Use of Peripheral Nerve Blocks for Total hip Arthroplasty.

PURPOSE OF REVIEW: The purpose of this review is to summarize the recent literature regarding regional anesthesia (RA) techniques and outcomes for total hip arthroplasty (THA) in the face of changing surgical techniques and perioperative considerations. RECENT FINDINGS: Based on large meta-analyses, peripheral nerve blocks are indicated for THA. Each block has its own risks and benefits and data for outcomes for particular techniques are limited. New surgical techniques, improved use of multimodal analgesia, and improved ultrasound guided regional anesthetics lead to better pain control for patients undergoing THA with less associated risks. Block selection continues to be influenced by provider comfort, surgical approach, patient anatomy, and postoperative goals. Head-to-head studies of particular nerve blocks are warranted.

Nicolau syndrome following intramuscular naltrexone injection.

There are a variety of possible adverse drug reactions that can have differing presentations. Recognizing these presentations and the temporal relationship between drug intake and reaction is essential in preventing severe and potentially fatal results. We present a patient who had a sudden post-injection inflammatory response consistent with Nicolau syndrome after a 6 month course of repeated intramuscular naltrexone injections.

Tackling bisexual erasure: An explorative comparison of bisexual, gay and straight cisgender men's body image.

Previous body image research often grouped both gay and bisexual men into a single category: sexual minoritised men, limiting our understanding of how sexual identity influences body image. However, there is strong reason to believe that bisexual and gay men experience distinct body image concerns. Here, we explored motivations to alter one's leanness and muscularity, as well as (dis)satisfaction with body fat, muscularity, height and penis size, and functionality appreciation across gay, bisexual, and straight cisgender men. We sampled 378 white participants aged 18 to 85 (nbisexual = 125, ngay = 128, nstraight = 125). We found that bisexual men were significantly less motivated to be lean and showed lower muscularity dissatisfaction relative to gay men but showed comparable levels to straight men. Our findings demonstrate that despite research perceiving the body image of bisexual and gay men as homogenous, they experience differences in their body image concerning leanness and muscularity dissatisfaction. Future body image research should incorporate this understanding by not artificially grouping bisexual and gay cisgender men and instead acknowledging the potential uniqueness in their experiences.

Potassium channel modulators and schizophrenia: an overview of investigational drugs.

INTRODUCTION: Schizophrenia is a severe mental illness comprising positive, negative, and cognitive symptoms. Existing pharmacologic options exert their actions on the dopamine receptor but are largely ineffective at treating negative and cognitive symptoms. Alternative pharmacologic options that do not act directly on the dopamine receptor are being investigated, including potassium channel modulators. It has been hypothesized that dysfunctional fast-spiking parvalbumin-positive GABA interneurons, regulated by Kv3.1 and Kv3.2 potassium channels, contribute to the symptoms of schizophrenia, making potassium channels an area of clinical interest. AREAS COVERED: This review will highlight potassium channel modulators for the treatment of schizophrenia, with a focus on AUT00206. Background on Kv3.1 and Kv3.2 potassium channels will be explored. Our search strategy included a literature review utilizing PubMed, Clinicaltrials.gov, and sources available on the manufacturer's website. EXPERT OPINION: Initial data on potassium channel modulators is promising; however, further study is needed, and existing evidence is limited. Early data suggests that dysfunctional GABA interneurons can be ameliorated through modulators of Kv3.1 and Kv3.2 channels. AUT00206 has been shown to improve dopaminergic dysfunction induced by ketamine and PCP, improve resting gamma power in patients with schizophrenia, impact dopamine synthesis capacity in a subgroup of individuals with schizophrenia, and affect reward anticipation-related neural activation.

Suicidal ideation and self-harm following K2 use.

INTRODUCTION: There is emerging evidence of adverse effects associated with K2 and similar synthetic cannabinoid compounds marketed as herbal alternatives to marijuana. Few studies were identified regarding the psychiatric effects of K2, including suicidal ideation, and to our knowledge none have been written related to self-harm following use of K2. CASE REPORT: A healthy 20-year-old single Caucasian male with no previous psychiatric diagnoses or treatment was brought by police to the ED with acute agitation, confusion, suicidal ideation, and self-inflicted trauma after smoking K2. Evaluation in the ED was notable for agitation, significant abrasions, respiratory rate of 30, negative UDS, and sinus tachycardia on EKG. Once medically stabilized, he was transferred to the inpatient psychiatric unit for continued monitoring. Upon evaluation on the psychiatric unit the following day, his symptoms had completely resolved, he continued to deny any previous psychiatric history, and was discharged home. CONCLUSION: K2 and other synthetic cannabinoids have been shown to have significant medical and psychiatric adverse effects and they are still readily available for purchase. Evidence is limited regarding the psychiatric effects; however, synthetic cannabinoid products may potentially lead to suicidal ideation and self-harm behaviors amongst many other psychiatric symptoms.The long-term risks are still unclear, but some studies suggest the possibility of inducing chronic psychotic symptoms and worsening underlying psychiatric illness. Continued research is needed regarding the effects of these substances as well as an increase in public awareness of the risks.

Men's reflections on their body image at different life stages: A thematic analysis of interview accounts from middle-aged men.

This study investigates how men's body image develops over time. A total of 14 men aged between 45 and 67 years completed in-depth interviews where they discussed their body image since childhood, prompted in some cases by photographs of themselves at different ages that they brought to the interviews. Transcripts were analysed using inductive thematic analysis. From the participants' accounts, it was evident that body concerns did not steadily improve or worsen, but waxed and waned over time. Results are discussed in relation to understanding changing body concerns in men's lives, and the implications of these for future research and practice.

Chronic kidney disease as a risk factor for Clostridium difficile infection.

INTRODUCTION: Clostridium difficile-associated diarrhoea (CDAD) is the most common cause of nosocomial diarrhoea in the USA. In this study, we sought to determine the association between chronic kidney disease (CKD) and CDAD. METHODS: A case-control study was designed to determine the association between CKD and CDAD in an urban hospital. Over a 2-year period, all patients diagnosed with CDAD (n = 188) were included as cases and the prevalence of CKD was calculated. Age- and sex-matched patients without CDAD were considered as controls with a ratio of 2:1 controls to cases. The prevalence of different stages of advanced CKD (stages 3-5) was determined and compared between groups. Also the calculated odds ratios (OR) were adjusted for multiple possible confounding variables using logistic regression analysis. RESULTS: There was no significant difference in prevalence of advanced CKD between cases and controls (OR = 1.38, 95% confidence intervals (CI) = 0.90-2.12, P = 0.1365). The association between CKD and CDAD remained insignificant in subjects with CKD stages 3-5 who were not on dialysis (OR = 1.07, 95% CI = 0.65-1.77), P = 0.7970). However, the group with end-stage renal disease on dialysis showed a significant association (OR = 2.60, 95% CI = 1.25-5.41, P = 0.0165). Controlling for antibiotics as a possible confounding variable, yielded an OR that was not statistically significant (OR = 2.05, 95% CI = 0.94-4.47, P = 0.07), but still showing a trend towards increased risk. CONCLUSION: End-stage renal disease may increase the risk of acquiring CDAD through unknown mechanisms. This suggests implementing better surveillance strategies for these patients and eliminating the known risk factors for CDAD.

Protein kinase A serves as a primary pathway in activation of Nur77 expression by gonadotropin-releasing hormone in the LbetaT2 mouse pituitary gonadotroph tumor cell line.

Nur77 belongs to a subfamily of nuclear receptors that includes two other members, Nor-1 and Nurr1. It plays an important role in a number of biological processes, including regulation of signaling functions in the hypothalamo-pituitary-adrenal axis, regulation of thymocyte apoptosis, regulation of steroidogenesis and regulation of tumor cell proliferation and apoptosis. In previous studies, using DNA microarray analysis of the effects of the gonadotropin-releasing hormone (GnRH) on the mouse pituitary gonadotroph cell line LbetaT2, we identified Nur77 as one of the highly regulated immediate early genes involved in this response, with >40-fold upregulation after 1 h of treatment of the cells with the GnRH agonist [D-Ala6GnRH (GnRHA)]. GnRH is a hypothalamic decapeptide that stimulates the secretion and expression of gonadotropins (follicle stimulating hormone, FSH and luteinizing hormone releasing hormone, LH) from anterior pituitary through activation of high affinity receptors present on cell membrane of pituitary gonadotropes. In addition to pituitary, the presence of GnRH high affinity receptors has been reported in various cancers and cancer cell lines. In addition, GnRH and its analogs are clinically used in the treatment of prostate cancer. To elucidate the molecular mechanism involved in regulation of Nur77 by GnRH, we first confirmed upregulation of Nur77 in response to GnRH analog (GnRHA) in LbetaT2 cells. Nur77 mRNA was upregulated within 30 min of GnRHA treatment and returned to nearly basal level after 24 h of treatment. Nur77 protein expression was upregulated after 2 h of treatment and remained steady even after 12 h of treatment. The expression of Nur77 mRNA was induced by GnRHA in a dose-dependent manner. Induction of Nur77 expression was stimulated on treatment of cells with forskolin and 8-Br-cAMP, whereas H-89, a specific inhibitor of PKA pathway significantly inhibited GnRHA-induced Nur77 expression. Treatment of cells with both H-89 and EGTA completely blocked the GnRHA-induced expression of Nur77, indicating that both calcium and cAMP/PKA play an important role in regulation of Nur77 expression by GnRHA. Analysis of the protein kinase C (PKC) signaling pathway using specific inhibitors for PKC, Erk1/2, p38 and JNK demonstrated that these pathways are not involved in GnRHA-induced Nur77 expression. Based on our results, we conclude that activation of protein kinase A is the major mechanism regulating the expression of Nur77 by GnRH which may serve as a down-stream signaling gene to mediate the antitumor effects of GnRH.

Global variations in the level of cancer-related research activity and correlation to cancer-specific mortality: Proposal for a global curriculum.

INTRODUCTION: The aim of this study was to analyze global variations in the level of cancer-related research activity and correlate this with cancer-specific mortality. METHODS: The SCOPUS database was explored to obtain data relating to the number of cancer-related publications per country. Cancer-specific mortality rates were obtained from the World Health Organization. Global variations in the level of scholarly activity were analyzed and correlated with variations in cancer-specific mortality. RESULTS: Data for 142 countries were obtained and significant variations in the level of research activity was noted. The level of research activity increased with rising socio-economic status. The United States was the most prolific country with 222,300 publications followed by Japan and Germany. Several countries in different regions of the world had a low level of research activity. An inverse relationship between the level of research activity and cancer-specific mortality was noted. This relationship persisted even in countries with a low level of research activity. The socioeconomic status of a nation and geographic location (continent) had a mixed influence with an overall apparent correlation with cancer-related research activity. CONCLUSION: This study demonstrates significant global variation in the level of cancer-related research activity and a correlation with cancer-specific mortality. The presence of a minimum set of standards for research literacy, as proposed by the European Society of Surgical Oncology and the Society of Surgical Oncology may contribute to enhanced research activity and improve outcomes for cancer patients worldwide.

Small interfering RNA against PTTG: a novel therapy for ovarian cancer.

Ovarian epithelial cancer is a significant cause of death among women, accounting for 5% of all female cancer-related fatalities. A lack of reliable detection methods and resistance to chemotherapy agents are considerable obstacles in the treatment of this cancer. Recently, high-level expression of the pituitary tumor transforming gene (PTTG) was found in a wide range of tumors, including ovarian cancers. Elevated PTTG levels were found to induce cellular transformation in vitro and tumor formation in nude mice. Therefore, we hypothesize a correlation exists between the levels of PTTG expression and tumorigenesis, and that down-regulation of PTTG levels will result in the suppression of tumor growth. We used small interfering RNA (siRNA) to silence PTTG expression in human A2780 ovarian carcinoma cells and assessed the effect of PTTG silencing in tumor formation in vitro and in vivo. The siRNA directed against PTTG reduced its expression at both the mRNA and protein levels. A fifty percent reduction in cell proliferation was achieved in cells constitutively expressing PTTG siRNA compared to vector or control-siRNA transfected cells. Furthermore, colony formation in soft agar was reduced by 70% in PTTG siRNA stable cell lines. Using nude mice, we showed that animals injected with A2780 cells constitutively expressing PTTG-siRNA decreased the incidence of tumor development and tumor growth. Taken together, these results strongly suggest that PTTG may serve as an important molecular target for the discovery of new anticancer agents and treatment strategies.

Ectopic expression of PTTG1/securin promotes tumorigenesis in human embryonic kidney cells.

BACKGROUND: Pituitary tumor transforming gene1 (PTTG1) is a novel oncogene that is expressed in most tumors. It encodes a protein that is primarily involved in the regulation of sister chromatid separation during cell division. The oncogenic potential of PTTG1 has been well characterized in the mouse, particularly mouse fibroblast (NIH3T3) cells, in which it induces cell proliferation, promotes tumor formation and angiogenesis. Human tumorigenesis is a complex and a multistep process often requiring concordant expression of a number of genes. Also due to differences between rodent and human cell biology it is difficult to extrapolate results from mouse models to humans. To determine if PTTG1 functions similarly as an oncogene in humans, we have characterized its effects on human embryonic kidney (HEK293) cells. RESULTS: We report that introduction of human PTTG1 into HEK293 cells through transfection with PTTG1 cDNA resulted in increased cell proliferation, anchorage-independent growth in soft agar, and formation of tumors after subcutaneous injection of nu/nu mice. Pathologic analysis revealed that these tumors were poorly differentiated. Both analysis of HEK293 cells transiently transfected with PTTG1 cDNA and analysis of tumors developed on injection of HEK293 cells that had been stably transfected with PTTG1 cDNA indicated significantly higher levels of secretion and expression of bFGF, VEGF and IL-8 compared to HEK293 cells transfected with pcDNA3.1 vector or uninvolved tissues collected from the mice. Mutation of the proline-rich motifs at the C-terminal of PTTG1 abolished its oncogenic properties. Mice injected with this mutated PTTG1 either did not form tumors or formed very small tumors. Taken together our results suggest that PTTG1 is a human oncogene that possesses the ability to promote tumorigenesis in human cells at least in part through the regulation of expression or secretion of bFGF, VEGF and IL-8. CONCLUSIONS: Our results demonstrate that PTTG1 is a potent human oncogene and has the ability to induce cellular transformation of human cells. Overexpression of PTTG1 in HEK293 cells leads to an increase in the secretion and expression of bFGF, VEGF and IL-8. Mutation of C-terminal proline-rich motifs abrogates the oncogenic function of PTTG1. To our knowledge, this is the first study demonstrating the importance of PTTG1 in human tumorigenesis.

Embracing synthetic lethality of novel anticancer therapies.

INTRODUCTION: The significant challenge posed by cancer to human healthcare has led to the exploration of new approaches to combat it. Synthetic lethality (SL) is one such emerging area in the development of novel anticancer therapies. SL can be described as lethality (cell death) resulting from the combination of the two mutations, wherein the mutation in either of the two codependent genes in normal or cancer cells is viable. This concept is specifically being exploited in cancer research for selectively targeting specific tumor cells. AREAS COVERED: In this review, the authors summarize studies of SL-based novel anticancer therapies. The review highlights some of the selected advances in DNA damage response pathway-related SL pairs, particularly poly (ADP-ribose) polymerase (PARP) and SL pairs involved in mitochondrial death signaling pathways published in the last 3 years. EXPERT OPINION: Most of the currently used chemotherapeutic agents will destroy cells irrespective of whether they are cancer cells or fast growing normal cells; but SL is one of the approaches being developed with potential as a selective cancer therapy. PARP inhibitors, such as olaparib, are useful in BRCA mutated cancer cells and are also used in combination with other drug to enhance their efficacy. Research on PARP inhibitors is progressing at a good pace but there are still some significant challenges that must be addressed.

Sterile syringe access conditions and variations in HIV risk among drug injectors in three cities.

AIM: Better sterile syringe access should be associated with a lower likelihood of syringe re-use and receptive syringe sharing, although few empirical studies have examined gradients in syringe access using both individual and ecological data. In this study, we compare syringe re-use and receptive syringe sharing among injection drug users (IDUs) with syringe exchange program (SEP) and legal over-the-counter pharmacy access with limits on syringes that can be purchased, exchanged or possessed to IDUs with no pharmacy sales but unlimited syringe access through SEPs. We address three questions: (1) Does residing in an area with no legal syringe possession increase the likelihood of police contact related to possessing drug paraphernalia? (2) Among direct SEP users, is use of more permissive SEPs associated with less likelihood of syringe re-use and receptive syringe sharing? (3) Among non-SEP users, is residing in an area with pharmacy access associated with lower likelihood of syringe re-use and receptive syringe sharing? DESIGN: Quantitative survey of IDUs recruited from SEPs, subject nomination and outreach methods. Multivariate analyses compared police contact, syringe re-use and receptive syringe sharing among IDUs recruited in three cities. FINDINGS: In multivariate analyses, we found that police contact was associated independently with residing in the area with no legal possession of syringes; among SEP users, those with access to SEPs without limits had lower syringe re-use but not lower syringe sharing; and that among non-SEP users, no significant differences in injection risk were observed among IDUs with and without pharmacy access to syringes. CONCLUSION: We found that greater legal access to syringes, if accompanied by limits on the number of syringes that can be exchanged, purchased and possessed, may not have the intended impacts on injection-related infectious disease risk among IDUs.

Apoptosis-inducing agents: a patent review (2010 - 2013).

INTRODUCTION: Apoptosis is an important and extensively studied pathway of programmed cell death, which is central to different physiological processes. Varied pathological implications, not limited to cancer and neurodegenerative diseases, occur if a slight dysfunction happens in the intricate apoptotic pathway. Therefore, it has become one of the prime molecular target for drug discovery and development particularly for diseases like cancer. AREAS COVERED: As a promising drug target in the development of cancer chemotherapeutics, apoptosis has received extensive attention and hundreds of thousands of reports have been published. In the present review, the patents filed/published on apoptosis-inducing agents during the period of 2010 - 2013 have been compiled and discussed. EXPERT OPINION: Most of the chemotherapeutics employed in cancer treatment leads to suppression of tumor via cell death irrespective of the mechanism of action or molecular target. No effective drug has emerged from the direct activation/inhibition of apoptotic regulatory proteins and of late some potential drugs, such as oblimersen, navitoclax, etc., targeting Bcl-2 family of proteins are under clinical trials. However, most of these molecules lacks efficacy accompanied with significant toxicity and resistance. Concerted efforts are required such as combination therapies and identification of newer selective inhibitor to overcome these limitations.