Pain-relieving effectiveness, quality of life and tolerability of repeated capsaicin 8% patch treatment of peripheral neuropathic pain in Scandinavian clinical practice.

CONTEXT: Clinical trials have demonstrated the efficacy and safety of the capsaicin 8% patch in patients with peripheral neuropathic pain (PNP); however, few studies have assessed this treatment in a clinical practice. OBJECTIVE: To determine whether treatment and re-treatment with the capsaicin 8% patch reduce PNP intensity in clinical practice. METHODS: Three non-interventional, observational studies were concurrently conducted in Denmark, Norway and Sweden. Patients with probable or definite PNP received one or two treatments with the capsaicin 8% patch according to usual clinical practice. All analyses were performed on combined data. RESULTS: Overall, 382 and 181 patients received treatment and re-treatment, respectively, with the capsaicin 8% patch. At the group level, a significant reduction in mean level of 'usual pain' intensity (Numerical Pain Rating Scale) over the last 24 h' score was observed from baseline to Weeks 2 through 8 [-1.05 (95% confidence interval: -1.27, 0.82); p < 0.001] with 28% and 31% of patients reporting a ≥30% reduction in pain after first treatment and re-treatment, respectively. Improvements in health-related quality of life (EQ-5D-3L index) and overall health status (Patient Global Impression of Change) were observed early (Week 1) and throughout the treatment periods. Most application site reactions subsided within a week after treatment. Following treatment and re-treatment, 57% and 71% of patients, respectively, were willing to undergo further treatment with the capsaicin 8% patch. CONCLUSION: In Scandinavian clinical practice, capsaicin 8% patch treatment was associated with significant reductions in pain intensity and was well tolerated with over half of patients willing to undergo re-treatment.

Measurements of Brownian relaxation of magnetic nanobeads using planar Hall effect bridge sensors.

We compare measurements of the Brownian relaxation response of magnetic nanobeads in suspension using planar Hall effect sensors of cross geometry and a newly proposed bridge geometry. We find that the bridge sensor yields six times as large signals as the cross sensor, which results in a more accurate determination of the hydrodynamic size of the magnetic nanobeads. Finally, the bridge sensor has successfully been used to measure the change in dynamic magnetic response when rolling circle amplified DNA molecules are bound to the magnetic nanobeads. The change is validated by measurements performed in a commercial AC susceptometer. The presented bridge sensor is, thus, a promising component in future lab-on-a-chip biosensors for detection of clinically relevant analytes, including bacterial genomic DNA and proteins.

Late effects of early growth hormone treatment in Down syndrome.

OBJECTIVE: Down syndrome (DS) is associated with short stature and psychomotor delay. We have previously shown that growth hormone (GH) treatment during infancy and childhood normalizes growth velocity and improves fine motor skill performance in DS. The aim of this study was to investigate late effects of early GH treatment on growth and psychomotor development in the DS subjects from the previous trial. DESIGN: Twelve of 15 adolescents with DS (3 F) from the GH group and 10 of 15 controls (5 F) participated in this follow-up study. Fifteen other subjects with DS (6 F) were included as controls in anthropometric analyses. Cognitive function was assessed with the Leiter International Performance Scale-Revised (Leiter-R) and selected subtests of the Wechsler Intelligence Scale for Children, Third edition (WISC-III). The Bruininks-Oseretsky Test of Motor Proficiency, Second edition (BOT-2), was used to assess general motor ability. RESULTS: Although early GH treatment had no effect on final height, the treated subjects had a greater head circumference standard deviation score (SDS) than the controls (-1.6 SDS vs. -2.2 SDS). The adolescents previously treated with GH had scores above those of the controls in all subtests of Leiter-R and WISC-III, but no difference in Brief IQ-score was seen between the groups. The age-adjusted motor performance of all subjects was below -2 SD, but the GH-treated subjects performed better than the controls in all but one subtest. CONCLUSION: The combined finding of a greater head circumference SDS and better psychomotor performance indicates that DS subjects may benefit from early GH treatment.

Microscopic mechanisms influencing the volume amplified magnetic nanobead detection assay.

The volume amplified magnetic nanobead detection assay [Strömberg, M., Göransson, J., Gunnarsson, K., Nilsson, M., Svedlindh, P., Strømme, M., 2008. Nano Letters 8, 816-821] was investigated with respect to bead size, bead surface coverage of probe oligonucleotides, bead concentration and rolling circle amplification (RCA) time, with the objective to improve the understanding of the microscopic mechanisms influencing the assay. The most important findings for future biosensor development were the following: (i) small beads exhibit a much reduced tendency to cross-link several RCA products, thus enabling use of both complex magnetisation turn-on and turn-off detection strategies, whereas larger beads only allow for turn-off detection; (ii) small beads exhibit faster immobilisation kinetics, thus reducing the time for diagnostic test completion, and also immobilise in larger numbers than larger beads. Finally, (iii) by demonstrating qualitative dual-target detection of bacterial DNA sequences using 130 and 250nm beads, the bioassay was shown to allow for multiplexed detection.

Differences in expression, actions and cocaine regulation of two isoforms for the brain transcriptional regulator NAC1.

BTB/POZ proteins can influence the cell cycle and contribute to oncogenesis. Many family members are present in the mammalian CNS. Previous work demonstrated elevated NAC1 mRNA levels in the rat nucleus accumbens in response to cocaine. NAC1 acts like other BTB/POZ proteins that regulate transcription but is unusual because of the absence of identifiable DNA binding domains. cDNAs were isolated encoding two NAC1 isoforms differing by only 27 amino acids (the longer isoform contains 514 amino acids). The mRNAs for both isoforms were simultaneously expressed throughout the rat brain and peripheral tissues. Semi-quantitative reverse transcription-polymerase chain reaction analysis revealed that the mRNA of the longer isoform was more abundant than the mRNA of the shorter isoform. Western blot analysis demonstrated a similar unequal distribution between the isoforms in the CNS. The longer isoform was the more abundant of the two NAC1 proteins and the ratio between them differed throughout the rat brain. The shorter isoform was not detected in most of the examined peripheral tissues, suggesting differences from the CNS in post-transcriptional processing. Both isoforms repressed transcription in H293T cells using a Gal4-luciferase reporter system. However, the shorter isoform did not repress transcription as effectively as the longer isoform. Transfection of different ratios for both isoforms, in order to replicate the relative amounts observed throughout the CNS, supported an interaction between the isoforms. The net effect on transcriptional repression was determined by the ratio of the two NAC1 isoforms. Each isoform exhibited the subnuclear localization that is characteristic of many BTB/POZ proteins. A rapid and transient increase in the level of the shorter isoform occurred in the nucleus accumbens 2 h following a single i.p. cocaine injection. We conclude that the two isoforms of NAC1 may differentially affect neuronal functions, including the regulation of cocaine-induced locomotion.

Effect of acamprosate and naltrexone, alone or in combination, on ethanol consumption.

Both acamprosate and naltrexone have demonstrated clinical utility in reducing relapse to alcohol use in recovering alcoholics. The present experiments examined the effects of acamprosate and naltrexone, either alone or in combination, on basal ethanol consumption in a limited-access model with the use of outbred Wistar rats. Naltrexone, 0.1 mg/kg, significantly reduced ethanol consumption as previously reported. Acamprosate, 50 mg/kg, did not significantly reduce ethanol consumption when administered alone and provided no evidence of additive or synergistic effects when combined with naltrexone. Acamprosate, 200 mg/kg, produced a modest reduction in ethanol consumption when administered alone but no evidence of additive or synergistic effects when combined with naltrexone. From these findings, it is suggested that a combination approach of these drugs may not be any more effective than monotherapy.

The effect of gamma-vinyl-GABA on the consumption of concurrently available oral cocaine and ethanol in the rat.

It has frequently been reported that a high percentage of individuals, identified as either alcohol- or cocaine-dependent, concurrently abuse both drugs. The experiments reported here represent a continuing effort to develop an animal model to predict the effects of a potential pharmacotherapeutic agent on concurrently available oral ethanol and cocaine. These experiments utilized drinkometer circuitry to assess the effects of gamma-vinyl-GABA (GVG), a gamma-aminobutyric acid (GABA) transaminase inhibitor, on the consumption and temporal pattern of responses for orally self-administered ethanol and cocaine. The results of these experiments showed that GVG, at doses of 100, 200 and 300 mg/kg, reduced both ethanol and cocaine consumption in a dose-related manner. When compared to vehicle, GVG at all doses significantly reduced ethanol consumption while consumption of cocaine was significantly reduced only at 300 mg/kg. This is consistent with data showing that GVG reduces consumption of these drugs when administered alone and data showing that GVG is more potent in reducing ethanol-induced compared to cocaine-induced extracellular dopamine in the nucleus accumbens. Analysis of the temporal pattern of drinking across the session suggests that GVG's effects are due to a disruption of the reinforcing properties of ethanol and cocaine rather than a more general reduction in motor behavior. These data suggest that GVG has potential for clinical use in populations that abuse either alcohol or cocaine alone or in combination.

The effect of antagonists selective for mu- and delta-opioid receptor subtypes on alcohol consumption in C57BL/6 mice.

Several studies have demonstrated that non-selective opioid receptor antagonists effectively reduce alcohol consumption in both animal models and at the clinical level. However, research examining the contribution of specific opioid receptor subtypes to this effect has yielded conflicting results. Some of these studies have shown that the effect is contingent upon the action of mu receptors while others have suggested that delta receptors are primarily responsible. The data reported here re-examine this question using the alcohol-preferring C57BL/6 mice. The results of this experiment demonstrate that D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP), a mu-selective antagonist, and naltrindole, a delta-selective antagonist, are equally effective at reducing alcohol consumption in a limited access model compared to a saline control group. While there was no specific comparison of the effects of these drugs on alternative appetitive behavior, neither of these drugs had effects on measured off-session food or water consumption. The results of this experiment suggest that alcohol consumption is mediated by both mu- and delta-opioid receptor subtypes.

6-beta-naltrexol reduces alcohol consumption in rats.

BACKGROUND: In humans, 6-beta-naltrexol is the major metabolite of naltrexone, and its effectiveness at suppressing alcohol consumption in any species has not been previously investigated. Naltrexone is an opiate antagonist that reduces excessive drinking in many species, including humans with alcohol dependence. Whether 6-beta-naltrexol is an active metabolite that contributes to the efficacy of naltrexone remains unknown. METHODS: Placebo and four doses of 6-beta-naltrexol were given by intraperitoneal injection to outbred Wistar rats and alcohol consumption was measured using a limited access model. RESULTS: 6-beta-Naltrexol reduced alcohol consumption in a dose-dependent manner. At doses 7.5, 12.5, and 25 mg/kg, 6-beta-naltrexol significantly decreased consumption of a 6% ethanol solution compared with saline control groups. CONCLUSIONS: These data suggest that there may be a potential clinical use for 6-beta-naltrexol in recovering alcoholics.

The NMDA receptor partial agonist, 1-aminocyclopropanecarboxylic acid (ACPC), reduces ethanol consumption in the rat.

The present studies assessed the effects of both systemic and intraaccumbens injections of 1-aminocyclopropanecarboxylic acid (ACPC), and NMDA partial agonist, on ethanol consumption in a limited access procedure in Wistar rats. Systemically administered ACPC reduced ethanol consumption in a dose-dependent manner, while a single dose of ACPC administered bilaterally into the nucleus accumbens also reversibly reduced ethanol consumption. Indirect measures of general appetitive behavior showed no effect of ACPC on weight or water intake, which suggests that this effect of ACPC may be specific to ethanol. These data are compatible with the role of NMDA receptors in modulating ethanol consumption and provide the first data showing that ACPC can reduce ethanol consumption. ACPC has neuroprotective effects and does not show the psychotomimetic effects observed with NMDA receptor agents. Thus, ACPC may be helpful in future clinical studies designed to reduce alcohol use.

Cladribine for untreated or early low-grade non-Hodgkin's lymphoma.

PATIENTS AND METHODS: Forty-four patients, with low-grade non-Hodgkin's lymphoma (LG-NHL) were included in a phase II study between June 1993 and May 1995 and treated with cladribine (CdA) 0.12 mg/kg as a 2 h i.v. infusion daily x 5, repeated after 28 days for up to 6 courses. Thirty-four patients were previously untreated and 10 had progressive disease after initial response to limited chlorambucil treatment. Five patients had also received involved field radiotherapy. Eight patients had mantle cell lymphomas, 22 follicle centre lymphomas, 5 lymphoplasmacytoid lymphomas, 4 small cell lymphocytic lymphomas, 4 marginal zone B-cell lymphomas and I had unclassified low-grade NHL. The response rate was 64%, with 11 (25%) CR and 17 (39%) PR while 5 (11%) patients progressed during treatment. The response rate was similar in previously treated and untreated patients. The median number of CdA courses delivered was 3 (1-6) in non-responding patients and 6 (2-6) in responders. Median survival from inclusion was not reached with a median follow-up of 40 months. The median time to progression was 7 mo for all patients, 25+ mo for CR and 16 mo for PR patients. Toxicity was sometimes severe with 2 treatment related deaths, one infectious related and one due to a mucocutaneous syndrome and pulmonary microembolism. In addition, 5 grade 3 or 4 infectious episodes were seen. Seven patients experienced grade 3 or 4 thrombocytopenia and 20 had grade 3 or 4 neutropenia. We conclude that the majority of patients with low-grade non-Hodgkin's lymphoma respond to CdA but that the adverse effects may be severe.

A comparison of the effects of the opioid antagonists naltrexone, naltrindole, and beta-funaltrexamine on ethanol consumption in the rat.

The effects of the universal opioid antagonist naltrexone were compared to the delta-selective opioid antagonist naltrindole and the mu-selective opioid antagonist beta-funaltrexamine on ethanol consumption in the absence of food or fluid deprivation using a limited access procedure in Wistar rats. Both naltrexone, at doses of 0.1, 0.25, 0.5, 1.0, 3.0, and 10 mg/kg, and beta-funaltrexamine, at doses of 5.0 and 20.0 mg/kg, significantly decreased consumption of a 6% ethanol solution compared to saline control groups. Naltrindole, at doses of 5.0 and 15.0 mg/kg, failed to significantly reduce ethanol consumption. In addition, the highest doses of naltrexone, which antagonize delta as well as mu-opioid receptors, did not differ significantly from the lowest doses in their ability to reduce ethanol consumption. These data suggest that ethanol consumption using the limited access paradigm in the outbred rat is modulated by mu rather than delta-opioid receptors. Although this is not consistent with other data showing that delta antagonists decrease ethanol consumption, it is suggested that these difference may be related to the alcohol-preferring rats used in those experiments.

Effects of naltrexone administered repeatedly across 30 or 60 days on ethanol consumption using a limited access procedure in the rat.

The present study examined the effects of naltrexone, 1.0 mg/kg, administered repeatedly across both 30 and 60 days on the consumption of an unsweetened ethanol solution by outbred Wistar rats in a limited access procedure. Naltrexone significantly suppressed consumption of ethanol across both 30 and 60 days. These results provide no evidence for the development of tolerance based on such factors as receptor upregulation or supersensitivity due to the repeated administration of naltrexone across extended periods. Ethanol consumption during the final one-third of the naltrexone sessions, for both the 30- and 60-day groups, was significantly lower than during the initial sessions. These results suggest an associative component. That is, the rats apparently learned that ethanol consumption was no longer reinforcing across repeated exposures. After termination of naltrexone treatment, consumption of ethanol immediately increased. However, consumption in those rats who were administered naltrexone for 60 days remained significantly suppressed, compared with consumption in those rats who were administered naltrexone for 30 days. These results suggest that naltrexone reduces ethanol consumption by blocking endogenous opioid receptors that mediate, at least in part, ethanol's reinforcing properties. In addition, these data suggest that longer clinical use of naltrexone, as a pharmacological adjunct to psychosocial treatment for alcohol-dependent patients, may be beneficial in reducing the number of relapses experienced.

Low dose of morphine and the consumption of a sweetened ethanol solution: differential effects on acquisition and maintenance.

The influence of a low dose of morphine was investigated on the acquisition and maintenance of consumption of a sweetened ethanol solution with water as the alternative in a two-bottle choice procedure. During acquisition in Experiment 1, morphine failed to significantly increase the consumption of a sweetened ethanol solution compared to either a postinjection period in the same animals or a no-treatment control group. Although morphine significantly increased sweetened ethanol consumption when compared to a saline control group, this appears to be due to a stress response to the injections, which suppressed ethanol consumption in the saline animals. During maintenance in Experiment 2, morphine significantly increased consumption of sweetened ethanol in all groups compared to consumption following saline control injections. There was no difference in this effect among the three groups, suggesting that prior history with morphine was not a factor. In addition, rats that were exposed to morphine during both experiments drank significantly more sweetened ethanol following injections in Experiment 2 than in Experiment 1. This suggests that morphine's potentiation of ethanol consumption is due to its interaction with endogenous opioid receptors that modulate the reward value of ethanol rather than more general mechanisms affecting satiety or taste. The results of these experiments provide support for both the Deficit and Surfeit Hypotheses of ethanol consumption, both of which suggest that endogenous opioid receptors are responsible, in part, for ethanol's reinforcing properties.

The effects of ethanol on a measure of conditioned fear in mice.

The effects of ethanol on conditioned freezing, a species-specific defensive behavior used as an assay of fear, was examined in mice. In Experiment 1, ethanol, 1.2 g/kg, significantly increased freezing compared to a saline control when the mice were reexposed to a context in which they were previously shocked. Experiment 2, which administered ethanol or saline to no-shock control animals, demonstrated that the potentiated freezing produced by ethanol in Experiment 1 was specific to the interaction of ethanol and the stress response. These results suggest that both the qualitative and quantitative dimensions of the environmental stressor, as well as the dose of ethanol used, may be critical for determining ethanol's effect on a stress response.

Morphine enhances selection of both sucrose and ethanol in a two-bottle test.

The influence of a low dose of morphine on the self-selection of alcohol and sucrose solutions is investigated. When given a choice between sucrose sweetened ethanol and plain water, rats show a significant preference for the sweetened ethanol. However, when given a choice between sweetened ethanol and sweetened water, rats increase consumption of sweetened water. These results suggest that the low-dose morphine enhancement of sweetened alcohol solutions is mediated by the reinforcing properties of sucrose not ethanol. However, when rats receive small doses of morphine and a choice between unsweetened ethanol and water, the rats increase consumption of ethanol. Therefore, a low dose of morphine enhances the self-selection of both sucrose and ethanol solutions. This provides additional confirmation that opioids may enhance the rewarding properties of a variety of appetite reinforcers.

Prognostic significance of proliferative and apoptotic fractions in low grade follicle center cell-derived non-Hodgkin's lymphomas.

BACKGROUND: The biologic parameters, DNA ploidy and proliferative activity, have been suggested as prognostic factors in non-Hodgkin's lymphoma (NHL). However, reports on the prognostic importance of these factors in follicle center cell-derived (FCC) centroblastic/centrocytic (CB/CC) NHL patients with long follow-up are scarce. METHODS: Apoptotic fractions were quantified in 60 patients with CB/CC NHL by in situ labeling of DNA strand breaks in nuclei [TdT-mediated dUTP/dATP in situ 3'OH--end labeling (TUNEL)]. The findings were related to S-phase and MIB-1 counts, DNA ploidy, and clinical outcome. RESULTS: In CB/CC NHL, the percentages of proliferating and apoptotic cells were lower than in reactive germinal centers (GC; P < 0.05; mean, 0.188 vs 3.263% and 19.05 vs. 69.4% for TUNEL and MIB-1 positive cells in CB/CC and GC, respectively). Significantly higher percentages of MIB-1 and TUNEL positive cells were observed in patients with complete remission when compared with the partial remission / no response group (P < 0.01). The size of proliferative and apoptotic fractions did not correlate with the overall survival of the patients. However, follicular and diffuse growth pattern, elevated serum lactic dehydrogenase, advanced stage, and age indicated a lower probability of 5- and 10-year survival. CONCLUSIONS: The investigation of proliferative and apoptotic fractions in FCC lymphomas may help to define groups of patients to who would benefit from aggressive, high dose therapy protocols and patients to whom less aggressive strategies can be applied safely.

The misrepresentation of the human pelvis.

A representative series of illustrations of the human bony pelvis dating from the sixteenth century to the present is used to demonstrate the persistent misrepresentation in the orientation of the pelvis and in the nomenclature. Early erroneous concepts were probably strongly reinforced by publications of the Belgian anatomist Vesalius in the sixteenth century. In mounting the vertebrae on a vertical iron rod, he erased much of the sacral curvature and, as a consequence, the orientation of the rest of the pelvis was distorted. True versions of the pelvis were executed by Leonardo da Vinci before the time of Vesalius but these drawings were apparently among those that were lost for many years. A relatively small number of similarly accurate depictions of the bony pelvis have appeared down through the centuries and some of these are also included. A persistent error in many anatomical textbooks used today presents a modified inferior view of the pelvis as the "front view" and a nearly accurate front view as a "view from above." No definitive conclusion can be reached concerning the reason(s) for the remarkably long persistence of this error. The figures referenced are presented in the Gallery immediately following this article.

Dermal extracellular lipid in birds.

A light and electron microscopic study of the skin of domestic chickens, seagulls, and antarctic penguins revealed abundant extracellular dermal lipid and intracellular epidermal lipid. Dermal lipid appeared ultrastructurally as extracellular droplets varying from less than 1 micron to more than 25 microns in diameter. The droplets were often irregularly contoured, sometimes round, and of relatively low electron density. Processes of fibrocytes were often seen in contact with extracellular lipid droplets. Sometimes a portion of such a droplet was missing, and this missing part appeared to have been "digested away" by the cell process. In places where cells or cell processes are in contact with fact droplets, there are sometimes extracellular membranous whorls or fragments which have been associated with the presence of fatty acids. Occasionally (in the comb) free fat particles were seen in intimate contact with extravasated erythrocytes. Fat droplets were seen in the lumen of small dermal blood and lymph vessels. We suggest that the dermal extracellular lipid originates in the adipocyte layer and following hydrolysis the free fatty acids diffuse into the epidermis. Here they become the raw material for forming the abundant neutral lipid contained in many of the epidermal cells of both birds and dolphins. The heretofore unreported presence and apparently normal utilization of abundant extracellular lipid in birds, as well as the presence of relatively large droplets of neutral lipid in dermal vessels, pose questions which require a thorough reappraisal of present concepts of the ways in which fat is distributed and utilized in the body.