Five Freely Circulating miRNAs and Bone Tissue miRNAs Are Associated With Osteoporotic Fractures

Osteoporosis as a systemic skeletal disorder is characterized by increased bone fragility and the risk of fractures. According to the World Health Organization, osteoporosis is one of the 10 most common diseases and affects approximately 75 million people in Europe, the United States, and Japan. In this context, the identification of specific microRNA (miRNA) signatures is an important step for new diagnostic and therapeutic approaches. The focus of interest on miRNAs as biomarkers came with new publications identifying free circulating extracellular miRNAs associated with various types of cancer. This study aimed to identify specific miRNAs in patients with osteoporotic fractures compared with nonosteoporotic fractures. For the array analysis, miRNAs were isolated from the serum of 20 patients with hip fractures, transcribed, and the samples were pooled into 10 osteoporotic and 10 nonosteoporotic specimens. With each pool of samples, human serum and plasma miRNA PCR arrays were performed, which are able to identify 83 different miRNAs. Subsequently, a separate validation analysis of each miRNA found to be regulated in the array followed with miRNA samples isolated from the serum of 30 osteoporotic and 30 nonosteoporotic patients and miRNA samples isolated from the bone tissue of 20 osteoporotic and 20 nonosteoporotic patients. With the validation analysis of the regulated miRNAs, we identified 9 miRNAs, namely miR‐21, miR‐23a, miR‐24, miR‐93, miR‐100, miR‐122a, miR‐124a, miR‐125b, and miR‐148a, that were significantly upregulated in the serum of patients with osteoporosis. In the bone tissue of osteoporotic patients, we identified that miR‐21, miR‐23a, miR‐24, miR‐25, miR‐100, and miR‐125b displayed a significantly higher expression. A total of 5 miRNAs display an upregulation both in serum and bone tissue. This study reveals an important role for several miRNAs in osteoporotic patients and suggested that they may be used as biomarkers for diagnostic purposes and may be a target for treating bone loss and optimizing fracture healing in osteoporotic patients. © 2014 American Society for Bone and Mineral Research.     

Ethnicity,self-care,and use of medical care among the elderly with joint symptoms

Elderly individuals with self-reported joint symp-toms representing three ethnic groups (i.e., blacks [n = 105], Hispanics[n = 100], and whites of Eastern European origin [n = 112] answered questions about their use of self-care and medical care for these symptoms. Ethnic groups differed in both self-care practices and their use of medical care for joint symptoms. Multiple regression analyses demonstrated that arthritis-specific and general health status were better predictors than ethnicity of the tendency to rely on self-care and medical care. There was no evidence that self-care served as a substitute for medical care.     

Neoadjuvant immunotherapy with combined ipilimumab and nivolumab in patients with melanoma with primary or in transit disease

The introduction of new therapeutic agents has revolutionized the treatment of metastatic melanoma. The approval of adjuvant anti-programmed death-1 monotherapy with nivolumab or pembrolizumab, and dabrafenib plus trametinib has recently set a new landmark in the treatment of stage III melanoma. Now, clinical trials have shown that immune checkpoint blockade can be performed in a neoadjuvant setting, an approach established as a standard therapeutic approach for other tumour entities such as breast cancer. Recent studies suggest that a pathological response achieved by neoadjuvant immunotherapy is associated with long-term tumour control and that short neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy. Most recently, neoadjuvant ipilimumab plus nivolumab in stage III melanoma was reported. With two courses of dose-optimized ipilimumab (1 mg kg⁻¹) combined with nivolumab (3 mg kg⁻¹), pathological responses were observed in 77% of patients, while only 20% of patients experienced grade 3 or 4 adverse events. However, the neoadjuvant trials employing combined immune checkpoint blockade conducted so far have excluded patients with in transit metastases, a common finding in stage III melanoma. Here we report four patients with in transit metastases or an advanced primary tumour who have been treated with neoadjuvant ipilimumab plus nivolumab according to the OpACIN-neo trial scheme (arm B). All patients achieved radiological disease control and a pathological response. None of the patients has relapsed so far. Linked Comment:   Blankenstein and van Akkooi. Br J Dermatol 2020; 183 :421–422 .     

Effects of 8-OH-DPAT and fluoxetine on activity and attack by female mice towards lactating intruders

1. The impact of the serotoninergic receptor on the attack directed by female mice towards lactating intruders was assessed by studying the effects of 8-OH-DPAT (a serotoninergic agonist) and fluoxetine (an inhibitor of serotonin reuptake) on this paradigm at a range of doses and post-injection durations. 2. The specificity of these drug actions behaviour were examined by studying their effects on wheel running activity and performance in the open field. Non-sedative doses of 200 and 250 micrograms/kg of 8-OH-DPAT reduced attack by resident females on lactating intruders. 3. Higher doses (12-16 mg/kg) of fluoxetine reduced activity measures whereas lower non-sedative doses (up to 8 mg/kg) were without action on this aggression paradigm. 4. Additional studies with specific serotoninergic drugs are needed to clarify the role of this transmitter in attack by female mice on lactating intruders.     

Initial findings concerning a sexual knowledge questionnaire

SUMMARY: The authors describe a 69 item sexual knowledge questionnaire that covers the areas: physiology, pregnancy, the sex act, masturbation, contraception, types of sexuality, and venereal disease. There is also a ‘Belief in Myths’ scale. Mean scores for delinquent boys and young mentally handicapped adults are given, with the latter having lower scores. All areas correlate with total score. The handicapped group showed increased sexual knowledge when re-tested after a human relations course. A control group, tested after the same interval, showed only random changes. Further research is suggested.     

Growth hormone, somatomedin levels and growth regulation in Turner's syndrome

In a total of 56 children and adolescents with Turner's syndrome (41 with karyotype 45,X) basal serum levels of somatomedin bioactivity, Sm-C/IGF-I (RIA), IGF II (RIA), GH response to arginine and GHRH (GRF(1-29)NH2), and spontaneous GH secretion during 5.5 h of deep sleep were determined in a cross-sectional manner. GH responses to GRF and arginine as well as IGF-II levels were found to be in the normal range. Levels of somatomedin bioactivity were higher than normal before a bone age of 10 years, in the low-normal range thereafter, and below normal in some patients. Levels of Sm-C/IGF-I were found normal before and low-normal after a bone age of ten years. There was a trend towards increasing Sm-C/IGF-I levels with age. In contrast to the normal pattern, spontaneous sleep-related GH secretion was declining with age and did not show the puberty-associated rise. These findings suggest a normally functioning growth hormone-somatomedin axis in Turner's syndrome with alterations of its functioning level occurring secondarily as a result of absent gonadal activation. In single patients abnormally low growth hormone and/or somatomedin secretion may be present.     

Phylogeny and expression divergence of metabotropic glutamate receptor genes in the brain of zebrafish (Danio rerio)

Glutamate, the most abundant excitatory neurotransmitter of the central nervous system, modulates synaptic transmission and neuronal excitability via metabotropic glutamate receptors (mGluRs). These receptors are essential components for diverse cognitive functions and they represent potential drug targets for the treatment of a number of neurological and psychiatric disorders. Here we describe the phylogenetic relation and mRNA distribution of zebrafish mGluRs. In comparison to the eight mglurs present in the mammalian genome, we identified 13 different mglur genes in the zebrafish genome. In situ hybridization experiments in zebrafish revealed widespread expression patterns for the different mglurs in the central nervous system, implicating their significance in diverse neuronal functions. Prominent mglur expression is found in the olfactory bulb, the optic tectum, the hypothalamus, the cerebellum, and the retina. We show that expression pattern of paralogs generated by the teleost‐specific whole genome duplication is overlapping in some brain regions but complementary in others, suggesting sub‐ and/or neofunctionalization in the latter. Group I mglurs are similarly expressed in brain areas of both larval and adult zebrafish, suggesting that their functions are comparable during these stages. J. Comp. Neurol. 521:1449–1469, 2013. © 2012 Wiley Periodicals, Inc.