulder pain were included in the study. The patients were placed in sitting position, and when the operator decided that the needle was in the correct place under US guidance, the time duration until that time and the current amplitude in that location were recorded. Current intensity was obtained by gradually increasing the amplitude until patient feels parestesia over the shoulder area or contractions of the supraspinatus or infraspinatus muscles. Out of 27 patients, in five patients current intensity was between 0.1 and 0.8 mA (successful) and time duration was 2.52 ± 1.67 min in this group; in 19 patients, current intensity was between 0.9 and 1.4 mA (semi-successful) and time duration was 1.86 ± 1.02 min in this group; in three patients, current intensity was ≥ 1.5 mA (unsuccessful) and time duration was 2.41 ± 1.02 min in this group. Our results show that the needle could not reach sufficient proximity to the suprascapular nerve with only US guidance by means of NS current intensity.

Psychological stress and aging: role of glucocorticoids (GCs).

Psychological stress has extreme adverse consequences on health. However, the molecular mechanisms that mediate and accelerate the process of aging due to stress hormone are not well defined. This review has focused on diverse molecular paths that come out in response to chronic psychological stress via releasing of excessive glucocorticoids (GCs), involved in the aging process. GCs suppress transcription of nuclear cell adhesion molecules which impair synaptic plasticity, memory formation, and cognitive ability. Again, GCs promote muscle atrophy by means of motivating ubiquitin proteasome system and can repress muscle protein synthesis by inhibition of PI3-kinase/Akt pathway. GCs also inhibit interleukin-2 synthesis through suppressing T cell receptor signal that leads to loss of T cell activation, proliferation, and B-cell activation. Moreover, GCs increase the expression of collagenase-3, RANK ligand, and colony stimulating factor-1 that induce bone resorption. In general, stress-induced GCs can play causal role for aging and age-related disorders.

Consistency between physical medicine and rehabilitation specialists and a radiologist in interpretation of lumbosacral radiographs.

OBJECTIVE: To investigate intra- and inter-observer reliability among physical medicine and rehabilitation specialists and a radiologist in interpretation of plain lumbar spine X-ray films in patients with low back pain. METHODS: Three assessors (A: a resident of PM&R, B: an experienced PM&R specialist, C: an experienced radiologist) read the standard lumbosacral plain radiographs of 79 patients with 2-3 month time interval. Each assessor recorded the presence or absence of abnormalities on the radiograph according to a standardized assessment form. RESULTS: For assessors B and C, all kappa values were > 0.40. Transitional vertebrae abnormalities reached to the highest agreement ratio. The intrarater agreement showed higher kappas than the interrater agreement. The radiologists had the highest intrarater agreement, closely followed by the experienced PM&R specialist. Agreement among three assessors was substantial in sacralisation, lumbarisation and facet joint pathologies. CONCLUSION: We usually obtained a good intrarater agreement, especially for the experienced PM&R specialist and the radiologist indicating that experience increases diagnostic consistency. Besides the systematic differences in radiographic interpretation between the assessors, institutional specific conditions (esp. patient profile and regularities) may cause the phycians to pay more attention to a specific group of pathologies.

Protective effect of liposomal formulation of tuftsin (a naturally occurring tetrapeptide) against cyclophosphamide-induced genotoxicity and oxidative stress in mice.

Tuftsin, a naturally occurring tetrapeptide with a sequence Thr-Lys-Pro-Arg was evaluated for its in vivo protective effect against cyclophosphamide-induced genotoxicity and oxidative stress in Swiss albino mice. The anticancer drug cyclophosphamide (CP) was administered intra-peritonially to induce mutagenic effect. The drug treatment caused significant increase in chromosomal aberrations, formation of micronucleated polychromatic erythrocytes (MNPCE's), as well as oxidative stress and decrease in lipid peroxidation in liver of the animals. The pretreatment with tuftsin abolished such effects in dose-dependent manner and also increased mitotic index in the experimental animals. Results of the present study validated chemo-preventive properties of tuftsin against CP-induced chromosomal mutations and cellular injury of liver by oxidative stress.

PLGA-microsphere mediated clearance of bilirubin in temporarily hyperbilirubinemic rats: an alternate strategy for the treatment of experimental jaundice.

In the present study, we have demonstrated the suitability of microspheres in removal of plasma bilirubin from systemic circulation of hyperbilirubinemic rats. Poly (lactide co-glycolide) microspheres (PLGA microspheres) have been shown to bind with bilirubin in both a concentration and time dependent manner. The binding affinity of bilirubin to microspheres was enhanced when rat serum albumin (RSA) was loaded into the microspheres. On evaluating the potential of microspheres in elimination of bilirubin from the systemic circulation, RSA bearing microspheres were found to be competent in both removing bilirubin from the systemic circulation and controlling elevated plasma levels of liver function enzymes in temporarily hyperbilirubinemic rats. On the basis of results of the present study, we suggest that microsphere-based delivery system may help in development of safe, effective and alternate strategy for the treatment of hyperbilirubinemic conditions in model animals.

Low birthweight babies in the Third World: maternal nursing versus professional nursing care.

Severe nursing shortage adds to the high mortality of low birthweight babies in developing countries. To study the efficacy of maternal nursing care we conducted a prospective matched case-control study. Outcome was compared in low birthweight babies nursed by mothers (mothers' group, n = 151, cases), versus professional nurses (nurses' group, n = 211, controls). Irrespective of condition on admission, weight gain was significantly higher (p < 0.001) and overall mortality rate significantly lower (p < 0.001) in the mothers' group. Mortality was also lower in the mothers' group for babies with pathological jaundice, skin/umbilical sepsis, and no disease except low birthweight (p < 0.001). Intercurrent diarrhoea, aspiration pneumonia, and septicaemia did not differ. Training mothers to nurse their low birthweight babies can significantly reduce mortality rates and decrease workload on nurses. Policy formulation using this approach can save costs in developing countries.

Acute alcohol intoxication: prevalence, recognition and medicolegal importance.

OBJECTIVE: To highlight the clinical criteria of persons who are accused of being under the intoxicating effect of alcohol brought to medicolegal officer by the police. METHODS: Included cases of alcohol intoxication reported to the medicolegal sections of three major government hospitals of Karachi i.e., Jinnah Post Graduate Medical Centre, Civil Hospital and Abbasi Shaheed Hospital, Karachi, during the period January to December 1996. RESULTS: During one year of study, 338 persons were brought from police stations all over Karachi to the medicolegal sections of the above three hospitals. Out of these, 260 persons were disposed off by the medicolegal officers by use of their clinical judgement, 78 persons were suspected to be under the effect of alcohol intoxication and were referred to the chemical examiner where urine and blood analysis for alcohol was positive in 40 and negative in 38 cases. Only one fatal case of alcohol intoxication was reported to the chemical examiner and the viscera sent for examination were positive for alcohol. CONCLUSION: The incidence of the positive cases of alcohol intoxication on laboratory analysis was 11.8% while negative results were obtained in 11.2% cases, out of 23% cases referred to the chemical examiner, indicating that the bulk of cases i.e. 76.9% were disposed off on clinical criteria only which is a crude method of assessment of cases of acute alcohol intoxication.

Maternal sociocultural status: a novel assessment of risk for the birth of small for gestational age, low birth weight infants.

OBJECTIVES: We assessed the significance of material sociocultural status within the family as a risk factor for low birth weight-small for gestational age (LBW-SGA) births using a novel scoring system and also isolated related medical risk factors. METHODS: A prospective matched pairs case control study of 396 LBW-SGA infants (cases) and 396 term, appropriate for gestational age infants (controls) was set up. RESULTS: Low maternal sociocultural status (p = 0.02) was significantly associated with LBW-SGA births as were nonregistration for antenatal care (p = 0.001), maternal weight at delivery < 50 kg (p < 0.0001), antepartum hemorrhage/preeclampsia (p < 0.01), primigravidity and previous small baby (p <0001). Other risk factors included birth interval < 24 m (p < 0.001) and poor maternal or paternal education (p < 0.05). Conditional logistic regression identified maternal weight at delivery < 50 kg (OR 4.8, 95% C.I. 3.0-7.6), lack of antenatal care (OR 2.0, 95% C.I. 1.4-2.9), antepartum hemorrhage/preeclampsia (OR 4.3, 95% C.I. 1.7-10.8) and previous small baby (OR 4.3, 95% C.I. 2.1-8.9) as independent risk factors. CONCLUSIONS: Low sociocultural status of the mother within the family is significantly associated with having a LBW-SGA baby. Further studies are warranted to study this risk factor.