Child maltreatment (CM) is associated with mental and physical health disorders in adulthood. Some studies have identified elevated markers of systemic inflammation in adult survivors of CM, and ...inflammation may mediate the association between CM and later health problems. However, there are methodological inconsistencies in studies of the association between CM and systemic inflammation and findings are conflicting. We performed a systematic review to examine the association of CM with systemic inflammation in adults.
A pre-registered systematic review was performed following PRISMA guidelines. Medline, Embase, Scopus and PsychInfo were searched for studies of the association of CM with blood markers of inflammation in adults. Quality was assessed using the Crowe Critical Appraisal Tool. We had intended to perform a meta-analysis, but this was not possible due to variation in study design and reporting.
Forty-four articles met criteria for inclusion in the review. The most widely reported biomarkers were C-Reactive Protein (CRP) (n = 27), interleukin-6 (IL-6) (n = 24) and Tumour Necrosis Factor-alpha (TNF-a) (n = 17). Three studies were prospective (all relating to CRP) and the remainder were retrospective. 86% of studies were based in high income countries. In the prospective studies, CM was associated with elevated CRP in adulthood. Results of retrospective studies were conflicting. Methodological issues relating to the construct of CM, methods of analysis, and accounting for confounding or mediating variables (particularly Body Mass Index) may contribute to the uncertainty in the field.
There is some robust evidence from prospective studies that CM is associated with elevated CRP in adulthood. We have identified significant methodological inconsistencies in the literature and have proposed measures that future researchers could employ to improve consistency across studies. Further prospective, longitudinal, research using robust and comparable measures of CM with careful consideration of confounding and mediating variables is required to bring clarity to this field.
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Inhibition of FAAH, the enzyme that preferentially metabolises the endocannabinoid anandamide (AEA), using PF3845, attenuates social deficits in male rats prenatally exposed to ...valproic acid (VPA), an environmental animal model of autism.
Autism spectrum disorders are a group of neurodevelopmental disorders characterised by impaired social interaction, deficits in communication and repetitive stereotyped behaviours. The endocannabinoid system plays an important role in modulating emotionality and social responding, however there have been a paucity of studies investigating this system in autistic animal models. This study investigated the effect of inhibiting fatty acid amide hydrolyase (FAAH), the anandamide catabolic enzyme, on behavioural responding in the valproic acid (VPA) rat model of autism. Male rats prenatally exposed to VPA exhibit an autistic-like behavioural phenotype exemplified as thermal hypoalgesia, reduced social and exploratory behaviour, and enhanced repetitive behaviour. Systemic administration of the FAAH inhibitor PF3845 (10mg/kg) attenuated the deficit in social behaviour observed in VPA exposed male animals without altering nociceptive, repetitive or exploratory behaviour. In comparison, female VPA exposed rats displayed enhanced repetitive and reduced exploratory behaviour, but no change in social behaviour or thermal nociceptive responding. PF3845 did not alter social, repetitive or thermal nociceptive responding, but reduced exploratory behaviour in a social context in VPA-, but not saline-, exposed females. These data indicate that FAAH inhibition elicits sexual dimorphic effects on behavioural responding in VPA exposed rodents, and support an important role for FAAH in the regulation of social behavioural deficits in autistic males.
Studies on the impacts of child maltreatment (CM) have been conducted in diverse areas. Mechanistic understanding of the complex interplay between factors is lacking. Hallmarking is an approach which ...identifies common factors across studies and highlights the most robust findings.
In a review of systematic reviews and meta-analyses, we addressed the following questions: 1) What are the hallmarks associated with exposure to CM across the bio-ecological spectrum? 2) What is the strength of evidence to support each hallmark? 3) What are the gaps that future research should address?
A comprehensive literature search was carried out to find relevant systematic reviews or meta-analyses. 269 articles were read in full and 178 articles, encompassing more than 6000 original papers, were included in the final synthesis. All reviews were independently rated for quality by at least 2 reviewers using AMSTAR-2.
Of 178 review articles, 6 were rated as high quality (all meta-analyses) and 46 were rated as medium quality. Most were from high income countries.
Based on the most commonly reported high-quality research findings we propose that the hallmarks of exposure to child maltreatment are: Increased risk of psychopathology; Increased risk of obesity; Increased risk of high- risk sexual behaviours, Increased risk of smoking; and Increased risk of child maltreatment in children with disabilities. Research gaps include a lack of focus on complexity and resilience. Little can be concluded about directions of causality or mechanisms. Adequately powered prospective studies are required to move the field forward.
In human cancers, loss of PTEN, stabilization of hypoxia inducible factor-1α, and activation of Ras and AKT converge to increase the activity of a key regulator of glycolysis, ...6-phosphofructo-2-kinase (PFKFB3). This enzyme synthesizes fructose 2,6-bisphosphate (F26BP), which is an activator of 6-phosphofructo-1-kinase, a key step of glycolysis. Previously, a weak competitive inhibitor of PFKFB3, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), was found to reduce the glucose metabolism and proliferation of cancer cells. We have synthesized 73 derivatives of 3PO and screened each compound for activity against recombinant PFKFB3. One small molecule, 1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15), was selected for further preclinical evaluation of its pharmacokinetic, antimetabolic, and antineoplastic properties in vitro and in vivo. We found that PFK15 causes a rapid induction of apoptosis in transformed cells, has adequate pharmacokinetic properties, suppresses the glucose uptake and growth of Lewis lung carcinomas in syngeneic mice, and yields antitumor effects in three human xenograft models of cancer in athymic mice that are comparable to U.S. Food and Drug Administration-approved chemotherapeutic agents. As a result of this study, a synthetic derivative and formulation of PFK15 has undergone investigational new drug (IND)-enabling toxicology and safety studies. A phase I clinical trial of its efficacy in advanced cancer patients will initiate in 2013 and we anticipate that this new class of antimetabolic agents will yield acceptable therapeutic indices and prove to be synergistic with agents that disrupt neoplastic signaling.
Objective To evaluate the effectiveness of exercise in the treatment of people with subacromial impingement syndrome (SAIS). Methods A systematic review and meta-analysis were conducted. Ten ...electronic databases were searched from the dates of their inception until August 2010. Included studies were randomized controlled trials investigating exercise in the management of SAIS. Outcomes were pain, strength, function, and quality of life. Data were summarized qualitatively using a best evidence synthesis. Treatment effect size and variance of individual studies were used to give an overall summary effect and data were converted to standardized mean difference with 95% confidence intervals (standardized mean difference (SMD) (CI)). Results Sixteen studies were included ( n = 1162). There was strong evidence that exercise decreases pain and improves function at short-term follow-up. There was also moderate evidence that exercise results in short-term improvement in mental well-being and a long-term improvement in function for those with SAIS. The most common risk of bias across the studies was inadequately concealed treatment allocation. Six studies in the review were suitable for meta-analysis. Exercise had a small positive effect on strength of the rotator cuff in the short term (SMD −0.46 (−0.76, 0.16); P = 0.003) and a small positive effect on long-term function (SMD −0.31 (−0.57, 0.04); P = 0.02). Conclusions Physiotherapy exercises are effective in the management of SAIS. However, heterogeneity of the exercise interventions, coupled with poor reporting of exercise protocols, prevented conclusions being drawn about which specific components of the exercise protocols (ie, type, intensity, frequency and duration) are associated with best outcomes.
Abstract There is a paucity of data on the role of microglia and neuroinflammatory processes in the association between chronic pain and depression. The current study examined the effect of the ...microglial inhibitor minocycline on depressive-like behaviour, spinal nerve ligation (SNL)-induced mechanical and cold allodynia and associated changes in the expression of genes encoding microglial markers (M1 vs. M2 polarisation) and inflammatory mediators in the prefrontal cortex in the olfactory bulbectomised (OB) rat model of depression. Acute minocycline administration did not alter OB-induced depressive-like behaviour but prevented SNL-induced mechanical allodynia in both OB and sham rats. In comparison, chronic minocycline attenuated OB-induced depressive-like behaviour and prevented the development of SNL-induced mechanical allodynia in OB, but not sham, rats. Further analysis revealed that SNL-induced mechanical allodynia in OB rats was attenuated by chronic minocycline at almost all time-points over a 2 week testing period, an effect observed only from day 10 post-SNL in sham rats. Chronic administration of minocycline reduced the expression of CD11b, a marker of microglial activation, and the M1 pro-inflammatory cytokine IL-1β, in the prefrontal cortex of sham-SNL animals. In comparison, the expression of the M2 microglia marker (MRC2) and anti-inflammatory cytokine IL-10 was increased, as were IL-1β, IL-6 and SOCS3, in the prefrontal cortex of OB-SNL animals following chronic minocycline. Thus, chronic minocycline attenuates neuropathic pain behaviour and modulates microglial activation and the central expression of inflammatory mediators in a manner dependent on the presence or absence of a depressive-like phenotype.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy that contributes to <1% of all hematologic neoplasms. Before the introduction of various targeted ...agents, the therapeutic approach was based on regimens used for acute lymphoblastic or myeloid leukemia and non-Hodgkin's lymphoma (e.g. hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high dose methotrexate and cytarabine) and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) -based regimens) followed by allogeneic stem cell transplantation for eligible patients. Given that this disease primarily affects older patients, there is a significant barrier to using these highly toxic regimens, even though these regimens are usually associated with the most durable response.
In this review, we briefly discuss outcomes with the use of leukemia-based induction regimens as well as the use of stem cell transplant. We also review low-intensity chemotherapeutic regimens. Finally, we will describe both preclinical and early clinical data regarding novel targeted strategies for treating BPDCN without the use of cytotoxic chemotherapy, with a focus on the use of CD123 directed therapy.
While the current standard treatment for BPDCN is acute leukemia-based regimen followed by hematopoietic stem cell transplantation for transplant-eligible patients, there are very promising results for CD123 directed therapies. The future of BPDCN treatment may include targeted therapies without the need for cytotoxic chemotherapy.
•FAAH inhibition attenuates TLR3-mediated microglia/macrophage activation in the hypothalamus.•FAAH inhibition attenuates TLR3-mediated fever and allodynia, but not hypolocomotion or body weight ...loss.•FAAH inhibition attenuates TLR3-mediated anxiety-, but not depressive-like behavior.
Aberrant activation of toll-like receptor (TLR)s results in persistent and prolonged neuroinflammation and has been implicated in the pathogenesis and exacerbation of psychiatric and neurodegenerative disorders. TLR3 coordinates the innate immune response to viral infection and recent data have demonstrated that inhibiting fatty acid amide hydrolase (FAAH), the enzyme that primarily metabolizes anandamide, modulates TLR3-mediated neuroinflammation. However, the physiological and behavioural consequences of such modulation are unknown. The present study examined the effect of URB597, a selective FAAH inhibitor, on neuroinflammation, physiological and behavioural alterations following administration of the TLR3 agonist and viral mimetic poly I:C to female rats. URB597 attenuated TLR3-mediated fever, mechanical and cold allodynia, and anxiety-like behaviour in the elevated plus maze and open field arena. There was no effect of URB597 on TLR3-mediated decreases in body weight and no effect in the sucrose preference or forced swim tests. URB597 attenuated the TLR3-mediated increase in the expression of CD11b and CD68, markers of microglia/macrophage activation. In summary, these data demonstrate that enhancing FAAH substrate levels suppresses TLR3-mediated microglia/macrophage activation and associated changes in fever, nociceptive responding and anxiety-related behaviour. These data provide further support for FAAH as a novel therapeutic target for neuroinflammatory disorders.
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