Does the efficacy of neurodynamic treatments depend on the presence and type of criteria used to define neural mechanosensitivity in spinally-referred leg pain? A systematic review and meta-analysis.

Background: It remains unclear whether definite neural mechanosensitivity (NM) is required for neural mobilisations to be beneficial in people with spinally referred leg pain. Objective: To determine whether the efficacy of neural mobilisations in patients with spinally referred leg pain depends on the presence and type of criteria used to define NM. Method: PubMed, CINAHL, Cochrane Central Register of Controlled Trials, PEDro and Science Direct were searched from 1980 to March 2020. Randomised controlled trials evaluating the efficacy of neural mobilisations on pain and disability in spinally referred leg pain were included. Studies were grouped according to the certainty of NM into NMdefinite, NMunclear, NMuntested and NMabsent. Effects on pain and disability and subgroup differences were examined. Results: We identified 21 studies in 914 patients (3 NMdefinite, 16 NMunclear, 2 NMuntested, 0 NMabsent). Meta-analysis revealed medium to large effect sizes on pain for neurodynamic compared to control interventions in NMdefinite and NMunclear groups. For disability, neurodynamic interventions had medium to large effects in NMunclear but not NMdefinite groups. NMuntested studies could not be pooled. Conclusion: The nonexistence of studies in patients with negative neurodynamic tests prevents inferences whether neural mobilisations are effective in the absence of NM. The criteria used to define NM may not impact substantially on the efficacy of neural mobilisations. The mostly high risk of bias and heterogeneity prevents firm conclusions. Clinical implications: Neural mobilisations seem beneficial to reduce pain and disability in spinally referred leg pain independent of the criteria used to interpret neurodynamic tests.

Susceptibility of Rice to Oebalus pugnax (F.) (Hemiptera: Pentatomidae) Feeding at Different Levels of Grain Maturity and Impacts on Insecticide Termination.

The stages of rice, Oryza sativa L. (Poales: Poaceae), grain maturity that are most susceptible to rice stink bug, Oebalus pugnax (F.), damage have been identified; however, the stage at which they are no longer capable of causing appreciable damage during grain maturity is unclear. The objective of this study was to determine the susceptibility of rice to rice stink bug feeding at different levels of grain maturity and determine an insecticide termination timing. Rice stink bug damage was examined using five levels of grain maturity described as percent of kernels reaching mature straw coloration referred to as hard dough (20, 40, 60, 80, and 100%) across a range of infestation levels using single panicle sleeve cages and large cages. Hybrid and conventional cultivar rice panicles at 20, 40, and 60% hard dough were found to be susceptible to indirect yield loss, as two rice stink bugs per panicle resulted in over 7% peck. In large cage trials, 25 rice stink bugs caused 0.7-1% peck to hybrid and conventional rice plots at 20% hard dough. Much less damage was observed once rice reached 60% hard dough, where peck averages only reached 0.4%. Decreased damage at 60% hard dough was validated using uncaged trials where 0.4% additional peck was observed in unsprayed plots. These data indicate that rice in the early stages of hard dough is susceptible to large levels of indirect yield loss, but unless significant densities of rice stink bug are present at 60% hard dough, no more sampling or applications are necessary.

Neck pain in South Africa: An overview of the prevalence, assessment and management for the contemporary clinician.

BACKGROUND: Neck pain is a prevalent condition and is associated with high levels of disability and pain. The long-term prognosis can be poor, and therefore effective management in the acute stage is important. OBJECTIVES: To provide an overview of the prevalence of neck pain and physiotherapy management and to provide evidence-informed recommendations for clinical practice within a South African context. METHOD: The literature was reviewed considering prevalence, risk factors and examination. Management recommendations were derived from the highest levels of evidence of clinical practice guidelines, systematic reviews and randomised clinical trials. RESULTS: Neck pain is classified into four grades, and three trajectories of recovery have been identified. Although the incidence of neck pain globally is high, in the South African context the majority of the population have limited access to physiotherapy management. Sound clinical reasoning is important in the assessment and decision-making process for management. Exercise, and mobilisation or manipulation are effective treatment options in the management of most types of neck pain. Other physical modalities such as needling, transcutaneous electrical nerve stimulation, laser and intermittent traction may be used as an adjunct to management. CONCLUSION: The burden of neck pain globally is high; however, there is a lack of information on current practice, prevalence and burden of neck pain in the South African context. Sound evidence-informed clinical reasoning to inform a working diagnosis and to enable patient-centred management is important. CLINICAL IMPLICATIONS: A thorough assessment is essential to gather information to formulate hypotheses regarding diagnosis and prognosis for neck pain. Exercise, and mobilisation or manipulation are effective management options.

Geographic Variation in Phosphine Resistance Among North American Populations of the Red Flour Beetle (Coleoptera: Tenebrionidae).

The red flour beetle, Tribolium castaneum (Herbst), is a common stored-product pest found worldwide. Phosphine, hydrogen phosphide (PH3), is the most commonly used fumigant for stored grains, for which genetically based resistance has been recorded for several pest species. This study assessed phosphine resistance in 25 T. castaneum populations from across the United States and Canada using a discriminating dose bioassay. Dose-mortality assays were conducted with adults from seven of these populations to categorize weak and strong resistance phenotypes. Phosphine resistance was detected in 12 out of the 25 populations, and the frequency of resistance within populations varied from 2% in Victoria, TX, to 100% in Red Level, AL. Two resistant populations from Kansas that had been sampled three years earlier were found to have similar resistance frequencies in the current study. None of the four Canadian populations had any detectable resistance among the insects tested. Resistance ratio calculations from LC50 value in resistant populations relative to the LC50 for the laboratory susceptible strain allowed resistance phenotypes to be assigned as either weak resistance, at 5- to 26-fold resistance relative to susceptible, or strong resistance at 95- to 127-fold relative to susceptible. This study suggests that proper resistance assessment techniques can help to determine occurrence of phosphine resistance in populations of T. castaneum and can further characterize the strength of resistance present. These data can be used to support resistance management programs that consider either cessation or modification of phosphine fumigation to control T. castaneum.

The effect of neural mobilisation on cervico-brachial pain: design of a randomised controlled trial.

BACKGROUND: Neck pain is a common musculoskeletal complaint and is often associated with shoulder or arm pain. There is a paucity of information on effective treatment for neck and arm pain, such as radiculopathy or cervico-brachial pain. Guidelines recommend neck mobilisation/ manipulation, exercises and advice as the treatment for neck pain, and neck and arm pain. There are a few studies that have used neural mobilisation as the treatment for cervico-brachial pain. Although results seem promising the studies have small sample sizes that make it difficult to draw definite conclusions. METHODS: A randomised controlled trial will be used to establish the effect of neural mobilisation on the pain, function and quality of life of patients with cervico-brachial pain. Patients will be recruited in four physiotherapy private practices and randomly assigned to usual care or usual care plus neural mobilisation. DISCUSSION: In clinical practice neural mobilisations is commonly used for cervico-brachial pain. Although study outcomes seem promising, most studies have small participant numbers. Targeting the neural structures as part of the management plan for a subgroup of patients with nerve mechano-sensitivity seems feasible. Patients with neuropathic pain and psychosocial risk factors such as catastrophising, respond poorly to treatment. Although a recent study found these patients less likely to respond to neural mobilisation, the current study will be able to assess whether neural mobilisation has any added benefit compared to usual care. The study will contribute to the knowledge base of treatment of patients with cervico-brachial pain. The findings of the study will be published in an appropriate journal. TRIAL REGISTRATION NUMBER: PACTR201303000500157.

Assessing a Norwegian translation of the Organizational Climate Measure.

This study investigated the Norwegian translation of the Organizational Climate Measure developed by Patterson and colleagues. The Organizational Climate Measure is a global measure of organizational climate based on Quinn and Rohrbaugh's competing values model. The survey was administered to a Norwegian branch of an international service sector company (N = 555). The results revealed satisfactory internal reliability and interrater agreement for the 17 scales, and confirmatory factor analysis supported the original factor structure. The findings gave preliminary support for the Organizational Climate Measure as a reliable measure with a stable factor structure, and indicated that it is potentially useful in the Norwegian context.

PEST-domain-enriched tyrosine phosphatase and glucocorticoids as regulators of anaphylaxis in mice.

BACKGROUND: PEST-domain-enriched tyrosine phosphatase (PEP) is a protein tyrosine phosphatase exclusively expressed in hematopoietic cells. It is a potent negative regulator of T-cell receptor signalling that acts on receptor-coupled protein tyrosine kinases. PEST-domain-enriched tyrosine phosphatase is also expressed in mast cell and is positively regulated by glucocorticoids, but its function is unknown. In this communication, the function of PEP is analysed in mast cells. METHODS: Signal transduction cascades following IgE receptor cross-linking were compared in bone marrow-derived mast cells (BMMC) from PEP(-/-) and PEP(+/+) mice. Furthermore, antigen-induced passive systemic anaphylaxis (PSA) was analysed in PEP(+/+) and PEP(-/-) mice. RESULTS: Bone marrow-derived mast cells from PEP(-/-) mice showed impaired PLCγ1 phosphorylation and Ca(2+) mobilization. Additionally, mice deficient in PEP showed impaired mast cell degranulation and were less susceptible to PSA. Treatment of wild-type BMMC or mice with an Au(I)-phosphine complex that selectively inhibits PEP activity produced defects in Ca(2+) signalling pathway and reduced anaphylaxis similar to that caused by the deletion of the PEP gene. Glucocorticoid that negatively regulates a wide range of mast cell action increased PEP expression and only partially inhibited anaphylaxis. However, glucocorticoid potently inhibited anaphylaxis when combined with the PEP inhibitor. CONCLUSIONS: PEST-domain-enriched tyrosine phosphatase is an important positive regulator of anaphylaxis. Pharmacological inhibition of its activity together with glucocorticoid administration provide an effective rescue for PSA in mice.

Effects of socio-emotional stressors on ventilation rate and subjective workload during simulated CPR by lay rescuers.

Several studies have documented the occurrence of high ventilation rates during cardiopulmonary resuscitation, but to date, there have been no scientific investigation of the causes of hyperventilation. The objective of the current study was to test the effects of socio-emotional stressors on lay rescuers' ventilation rate in a simulated resuscitation setting using a manikin model. A within-subjects experiment with randomized order of conditions tested lay rescuers' ventilation rate on an intubated manikin during exposure to socio-emotional stressors and during a control condition where no external stressors were present. Ventilation rates and subjective workload were significantly higher during exposure to socio-emotional stressors than during the control condition. All but one of the nine participants ventilated at a higher ventilation rate in the experimental condition. All nine participants rated the subjective workload to be higher during exposure to socio-emotional stressors. Hence, exposure to socio-emotional stressors is associated with increased ventilation rates performed by lay rescuers during simulated cardiac arrest using a manikin model. These findings might have implications for the understanding of the type of situations which hyperventilation may occur. Awareness of these situations may have implications for training of lay rescues.

Overexpression and gene amplification of BAG-1L in hormone-refractory prostate cancer.

BAG-1L (Bcl-2-associated anthanogene 1) has been found to interact with androgen receptor (AR), and has been suggested to be involved in the development of prostate cancer. In order to determine the presence of genetic and/or expression alterations of BAG-1L in prostate cancer, we analysed human prostate cancer cell lines and xenografts as well as patient samples of untreated, hormone-naïve, and hormone-refractory prostate carcinomas for sequence variations using denaturing high-performance liquid chromatography (DHPLC), for gene copy number using fluorescence in situ hybridization (FISH), and for expression using both quantitative RT-PCR and immunostaining. Only one sequence variation was found in all 37 cell lines and xenografts analysed. BAG-1 gene amplification was detected in two xenografts. In addition, gene amplification was found in 6 of 81 (7.4%) hormone-refractory clinical tumours, whereas no amplification was found in any of the 130 untreated tumours analysed. Additionally, gain of the BAG-1 gene was observed in 27.2% of the hormone-refractory tumours and in 18.5% of the untreated carcinomas. In a set of 263 patient samples, BAG-1L protein expression was significantly higher in hormone-refractory tumours than in primary tumours (p = 0.002). Altogether, these data suggest that amplification and overexpression of BAG-1L may be involved in the progression of prostate cancer.

Aplidin induces JNK-dependent apoptosis in human breast cancer cells via alteration of glutathione homeostasis, Rac1 GTPase activation, and MKP-1 phosphatase downregulation.

Aplidin is an antitumor agent in phase II clinical trials that induces apoptosis through the sustained activation of Jun N-terminal kinase (JNK). We report that Aplidin alters glutathione homeostasis increasing the ratio of oxidized to reduced forms (GSSG/GSH). Aplidin generates reactive oxygen species and disrupts the mitochondrial membrane potential. Exogenous GSH inhibits these effects and also JNK activation and cell death. We found two mechanisms by which Aplidin activates JNK: rapid activation of Rac1 small GTPase and downregulation of MKP-1 phosphatase. Rac1 activation was diminished by GSH and enhanced by L-buthionine (SR)-sulfoximine, which inhibits GSH synthesis. Downregulation of Rac1 by transfection of small interfering RNA (siRNA) duplexes or the use of a specific Rac1 inhibitor decreased Aplidin-induced JNK activation and cytotoxicity. Our results show that Aplidin induces apoptosis by increasing the GSSG/GSH ratio, a necessary step for induction of oxidative stress and sustained JNK activation through Rac1 activation and MKP-1 downregulation.

BAG-1 family of cochaperones in the modulation of nuclear receptor action.

BAG-1 is a family of cochaperones consisting of at least four polypeptides BAG-1L, BAG-1M/RAP46, BAG-1 and p29. These proteins are translated from the same mRNA at alternative translation initiation sites. They possess conserved carboxy-terminal sequences which enable them to bind and inhibit the action of the molecular chaperone Hsp70/Hsc70. BAG-1 was the first member in the family of the BAG-1 proteins to be isolated. It was identified as an anti-apoptotic protein because of its ability to bind and augment the activity of the anti-death protein, Bcl-2. Since then other BAG-1 proteins have been identified and shown to interact with several cellular factors including nuclear receptors. Recent findings show that the effect of the BAG-1 proteins on nuclear receptors ranges from inhibition to enhancement of the transactivation functions of the receptors. Available data on the negative regulation of glucocorticoid receptor (GR) action by the BAG-1 proteins identify two modes of action: inhibition of the hormone binding activity of the GR and a more direct nuclear action at the level of regulation of the transactivation function of the receptor. In the latter case, the BAG-1 proteins repress DNA binding by the GR in a process that requires prior binding of Hsp70/Hsc70 to the receptor. Positive regulatory action of the BAG-1 proteins on nuclear receptors has also been reported which may involve yet other mechanisms. This review puts together recent findings on the action the BAG-1 proteins and presents them as a novel group of regulators of action of nuclear receptor.

Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1.

Glucocorticoids inhibit the proinflammatory activities of transcription factors such as AP-1 and NF-kappa B as well as that of diverse cellular signaling molecules. One of these signaling molecules is the extracellular signal-regulated kinase (Erk-1/2) that controls the release of allergic mediators and the induction of proinflammatory cytokine gene expression in mast cells. The mechanism of inhibition of Erk-1/2 activity by glucocorticoids is unknown. Here we report a novel dual action of glucocorticoids for this inhibition. Glucocorticoids increase the expression of the MAP kinase phosphatase-1 (MKP-1) gene at the promoter level, and attenuate proteasomal degradation of MKP-1, which we report to be triggered by activation of mast cells. Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation. In NIH-3T3 fibroblasts, although glucocorticoids up-regulate the MKP-1 level, they do not attenuate the proteasomal degradation of this protein and consequently they are unable to inhibit Erk-1/2 activity. These results identify MKP-1 as essential for glucocorticoid-mediated control of Erk-1/2 activation and unravel a novel regulatory mechanism for this anti-inflammatory drug.

Azone enhances clinical effectiveness of an optimized formulation of triamcinolone acetonide in atopic dermatitis.

BACKGROUND: Atopic dermatitis is a chronic, relapsing condition affecting up to 14% of the population in Western countries. Topical corticosteroids are the mainstay of treatment. Triamcinolone acetonide, a corticoid of intermediate potency, has proven useful in the treatment of atopic dermatitis. AIM: To evaluate the effectiveness of a triamcinolone acetonide-laurocapram combination in the treatment of atopic dermatitis. METHODS: One hundred and fifty patients were enrolled in a three-arm, parallel group, controlled clinical trial evaluating the effectiveness of a triamcinolone acetonide (0.05%) and laurocapram combination, applied twice daily for 2 weeks, in the treatment of atopic dermatitis. Fifty patients received triamcinolone acetonide-laurocapram (TNX), 50 triamcinolone acetonide (TN), and 50 a vehicle control formulation (AN). Response to treatment was evaluated by change in disease severity at 6 h, at 3, 8, and 15 days after the start of treatment, and by the global change in disease status. RESULTS: TNX effected a significantly higher degree of improvement in the signs and symptoms of atopic dermatitis (erythema, induration, and pruritus) and a greater overall improvement in disease status compared with treatment with TN or AN. Treatment-associated side-effects were local reactions, occurring in three, two, and six patients in the TNX, TN, and AN groups, respectively. CONCLUSIONS: The results suggest that the incorporation of laurocapram in the formulation enhances the effectiveness of triamcinolone acetonide, without compromising its safety profile.

Expression level-dependent contribution of glucocorticoid receptor domains for functional interaction with STAT5.

The action of the glucocorticoid receptor (GR) on beta-casein gene transcription serves as a well-studied example of a case where the action of the GR is dependent on the activity of another transcription factor, STAT5. We have investigated the domain-requirement of the GR for this synergistic response in transfection experiments employing GR mutants and CV-1 or COS-7 cells. The results were influenced by the expression levels of the GR constructs. At low expression, STAT5-dependent transactivation by mutants of the GR DNA binding domain or N-terminal transactivation domain was impaired and the antiglucocorticoid RU486 exhibited a weak agonistic activity. When the N-terminal region of the GR was exchanged with the respective domain of the progesterone receptor, STAT5-dependent transactivation was reduced at low and high expression levels. Only at high expression levels did the GR exhibit the properties of a coactivator and enhanced STAT5 activity in the absence of a functional DNA binding domain and of GR binding sites in the proximal region of the beta-casein gene promoter. Furthermore, at high GR expression levels RU486 was nearly as efficient as dexamethasone in activating transcription via the STAT5 dependent beta-casein gene promoter. The results reconcile the controversial issue regarding the DNA binding-independent action of the GR together with STAT5 and provide evidence that the mode of action of the GR depends not only on the type of the particular promoter at which it acts but also on the concentration of the GR. GR DNA binding function appears to be mandatory for beta-casein gene expression in mammary epithelial cells, since the promoter function is completely dependent on the integrity of GR binding sites in the promoter.

Alteration of the stability of Bag-1 protein in the control of olfactory neuronal apoptosis.

Normal apoptosis occurs continuously in the olfactory neuroepithelium of adult vertebrates, making it a useful model for studying neuronal apoptosis. Here we demonstrate that overexpression of the anti-apoptotic Bag-1 gene in olfactory neuronal cells confers a strong resistance to apoptosis. Conversely decreased levels of Bag-1 were found to precede a massive wave of olfactory neuronal apoptosis triggered by synaptic target ablation. We show that the decrease is brought about by ubiquitination and subsequent degradation of the Bag-1 protein. The ring finger protein Siah-2 is a likely candidate for the ubiquitination reaction since Siah-2 mRNA accumulated in lesioned olfactory neuroepithelium and overexpression of Siah-2 stimulated Bag-1 ubiquitination and degradation in transient expression assays. These results together identify destabilization of Bag-1 as a necessary step in olfactory neuronal apoptosis.

Hsp70-RAP46 interaction in downregulation of DNA binding by glucocorticoid receptor.

Receptor-associating protein 46 (RAP46) is a cochaperone that regulates the transactivation function of several steroid receptors. It is transported into the nucleus by a liganded glucocorticoid receptor where it downregulates DNA binding and transactivation by this receptor. The N- and C-termini of RAP46 are both implicated in its negative regulatory function. In metabolic labelling experiments, we have shown that the N-terminus of RAP46 is modified by phosphorylation, but this does not contribute to the downregulation of glucocorticoid receptor activity. However, deletion of a sequence that binds 70 kDa heat shock protein (Hsp70) and the constitutive isoform of Hsp70 (Hsc70) at the C-terminus of RAP46 abrogated its negative regulatory action. Surface plasmon resonance studies showed that RAP46 binds the glucocorticoid receptor only when it has interacted with Hsp70/Hsc70, and confocal immunofluorescence analyses revealed a nuclear transport of Hsp70/Hsc70 by the liganded receptor. Together these findings demonstrate an important contribution of Hsp70/Hsc70 in the binding of RAP46 to the glucocorticoid receptor and suggest a role for this molecular chaperone in the RAP46-mediated downregulation of glucocorticoid receptor activity.

Initial clinical trial of a high-affinity retinoic acid receptor ligand (LGD1550).

Retinoids mediate their biological response by binding to specific nuclear receptors, including retinoic acid receptors and/or retinoid X receptors. LGD1550 is a high-affinity ligand for all three retinoic acid receptors (alpha, beta, and gamma isoforms) and a potent inhibitor of AP-1, a protein that is closely linked with trophic responses and malignant transformation. We conducted a dose ranging study to evaluate the pharmacokinetics, safety, clinical tolerance, and potential efficacy of this drug in patients with advanced cancer. Twenty-seven patients received oral doses of LGD1550 once per day at doses ranging from 20-400 microg/m2. Skin toxicity was the dose-limiting reaction at the 400 microg/m2 daily dose level. Less prominent reactions included nausea and headache. No major antitumor effects were observed. Pharmacokinetic studies in 15 patients at five dose levels showed that the peak plasma concentration (Cmax) and areas under the plasma concentration-time curve on day 1 were dose-proportional and were similar to values obtained on days 15, 29, and 84. Unlike other retinoids, LGD1550 did not induce its own metabolism, and there was little evidence of drug accumulation. The t1/2 was approximately 5 h after both the initial and repeated doses. We conclude that once-daily doses of LGD1550 of up to 300 microg/m2 are relatively well tolerated. Additional clinical explorations are warranted, especially in patients with cancers of the prostate, thyroid, head and neck, and cervix.

BAG-1M: a potential specificity determinant of corticosteroid receptor action.

BAG-1M is a eukaryotic cochaperone that associates with several proteins, including the glucocorticoid receptor (GR). It down-regulates GR-mediated transactivation by a mechanism that requires its prior recruitment by the liganded receptor from cytoplasm into the nucleus. In the nucleus, it uses a repeated sequence motif ([EEX4]8) at its NH2 terminus to inhibit DNA binding, as well as transactivation functions of the receptor. The mineralocorticoid receptor (MR), a structural and functional homologue of the GR, is unable to translocate BAG-1M into the nucleus, and its transactivation function is also not affected by this protein. This differential regulation of GR and MR activity could be relevant in classic mineralocorticoid tissues such as the kidney in which GR activity needs to be repressed to allow the MR to exert its action. In in situ hybridization studies, we show that BAG-1M is expressed in the kidney. Its expression pattern, especially in the developing kidney, correlated well with that of the GR. We therefore postulate that BAG-1M may be a specificity determinant in GR and MR action, and may feature prominently in the control of GR activity in kidney development.