Central sensitization as a determinant of patients' benefit from total hip and knee replacement.

BACKGROUND: Discrepancies exist between osteoarthritic joint changes and pain severity before and after total hip (THR) and knee (TKR) replacement. This study investigated whether the interaction between pre-operative widespread hyperalgesia and severity of radiographic osteoarthritis (OA) was associated with pain severity before and after joint replacement. METHODS: Data were analysed from 232 patients receiving THR and 241 receiving TKR. Pain was assessed pre-operatively and at 12 months post-operatively using the WOMAC Pain Scale. Widespread hyperalgesia was assessed through forearm pressure pain thresholds (PPTs). Radiographic OA was evaluated using the Kellgren and Lawrence scheme. Statistical analysis was conducted using multilevel models, and adjusted for confounding variables. RESULTS: Pre-operative: In knee patients, there was weak evidence that the effect of PPTs on pain severity was greater in patients with more severe OA (Grade 3 OA: ß = 0.96 vs. Grade 4: ß = 4.03), indicating that in these patients higher PPTs (less widespread hyperalgesia) was associated with less severe pain. In hip patients, the effect of PPTs on pain did not differ with radiographic OA (Grade 3 OA: ß = 3.95 vs. Grade 4: ß = 3.67). Post-operative: There was weak evidence that knee patients with less severe OA who had greater widespread hyperalgesia benefitted less from surgery (Grade 3 OA: ß = 2.28; 95% CI -1.69 to 6.25). Conversely, there was weak evidence that hip patients with more severe OA who had greater widespread hyperalgesia benefitted more from surgery (Grade 4 OA: ß = -2.92; 95% CI -6.58 to 0.74). CONCLUSIONS: Widespread sensitization may be a determinant of how much patients benefit from joint replacement, but the effect varies by joint and severity of structural joint changes. SIGNIFICANCE: Pre-operative widespread hyperalgesia and radiographic osteoarthritis (OA) severity may influence how much patients benefit from joint replacement. Patients undergoing knee replacement with less severe OA and greater widespread hyperalgesia benefitted less from surgery than patients with less hyperalgesia. Patients undergoing hip replacement with more severe OA and greater widespread hyperalgesia benefitted more than patients with less hyperalgesia.

Reactogenicity, safety and immunogenicity of a protein-based pneumococcal vaccine in Gambian children aged 2-4 years: A phase II randomized study.

Pneumococcal conjugate vaccines (PCVs) have been successful in preventing invasive pneumococcal disease but effectiveness has been challenged by replacement of vaccine serotypes with non-vaccine serotypes. Vaccines targeting common pneumococcal protein(s) found in most/all pneumococci may overcome this limitation. This phase II study assessed safety and immunogenicity of a new protein-based pneumococcal vaccine containing polysaccharide conjugates of 10 pneumococcal serotypes combined with pneumolysin toxoid(dPly) and pneumococcal histidine triad protein D(PhtD) (PHiD-CV/dPly/PhtD-30) in African children. 120 Gambian children (2-4 years, not previously vaccinated against Streptococcus pneumoniae) randomized (1:1) received a single dose of PHiD-CV/dPly/PhtD-30 or PCV13. Adverse events occurring over 4 d post-vaccination were reported, and blood samples obtained pre- and 1-month post-vaccination. Serious adverse events were reported for 6 months post-vaccination. Solicited local and systemic adverse events were reported at similar frequency in each group. One child (PHiD-CV/dPly/PhtD-30 group) reported a grade 3 local reaction to vaccination. Haematological and biochemical parameters seemed similar pre- and 1-month post-vaccination in each group. High pre-vaccination Ply and PhtD antibody concentrations were observed in each group, but only increased in PHiD-CV/dPly/PhtD-30 vaccinees one month post-vaccination. One month post-vaccination, for each vaccine serotype ≥96.2% of PHiD-CV/dPly/PhtD-30 vaccinees had serotype-specific polysaccharide antibody concentrations ≥0.20µg/mL except serotypes 6B (80.8%) and 23F (65.4%), and ≥94.1% had OPA titres of ≥8 except serotypes 1 (51.9%), 5 (38.5%) and 6B (78.0%), within ranges seen in PCV13-vaccinated children. A single dose of PHiD-CV/dPly/PhtD-30 vaccine, administered to Gambian children aged 2-4 y not previously vaccinated with a pneumococcal vaccine, was well-tolerated and immunogenic.

A new TB vaccine, MVA85A, induces durable antigen-specific responses 14 months after vaccination in African infants.

This study aimed to evaluate the durability of the immunogenicity of MVA85A beyond infancy. Participants in an immunogenicity study of MVA85A administered at age of 4 months had additional evaluation 14 months after initial vaccination for IFN-γ ELISPOT responses to Ag85A peptide and ESAT6/CFP-10 and tuberculin skin test (TST). 112 children participated in this study. The anthropometry, biochemical and haematological safety profile were similar between the MVA85A recipients and controls. MVA85A recipients still had significantly higher immune responses to Ag85A compared to the controls. The majority of these children had negative responses to the TST as well as the ESAT6/CFP-10 antigens. In summary, MVA85A-vaccinated children had a persistently higher Ag85A immune response 14 months following vaccination than controls. All the children had negligible evidence of latent infection with M. tuberculosis (Mtb), suggesting that deploying a prophylactic vaccine against Mtb infection at this age could still be effective in this setting.

Pharmacological evidence favouring the use of Nauclea latifolia in malaria ethnopharmacy: effects against nociception, inflammation, and pyrexia in rats and mice.

AIM OF THE STUDY: Nauclea latifolia Smith is used traditionally in the treatment of uncomplicated malaria and painful conditions among its several other applications. The objective of this study is to investigate the pharmacological activities of the plant relevant to the symptomatic treatment of malaria fever and other painful conditions as an initial step towards developing an effective therapy for the symptomatic management of malaria fever and relief of other painful conditions. MATERIALS AND METHODS: Various concentrations of the aqueous extract of the root bark of this plant were evaluated for its anti-nociceptive, anti-inflammatory and anti-pyretic activities in mice and rats. Investigation of the anti-nociceptive activities was performed using the acetic acid-induced abdominal constriction and hot-plate tests in mice and formalin-induced pain test in rats, as models of nociception. The extract was also investigated for its effect against inflammation induced by egg-albumin and pyrexia induced by yeast in rats. RESULTS: Our data showed that the aqueous extract of Nauclea latifolia root bark (50-200mg/kg p.o.) significantly (P<0.05) attenuated writhing episodes induced by acetic acid and increased the threshold for pain perception in the hot-plate test in mice, dose-dependently. The product also remarkably decreased both the acute and delayed phases of formalin-induced pain in rats and also caused a significant reduction in both yeast-induced pyrexia and egg-albumin-induced oedema in rats. These effects were produced in a dose-dependent manner. CONCLUSION: The results suggest the presence of biologically active principles in the extract with anti-nociceptive, anti-inflammatory and anti-pyretic activities that justifies its use in malaria ethnopharmacy and subsequent development for clinical application.

Neuropharmacological effects of the aqueous extract of Nauclea latifolia root bark in rats and mice.

The present study evaluated the neuropharmacological effects of the aqueous extract of Nauclea latifolia root bark in rodents. Effects on the spontaneous motor activity (SMA), exploratory behaviour, pentobarbital sleeping time, apomorphine-induced stereotypic behaviour and motor coordination (rota-rod performance) were investigated. The extract (50-200 mg/kg p.o.) significantly (P<0.05) decreased the SMA and exploratory behaviour in mice and prolonged pentobarbital sleeping time in rats dose-dependently. The extract also remarkably attenuated the intensity of apomorphine-induced stereotypy dose-dependently in mice, but had no effect on motor coordination as determined by the performance on rota-rod. These results indicate the presence of psychoactive substances in the aqueous extract of the root bark of Nauclea latifolia.

Heart failure complicating tetralogy of Fallot.

BACKGROUND: Heart failure is considered to be an unusual complication of uncorrected tetralogy of Fallot. PATIENTS AND METHOD: Three adolescents with tetralogy of Fallot, presenting in congestive cardiac failure are presented. Two died. Myocardial infarction was found in the only patient that underwent autopsy, and is thought to be an important aetiological factor in the development of the heart failure in the patients. CONCLUSION: The cases presented illustrate the fact that heart failure complicating tetralogy of Fallot may not be as uncommon as was previously thought to be the case, especially in older children. There is a need for early diagnosis and expeditious institution of appropriate management before such complications occur.

Central nervous system activity of the methanol extract of Ficus platyphylla stem bark.

The central nervous system (CNS) activity of the methanolic extract of Ficus platyphylla stem bark was studied on locomotor activity, pentobarbital sleeping time, exploratory behaviour, amphetamine-induced hyperactivity, apomorphine-induced stereotypy, active-avoidance and performance on tread mills (rota-rod), using mice and rats. The results revealed that the extract significantly reduced the locomotor and exploratory activities in mice, prolonged pentobarbital sleeping time in rats, attenuated amphetamine-induced hyperactivity and apomorphine-induced stereotypy in mice, dose-dependently. The extract significantly suppressed the active-avoidance response in rats, with no significant effect on motor co-ordination as determined by the performance on rota-rod. The results suggest that the extract may possess sedative principles with potential neuroleptic properties.

Integration in descending motor pathways controlling the forelimb in the cat. 7. Effects from the reticular formation on C3-C4 propriospinal neurones.

Effects of stimulation in the medullary reticular formation (RF) on C3-C4 propriospinal neurones (PNs) were investigated in two series of experiments: (1) indirectly by analyzing how propriospinal transmission to forelimb motoneurones is modified by reticular stimuli; (2) directly by intracellular recording from C3-C4 neurones, which were identified as propriospinal by their antidromic activation from the C6 segment. Propriospinally mediated disynaptic EPSPs evoked in motoneurones from the pyramid (Pyr) and the red nucleus (NR) were effectively facilitated by conditioning stimulation in the RF with a time course of facilitation indicating monosynaptic linkage to the PNs. Propriospinally mediated trisynaptic IPSPs were facilitated less regularly and sometimes instead depressed by conditioning stimulation in the RF. The depression is at least partly due to inhibition of the first order PNs. Recording from C3-C4 PNs revealed that many of them were excited or inhibited by single stimuli in the RF. The brief latency of the EPSPs evoked in these neurones shows monosynaptic linkage from fast reticulospinal fibres. Some IPSPs were similarly monosynaptically evoked from fast fibres and observations are presented suggesting that longer latency IPSPs are monosynaptically mediated by slower fibres. Facilitation of propriospinal transmission to motoneurones as well as the EPSPs and IPSPs in PNs were evoked from a region within or close to the nucleus reticularis gigantocellularis. Convergence of monosynaptic EPSPs from Pyr, NR, tectum, and RF was common in C3-C4 PNs. Linear summation of the EPSPs from RF with those evoked from cortico-, rubro-, or tectospinal tracts shows that the former are not due to stimulation of collaterals which the latter tracts may have in RF. Mediation of the EPSPs and IPSPs by descending, rather than by antidromically activated ascending fibres, was indicated by temporal facilitation produced by RF stimuli, subliminal for evoking monosynaptic PSPs in the PNs. Stimulation of the labyrinth did not evoke disynaptic PSPs in any of the PNs investigated. It is concluded that the C3-C4 PNs projecting to forelimb motoneurones can be excited not only from the cortico-, rubro-, and tectospinal tracts (Illert et at. 1977, 1978) but also by reticulospinal fibres.

Crosses and uncrossed synaptic actions on motoneurones of back muscles in the cat.

Intracellular recording from motoneurones of back muscles was used to analyze their synaptic input. The sample included motoneurones located in Th13--L2 spinal segments, identified by their antidromic invasion following stimulation of medial, intermediate and lateral branches of the dorsal rami. The motoneurones were monosynaptically excited from lowest threshold ipsilateral afferents and from ipsilateral descending spinal tracts. Polysynaptic EPSPs and/or IPSPs were evoked in them from higher threshold ipsilateral and contralateral afferents and from descending spinal tracts, and recurrent inhibition was evoked from ipsilateral motor axon collaterals. There was no evidence of crossed disynaptic inhibition from group I afferents, or crossed recurrent inhibition of these neurones. Supplementary records from another group of neurones in Th13--L2 segments, unidentified but likely to innervate other back or abdominal muscles, showed monosynaptic and polysynaptic PSPs of the same origin, and in addition disynaptic IPSPs and disynaptic EPSPs from contralateral ventral roots. The crossed IPSPs had features of the crossed recurrent IPSPs, while the crossed EPSPs appeared to be more likely evoked by some afferents passing via the ventral roots. Generally, the input to the investigated neurones showed greatest similarities to the input to motoneurones of neck muscles and differed from that reported for tail motoneurones.

On the specificity of histamine H2-receptor antagonists in the rat cerebral cortex.

The effects of iontophoretically applied histamine H2-receptor antagonists and their antagonism of various amines, acetylcholine (ACh), and adenosine 5'-monophosphate (5'-AMP) were studied on spontaneously active rat cerebral cortical neurons. Metiamide selectively blocked the depressant actions of histamine. Burimamide, in amounts necessary for histamine antagonism, also antagonized the depressant effects of noradrenaline, dopamine, and 5-hydroxytryptamine. Neither antagonist affected 5'-AMP-induced depressions, but both reduced or blocked the excitatory actions of ACh. It is concluded that metiamide may be useful as a reliable antagonist of H2 receptors on cerebral cortical neurons.