Biologic therapies for refractory juvenile dermatomyositis: five years of experience of the Childhood Arthritis and Rheumatology Research Alliance in North America.

BACKGROUND: The prognosis of children with juvenile dermatomyositis (JDM) has improved remarkably since the 1960's with the use of corticosteroid and immunosuppressive therapy. Yet there remain a minority of children who have refractory disease. Since 2003 the sporadic use of biologics (genetically-engineered proteins that usually are derived from human genes) for inflammatory myositis has been reported. In 2011-2016 we investigated our collective experience of biologics in JDM through the Childhood Arthritis and Rheumatology Research Alliance (CARRA). METHODS: The JDM biologic study group developed a survey on the CARRA member experience using biologics for Juvenile DM utilizing Delphi consensus methods in 2011-2012. The survey was completed online by the CARRA members interested in JDM in 2012. A second survey was similarly developed that provided more opportunity to describe their experiences with biologics in JDM in detail and was completed by CARRA members in Feb 2013. During three CARRA meetings in 2013-2015, nominal group techniques were used for achieving consensus on the current choices of biologic drugs. A final survey was performed at the 2016 CARRA meeting. RESULTS: One hundred and five of a potential 231 pediatric rheumatologists (42%) responded to the first survey in 2012. Thirty-five of 90 had never used a biologic for Juvenile DM at that time. Fifty-five of 91 (denominators vary) had used biologics for JDM in their practice with 32%, 5%, and 4% using rituximab, etanercept, and infliximab, respectively, and 17% having used more than one of the three drugs. Ten percent used a biologic as monotherapy, 19% a biologic in combination with methotrexate (mtx), 52% a biologic in combination with mtx and corticosteroids, 42% a combination of a biologic, mtx, corticosteroids (steroids), and an immunosuppressive drug, and 43% a combination of a biologic, IVIG and mtx. The results of the second survey supported these findings in considerably more detail with multiple combinations of drugs used with biologics and supported the use of rituximab, abatacept, anti-TNFα drugs, and tocilizumab in that order. One hundred percent recommended that CARRA continue studying biologics for JDM. The CARRA meeting survey in 2016 again supported the study and use of these four biologic drug groups. CONCLUSIONS: Our CARRA JDM biologic work group developed and performed three surveys demonstrating that pediatric rheumatologists in North America have been using multiple biologics for refractory JDM in numerous scenarios from 2011 to 2016. These survey results and our consensus meetings determined our choice of four biologic therapies (rituximab, abatacept, tocilizumab and anti-TNFα drugs) to consider for refractory JDM treatment when indicated and to evaluate for comparative effectiveness and safety in the future. Significance and Innovations This is the first report that provides a substantial clinical experience of a large group of pediatric rheumatologists with biologics for refractory JDM over five years. This experience with biologic therapies for refractory JDM may aid pediatric rheumatologists in the current treatment of these children and form a basis for further clinical research into the comparative effectiveness and safety of biologics for refractory JDM.

Transcranial focal electrical stimulation via tripolar concentric ring electrodes does not modify the short- and long-term memory formation in rats evaluated in the novel object recognition test.

Noninvasive transcranial focal electrical stimulation (TFS) via tripolar concentric ring electrodes (TCREs) has been under development as an alternative/complementary therapy for seizure control. Transcranial focal electrical stimulation has shown efficacy in attenuating penicillin-, pilocarpine-, and pentylenetetrazole-induced acute seizures in rat models. This study evaluated the effects of TFS via TCREs on the memory formation of healthy rats as a safety test of TFS. Short- and long-term memory formation was tested after the application of TFS using the novel object recognition (NOR) test. The following independent groups were used: naïve, control (without TFS), and TFS (treated). The naïve, control, and stimulated groups spent more time investigating the new object than the familiar one during the test phase. Transcranial focal electrical stimulation via TCREs given once does not modify the short- and long-term memory formation in rats in the NOR test. Results provide an important step towards a better understanding for the safe usage of TFS via TCREs.

What influences midwives in estimating labour pain?

BACKGROUND: Clinicians' estimates of patients' pain are frequently used as a basis for delivering care, and the characteristics of the clinician and of the patient influence this estimate. METHODS: We studied pain estimation by midwives attending women in uncomplicated labour. Sixty-six practising midwives of varied age, ethnicity and professional experience were asked to complete a trait empathy measure and then to estimate the maximum pain and anxiety experienced by six women whose filmed labour contractions they viewed. Additionally, they rated similarity to the labouring women in ethnicity, and described their beliefs about pain expression according to ethnicity. RESULTS: Midwife estimates of pain and anxiety were highly correlated. Longer professional experience was associated with lower pain estimates, while more births to the midwife herself was associated with higher pain estimates. A multiple regression model identified number of births to the midwife herself, and two components of empathy (perspective taking and identification), to be important in predicting midwife pain estimates for women in labour. Midwives expressed clear beliefs about women's expression of pain during labour according to ethnicity, but these beliefs were not consistent across midwives, even between midwives of similar ethnicity. CONCLUSION: Midwives' personal characteristics can bias the estimation of pain in woman in labour and therefore influence treatment.

Altered hippocampal circuit function in C3H alpha7 null mutant heterozygous mice.

The alpha7 subtype of nicotinic receptor is highly expressed in the hippocampus where it is purported to modulate release of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). The alpha7 receptor-mediated release of GABA is thought to contribute to hippocampal inhibition (gating) of response to repetitive auditory stimulation. This hypothesis is supported by observations of hippocampal auditory gating deficits in mouse strains with low levels of hippocampal alpha7 receptors compared to strains with high levels of hippocampal alpha7 receptors. The difficulty with comparisons between mouse strains, however, is that different strains have different genetic backgrounds. Thus, the observed interstrain differences in hippocampal auditory gating might result from factors other than interstrain variations in the density of hippocampal alpha7 receptors. To address this issue, hippocampal binding of the alpha7 receptor-selective antagonist alpha-bungarotoxin as well as hippocampal auditory gating characteristics were compared in C3H wild type and C3H alpha7 receptor null mutant heterozygous mice. The C3H alpha7 heterozygous mice exhibited significant reductions in hippocampal alpha7 receptor levels and abnormal hippocampal auditory gating compared to the C3H wild type mice. In addition, a general increase in CA3 pyramidal neuron responsivity was observed in the heterozygous mice compared to the wild type mice. These data suggest that decreasing hippocampal alpha7 receptor density results in a profound alteration in hippocampal circuit function.

An evaluation of the clinical and cost-effectiveness of pulmonary artery catheters in patient management in intensive care: a systematic review and a randomised controlled trial.

OBJECTIVES: To evaluate the clinical and cost-effectiveness of managing critically ill patients in adult, general intensive care with or without pulmonary artery catheters (PACs). DESIGN: An open, multi-centre, randomised controlled trial with economic evaluation (cost-utility and cost-effectiveness analysis). SETTING: The setting was general (mixed medical/surgical) intensive care units (ICUs) in the UK admitting adults. PARTICIPANTS: Adult patients in participating ICUs deemed by the responsible treating clinician to require management with a PAC. INTERVENTIONS: These were insertion of a PAC and subsequent clinical management, at the discretion of the responsible treating clinicians, using data derived from the PAC. The control group were managed without a PAC but with the option of using alternative cardiac output monitoring devices. MAIN OUTCOME MEASURES: The main outcome measure was hospital mortality. Secondary outcome measures were length of stay in the ICU, length of stay in an acute hospital and organ-days of support in the ICU. For the economic evaluation, the main outcome measure was quality-adjusted life-years (QALYs) and the secondary outcome measure was hospital mortality. RESULTS: Sixty-five ICUs in the UK participated. Of these, 43 (66%) used alternative cardiac output monitoring devices in control group patients. A total of 1263 patients were identified as being eligible for the trial. Of these, 1041 (82.4%) were randomised and allocated to management with (n = 519) or without (n = 522) a PAC. There were no losses to follow-up. However, 27 patients (13 in the PAC group and 14 in the control group) were withdrawn from the trial because either the patient withdrew consent on recovering mental competency or the relatives withdrew agreement following randomisation. Data on 1014 patients were included in the analysis. Participants in the two groups had similar baseline characteristics. There was no difference in hospital mortality for patients managed with (68.4%) or without (65.7%) a PAC. The adjusted hazard ratio (PAC versus no PAC) was 1.09 [95% confidence interval (CI) 0.94 to 1.27]. There was no difference in the median length of stay in ICU, the median length of stay in an acute hospital or mean organ-days of support in ICU between the two groups. The economic evaluation found that the expected cost per QALY gained from the withdrawal of PAC was 2985 pounds. The expected cost per life gained from the withdrawal of PAC was 22,038 pounds. CONCLUSIONS: Clinical management of critically ill patients with a PAC, as currently practised in the UK, neither improves hospital survival for adult, general intensive care patients nor reduces length of stay in hospital. The lack of demonstrable benefit from a device previously believed to be beneficial could be explained by statistical chance, by misinterpretation of PAC-derived data, by ineffective treatment strategies based on data correctly interpreted using the current paradigm or by subsequent inaction following insertion of the device. It is also possible that detailed data on haemodynamics, however used, cannot modify the disease process sufficiently to influence disease outcome. The economic evaluation, using decision analysis techniques rather than conventional hypothesis testing, suggests that the withdrawal of the PAC from routine clinical practice in the NHS would be considered cost-effective in the current decision-making climate, and might result in lives or life-years being saved at modest cost. With the declining use of PACs in the UK and the findings of this report indicating no overall benefit from management with a PAC, it should now be possible to examine protocolised management with a PAC in selected groups of critically ill patients against appropriate controls, something that was difficult while PACs were the considered standard of care.

Phosphorus, arbuscular mycorrhizal fungi and performance of the wetland plant Lythrum salicaria L. under inundated conditions.

The role of arbuscular mycorrhizal (AM) fungi in aquatic and semi-aquatic environments is poorly understood, although they may play a significant role in the establishment and maintenance of wetland plant communities. We tested the hypothesis that AM fungi have little effect on plant response to phosphorus (P) supply in inundated soils as evidenced by an absence of increased plant performance in inoculated (AM+) versus non-inoculated (AM-) Lythrum salicaria plants grown under a range of P availabilities (0-40 mg/l P). We also assessed the relationship between P supply and levels of AM colonization under inundated conditions. The presence of AM fungi had no detectable benefit for any measures of plant performance (total shoot height, shoot dry weight, shoot fresh weight, root fresh weight, total root length or total root surface area). AM+ plants displayed reduced shoot height at 10 mg/l P. Overall, shoot fresh to dry weight ratios were higher in AM+ plants although the biological significance of this was not determined. AM colonization levels were significantly reduced at P concentrations of 5 mg/l and higher. The results support the hypothesis that AM fungi have little effect on plant response to P supply in inundated conditions and suggest that the AM association can become uncoupled at relatively high levels of P supply.

Intragastric DMXB-A, an alpha7 nicotinic agonist, improves deficient sensory inhibition in DBA/2 mice.

BACKGROUND: Abnormal sensory inhibition is observed in the majority of schizophrenic patients. DBA/2 mice spontaneously exhibit a similar deficit in sensory inhibition and thus provide a model for drug development targeted to this physiologic abnormality. The impaired sensory inhibition is characterized by diminished response of the hippocampal evoked potential to the second of closely paired auditory stimuli (500-m/sec interstimulus interval). Subnormal levels of hippocampal alpha7 nicotinic cholinergic receptors are associated with the deficient sensory inhibition in both DBA/2 mice and people with schizophrenia. METHODS: Our study examined the inhibition of the P20-N40 auditory evoked potential in DBA/2 mice after intragastric administration of DMXB-A (3-2,4-dimethoxybenzylidine anabaseine), an alpha7 nicotinic receptor partial agonist. After presentation of auditory stimuli, electroencephalographic responses were recorded and measured to monitor the effects of the DMXB-A, alone and in combination with selective nicotinic antagonists. RESULTS: Gastric administration of DMXB-A (10 mg/kg) improved sensory inhibition in DBA/2 mice. This improvement was blocked by alpha-bungarotoxin, but not mecamylamine, indicating that DMXB-A exerts its effects through the alpha7 nicotinic receptor. CONCLUSIONS: Intragastrically administered DMXB-A improves deficient sensory inhibition in DBA/2 mice through stimulation of alpha7 nicotinic receptors. These studies agree with results from previous studies with subcutaneously administered DMXB-A.

Chronic corticosterone treatment alters sensory gating in C3H mice.

Two methods of evaluating inhibitory sensory processing are prepulse inhibition of acoustic startle (PPI) and gating of auditory evoked potentials. Studies using both methods suggest nicotinic acetylcholinergic receptor modulation of gating, specifically the alpha-bungarotoxin (alpha-BTX) binding site (alpha7 receptor subtype). However, recent assessment of alpha7 null mutant mice failed to demonstrate any effect of the loss of this receptor in either gating paradigm. An alternate approach to assessing the effects of the alpha7 receptor is to reduce its numbers in mature inbred mice, thus, avoiding the twin problems of background and developmental compensation inherent in null mutant mouse studies. Numerous studies have shown that chronic corticosterone (CCS) treatment selectively reduces alpha-BTX binding sites. C3H mice were adrenalectomized and implanted with corticosterone or cholesterol (control) pellets. After 8 days, they were tested in one of the gating paradigms. PPI and auditory gating were significantly diminished in corticosterone-treated mice concomitant with a reduction in alpha-BTX binding in several brain regions. Cholesterol-treated mice had no change in either paradigm. Nicotine treatment (1 mg/kg) produced significant improvement in both paradigms in corticosterone-treated mice. These data agree with previous pharmacological studies suggesting modulation of gating occurs through a nicotinic receptor.

Hippocampal and cortical sensory gating in rats: effects of quinpirole microinjections in nucleus accumbens core and shell.

Sensory processing disturbances, as measured in the P50/sensory gating paradigm, have been linked to aberrant auditory information processing and sensory overload in schizophrenic patients. In this paradigm, the response to the second of paired-click stimuli is attenuated by an inhibitory effect of the first stimulus. Sensory gating has been observed in most healthy human subjects and normal laboratory rats. Because mesolimbic dopamine has been implicated in other filtering disturbances such as prepulse inhibition of the acoustic startle response and given the fact that amphetamine and apomorphine have been shown to disrupt gating, this study was performed to investigate the role of mesolimbic dopamine in sensory gating. The dopamine D2 receptor agonist quinpirole (10 microg/0.5 microl) was injected bilaterally in nucleus accumbens core and shell and effects on cortical and hippocampal sensory gating were investigated. Also, effects of the dopamine D2 receptor antagonist haloperidol (0.1 mg/kg, subcutaneously) as pretreatment were studied. First, quinpirole significantly reduced both the amplitude to the first click and gating as measured in the cortex and in the hippocampus. There was a tendency for the quinpirole effects on hippocampal gating to be more pronounced in rats injected in the shell. Secondly, haloperidol did not antagonize effects of quinpirole on hippocampal parameters, whereas haloperidol pretreatment fully antagonized quinpirole effects on cortical parameters. In conclusion, gating can be significantly reduced when a dopamine agonist is specifically targeted at mesolimbic dopamine D2 receptors. However, an important consideration is that the dopaminergic effects in the present study on gating are predominantly mediated by the effects on the amplitude to the first click. This has also been suggested for systemic amphetamine injections in rats and schizophrenic patients. This casts doubt on whether dopamine receptor activation affects the putative inhibitory process between the first and the second stimulus.

Inhibition of nitric oxide synthase prevents alpha 7 nicotinic receptor-mediated restoration of inhibitory auditory gating in rat hippocampus.

The hippocampus rapidly inhibits its response to repetitive auditory stimulation, an example of an auditory sensory gating mechanism involved in human psychopathology. The neuronal basis of this inhibitory gating mechanism has been investigated in rats. Activation of the alpha 7 nicotinic receptor is required. alpha 7 nicotinic receptor activation also releases nitric oxide in the hippocampus and blockade of nitric oxide synthase reduces inhibitory gating of auditory response. There has not been a direct demonstration that blockade of nitric oxide synthase specifically prevents alpha 7 nicotinic receptor activation of the inhibition of auditory response. Therefore, the goal of the present study was to determine whether this functional effect of alpha 7 receptor activation requires release of nitric oxide. Lesions of the fimbria-fornix disrupt auditory gating by preventing cholinergic stimulation of the hippocampus. Following recovery from this surgery, rats were administered 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A; 10 mg/kg, sc), an agonist at the alpha 7 receptor. DMXB-A restored auditory gating in the fimbria-fornix-lesioned rats, indicating that activation of the alpha 7 nicotinic receptor alone is sufficient to restore auditory gating following lesions of the fimbria-fornix. However, intracerebroventricular infusion of N(omega)-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, blocked the DMXB-A-mediated restoration of auditory gating; infusion of the inactive D-enantiomer did not. Restoration of auditory gating by DMXB-A in the fimbria-fornix-lesioned rats was blocked by intracerebroventricular infusion of alpha-bungarotoxin, but not by mecamylamine or dihydro-beta-erythroidine. Together, these data support the hypothesis that nitric oxide mediates alpha 7 nicotinic receptor activation of gating of auditory response in rat hippocampus.

Hippocampal auditory gating in the hyperactive mocha mouse.

The mouse mutants mocha (mh) and mocha2J (mh2J) result from separate mutations in the same gene (AP-3 delta) that arose independently on different backgrounds of inbred strains. They exhibit a neurological phenotype that includes hyperactivity, an epileptiform EEG and changes in the basic function of the hippocampus. Depth electrode recordings of hippocampal auditory evoked potentials revealed that the response to the first of two paired tones was significantly enhanced in mocha and mocha2J, as compared with littermate controls. The pronounced theta rhythm characteristic of unanesthetized mocha mice was not observed in these chloral-hydrate anesthetized mice, whereas spike discharge activity was frequently present in the recordings.

Kainic acid lesions in adult rats as a model of schizophrenia: changes in auditory information processing.

Previous studies have suggested that intracerebroventricular kainic acid injections alter brain anatomy and neurochemistry in a manner similar to what is observed in schizophrenic patients. Disturbances in sensory information processing are one of the major symptoms of schizophrenia. Thus, the present experiments were designed to evaluate the hypothesis that hippocampal damage, induced by administration of kainic acid, would alter the processing of auditory stimuli in a paired-click paradigm. Adult male Sprague-Dawley rats were implanted for surface recording of auditory evoked potentials. At the time of electrode implantation, the rats also received bilateral injections of either kainic acid or the vehicle solution. In vehicle-treated rats, the midlatency N40 component of the auditory evoked potential was diminished in amplitude by approximately 60% in response to the second of a pair of clicks delivered 0.5 s apart. By contrast, no reduction of the N40 wave evoked by the second click was observed in kainate-treated rats. Further, administration of haloperidol, a prototypical neuroleptic agent, did not improve this auditory processing dysfunction in kainate-treated animals. Loss of auditory filtering in the paired-click paradigm and a lack of response to haloperidol in this test are typically observed in schizophrenic humans. Thus, the present results demonstrate that kainate-lesioned rats possess a functional schizophrenia-like abnormality, further reinforcing the utility of this model system for studying the basic neurobiology of schizophrenia-induced sensory processing deficits.

Targeted disruption of the tumor necrosis factor-alpha gene: metabolic consequences in obese and nonobese mice.

To address the hypothesis that tumor necrosis factor (TNF)-alpha has a role in obesity-associated insulin resistance or the regulation of in vivo lipid metabolism, mice with targeted disruption of the TNF-alpha gene were generated and studied. The absence of TNF-alpha protein in TNF-null (-/-) mice was confirmed. Lean or obese (gold-thioglucose [GTG]-injected) homozygous (-/-) mice were compared with lean or obese age- and sex-matched wild-type (+/+) mice derived from the same line at 13, 19, and 28 weeks of age. The following parameters were significantly affected in lean -/- versus +/+ mice: Body weight was not affected until week 28 (decreased by 14%); epididymal fat pad weight also decreased (25%) at this time, as did percentage body fat (16%), while percentage body protein was increased 13%. Fed plasma insulin levels decreased 47% (28 weeks), triglyceride levels decreased (all three ages; maximum 35% at 19 weeks), and fed plasma leptin decreased 33% (28 weeks). Fasting glucose was slightly (10%) reduced, but the glucose response to an oral glucose tolerance test (OGTT) was not affected. There was a trend (NS) toward increased total adipose tissue lipoprotein lipase in -/- versus +/+ mice. GTG-treatment resulted in obese -/- and +/+ mice with equal mean body weights (42 and 58% increased weight versus lean mice). The following parameters were significantly different in obese -/- mice: fasting plasma glucose decreased 13% (28 weeks), fed plasma insulin decreased 67% (28 weeks), and insulin response to OGTT was decreased by 50%. For both groups of obese mice, glucose levels during the OGTT were substantially increased compared with those in lean mice; however, mean stimulated glucose levels were 20% lower in obese -/- versus +/+ mice. We conclude 1) that TNF-alpha functions to regulate plasma triglycerides and body adiposity and 2) that although TNF-alpha contributes to reduced insulin sensitivity in older or obese mice, the absence of TNF-alpha is not sufficient to substantially protect against insulin resistance in the GTG hyperphagic model of rodent obesity.

Rats reared in social isolation show schizophrenia-like changes in auditory gating.

Central sensory filtering processes can be demonstrated using a paired stimulus paradigm. Normal humans show a diminished vertex-recorded midlatency auditory-evoked potential to the second of paired clicks (0.5 s apart), a phenomenon termed auditory gating. Schizophrenics routinely fail to suppress the response to the second stimulus; thus, they do not gate. Previous animal studies of auditory gating have used psychotomimetic drug administration to induce a schizophrenia-like loss. However, a nonpharmacologic model of deficient gating would be advantageous. Isolation rearing of weanling rats produces impaired prepulse startle inhibition similar to that observed in schizophrenics. The present studied examined the effects of rearing status upon auditory gating. Male Sprague-Dawley rats raised in social isolation (ISO) were compared to socially raised rats (SOC). Across 10 baseline recording sessions, SOC rats showed substantial gating, while ISO rats failed to gate. Abnormal auditory gating is transiently normalized by nicotine, but not haloperidol, in schizophrenics. ISO rats given nicotine bitartrate showed gating in the normal range for 60 min. By contrast, haloperidol failed to normalize gating in ISO rats. Thus, isolation rearing of weanling rats appears to produce a stable schizophrenia-like gating deficiency that shows the same pattern of response to pharmacological interventions.

Genetic correlation of inhibitory gating of hippocampal auditory evoked response and alpha-bungarotoxin-binding nicotinic cholinergic receptors in inbred mouse strains.

One function of the hippocampus is to ascertain the novelty of incoming sensations and encode significant new information into memory. The regulation of response to repeated stimuli may prevent overloading of this function by redundant sensory input. Recent pharmacological studies implicate the role of alpha-bungarotoxin-sensitive nicotinic cholinergic receptors in the inhibition of hippocampal response to repeated auditory stimuli. The number of hippocampal alpha-bungarotoxin-sensitive receptors has a major genetic determinant, as demonstrated by a significant variance between different inbred mouse strains. The purpose of the present study was to determine whether there was a related genetic correlation for the gating of auditory response. Nine inbred mouse strains, representing a continuum of hippocampal alpha-bungarotoxin binding, were tested for the electrophysiological response to repeated auditory stimulation, followed by whole hippocampus membrane alpha-bungarotoxin binding studies. Several parameters of the auditory evoked response showed significant genetic variance over the nine strains, and a significant correlation was found between hippocampal alpha-bungarotoxin binding and both the amplitude of the initial evoked response and its inhibition to repeated auditory stimuli. There was no correlation of the auditory evoked response with high-affinity nicotine binding. These data further support the hypothesis that alpha-bungarotoxin-sensitive nicotinic receptors are involved in the regulation of hippocampal response to repeated auditory stimuli and suggest that this function is genetically controlled.

Induction of increased levels of proteoglycan fragments in synovial fluid (SF) and increased levels of stromelysin in cartilage, synovium and SF by intraarticular injection of canine monocyte conditioned medium into dogs.

OBJECTIVE: To study the effects of the intraarticular injection of canine monocyte conditioned medium (cMCM) into dogs on proteoglycan fragment and stromelysin levels in the joint. METHODS: cMCM was injected intraarticularly into dogs, and the levels of proteoglycan fragments in synovial fluid (SF) as well as stromelysin levels in cartilage, synovium, and SF were assessed after 12 h. RESULTS: There was a 4-fold increase of proteoglycan fragment levels and a 6-fold increase in stromelysin levels in SF, and a 4.4-fold increase in stromelysin levels in cartilage extracts. Elevated mRNA levels were detected in both synovium and cartilage. By immunofluorescence staining, stromelysin was localized in chondrocytes throughout the cartilage and in synovial cells. CONCLUSION: Intraarticular injection of cMCM stimulated the expression of stromelysin mRNA and protein in cartilage and synovium and caused marked increases in stromelysin protein and proteoglycan fragment levels in SF.

My room--not theirs! A case study of music during childbirth.

The more holistic goals of midwifery are emphasised in this paper through the therapeutic application of music. Material resulting from an interview with a mother after the birth of her first child is used to demonstrate many of the psychological and socio-psychological benefits of listening to music during labour. Several of these benefits were experienced not only by the mother-to-be but also by her partner and the hospital staff. In the outlining of numerous advantages for employing music listening in birthing situations--in particular, comfort and security, self-esteem, socialisation and personal control--the importance of music as a nursing intervention is stressed.

Nisin treatment for inactivation of Salmonella species and other gram-negative bacteria.

Nisin, produced by Lactococcus lactis subsp. lactis, has a broad spectrum of activity against gram-positive bacteria and is generally recognized as safe in the United States for use in selected pasteurized cheese spreads to control the outgrowth and toxin production of Clostridium botulinum. This study evaluated the inhibitory activity of nisin in combination with a chelating agent, disodium EDTA, against several Salmonella species and other selected gram-negative bacteria. After a 1-h exposure to 50 micrograms of nisin per ml and 20 mM disodium EDTA at 37 degrees C, a 3.2- to 6.9-log-cycle reduction in population was observed with the species tested. Treatment with disodium EDTA or nisin alone produced no significant inhibition (less than 1-log-cycle reduction) of the Salmonella and other gram-negative species tested. These results demonstrated that nisin is bactericidal to Salmonella species and that the observed inactivation can be demonstrated in other gram-negative bacteria. Applications involving the simultaneous treatment with nisin and chelating agents that alter the outer membrane may be of value in controlling food-borne salmonellae and other gram-negative bacteria.

Unusual structure of the exopolysaccharide of Rhizobium leguminosarum bv. viciae strain 248.

The exopolysaccharide from R. leguminosarum bv. viciae strain 248 differs from those of other Rhizobium strains with similar symbiotic behavior. 13C-N.m.r. spectroscopy of fragments generated by partial hydrolysis, together with methylation analysis and 13C-n.m.r. spectroscopy of the enzymically depolymerised exopolysaccharide, indicated the following nonasaccharide repeating-unit: [formula: see text] The locations of the acetyl and 3-hydroxybutanoyl substituents in the exopolysaccharide are assigned provisionally. R. leguminosarum bv. viciae strain 248, cured of its Sym plasmid pRL1JI, synthesised an exopolysaccharide in which the sites and degree of substitution were unchanged. A Tn5 mutant, derived from strain 248 and unable to induce nodules, synthesised small amounts of EPS that lacked galactose.