Background
Conventional tonic spinal cord stimulation (SCS) is an effective treatment for patients with therapy‐resistant complex regional pain syndrome (CRPS). Although the therapeutic effect of SCS ...can diminish over time due to tolerance, pain control can be regained by changing the pulse width and the amplitude and/or by increasing the stimulation frequency. This multicentre, double‐blind, randomized and placebo‐controlled crossover trial was conducted to investigate whether more effective pain reduction is achieved with different frequencies (trial registration, current controlled trials, ISRCTN 36655259).
Methods
The investigated settings are as follows: standard 40, 500, 1200 Hz, burst and placebo stimulation. All five were programmed in random order during the 10‐week crossover period (2 weeks/setting). The primary outcome parameters were scores on the visual analogue scale (VAS), McGill Pain Questionnaire (MPQ) and the Global Perceived Effect (GPE); at the end of the crossover period, patients decided which SCS setting they preferred. A linear mixed models analysis was performed in 29 patients who completed the crossover trial.
Results
Significant pain reduction and GPE satisfaction was achieved with four SCS settings compared with placebo stimulation, and these four settings did not differ significantly from each other. Standard stimulation was preferred by 48% of the patients, while 52% preferred non‐standard stimulation. Other than pain reduction, factors such as user‐friendliness, comfort and recharging time may have influenced the patient's final decision for the preferred stimulation setting.
Conclusions
Apparently, for various reasons, patients have a preference for different SCS setting. Therefore, future neuromodulation should aim to implement customized individual patient care by incorporating all stimulation options in one device.
Significance
This study demonstrates that standard frequency SCS is an effective therapy for patients with CRPS. However, it also demonstrates that patients can often gain better pain reduction with non‐standard frequencies of SCS. Furthermore, it shows that the preferred stimulation setting is not solely driven by the amount of pain reduction, but is also influenced by which stimulation setting feels most comfortable and provides the best user‐friendliness. Therefore, we strive to maximize the therapeutic effects of SCS in as many patients as possible. This can be achieved with customized individual patient care by incorporating the various frequencies and waveforms into one single device.
We have studied the mode of action of the insecticide spirotetramat in the nematode Caenorhabditis elegans. A combination of symptomology, forward genetics and genome editing show that spirotetramat ...acts on acetyl-CoA carboxylase (ACC) in C. elegans, as it does in insects. We found C. elegans embryos exposed to spirotetramat show a cell division defect which closely resembles the phenotype of loss-of-function mutations in the gene pod-2, which encodes ACC. We then identified two mutations in the carboxyl transferase domain of pod-2 (ACC) which confer resistance and were confirmed using CRISPR/Cas9. One of these mutations substitutes an invertebrate-specific amino acid with one ubiquitous in other taxa; this residue may, therefore, be a determinant of the selectivity of spirotetramat for invertebrates. Such a mutation may also be the target of selection for resistance in the field. Our study is a further demonstration of the utility of C. elegans in studying bioactive chemicals.
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•Spirotetramat targets acetyl-CoA carboxylase in C. elegans.•Target site mutations identify mechanisms for selectivity and resistance evolution.•C. elegans offers multiple routes for understanding chemical mechanism of action.
Essentials
peroxisome proliferator‐activated receptor γ (PPARγ) agonists inhibit platelet function.
PPARγ agonists negatively regulate outside‐in signaling via integrin αIIbβ3.
PPARγ agonists disrupt ...the interaction of Gα13 with integrin β3.
This is attributed to an upregulation of protein kinase A activity.
Summary
Background
Agonists for the peroxisome proliferator‐activated receptor (PPARγ) have been shown to have inhibitory effects on platelet activity following stimulation by GPVI and GPCR agonists.
Objectives
Profound effects on thrombus formation led us to suspect a role for PPARγ agonists in the regulation of integrin αIIbβ3 mediated signaling. Both GPVI and GPCR signaling pathways lead to αIIbβ3 activation, and signaling through αIIbβ3 plays a critical role in platelet function and normal hemostasis.
Methods
The effects of PPARγ agonists on the regulation of αIIbβ3 outside‐in signaling was determined by monitoring the ability of platelets to adhere and spread on fibrinogen and undergo clot retraction. Effects on signaling components downstream of αIIbβ3 activation were also determined following adhesion to fibrinogen by Western blotting.
Results
Treatment of platelets with PPARγ agonists inhibited platelet adhesion and spreading on fibrinogen and diminished clot retraction. A reduction in phosphorylation of several components of αIIbβ3 signaling, including the integrin β3 subunit, Syk, PLCγ2, focal adhesion kinase (FAK) and Akt, was also observed as a result of reduced interaction of the integrin β3 subunit with Gα13. Studies of VASP phosphorylation revealed that this was because of an increase in PKA activity following treatment with PPARγ receptor agonists.
Conclusions
This study provides further evidence for antiplatelet actions of PPARγ agonists, identifies a negative regulatory role for PPARγ agonists in the control of integrin αIIbβ3 outside‐in signaling, and provides a molecular basis by which the PPARγ agonists negatively regulate platelet activation and thrombus formation.
Essentials
Heat shock protein 47 (HSP47), a collagen specific chaperone is present on the platelet surface.
Collagen mediated platelet function was reduced following blockade or deletion of HSP47.
...GPVI receptor regulated signalling was reduced in HSP47 deficient platelets.
Platelet HSP47 tethers to exposed collagen thus modulating thrombosis and hemostasis.
Summary
Objective
Heat shock protein 47 (HSP47) is an intracellular chaperone protein that is vital for collagen biosynthesis in collagen secreting cells. This protein has also been shown to be present on the surface of platelets. Given the importance of collagen and its interactions with platelets in triggering hemostasis and thrombosis, in this study we sought to characterize the role of HSP47 in these cells.
Methods and Results
The deletion of HSP47 in mouse platelets or its inhibition in human platelets reduced their function in response to collagen and the GPVI agonist (CRP‐XL), but responses to thrombin were unaltered. In the absence of functional HSP47, the interaction of collagen with platelets was reduced, and this was associated with reduced GPVI‐collagen binding, signalling and platelet activation. Thrombus formation on collagen, under arterial flow conditions, was also decreased following the inhibition or deletion of HSP47, in the presence or absence of eptifibatide, consistent with a role for HSP47 in enhancing platelet adhesion to collagen. Platelet adhesion under flow to von Willebrand factor was unaltered following HSP47 inhibition. Laser‐induced thrombosis in cremaster muscle arterioles was reduced and bleeding time was prolonged in HSP47‐deficient mice or following inhibition of HSP47.
Conclusions
Our study demonstrates the presence of HSP47 on the platelet surface, where it interacts with collagen, stabilizes platelet adhesion and increases collagen‐mediated signalling and therefore thrombus formation and hemostasis.
Spinal cord stimulation (SCS) is an effective therapy to treat most patients with complex regional pain syndrome (CRPS); however, the effect is not always maintained over time. We present a case ...report of a patient successfully treated with burst SCS after a diminishing effect of conventional tonic stimulation.
Burst stimulation is a novel method of SCS consisting of delivering 5 spikes at 500 Hz, 40 times/s (pulse width 1 mseconds). The current output is set to a subthreshold level for paresthesia in the supine position.
Report of a case: A 65‐year‐old woman with CRPS in the left upper extremity experienced a diminishing effect of conventional tonic SCS over time, resulting in an increase of pain with a mean Numerical Rating Score (NRS) of 8. After treatment with burst SCS, the NRS declined to 2 and remained at that level for 2 years. An intermediate/brief period, due to increased CRPS activity, resulted in a higher pain score, which was successfully managed by increasing the burst stimulation to a higher level of subthreshold stimulation.
Discussion: In this patient with CRPS, burst SCS was successful in reducing pain scores that could no longer be achieved with conventional tonic stimulation. It appears that pain reduction with burst SCS can be sustained for a relatively long period of time.
Complex Regional Pain Syndrome (CRPS) is a disabling disease that is sometimes difficult to treat. Although spinal cord stimulation (SCS) can reduce pain in most patients with CRPS, some do not ...achieve the desired reduction in pain. Moreover, the pain reduction can diminish over time even after an initially successful period of SCS. Pain reduction can be regained by increasing the SCS frequency, but this has not been investigated in a prospective trial. This study compares pain reduction using five SCS frequencies (standard 40 Hz, 500 Hz, 1200 Hz, burst and placebo stimulation) in patients with CRPS to determine which of the modalities is most effective.
All patients with a confirmed CRPS diagnosis that have unsuccessfully tried all other therapies and are eligible for SCS, can enroll in this trial (primary implantation group). CRPS patients that already receive SCS therapy, or those previously treated with SCS but with loss of therapeutic effect over time, can also participate (re-implantation group). Once all inclusion criteria are met and written informed consent obtained, patients will undergo a baseline assessment (T0). A 2-week trial with SCS is performed and, if successful, a rechargeable internal pulse generator (IPG) is implanted. For the following 3 months the patient will have standard 40 Hz stimulation therapy before a follow-up assessment (T1) is performed. Those who have completed the T1 assessment will enroll in a 10-week crossover period in which the five SCS frequencies are tested in five periods, each frequency lasting for 2 weeks. At the end of the crossover period, the patient will choose which frequency is to be used for stimulation for an additional 3 months, until the T2 assessment.
Currently no trials are available that systematically investigate the importance of variation in frequency during SCS in patients with CRPS. Data from this trial will provide better insight as to whether SCS with a higher frequency, or with burst stimulation, results in more effective pain relief.
Current Controlled Trials ISRCTN36655259.
Cultures on corn of Fusarium moniliforme MRC 826 are known to cause leukoencephalomalacia in horses and to be toxic and hepatocarcinogenic in rats. Culture material of this F. moniliforme isolate has ...also been shown to exhibit cancer-promoting activity in a short-term cancer initiation-promotion bioassay with diethylnitrosamine-initiated rats and the induction of gamma-glutamyl-transpeptidase-positive (GGT+) foci as an endpoint after 4 weeks of promotion. This bioassay was used as a monitoring system to isolate cancer-promoting compounds from cultures of F. moniliforme MRC 826. Culture material was successively extracted with ethyl acetate and CH3OH-H2O (3:1). Most of the cancer-promoting activity was recovered in the CH3OH-H2O extract and remained in the aqueous phase following partitioning of the extract between CH3OH-H2O (1:3) and CHCl3. The CH3OH-H2O fraction was chromatographed on an Amberlite XAD-2 column, and the active fraction was eluted with CH3OH. This fraction was chromatographed on a silica gel column with CHCl3-CH3OH-CH3COOH (6:3:1) as eluent and further purified on a C18 reverse-phase column. Two pure compounds were isolated, and these have been chemically characterized and given the trivial names fumonisin B1 and B2. At least 2 g of the major compound fumonisin B1 was purified from 1kg of culture material. Fumonisin B1 in the diet (0.1%) significantly (P less than 0.001) induced the formation of GGT+ foci in the livers of initiated as well as noninitiated rats. The cancer-promoting effect of fumonisin B1 in rats was associated with a toxic effect, as evidenced by a significant (P less than 0.0005) reduction in weight gain during the 4-week promoting treatment. The principle pathological change in rats treated with fumonisin B1 was an insidious and progressive toxic hepatitis similar to that induced by toxic culture material of F. moniliforme MRC 826.
Veterinary education commenced in South Africa in 1920 at the Onderstepoort Veterinary Institute in South Africa in association with the Transvaal University College, now the University of Pretoria. ...Sir Arnold Theiler, Director of Veterinary Research and Education, was the first Dean. Today there are 46 veterinary training institutions in Africa of which 21 are in sub-Saharan Africa. Veterinary services are indispensable to the sustained health and wellbeing of animals and humans, and agricultural economies of countries worldwide. Veterinary education, postgraduate training, and research, and adequate numbers of veterinarians, are essential to satisfy the millennium development goals, the objectives of NEPAD and the African Union, and the agreements regulating international trade. The relevance of the veterinary profession internationally is currently subject to profound scrutiny. Its contributions are assessed against major environmental, demographic, political, disease, technological and economic needs. The scope of veterinary training in future will have to emphasise veterinary public health, food safety, emerging diseases, international trade, bioterrorism, and biomedical research, within the context of a one-health system focusing on the interface between wildlife, domesticated animals, humans, and their environment. Within the context of time available, it would mean reducing the time allocated to training in the field of companion animals. A brief history and scope of veterinary education; current international trends in veterinary education and provisioning; and some perspectives on future veterinary training and initiatives applicable to Africa are provided.
The presence of bovine tuberculosis (Mycobacterium bovis) in the Kruger National Park (KNP) was determined for the first time in 1990. It was diagnosed in an African buffalo (Syncerus caffer) bull, ...which was found recumbent and in an emaciated and moribund state near the south-western boundary fence. This prompted an investigation into the bovine tuberculosis (BTB) status of the KNP, with emphasis on its epidemiological determinants and risk factors. This report documents the findings of surveys that were conducted from 1990 to 1996. It was found that BTB had entered the KNP ecosystem relatively recently (+/- 1960), and has found favourable circumstances for survival and propagation in a fully susceptible and immunologically naive buffalo population. Indications are that it entered the KNP from across the southern river boundary, where the presence of infected domestic cattle herds had been documented. From there the infection spread through the southern buffalo population and is currently spreading in a northward direction. It was estimated that this northward spread took place at a rate of about 6 km per year; the prospect being that, if this rate of spread is maintained, the entire KNP may be affected in less than 30 years from now. Spillover from buffalo had already occurred in species such as chacma baboon (Papio ursinus), lion (Panthera leo), cheetah (Acinonyx jubatus), kudu (Tragelaphus strepsiceros) and leopard (Panthera pardus). Although there is no indication yet that these species act as maintenance hosts, the possibility is raised that these, or an as yet overlooked species, might assume such a role in future. In the KNP, BTB manifests itself as a chronic and predominantly subclinical disease in buffalo. It may take years for clinical signs to develop, and then only at a terminal stage, when emaciation is a constant feature. It is suspected that the time from infection to death is variable and dependent on the animal's immune response, which can be weakened by such factors as stress, old age or droughts. It was found that, in the interim, buffalo have a normal reproductive life. On necropsy, buffalo show almost exclusively lung and upper respiratory tract involvement, pointing to an aerogenous mode of transmission. Histologically, little sign of encapsulation of lesions was detected, which suggests that they are exceptionally susceptible to BTB and that most lesions are open and infectious and progressive, leading ultimately to death of the individual. Evidence also indicates that BTB is progressive within the herd context (92% being the highest prevalence rate thus far determined in a buffalo herd) as well as progressive within the KNP buffalo population (the implication being that virtually all buffalo herds in the KNP will eventually be infected). Preliminary data suggest a positive correlation between disease prevalence and mortality, with potential mortality reaching up to 10% in buffalo herds having BTB prevalence rates of 50 % and higher. Only the future will tell what the effect of the disease on the population dynamics of buffalo will be.
A semi-purified corn-based diet containing 50 mg/kg of pure (not less than 90%) fumonisin B1 (FB1), isolated from culture material of Fusarium moniliforme strain MRC 826, was fed to a group of 25 ...rats over a period of 26 months. A control group of 25 rats received the same diet without FB1. Five rats from each group were killed at 6, 12, 20 and 26 months. The liver was the main target organ in the FB1-treated rats and the hepatic pathological changes were identical to those previously reported in rats fed culture material of F.moniliforme MRC 826. All FB1-treated rats that died or were killed from 18 months onwards suffered from a micro- and macronodular cirrhosis and had large expansile nodules of cholangiofibrosis at the hilus of the liver. Ten out of 15 FB1-treated rats (66%) that were killed and/or died between 18 and 26 months developed primary hepatocellular carcinoma. Metastases to the heart, lungs or kidneys were present in four of the rats with hepatocellular carcinoma. No neoplastic changes were observed in any of the control rats. Chronic interstitial nephritis was present in the kidneys of FB1-treated rats killed after 26 months. No lesions were observed in the esophagus, heart or forestomach of FB1-treated rats and this is contrary to previous findings when culture material of the fungus was fed to rats. It is concluded that FB1 is responsible for the hepatocarcinogenic and the hepatotoxic but not all the other toxic effects of culture material of F.moniliforme MRC 826 in rats.
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