Distinguishing between nociceptive and neuropathic components in chronic low back pain using behavioural evaluation and sensory examination.

BACKGROUND: Diagnosis of chronic low back pain (CLBP) is traditionally predicated on identifying underlying pathological or anatomical causes, with treatment outcomes modest at best. Alternately, it is suggested that identification of underlying pain mechanisms with treatments targeted towards specific pain phenotypes may yield more success. Differentiation between nociceptive and neuropathic components of CLBP is problematic; evidence suggests that clinicians fail to identify a significant neuropathic component in many CLBP patients. The painDETECT questionnaire (PDQ) was specifically developed to identify occult but significant neuropathic components in individuals thought to have predominantly nociceptive pain. METHODS: Using the PDQ, we classified 50 CLBP patients into two distinct groups; those with predominantly nociceptive pain (Group 1) and those with a significant neuropathic component (Group 2). We characterised these two distinct CLBP sub-groups using a) questionnaire-based behavioural evaluation measuring pain-related function and quality of life, pain intensity and psychological well-being and b) sensory examination, using two-point and tactile threshold discrimination. OBJECTIVE: We sought to determine if differences in the pain phenotype of each CLBP sub-group would be reflected in sensory and behavioural group profiles. RESULTS: We report that Group 1 and Group 2 sub-groups demonstrate unique clinical profiles with significant differences in sensory tactile discrimination thresholds and in a wide range of behavioural domains measuring pain intensity, disability and psychological well-being. CONCLUSION: We have demonstrated distinct clinical profiles for CLBP patient sub-groups classified by PDQ. Our results give diagnostic confidence in using the PDQ to characterise two distinct pain phenotypes in a heterogeneous CLBP population.

c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression.

Despite 35 years of clinical trials, there is little improvement in 1-year survival rates for patients with metastatic melanoma, and the disease is essentially untreatable if not cured surgically. The paucity of chemotherapeutic agents that are effective for treating metastatic melanoma indicates a dire need to develop new therapies. Here, we found a previously unrecognized role for c-Abl and Arg in melanoma progression. We demonstrate that the kinase activities of c-Abl and Arg are elevated in primary melanomas (60%), in a subset of benign nevi (33%) and in some human melanoma cell lines. Using siRNA and pharmacological approaches, we show that c-Abl/Arg activation is functionally relevant because it is requiredfor melanoma cell proliferation, survival and invasion. Significantly, we identify the mechanism by which activated c-Abl promotes melanoma invasion by showing that it transcriptionally upregulates matrix metalloproteinase-1 (MMP-1), and using rescue approaches we demonstrate that c-Abl promotes invasion through a STAT3 → MMP-1 pathway. Additionally, we show that c-Abl and Arg are not merely redundant, as active Arg drives invasion in a STAT3-independent manner, and upregulates MMP-3 and MT1-MMP, in addition to MMP-1. Most importantly, c-Abl and Arg not only promote in vitro processes important for melanoma progression, but also promote metastasis in vivo, as inhibition of c-Abl/Arg kinase activity with the c-Abl/Arg inhibitor, nilotinib, dramatically inhibits metastasis in a mouse model. Taken together, these data identify c-Abl and Arg as critical, novel, drug targets in metastatic melanoma, and indicate that nilotinib may be useful in preventing metastasis in patients with melanomas harboring active c-Abl and Arg.

The involvement of nitric oxide synthase neurons in enteric neuropathies.

Nitric oxide (NO), produced by the neural nitric oxide synthase enzyme (nNOS) is a transmitter of inhibitory neurons supplying the muscle of the gastrointestinal tract. Transmission from these neurons is necessary for sphincter relaxation that allows the passage of gut contents, and also for relaxation of muscle during propulsive activity in the colon. There are deficiencies of transmission from NOS neurons to the lower esophageal sphincter in esophageal achalasia, to the pyloric sphincter in hypertrophic pyloric stenosis and to the internal anal sphincter in colonic achalasia. Deficits in NOS neurons are observed in two disorders in which colonic propulsion fails, Hirschsprung's disease and Chagas' disease. In addition, damage to NOS neurons occurs when there is stress to cells, in diabetes, resulting in gastroparesis, and following ischemia and reperfusion. A number of factors may contribute to the propensity of NOS neurons to be involved in enteric neuropathies. One of these is the failure of the neurons to maintain Ca(2+) homeostasis. In neurons in general, stress can increase cytoplasmic Ca(2+), causing a Ca(2+) toxicity. NOS neurons face the additional problem that NOS is activated by Ca(2+). This is hypothesized to produce an excess of NO, whose free radical properties can cause cell damage, which is exacerbated by peroxynitrite formed when NO reacts with oxygen free radicals.

Mucopolysaccharidosis type IVA (Morquio A disease): clinical review and current treatment.

Mucopolysaccharidosis IVA (MPS IVA), also known as Morquio A, is a rare, autosomal recessive disorder caused by a deficiency of the lysosomal enzyme N-acetylgalatosamine-6-sulfate-sulfatase (GALNS), which catalyzes a step in the catabolism of glycosaminoglycans (GAGs), keratan sulfate (KS) and chondroitin-6-sulfate (C6S). It leads to accumulation of the KS and C6S, mainly in bone and cornea, causing a systemic skeletal chondrodysplasia. MPS IVA has a variable age of onset and variable rate of progression. Common presenting features include elevation of urinary and blood KS, marked short stature, hypoplasia of the odontoid process, pectus carinatum, kyphoscoliosis, genu valgum, laxity of joints and corneal clouding; however there is no central nervous system impairment. Generally, MPS IVA patients with a severe form do not survive beyond the third decade of life whereas those patients with an attenuated form may survive over 70 years. There has been no effective therapy for MPS IVA, and care has been palliative. Enzyme replacement therapy (ERT) and hematopoietic stem cell therapy (HSCT) have emerged as a treatment for mucopolysaccharidoses disorders, including Morquio A disease. This review provides an overview of the clinical manifestations, diagnosis and symptomatic management of patients with MPS IVA and describes potential perspectives of ERT and HSCT. The issue of treating very young patients is also discussed.

The relationship between glial distortion and neuronal changes following intestinal ischemia and reperfusion.

BACKGROUND: Damage to mucosal epithelial cells, muscle cells and enteric neurons has been extensively studied following intestinal ischemia and reperfusion (I/R). Interestingly, the effects of intestinal I/R on enteric glia remains unexplored, despite knowledge that glia contribute to neuronal maintenance. Here, we describe structural damage to enteric glia and associated changes in distribution and immunoreactivity of the neuronal protein Hu. METHODS: The mouse small intestine was made ischemic for 3 h and reperfused from 1 to 12 h. Immunohistochemical localisation of glial fibrillary acidic protein (GFAP), Hu and TUNEL were used to evaluate changes. KEY RESULTS: At all time points glial cells became distorted, which was evident by their altered GFAP immunoreactivity, including an unusual appearance of bright perinuclear GFAP staining and the presence of GFAP globules. The numbers of neurons per ganglion area were significantly fewer in ganglia that contained distorted glia when compared with ganglia that contained glia of normal appearance. The distribution of Hu immunoreactivity was altered at all reperfusion time points. The presence of vacuoles and Hu granules in neurons was evident and an increase in nuclear Hu, relative to cytoplasmic Hu, was observed in ganglia that contained both normal and distorted glial cells. A number of neurons appeared to lose their Hu immunoreactivity, most noticeably in ganglia that contained distorted glial cells. TUNEL reaction occurred in a minority of glial cells and neurons. CONCLUSIONS & INFERENCES: Structural damage to gliofilaments occurs following I/R and may be associated with damage to neighboring neurons.

Evidence that TASK1 channels contribute to the background current in AH/type II neurons of the guinea-pig intestine.

Neurons that have AH (designation of neurons with a prominent and prolonged after hyperpolarizing potential that follows the action potential) electrophysiological characteristics and type II morphology (AH/type II neurons) are the first neurons in reflex circuits in the small intestine. Thus, the state of excitation of these neurons strongly influences the properties of enteric reflexes. The resting outward current in the type II neurons is reduced, causing depolarization and increased excitability, when protein kinase C (PKC) or synaptic inputs are activated, suggesting that regulation of background channels is an important determinant of the state of excitability of these neurons. However, the channels that carry the background current are not yet identified. We used intracellular microelectrodes to record from myenteric AH/type II neurons of the guinea-pig ileum, immunohistochemistry to localize channels and reverse transcriptase-polymerase chain reaction (RT-PCR) to characterize channel transcripts. The blockers of TASK1 channels, bupivacaine (1 mM) and methanandamide (10 muM), depolarized AH/type II neurons by 11.6 mV and 7.9 mV, respectively, and increased resting input resistance by about 30%. The reversal potential determined for the effect of bupivacaine was -92 mV, indicating that bupivacaine acts at K(+) channels, without significant action on other channel types that are open at rest. The membrane potential of type II neurons was depolarized by acidification to pH 6.4, but this depolarization was associated with decreased input resistance and was not reduced by bupivacaine. Thus an unidentified current that is activated by reduced pH masks effects on TASK channels. Slow excitatory post-synaptic potentials in the neurons were reduced in amplitude by methanandamide, suggesting that they are generated in part by closure of TASK1 channels. TASK1 immunoreactivity occurred in all type II neurons (determined by double labeling for IB4 and NeuN), but no type II neurons were immunoreactive for TASK2 or TASK3. These latter channels were localized to non-type II neurons. Transcripts for TASK1, TASK2, TASK3 and other two-pore-domain potassium channels were found in ganglion extracts. It is concluded that TASK1 channels contribute to the resting outward current in AH/type II neurons, and that neurotransmitters that evoke slow depolarizations in these neurons do so through the closure of resting K(+) channels that include TASK1 channels.

Stimulation of the neurokinin 3 receptor activates protein kinase C epsilon and protein kinase D in enteric neurons.

Tachykinins, acting through NK(3) receptors (NK(3)R), contribute to excitatory transmission to intrinsic primary afferent neurons (IPANs) of the small intestine. Although this transmission is dependent on protein kinase C (PKC), its maintenance could depend on protein kinase D (PKD), a downstream target of PKC. Here we show that PKD1/2-immunoreactivity occurred exclusively in IPANs of the guinea pig ileum, demonstrated by double staining with the IPAN marker NeuN. PKCepsilon was also colocalized with PKD1/2 in IPANs. PKCepsilon and PKD1/2 trafficking was studied in enteric neurons within whole mounts of the ileal wall. In untreated preparations, PKCepsilon and PKD1/2 were cytosolic and no signal for activated (phosphorylated) PKD was detected. The NK(3)R agonist senktide evoked a transient translocation of PKCepsilon and PKD1/2 from the cytosol to the plasma membrane and induced PKD1/2 phosphorylation at the plasma membrane. PKCepsilon translocation was maximal at 10 s and returned to the cytosol within 2 min. Phosphorylated-PKD1/2 was detected at the plasma membrane within 15 s and translocated to the cytosol by 2 min, where it remained active up to 30 min after NK(3)R stimulation. PKD1/2 activation was reduced by a PKCepsilon inhibitor and prevented by NK(3)R inhibition. NK(3)R-mediated PKCepsilon and PKD activation was confirmed in HEK293 cells transiently expressing NK(3)R and green fluorescent protein-tagged PKCepsilon, PKD1, PKD2, or PKD3. Senktide caused membrane translocation and activation of kinases within 30 s. After 15 min, phosphorylated PKD had returned to the cytosol. PKD activation was confirmed through Western blotting. Thus stimulation of NK(3)R activates PKCepsilon and PKD in sequence, and sequential activation of these kinases may account for rapid and prolonged modulation of IPAN function.

Concurrent intra-medullary and intra-cranial tuberculomas.

Although tuberculosis of the central nervous system is well known, the incidence of intra-medullary tuberculomas is low and a combination of intra-medullary with intra-cranial tuberculomas is extremely rare. This communication reports a case of disseminated (intra-medullary, intra-cerebellar and intra-cerebral) tuberculomas in a six-year-old girl initially presenting with a spinal tumour syndrome. Conservative treatment with anti-tuberculous medications and a short course of injectable steroids resulted in complete resolution of her symptoms.

Spinal fusion and instrumentation for paediatric neuromuscular scoliosis: retrospective review.

PURPOSE: A retrospective study was conducted to review the surgical results among 24 patients with neuromuscular scoliosis, who were treated with spinal instrumentation and fusion at the Department of Orthopaedic Surgery, National University Hospital, Singapore between March 1993 and December 1998. METHODS: We examined complete hospital records of patients who had scoliosis due to aetiologies such as spinal muscular atrophy, cerebral palsy, Duchenne muscular dystrophy, and congenital myopathies. The mean age of patients was 10.6 years (range, 6-14 years) and the mean follow-up duration was 5.5 years. RESULTS: 18 patients had posterior surgery alone, whereas 4 had an anterior release with posterior instrumentation, and 2 had an anterior fusion with instrumentation. The mean length of stay in the intensive care unit was 2 days and the mean duration of hospital stay was 11 days. The mean correction in scoliosis angle ranged from 75.6 degrees to 25.7 degrees. All patients could at least sit without support postoperatively. The one-second forced expiratory volume and forced vital capacity were, in general, maintained throughout the follow-up. There were 2 major complications and 2 minor ones; these were pseudarthrosis with rod breakage requiring revision, deep infection necessitating hardware removal, superficial infection that responded to antibiotics, and urinary tract infection requiring 3 weeks of antibiotic treatment. There were no deaths or any neurological complications after instrumentation. CONCLUSION: Spinal stabilisation and fusion in children with neuromuscular scoliosis is a safe and effective treatment modality. The effect of surgery on long-term pulmonary function, however, remains controversial and needs to be addressed.

Subsequent general anaesthesia in patients with a history of previous anaphylactoid/anaphylactic reaction to muscle relaxant.

Of 151 patients with a possible anaphylactoid/anaphylactic reaction to a muscle relaxant investigated over a 20-year period, follow-up for any subsequent general anaesthesia was complete in 145 (96%). One hundred and twenty-two anaesthetics in 72 patients were documented. There were no anaesthetic-related deaths. No subsequent reactions were seen if muscle relaxants were not used in the subsequent anaesthetic, nor were they in patients with severe reactions if the original intradermal test had been equivocal or negative. In the patients with a severe reaction and a positive intradermal test to one or more muscle relaxants, six out of 40 later anaesthetics using muscle relaxants were associated with clinical problems, three being probable anaphylactic reactions, whilst three were minor. Intradermal testing should be performed prior to surgery in this group of patients for the muscle relaxant(s) planned, or an anaesthetic technique which avoids relaxants should be used. This review should encourage other centres to undertake similar follow-up.

Growth failure in Prader-Willi syndrome is secondary to growth hormone deficiency.

Growth failure is a recognized feature of the Prader-Willi syndrome (PWS). Despite evidence that hypothalamic dysfunction accompanies the syndrome, the etiology of this growth failure remains controversial because most patients with PWS are obese. In order to contribute to resolution of this controversy, we performed a retrospective analysis of 16 obese and non-obese PWS children. GH deficiency was diagnosed in 12 of the 16 subjects and occurred independently of weight status. All of the non-obese subjects were GH deficient. Of the 4 GH-sufficient children, 2 were moderately obese and 2 were morbidly obese. One of these children had clinical evidence of GH deficiency including a low IGF-1 level. Only one of the children had evidence of GH deficiency and a normal IGF-1 level, a pattern that could be attributable to obesity. We conclude that most short children with PWS have growth hormone deficiency and that this deficiency probably results from hypothalamic dysfunction.

A hypersensitivity screening clinic following untoward reactions to anaesthesia.

Anaphylactoid or anaphylactic reactions to drugs used during general anaesthesia are potentially life threatening. It is important that they be differentiated from other types of cardio-respiratory collapse. At present a detailed history of the time sequence of events in relation to drug administration is of a greatest importance. Retrospective skin testing may then indicate which agent was involved, although false positives and false negatives may occur. Forty-nine patients who presented with a history of collapse during anaesthesia over a five year period were skin tested. Positive results were obtained in 22, ten gave inconclusive test results but a strongly suggestive history. The remainder were considered to have other causes for their clinical presentation. The incidence of severe reactions confirmed by history and by skin testing in this community is approximately 1:4000.