Controlled-release oxycodone and naloxone in the treatment of chronic low back pain: a placebo-controlled, randomized study.

BACKGROUND: For Canadian regulatory purposes, an analgesic study was required to complement previously completed, pivotal studies on bowel effects and analgesia associated with controlled-release (CR) oxycodone/CR naloxone. OBJECTIVES: To compare the analgesic efficacy and safety of CR oxycodone/CR naloxone versus placebo in patients with chronic low back pain. METHODS: Patients requiring opioid therapy underwent a two- to seven-day opioid washout before being randomly assigned to receive either 10 mg/5 mg CR oxycodone/CR naloxone or placebo every 12 h, titrated weekly according to efficacy and tolerability to 20 mg/10 mg, 30 mg/15 mg or 40 mg/20 mg every 12 h. After four weeks, patients crossed over to the alternative treatment for an additional four weeks. Acetaminophen/codeine (300 mg/30 mg every 4 h to 6 h as needed) was provided as rescue medication. RESULTS: Of the 83 randomized patients, 54 (65%) comprised the per-protocol population. According to per-protocol analysis, CR oxycodone/CR naloxone resulted in significantly lower mean (± SD)pain scores measured on a visual analogue scale (48.6 ± 23.1 mm versus 55.9 ± 25.4 mm; P=0.0296) and five-point ordinal pain intensity scores (2.1 ± 0.8 versus 2.4 ± 0.9; P=0.0415) compared with placebo. After the double-blinded phase, patients and investigators both preferred CR oxycodone/CR naloxone over placebo. These outcomes continued in the 79% of patients who chose to continue receiving CR oxycodone/CR naloxone in a six-month, open-label evaluation. CONCLUSIONS: In patients complying with treatment as per protocol, CR oxycodone/CR naloxone was effective for the management of chronic low back pain of moderate or severe intensity.

Cerebral pressure-flow relationship during cardiopulmonary bypass in the dog at normothermia and moderate hypothermia.

We studied cerebral autoregulation by analyzing cerebral pressure-flow curves during cardiopulmonary bypass (CPB) with alpha-stat (alpha-stat) acid-base management at 28 (n = 9) and 37 degrees C (n = 9) in two groups of dogs. Cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) were determined multiple times in each animal over an extensive range of cerebral perfusion pressure (CPP). The CPP was altered by changing perfusion flow rate. The dependence of CBF on CPP during normothermic and moderate hypothermic CPB was assessed using a block design analysis of covariance with CPP as the covariate. We anticipated maximal statistical power with this analysis to define if cerebral autoregulation was intact. This method of statistical analysis was compared with the conventional interpretation by linear regression analysis. Animals were administered sodium thiopental until an isoelectric electroencephalogram was obtained to assure stable depth of anesthesia independently of temperature effects. The animals were randomly assigned to either temperature group. The CBF was determined by injection of radioactive microspheres at each of five target CPPs randomly allocated (50, 60, 70, 80, and 90 mm Hg). The brain oxygen content difference was defined as arterial minus superior sagittal sinus (SSS) oxygen content. No difference in CPP, hemoglobin, arterial carbon dioxide tension, or pH was seen between groups at any time period. In both groups, total CBF (tCBF) increased significantly with increasing CPP (p = 0.012 and 0.017 for normothermic and hypothermic CPB, respectively; CPP as covariate). The between-group difference in slopes (CPP x temperature effect) approached statistical significance (p = 0.059).(ABSTRACT TRUNCATED AT 250 WORDS)

Limb girdle and facial weakness in female carriers of X-linked myotubular myopathy mutations.

Although X-linked myotubular myopathy (XLMTM) is a recessive disorder, heterozygous female carriers of MTM1 mutations may present with limb girdle and facial weakness. It is proposed that manifesting heterozygote females with XLMTM have a skewed pattern of X-chromosome inactivation. However, skewed X-chromosome inactivation was not detected in either the lymphocyte or muscle DNA of a woman who presented with limb girdle/facial weakness and was found to be heterozygous for the R224X mutation.

An interferon-gamma ELISPOT and immunohistochemical investigation of cytotoxic T lymphocyte-mediated tumour immunity in patients with paraneoplastic cerebellar degeneration and anti-Yo antibodies.

Eight patients with paraneoplastic cerebellar degeneration (PCD) and anti-Yo antibodies were investigated to determine whether there is any association between cytotoxic T lymphocyte (CTL) responses reactive with two previously defined Yo-derived, HLA-A2.1 restricted epitopes (cdr2-1 and cdr2-2) and the presence of tumour-infiltrating CD8+ CTLs. cdr2-1 and cdr2-2-specific CTL responses could not be detected in 5 HLA-A2.1(+) patients in an ex vivo interferon-gamma ELISPOT assay and only 2/9 tumour sections contained CD8(+) intratumoural lymphocytes suggesting a very limited role for CTL-mediated tumour immunity in this patient group, all of whom had evidence of widespread malignancy at the time of diagnosis and/or death.

Restricted IgG1 subclass of anti-Yo antibodies in paraneoplastic cerebellar degeneration.

Paraneoplastic cerebellar degeneration (PCD) occurs as a non-metastatic manifestation of cancer in a small proportion of patients with certain breast or gynaecological tumours, and is characterised by widespread Purkinje cell loss. Antibodies against a Purkinje cell cytoplasmic antigen, called Yo, that is expressed by the tumours, are present in the majority of these patients, but the pathogenic role of the antibodies is not clear. To characterise further the immune response in these cases, 13 anti-Yo positive sera were tested for IgG subclasses by immunohistochemistry and western blotting and, in four cases, PHA-stimulated cytokine secretion by peripheral blood lymphocytes was measured. Surprisingly, anti-Yo antibodies were entirely restricted to the IgG1 subclass, whereas antibodies against the small cell cancer-associated antigen, Hu, were found in all four IgG subclasses. There was a trend towards raised IgG1 levels in the total IgG of the anti-Yo positive patients and, in two, PHA-stimulated peripheral blood lymphocytes secreted raised levels of IFN-gamma. By contrast, in the other two cases tested, raised levels of IL-4 were secreted. Patients with PCD associated with anti-Yo antibodies appear to have strong immune responses that are polarised with respect to the IgG subclass and Th cytokine profiles.

Conventional and advanced imaging in neuromyelitis optica.

Myelitis and optic neuritis are prototypic clinical presentations of both multiple sclerosis and neuromyelitis optica. Once considered a subtype of multiple sclerosis, neuromyelitis optica, is now known to have a discrete pathogenesis in which antibodies to the water channel, aquaporin 4, play a critical role. Timely differentiation of neuromyelitis optica from MS is imperative, determining both prognosis and treatment strategy. Early, aggressive immunosuppression is required to prevent the accrual of severe disability in neuromyelitis optica; conversely, MS-specific therapies may exacerbate the disease. The diagnosis of neuromyelitis optica requires the integration of clinical, MR imaging, and laboratory data, but current criteria are insensitive and exclude patients with limited clinical syndromes. Failure to recognize the expanding spectrum of cerebral MR imaging patterns associated with aquaporin 4 antibody seropositivity adds to diagnostic uncertainty in some patients. We present the state of the art in conventional and nonconventional MR imaging in neuromyelitis optica and review the place of neuroimaging in the diagnosis, management, and research of the condition.

CNS demyelination and quadrivalent HPV vaccination.

Vaccination is generally considered safe in patients with multiple sclerosis (MS). We report five patients who presented with multifocal or atypical demyelinating syndromes within 21 days of immunization with the quadrivalent human papilloma virus (HPV) vaccine, Gardasil. Although the target population for vaccination, young females, has an inherently high risk for MS, the temporal association with demyelinating events in these cases may be explained by the potent immuno-stimulatory properties of HPV virus-like particles which comprise the vaccine. A prospective case-control study of patients with MS or clinically isolated demyelinating syndromes receiving the Gardasil vaccine may provide relevant safety data in this population.

Primary biliary cirrhosis: seeking the silent partner of autoimmunity.

Primary biliary cirrhosis is a disorder characterised by an intense inflammatory response in the septal and interlobular bile ducts and is considered to be an autoimmune disease. Evidence to suggest that chronic viral infection could be a crucial element in the development of biliary epithelial cell damage and activation of the associated autoimmune response is reviewed

A technique for simultaneously comparing the release of noradrenaline evoked by field stimulation and by propagated nerve impulses in rabbit ear arteries.

1. A technique has been described which utilized radiotracer methods to measure the release of transmitter noradrenaline, simultaneously, from segments of rabbit ear artery subjected to field stimulation and propagated nerve impulses. 2. The release of radioactivity from arteries labelled with 3H-noradrenaline was much greater in the segment subjected to field stimulation than in the segment stimulated by propagated nerve impulses. 3. The release of radioactivity from segments invaded by nerve impulses decreased progressively with increases in frequency through the range of 10-50 Hz, using 150 pulses at 10, 15, 20, 30 and 50 Hz. However, the release remained constant in the field stimulated segments throughout the frequency range used.

Comparison of the effects of phenoxybenzamine and uptake blockade on noradrenaline efflux from rabbit ear arteries evoked by field stimulation and propagated nerve impulses.

1. A comparison has been made of the effects of blockade of prejunctional alpha-adrenoreceptors and blockade of transmitter noradrenaline uptake in segments of rabbit ear arteries subjected to field stimulation or neuronally propagated impulses. 2. The relationship between evoked release and frequency of stimulation differed in artery segments subjected to field stimulation and those receiving propagated nerve impulses. However, the effectiveness of phenoxybenzamine in increasing stimulation-induced efflux of radioactivity decreased as the frequency of stimulation increased in artery segments subjected to either field stimulation or neuronally propagated impulses. 3. Blockade of neuronal and extraneuronal uptake had no effect on evoked efflux from field-stimulated artery segments but it did produce a marked and significant enhancement of release evoked by propagated nerve impulses.

Limbic encephalitis and antibodies to Ma2: a paraneoplastic presentation of breast cancer.

A patient with atypical medullary breast cancer is described who presented with symptoms of limbic encephalitis. The patient's serum and CSF contained antibodies that reacted with the nervous system and the tumour. These antibodies recognised Ma2, a neuronal protein related to paraneoplastic limbic and brainstem encephalitis in men with testicular tumours. This report highlights the importance of testing for paraneoplastic antineuronal antibodies in cases of unexplained limbic encephalitis and suggests screening for breast cancer in women with antibodies predominantly directed to Ma2.

Spinal anaesthesia for Caesarean section in a patient with a cervical arteriovenous malformation.

PURPOSE: Arteriovenous malformations (AVM) of the spinal cord are rare. We report the successful management of a patient with a cervical spinal cord AVM undergoing Caesarean section delivery, using a spinal anaesthetic. CLINICAL FEATURES: Based on previous radiological investigations, the patient was known to have an AVM at the third cervical level of her spinal cord. After application of monitors and intravenous administration of 1 L normal saline, a 25 g Whitacre needle was inserted into the subarachnoid space at the L3-4 interspace. Spinal anaesthesia was established with a solution consisting of hyperbaric spinal bupivacaine 12 mg, fentanyl 12.5 micrograms and epidural morphine 0.25 mg. There was no neurological deficit during hospital stay or after discharge. CONCLUSION: The safe outcome of spinal anaesthesia for our patient is encouraging. The presence of spinal cord AVM at the cervical region is not an absolute contraindication to spinal anaesthesia.

Prejunctional alpha-adrenoreceptors subserve a physiological role in cardiac noradrenergic transmission.

1 The question whether prejunctional alpha-adrenoreceptors subserve a physiological role in a noradrenaline-mediated autoinhibitory feedback loop has been studied in guinea-pig isolated atria by stimulating the accelerans nerve and measuring chronotropic responses and the release of radioactivity after labelling transmitter stores with 3H-noradrenaline. 2 Phentolamine (0.3 micrometer) significantly enhanced chronotropic responses when stimulation was with 0.5 Hz for 30 s, but the increase in the release of radioactivity was too small to be measured reliably. When the frequency of stimulation was increased to 4 Hz for 30 s, phentolamine significantly increased the release of radioactivity but the chronotropic response to stimulation was near maximal and phentolamine had no significant effect on it. 3 With prolonged stimulation (12 min) at the lower frequency (0.5 Hz), both the release of radioactivity and the chronotropic response to stimulation were significantly enhanced by phentolamine (3 micrometers). 4 The results support a physiological role for prejunctional alpha-adrenoreceptors in guinea-pig isolated atria.

Paraneoplastic brain stem encephalitis in a woman with anti-Ma2 antibody.

A woman developed brain stem encephalopathy in association with serum anti-Ma2 antibodies and left upper lobe lung mass. T2 weighted MRI of the brain showed abnormalities involving the pons, left middle and superior cerebellar peduncles, and bilateral basal ganglia. Immunohistochemical analysis for serum antineuronal antibodies was confounded by the presence of a non-neuronal specific antinuclear antibody. Immunoblot studies showed the presence of anti-Ma2 antibodies. A premortem tissue diagnosis of the lung mass could not be established despite two CT guided needle biopsies, and the patient died as a result of rapid neurological deterioration. The necropsy showed that the lung lesion was an adenocarcinoma which expressed Ma2 immunoreactive protein. Neuropathological findings included prominent perivascular inflammatory infiltrates, glial nodules, and neuronophagia involving the brain stem, basal ganglia, hippocampus and the dentate nucleus of the cerebellum. Ma2 is an autoantigen previously identified in patients with germ cell tumours of the testis and paraneoplastic brain stem and limbic encephalitis. Our patient's clinical and immunopathological findings indicate that this disorder can affect women with lung adenocarcinoma, and that the encephalitic changes predominate in those regions of the brain known to express high concentrations of Ma proteins.

Anti-Yo antibodies and cerebellar degeneration in a man with adenocarcinoma of the esophagus.

Serum antibodies to the Yo antigen are usually associated with paraneoplastic cerebellar degeneration arising in female patients with gynecological or breast malignancy and are rarely associated with other tumors. We report a male patient who presented with paraneoplastic cerebellar degeneration and anti-Yo antibodies following removal of an esophageal adenocarcinoma. This is only the third report of anti-Yo antibodies occurring in a male patient. The Yo antigen was expressed by the esophageal tumor but not in a frontal lobe cerebral metastasis identified at postmortem. Interestingly, CD8+ T-cell infiltration was also found in the tumor, but not in the metastasis, consistent with down-regulation of Yo expression by the tumor cells leading to evasion from immune-mediated tumor surveillance.

Treatment of proximal aortic hypertension after thoracic aortic cross-clamping in dogs. Phlebotomy versus sodium nitroprusside/isoflurane.

Thoracic aortic cross-clamping causes proximal aortic hypertension. Theoretically, the method used to treat hypertension can influence spinal cord perfusion pressure and neurologic outcome. Phlebotomy was compared to sodium nitroprusside/isoflurane in terms of ability to treat increased proximal mean aortic pressure (MAPp) after thoracic aortic cross-clamping in dogs. Dogs were assigned randomly to one of three groups depending on the method used to treat hypertension after cross clamping: 1) phlebotomy (n = 10); 2) sodium nitroprusside/isoflurane (n = 11); and 3) control (no treatment) (n = 8). In each dog, anesthesia was maintained with isoflurane in oxygen, 1.4% end-tidal. The thoracic aorta was occluded 2.5 cm distal to the left subclavian artery for 50 min and then was released. Hemodynamics, cerebrospinal fluid pressure (CSFP), and regional blood flows by the radioactive microsphere technique, were measured at 1) baseline; 2) 2 min after aortic cross-clamping; 3) after treatment of proximal aortic hypertension; 4) 5 min after aortic unclamping; and 5) 30 min after resuscitation. At 24 h, a neurologic assessment was performed. Thoracic aortic cross-clamping increased MAPp, decreased distal MAP (MAPd), and reduced lumbar spinal cord perfusion pressure (SCPPl), [SCPPl = MAPd - CSFP], in all three groups. Control of increased MAPp necessitated removal of 36 +/- 9 ml/kg of blood in the phlebotomy group. In the sodium nitroprusside/isoflurane group, sodium nitroprusside (16 micrograms.kg-1.min-1) was infused and end-tidal isoflurane concentration increased to 2.5 +/- 0.7%, restoring MAPp to baseline level.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized controlled trial of recombinant interferon-beta 1a in Guillain-Barré syndrome.

The authors recruited 19 nonambulant patients with Guillain-Barré syndrome into a pilot, double-blind, randomized, placebo-controlled safety trial of interferon beta 1a (IFN[beta]-1a) (Rebif). Participants received IFN[beta]-1a or placebo subcutaneously three times weekly, 22 microg for the first week and then 44 microg for up to 24 weeks, in addition to IV immunoglobulin (IVIg). IFN[beta] did not have any unexpected interaction with IVIg and there was no significant difference in rate of improvement.

The clinical and laboratory features of chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies.

The clinical and laboratory phenotype of a paraproteinaemic neuropathy syndrome termed chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies is described in a series of 18 cases. Previous single case reports have outlined some features of this syndrome. All 18 cases were defined by the presence of serum IgM antibodies which react principally with NeuAc (alpha2-8)NeuAc(alpha2-3)Gal-configured disialosyl epitopes common to many gangliosides including GDlb, GD3, GTlb and GQlb. In 17 out of 18 cases, the serum contained benign IgM paraproteins, and in four of these cases at least two IgM paraproteins were present. The IgM antibodies were also cold agglutinins in 50% of cases. The clinical picture comprised a chronic neuropathy with marked sensory ataxia and areflexia, and with relatively preserved motor function in the limbs. In addition, 16 out of 18 cases had motor weakness affecting oculomotor and bulbar muscles as fixed or as relapsing-remitting features. When present in their entirety, these clinical features have been described previously under the acronym CANOMAD: chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins and disialosyl antibodies. This distribution of clinical features is reminiscent of Miller Fisher syndrome, in which acute-phase anti-disialylated ganglioside IgG antibodies are found. Clinical electrophysiology and nerve biopsy show both demyelinating and axonal features. A partial response to intravenous immunoglobulin and other treatments is reported in some cases.