Do "central sensitization" questionnaires reflect measures of nociceptive sensitization or psychological constructs? A systematic review and meta-analyses.

ABSTRACT: Central sensitization (CS) is defined as an increased nociceptive responsiveness due to sensitization of neurons in the central nervous system, usually the result of prolonged nociceptive input or a disease state associated with noxious inputs (eg, polyarthritis). The concept of CS has recently been adopted in clinical assessments of chronic pain, but its diagnosis in humans may now include a wide range of hypervigilant responses. The purpose of this review is to ascertain whether self-report questionnaires linked with CS are associated with enhanced nociceptive responses or whether they measure sensitivity in a broader sense (ie, emotional responses). According to our published, PROSPERO-registered review protocol (CRD42021208731), a predefined search of studies that involve the Central Sensitization Inventory (CSI) or Pain Sensitivity Questionnaire (PSQ), correlated with either nociceptive sensory tests or emotional hypervigilance was conducted on MEDLINE, PsycINFO, and Web of Science. Correlations between the CSI or PSQ with our primary outcomes were extracted and meta-analysed. A review of 66 studies totalling 13,284 participants found that the CSI (but not the PSQ) strongly correlated with psychological constructs: depression, anxiety, stress, pain catastrophising, sleep, and kinesiophobia. The CSI and PSQ showed weak or no correlations with experimental measures of nociceptive sensitivity: pain thresholds, temporal summation, or conditioned pain modulation. The PSQ did, however, correlate strongly with phasic heat and tonic cold pain tests. The studies reviewed did not provide sufficient evidence that self-report measures reflect a canonical understanding of CS. The CSI more closely reflects psychological hypervigilance than increased responsiveness of nociceptive neurons.

Do "central sensitization" questionnaires reflect measures of nociceptive sensitization or psychological constructs? Protocol for a systematic review.

INTRODUCTION: Central sensitization (CS) was first defined in animal studies to be increased nociceptive responsiveness due to sensitization of neurons in the central nervous system, usually the result of prolonged nociceptive input or a disease state. Recently, the concept of CS has been adopted in clinical assessments of chronic pain, but its diagnosis in humans has expanded to include the enhancement of a wide range of nociceptive, sensory, and emotional responses. Many poorly understood pain disorders are referred to as "central sensitivity syndrome," a term associated with a broad range of hypervigilant sensory and emotional responses. Diagnosis often involves a review of medical records and an assessment of behaviour, emotional disposition, and overall sensitivity of a patient. Obviously, these assessments are unable to directly capture the responsiveness of nociceptive neurons. The purpose of this review is to ascertain whether self-report questionnaires associated with central sensitization and the diagnosis of central sensitivity syndrome are associated with enhanced nociceptive responses or whether they more validly measure sensitivity in a broader sense (ie, including emotional responses). METHODS: Following the PRISMA guidelines, a detailed search of studies that involve the Central Sensitization Inventory or Pain Sensitivity Questionnaire correlated with either nociceptive sensory tests (quantitative sensory testing) or emotional hypervigilance (anxiety, depression, stress, etc) will be conducted on MEDLINE, PsychINFO, and Web of Science. PERSPECTIVE: The review is expected to synthesize correlations between sensitivity questionnaires and nociceptive or emotional sensitivity to determine whether these questionnaires reflect a broadened understanding of the term "central sensitization."

Acute Responses to Resistance and High-Intensity Interval Training in Early Adolescents.

Harris, NK, Dulson, DK, Logan, GRM, Warbrick, IB, Merien, FLR, and Lubans, DR. Acute responses to resistance and high-intensity interval training in early adolescents. J Strength Cond Res 31(5): 1177-1186, 2017-The purpose of this study was to compare the acute physiological responses within and between resistance training (RT) and high-intensity interval training (HIIT) matched for time and with comparable effort, in a school setting. Seventeen early adolescents (12.9 ± 0.3 years) performed both RT (2-5 repetitions perceived short of failure at the end of each set) and HIIT (90% of age-predicted maximum heart rate), equated for total work set and recovery period durations comprising of 12 "sets" of 30-second work followed by 30-second recovery (total session time 12 minutes). Variables of interest included oxygen consumption, set and session heart rate (HR), and rate of perceived exertion, and change in salivary cortisol (SC), salivary alpha amylase, and blood lactate (BL) from presession to postsession. Analyses were conducted to determine responses within and between the 2 different protocols. For both RT and HIIT, there were very large increases pretrial to posttrial for SC and BL, and only BL increased greater in HIIT (9.1 ± 2.6 mmol·L) than RT (6.8 ± 3.3 mmol·L). Mean set HR for both RT (170 ± 9.1 b·min) and HIIT (179 ± 5.6 b·min) was at least 85% of HRmax. V[Combining Dot Above]O2 over all 12 sets was greater for HIIT (33.8 ± 5.21 ml·kg·min) than RT (24.9 ± 3.23 ml·kg·min). Brief, repetitive, intermittent forays into high but not supramaximal intensity exercise using RT or HIIT seemed to be a potent physiological stimulus in adolescents.

Adolescent physical activity levels: discrepancies with accelerometer data analysis.

This study investigated the effects of epoch length and cut point selection on adolescent physical activity intensity quantification using vertical axis and vector magnitude (VM) measurement with the ActiGraph GT3X+ accelerometer. Four hundred and nine adolescents (211 males; 198 females) aged 12-16 years of age wore accelerometers during waking hours. The GT3X+ acceleration counts were reintegrated into 1, 5, 15, 30 and 60 s epoch lengths for both vertical axis and VM counts. One cut point was applied to vertical axis counts and three different cut points were applied to VM counts for each epoch length. Significant differences (P < 0.01) in mean total counts per day were observed between vertical axis and VM counts, and between epoch lengths for VM only. Differences in physical activity levels were observed between vertical and VM cut points, and between epoch lengths across all activity intensities. Our findings illustrate the magnitude of differences in physical activity outcomes that occur between axis measurement, cut points and epoch length. The magnitude of difference across epoch length must be considered in the interpretation of accelerometer data and seen as a confounding variable when comparing physical activity levels between studies.

Anthocyanin leaf markings are regulated by a family of R2R3-MYB genes in the genus Trifolium.

Anthocyanin pigments accumulate to form spatially restricted patterns in plants, particularly in flowers, but also occur in vegetative tissues. Spatially restricted anthocyanin leaf markings are poorly characterised in plants, but are common in forage legumes. We hypothesised that the molecular basis for anthocyanin leaf markings in Trifolium spp. is due to the activity of a family of R2R3-MYB genes. R2R3-MYB genes were identified that are associated with the two classic pigmentation loci in T. repens. The R locus patterns 'red leaf', 'red midrib' and 'red fleck' are conditioned by a single MYB gene, RED LEAF. The 'diffuse red leaf' trait is regulated by the RED LEAF DIFFUSE MYB gene. The V locus was identified through mapping two V-linked traits, 'V-broken yellow' (Vby) and 'red leaflet' (Vrl). Two highly similar R2R3-MYB genes, RED V-a and RED V-b, mapped to the V locus and co-segregated with the RED V pigmentation pattern. Functional characterisation of RED LEAF and RED V was performed, confirming their function as anthocyanin regulators and identifying a C-terminal region necessary for transactivation. The mechanisms responsible for generating anthocyanin leaf markings in T. repens provide a valuable system to compare with mechanisms that regulate complex floral pigmentation.

A review of adolescent high-intensity interval training.

Despite the promising evidence supporting positive effects of high-intensity interval training (HIIT) on the metabolic profile in adults, there is limited research targeting adolescents. Given the rising burden of chronic disease, it is essential to implement strategies to improve the cardiometabolic health in adolescence, as this is a key stage in the development of healthy lifestyle behaviours. This narrative review summarises evidence of the relative efficacy of HIIT regarding the metabolic health of adolescents. Methodological inconsistencies confound our ability to draw conclusions; however, there is meaningful evidence supporting HIIT as a potentially efficacious exercise modality for use in the adolescent cohort. Future research must examine the effects of various HIIT protocols to determine the optimum strategy to deliver cardiometabolic health benefits. Researchers should explicitly show between-group differences for HIIT intervention and steady-state exercise or control groups, as the magnitude of difference between HIIT and other exercise modalities is of key interest to public health. There is scope for research to examine the palatability of HIIT as an exercise modality for adolescents through investigating perceived enjoyment during and after HIIT, and consequent long-term exercise adherence.

The impact of health checks for people with intellectual disabilities: a systematic review of evidence.

BACKGROUND: Health checks for people with intellectual disabilities (ID) have been recommended as one component of health policy responses to the poorer health of people with ID. This review summarises evidence on the impact of health checks on the health and well-being of people with ID. METHODS: Electronic literature searches and email contacts were used to identify literature relevant to the impact of health checks for people with ID. RESULTS: A total of 38 publications were identified. These involved checking the health of over 5000 people with ID from a range of countries including a full range of people with ID. Health checks consistently led to detection of unmet health needs and targeted actions to address health needs. CONCLUSIONS: Health checks are effective in identifying previously unrecognised health needs, including life-threatening conditions. Future research should consider strategies for optimising the cost-effectiveness or efficiency of health checks.

A three centre study of the variability of ankle foot orthoses due to fabrication and grade of polypropylene.

This study investigates if fabrication techniques employed at different orthotic centres affect the characteristics of the manufactured plastic orthoses. Plaster models were formed from the same master mould. The thickness and bending stiffness of the supplied polypropylene sheets were measured prior to fabrication. An orthotic technician at each of the 3 orthotic centres manufactured 4 homopolymer and 4 copolymer polypropylene ankle-foot orthoses (AFOs), following each centre's fabrication practice. Another technician at one of the orthotic centres manufactured an additional 4 homopolymer and 4 copolymer AFOs. The thickness, the dorsiflexion stiffness and plantarflexion stiffness of the 32 fabricated AFOs were monitored and compared. Analysis of the results suggests: Copolymer polypropylene sheets are supplied marginally thicker than homopolymer polypropylene sheets. The difference between the thickness of the 16 copolymer and 16 homopolymer AFOs was not significant. The thickness of the AFOs manufactured in copolymer was less consistent than homopolymer. Dorsiflexion stiffness of the copolymer AFOs was less consistent than homopolymer AFOs. Although the bending stiffness of the copolymer and homopolymer sheets differed significantly, there was no significant difference between the dorsiflexion stiffness of the copolymer and homopolymer AFOs. Plantarflexion stiffness was consistent for both the copolymer and the homopolymer AFOs and there was no significant difference between the plantarflexion stiffness of the copolymer and homopolymer AFOs. The thickness and flexural stiffness of the AFOs manufactured by 2 technicians at the same centre did not differ. These results are useful benchmarks for the flexural stiffness of AFOs.

Citizens who inject drugs: the 'Fitpack' study.

Most injecting drug users have never been in drug treatment yet much research is done on samples with high treatment rates drawn from agency and peer recruited populations. This study accessed drug injectors with little or no prior drug treatment, described their characteristics, BBVI risk behaviours and feedback on services. Its results challenge some stereotypes about citizens who inject drugs. A sample of 511 'hidden' drug injectors, of whom only 28.7% had any specialist drug treatment agency contact, completed a questionnaire which was distributed with 'Fitpack' needle packs sold through community pharmacies in WA. The mean age of respondents was 26.2 years, 43.4% were women, 44.3% were living with their sexual partner, 41.7% were parents, and 46.4% were employed, mostly in full time work. In the previous month 61.2% had injected less frequently than daily. The study accessed a diverse group of drug injectors not typically seen in agency and peer recruited research. They provided useful feedback about how harm reduction strategies among injectors can be improved. However, they also reported higher rates of injecting and sharing than found previously in traditionally recruited samples of injectors which suggests there is no room for complacency regarding the potential for blood-borne viral infection (BBVI) transmission in this group.

Comparison of bending stiffness of six different colours of copolymer polypropylene.

This paper compares the bending stiffness of 5 different colours of copolymer polypropylene (CCP) with that of natural copolymer polypropylene (NCP). Flesh coloured and natural sheets are supplied thicker than other pigmented sheet. The bending stiffness of a specimen may be defined as EI, i.e. the product of E, Young's modulus of elasticity and I, the 2nd moment of area. Strips of "as supplied" (AS) and "post-draped" (PD) specimen were clamped and subjected to bending to assess the effect of pigmentation on bending characteristics. The gradient of the graph of bending deflection delta versus bending moment enables EI to be estimated. The process of thermoforming polypropylene reduces EI, the bending stiffness. However, the manual draping and vacuum procedure introduces so many variables that it is difficult to quantify the effect of pigmentation. The E of a bent specimen may be estimated from the gradient of the graph of deltaI versus bending moment. In the case of AS sheet, the effect of pigmentation on E is inconclusive. PD specimens indicate a significant reduction in E due to thermoforming. This was verified by an electron-microscope study of AS and PD specimens. Draping an ankle-foot orthosis (AFO) results in a non-uniform wall thickness. The results of this study with respect to the effects of pigmentation on the bending stiffness of AFOs are inconclusive. More detailed studies require to be completed in order to confirm which factors are responsible for this non-uniformity in wall thickness and consequent variation in bending stiffness.

Modulation of vitronectin receptor-mediated osteoclast adhesion by Arg-Gly-Asp peptide analogs: a structure-function analysis.

This study details the investigation of induction of retractile shape change in the osteoclast through inhibition of adhesion between osteoclasts and matrix with (1) peptide analogs bearing an Arg-Gly-Asp (RGD) sequence, (2) antibodies to the integrin alpha V beta 3 vitronectin receptor, and (3) the RGD-containing snake venom peptide echistatin. Osteoclast retraction on dentin has been demonstrated for GRGDSP peptide, in contrast to the inactivity of the analog containing the conservative RGE sequence modification. An osteoclast adhesion assay employing rat or chick bone cells and serum-coated glass coverslips as substrate was developed for routine evaluation of inhibition of adhesion. Antibodies F4 and F11 to the beta 3 chain of rat vitronectin receptor were effective at submicromolar concentrations in rat osteoclasts (IC50 0.29 and 0.05 microM, respectively), whereas MAb 23C6 to human/chick vitronectin receptor was somewhat less effective against chick osteoclasts (IC50 1.6 microM). A rank order of RGD analog activity (mean IC50, microM) in the serum-coated glass adhesion assay was derived for the linear peptides GRGDSP (201 microM), GRGDTP (180 microM), Ac-RGDS-NH2 (84 microM), Ac-RGDV-NH2 (68 microM), RGDV (43 microM), GRGDS (38 microM), and RGDS (26 microM). The two most potent short peptides were the cyclic analog SK&F 106760 Ac-S,S-cyclo-(Cys-(N alpha Me)Arg-Gly-Asp-Pen)-NH2 (IC50 7.0 microM), and the Telios peptide H-Gly-S,S-cyclo-(Pen-Gly-Arg-Gly-Asp-Ser-Pro-Cys)-Ala-OH (IC50 6.6 microM). The snake venom peptide echistatin was the most potent substance evaluated in the serum-coated glass assay (IC50 0.78 nM) employing either rat or chick osteoclasts.(ABSTRACT TRUNCATED AT 250 WORDS)

A human lymphoid recombinant cell line with functional human immunodeficiency virus type 1 envelope.

Our goal has been to develop a safe and effective system that would allow us to explore the functions of the human immunodeficiency virus (HIV) envelope. We have generated a human lymphoid cell line (TF228.1.16) that stably expresses functional HIV envelope proteins on its cell surface, and therefore closely mimics the viral envelope and virus-infected cells. The TF228.1.16 line forms syncytia with human cells of the CD4+ phenotype and provides a facile virus-free cell-based assay for examining the mechanism of syncytia formation and for evaluating novel agents that may disrupt this process. The TF228.1.16 cells also provide an opportunity to present the HIV envelope proteins to the immune system in cellular form. In vitro immunization of human peripheral blood mononuclear cells (PBMC) and in vivo immunization of rhesus monkeys with this reagent results in the production of antibodies with neutralizing (anti-syncytia) activities. When the HIV envelope is expressed against the background of human lymphoid cells, it may exhibit immune protection with unique properties that have not yet been explored. Our results indicate that a virus-free cell system can play an important role in exploring the biology and function of HIV-envelope proteins without the interference of other viral components present in infected cells. This paper discusses these results, and examines the potential use of TF228.1.16 as a vaccine.

Beneficial effects of SK&F 105809, a novel cytokine-suppressive agent, in murine models of endotoxin shock.

SK&F 105809 is a structurally novel dual inhibitor of lipoxygenase and cyclooxygenase-mediated arachidonic acid (AA) metabolism, which has demonstrated antiinflammatory activity in rodent models of inflammation. In addition, the active metabolite of this compound, SK&F 105561, has been shown in vitro to inhibit the production of the inflammatory cytokine interleukin-1 (IL-1) in human monocytes stimulated with lipopolysaccharide (LPS). We report here that in vitro SK&F 105561 also blocks the production of tumor necrosis factor (TNF) from human monocytes (IC50 0.8-3 microM). Furthermore, in a murine model of endotoxin shock in which animals are injected with LPS in combination with D-galactosamine (D-gal), SK&F 105809 (10, 30, and 100 mg/kg p.o.), delivered 30 min prior to LPS/D-gal, caused a dramatic reduction in serum TNF (40-90%) and protected the animals from the lethal effects of this treatment. Similar results were obtained in a second model of endotoxin shock in which mice were sensitized with Propionibacterium acnes 10 days prior to LPS injection. In this system 100-fold higher levels of serum TNF are elicited than with the LPS/D-gal model. Treatment with SK&F 105809 (30 and 100 mg/kg p.o.) delivered 30 min prior to LPS resulted in 90-100% inhibition of serum TNF. Protection from the lethal effects of LPS was observed at these doses in the P. acnes/LPS model.

Structure-function analysis of human transforming growth factor-alpha by site-directed mutagenesis.

Site-directed mutants of transforming growth factor-alpha (TGF-alpha) were expressed in an Escherichia coli outer membrane protein A (ompA) expression/secretion vector under the transcriptional control of the lambda PL promoter. TGF-alpha mutant proteins were isolated from cell pellets using alkaline extraction with 0.1 M-Tris (pH 10.5). The levels of protein expression of 23 TGF-alpha mutants were comparable with those of wild-type TGF-alpha, as determined by immunoblotting and radioimmunoassay. An analysis of biological activity using as assays radioreceptor binding competition and colony formation in soft agar showed that the following mutations destroy the activity of TGF-alpha: Gly-19 to Val, Val-33 to Pro and Gly-40 to Val. Mutations of Arg-42 to Lys, Leu-48 to Ala, Tyr-38 to Trp or Phe-17 to Tyr significantly decrease, but do not destroy, biological activity when compared with the wild-type. Mutations in 14 other residues did not significantly alter receptor binding or colony-forming activity. These studies suggest that two domains localized at the surface of TGF-alpha are important in receptor binding and colony-forming activity. Domain I involves amino acid residues which include Tyr-38 and Leu-48; domain II includes residues Phe-15, Phe-17 and Arg-42.

Antagonism of TGF-alpha receptor binding and TGF-alpha induced stimulation of cell proliferation by methyl pheophorbides.

Over 4,500 natural product extracts were screened for their abilities to inhibit binding of radiolabeled TGF-alpha to A431 cells; several plant extracts were identified as potential leads with IC50 values of less than 30 micrograms/mL. The active components of one extract were purified to homogeneity and identified as the porphyrin structures, methyl pheophorbides a and b. These compounds inhibited both TGF-alpha receptor binding and the TGF-alpha induced proliferation of NRK-49F cells in soft agar. To construct a structure-function relationship, a series of commercially available porphyrin derivatives was evaluated. The most potent compound, hematoporphyrin IX, inhibited TGF-alpha functions in a dose-dependent fashion with IC50 values slightly lower than the methyl pheophorbides. Further studies revealed that inhibition of TGF-alpha binding was light dependent and that inhibition did not involve direct competition of porphyrins for the TGF-alpha binding site. To determine the specificity of inhibition, the porphyrins were tested in a number of other receptor-ligand assays. TNF-alpha and beta-adrenoceptor bindings were unaffected, whereas IL-1 beta binding to EL-4 membranes and platelet-derived growth factor induced thymidine incorporation in NIH-3T3 cells were both antagonized by the most active porphyrins. Inhibition of TGF-beta binding to NRK-49F cells and TGF-beta-induced growth of AKR-2B cells was also observed. In summary, we report that methyl pheophorbides are naturally occurring, photodynamic antagonists of TGF-alpha, and although the inhibitory properties of these molecules were not confined to TGF-alpha alone, some level of receptor selectivity was observed.

Reduction of TGF-beta activity abrogates growth promoting tumor cell-cell interactions in vivo.

We have shown in previous studies that metastatically-competent variant subpopulations (B5, C1) derived from a non-metastatic murine mammary adenocarcinoma (SP1) have a pronounced growth advantage over their non-metastatic tumor cell counterparts in primary tumors. As a result, primary tumors can be progressively overgrown by cells having the competence to spread elsewhere in the body. This occurs despite any evidence to indicate an intrinsic in vivo growth rate advantage of the metastatic cells when grown as isolated populations. This suggested that cell-cell interactions between metastatic and non-metastatic tumor populations may be involved in the metastatic cell growth dominance process. Evidence was therefore sought for growth factors released by SP1 cells which could preferentially stimulate the B5 or C1 variants and thereby mediate this cell-cell interaction process. We found that cocultures of SP1 and C1 or B5 cells with irradiated C1, B5, or SP1 "feeder" cells showed significant stimulation of C1 and B5 by SP1 "feeder" cells. Cell growth stimulation in response to EGF, TGF-alpha, TGF-beta 1, bFGF, PDGF, NGF, IGF-1, or IGF-2 demonstrated that only TGF-beta 1 could duplicate this effect. A repeat of the coculture experiment in the presence of specific neutralizing anti-TGF-beta antibodies was therefore undertaken and this was found to markedly reduce the stimulation of C1 or B5 cells by irradiated SP1 cells. Conditioned media from the SP1 and C1 cell lines was quantitated for TGF-beta activity and contained 4.5 ng/ml and 2.0 ng/ml, respectively. However, the majority of the TGF-beta released by SP1 cells was found to be spontaneously active, whereas 70% of the TGF-beta released by C1 cells was in its latent form. Scatchard analysis revealed approximately four times the number of TGF-beta receptors, of similar type and affinity, present on C1 as compared with SP1 cells. The in vitro results support the hypothesis that active TGF-beta released by SP1 cells may stimulate the proliferation of metastatic variant cells in a paracrine like fashion. In vivo evidence for this was obtained by showing that coinjection of irradiated SP1 cells could selectively stimulate tumor growth of viable C1 cells and this effect was markedly diminished by neutralizing polyclonal anti-TGF-beta antibodies. Taken together, the results suggest a novel role for TGF-beta in clonal evolution of malignant tumor growth and as a molecular mediator of tumor cell-tumor cell interactions involved in facilitating tumor progression.