Interleukin-6-mediated hyperalgesia/allodynia and increased spinal IL-6 expression in a rat mononeuropathy model

It has been suggested that neuroimmunologic mechanisms may be involved in the development and maintenance of neuropathic pain. To further address this concept, the immunoreactive spinal expression of the pro-inflammatory cytokine, interleukin-6 (IL-6), was determined in the mononeuropathy model in the rat, sciatic cryoneurolysis (SCN). This well-established animal model expresses behaviors suggestive of neuropathic pain in humans. Immunohistochemical localization in the spinal cord was determined at 3, 7, 14, 21, 35, and 120 days after SCN (n = 6 per time point). Immunoreactive IL-6 increased incrementally in the substantia gelatinosa and motoneurons over time following SCN as compared with normal rats. In an additional study, recombinant human IL-6 was administered intrathecally to normal and previously SCN-lesioned rats. Intrathecal IL-6 produced touch-evoked allodynia (increased sensitivity to a nonnoxious stimulus) in normal rats and thermal hyperalgesia (increased sensitivity to a noxious stimulus) in previously lesioned SCN rats. These results provide evidence that IL-6 may be involved in the cascade of events leading to the development and maintenance of behaviors suggestive of neuropathic pain following peripheral nerve injury.     

Capsaicin-evoked mechanical allodynia and hyperalgesia cross nerve territories. Evidence for a central mechanism

BACKGROUND: The finding in some patients with neuropathic pain that mechanical allodynia (pain evoked by light touch) and hyperalgesia (supranormal pain evoked by painful stimuli) extend beyond the territory of a single nerve or spinal sensory root (extraterritorial pain) often prompts a diagnosis of psychiatric illness. The hypothesis that focal nociceptive input in a single nerve territory can result in allodynia and hyperalgesia in a nerve territory adjacent to the input was investigated in normal human subjects. METHODS: On separate days, 13 healthy volunteers each received left radial and ulnar nerve blocks. After block of either nerve, sensation remaining for three classes of afferents (A beta low-threshold mechanoreceptors, A delta nociceptors, and C polymodal nociceptors) allowed inference of the nerve territory of the adjacent nerve, and the area of overlapping innervation. On a third day, 1,000 micrograms intradermal capsaicin was administered into a site such that C-nociceptor input was confined to the ulnar nerve territory. Areas of brush allodynia and pinprick hyperalgesia were determined. RESULTS: Spread of brush allodynia beyond all three borders of the ulnar nerve territory occurred in 9 of 13 patients (for these subjects, range 5-28 mm), whereas spread of pinprick hyperalgesia beyond all borders of the ulnar nerve territory occurred in 12 of 13 subjects (range 1-31 mm). Spread of brush allodynia beyond the A beta border of the ulnar nerve territory occurred in 10 of 13 subjects (range 4-35 mm); and spread of pinprick hyperalgesia beyond the A delta border of the ulnar nerve territory occurred in 12 of 13 subjects (range 1-31 mm). CONCLUSIONS: It is concluded that activation of C-nociceptors evokes a state of central sensitization that may manifest itself by the appearance of extraterritorial pain abnormalities.     

Peripheral morphine administration blocks the development of hyperalgesia and allodynia after bone damage in the rat

BACKGROUND: The current study aimed to assess whether local administration of morphine could block the development of hyperalgesia and allodynia in a rat model of osteotomy or bone damage. METHODS: Withdrawal responses to mechanical and thermal stimuli applied to the plantar surface of the hind paw were measured before and after bone damage. The bone was injured by drilling a 1-mm hole through the tibia during short-lasting general anesthesia. In separate groups of rats, the effects of administering morphine (20-80 microg), either into the marrow cavity or systemically, on the development of hyperalgesia and allodynia after bone damage were assessed. In an additional group of rats, a selective mu-opioid receptor antagonist, clocinnamox (0.15 mg), was administered into the marrow cavity before the administration of morphine (40 microg). RESULTS: In animals that received no drug treatment, hyperalgesia and allodynia peaked 2 h after injury. Injection of morphine (40 and 80 microg) into the marrow cavity immediately after bone injury prevented the development of hyperalgesia and allodynia. Clocinnamox (0.15 mg) injected into the marrow cavity before administration of morphine blocked the antihyperalgesic effect of morphine. CONCLUSION: This study shows that local application of a low dose of morphine effectively blocks the development of hyperalgesia and allodynia in a rat model of bone damage through mu-opioid receptor action. These findings provide further evidence that local application of morphine at the time of orthopedic surgery, bone graft, or bone marrow harvesting may reduce the amount of postoperative pain.     

Murine model for human secondary amyloidosis: genetic variability of the acute-phase serum protein SAA response to endotoxins and casein

The serum precursor SAA of the secondary amyloid protein AA has been detected by solid-phase radioimmunoassay as a normal serum alpha-globulin of mol wt 160,000, which dissociates to a more stable 12,500 dalton moiety on treatment with formic acid. In 12 strains of mice, including T-cell-deficient nude mice, treated with the amyloid-inducing agents lipopolysaccharide (LPS) or casein, SAA behaved as an acute-phase reactant. SAA concentration rose to about 750 mug/ml by 24 h and returned to less than 1 mug/ml by 48 h. Since the amyloid-resistant colchicine-treated mice and AJ mice had a normal SAA response to LPS, it appears that their resistance to amyloid induction is due to the nature of their SAA processing rather than decreased SAA production. C3H/HeJ mice, which have defective B-lymphocyte responses to LPS, required extremely high dosages of LPS to cause SAA elevation, although their SAA response to casein was normal. This suggests that SAA is an acute-phase protein produced as a result of B-lymphocyte stimulation. Preliminary evidence suggests that at the height of an acute SAA response, liver homogenates are particularly rich in protein AA cross-reacting material.     

Reliability of copper reduction methods for quantitation of glucosuria

In the present study we evaluated the reliability of the "2-drop" Clinitest method in determining the 24-h glucose spill of a diabetic patient. The urine glucose content over the 33 day study period was measured with a Beckman glucose analyzer that employed a glucose oxidase method. There was no statistical difference between the glucose content determined by the two methods. There was a mean error of +4.4 +/- 3.6% between the values obtained with the "2-drop" method and values obtained with glucose analyzer. The mean coefficient of variation for determining the glucose content of urine with the "2 drop" method was 19%. In a group of 10 normal volunteers we found that there was a falsely elevated glucose value in urines with osmolality of less than 295 mosm/kg when the "5-drop" method was used. The "2-drop" Clinitest and the Beckman analyzer could accurately determine glucose concentration even in these dilute urines. The "2-drop" Clinitest method is a useful and reasonably reliable method for evaluationg 24-h glucosuria.     

The Trimera mouse: generating human monoclonal antibodies and an animal model for human diseases

Monoclonal antibodies of human origin may have great therapeutic value in the treatment of cancer, autoimmune disorders and viral or bacterial infections. Several methods for generating human monoclonal antibodies exist; some are based on the transplantation of a functioning human immune system into severe combined immunodeficient (scid) mice or into Trimera mice, which are mice that have been lethally irradiated and radioprotected by transplantation of bone-marrow cells from scid mice. Trimera mice could be also used to develop animal models for human diseases by transplanting infected human tissue fragments and for creating models for cell therapy.     

The variability of human, BOLD hemodynamic responses

Cerebral hemodynamic responses to brief periods of neural activity are delayed and dispersed in time. The specific shape of these responses is of some importance to the design and analysis of blood oxygenation level-dependent (BOLD), functional magnetic resonance imaging (fMRI) experiments. Using fMRI scanning, we examine here the characteristics and variability of hemodynamic responses from the central sulcus in human subjects during an event-related, simple reaction time task. Specifically, we determine the contribution of subject, day, and scanning session (within a day) to variability in the shape of evoked hemodynamic response. We find that while there is significant and substantial variability in the shape of responses collected across subjects, responses collected during multiple scans within a single subject are less variable. The results are discussed in terms of the impact of response variability upon sensitivity and specificity of analyses of event-related fMRI designs.     

Hemispheric asymmetry reduction in older adults: The HAROLD model.

A model of the effects of aging on brain activity during cognitive performance is introduced. The model is called HAROLD (hemispheric asymmetry reduction in older adults), and it states that, under similar circumstances, prefrontal activity during cognitive performances tends to be less lateralized in older adults than in younger adults. The model is supported by functional neuroimaging and other evidence in the domains of episodic memory, semantic memory, working memory, perception, and inhibitory control. Age-related hemispheric asymmetry reductions may have a compensatory function or they may reflect a dedifferentiation process. They may have a cognitive or neural origin, and they may reflect regional or network mechanisms. The HAROLD model is a cognitive neuroscience model that integrates ideas and findings from psychology and neuroscience of aging. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The power of multiple methods and evidence sources: Raising the profile of Canadian counselling psychology research.

In counselling psychology, research and practice are viewed as mutually informative, and Canadian counselling psychologists conduct research in a wide range of areas, utilizing a wide range of research methods. However, there are few Canadian publications that give prominence to counselling psychology scholarly work. Over the past decade, two trends have become more prominent in the practice of counselling psychology: evidence-based practice and outcome-focused intervention. Traditionally, empirical evidence for the efficacy of practice interventions has come from randomized controlled trials. This fails to reflect the diversity of methods and practice that Canadian counselling psychologists utilize. To address this discrepancy, in this article we provide some alternate ways for obtaining empirical support for the predictive efficacy of counselling interventions. We conclude by addressing some challenges currently facing counselling psychologists in Canada (i.e., publication venues, funding for research, the connection between research and practice, preparation of students) and describing some ways for raising the profile of counselling psychology research and practice in Canada. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Bioanalytical calibration curves: variability of optimal powers between and within analytical methods

The objective of this study was to investigate the variability of optimal power models in contrast to common regression models within and between analytical methods, as well as the frequency of outlier rejection. This was done by fitting the power model to calibration curve data using the minimum sum of squared residuals as a curve selection criterion. The jackknife percent deviation was used for detecting outliers. The data were obtained from 2087 analytical batches for 91 projects using various analytical techniques. The most frequent regression model varied between analytical techniques while the median and interquartile range of the optimal powers were stable. Outlier rejection is highest in GC and LCMS in which the Wagner (Quadratic, log-log) is the most frequent model. These results suggest that the greatest source of variability in the ideal transformation may not be the analytical technique but other within-lab sources. Outlying values may be due to these other sources of variability as suggested by the outlier rejection profile.     

Skeletal muscle triacylglycerol in the rat: methods for sampling and measurement, and studies of biological variability

dTDP-L-dihydrostreptose: streptidine-6-phosphate dihydrostreptosyltransferase, an enzyme involved in the biosynthesis of streptomycin, has been purified from Streptomyces griseus to near homogeneity by a six-step procedure involving chromatography on streptidine-6-phosphate-Sepharose. By gel filtration the apparent Mr of the enzyme was found to be about 63 000. The subunit Mr found on sodium dodecylsulfate gels is about 35 000. The transferase is dependent on Mn2+ or Mg2+ ions. Co2+ is as effective as Mg2+. From the substrates tested only streptidine 6-phosphate was an acceptor for dihydrostreptose in the synthesis of O-alpha-L-dihydrostreptose(1 leads to 4)-streptidine 6-phosphate. No activity was found with streptidine, 2-deoxystreptamine and 4-deoxy-streptamine. The activity of the transferase in the course of fermentation runs parallel to the activity of dTDP-dihydrostreptose synthase and reaches a maximum after around 50 h of fermentation, just before appearance of streptomycin in the medium.     

Abnormalities of mechanoreceptors in a rat model of neuropathic pain: possible involvement in mediating mechanical allodynia

1. Peripheral nerve injury sometimes leads to the development of neuropathic pain. One of the symptoms of such neuropathic pain is mechanical allodynia, pain in response to normally innocuous mechanical stimuli. We hypothesized that sympathetically driven dysfunction of cutaneous mechanoreceptors is responsible for signaling mechanical allodynia. The present study was undertaken to identify the types of sensory receptors that potentially mediate mechanical allodynia, with the use of a rat neuropathic pain model we have developed. 2. One week to 10 days after tight ligations of the L5 and L6 spinal nerves on one side, the rats fully developed behavioral signs of mechanical allodynia on the affected hindlimb. Various cutaneous mechanoreceptors originating from the neuropathic foot were examined by single-fiber recordings from the L4 dorsal root. 3. Although no particular abnormalities were found in other types of cutaneous mechanoreceptors, an unusual type of mechanoreceptor was found to be innervating the neuropathic foot. The response characteristics of this type of receptor resemble those of rapidly adapting mechanoreceptors (RAs), but with low and irregular static discharges during a maintained mechanical stimulus. We termed this unusual type as a "modified rapidly adapting" mechanoreceptor (MRA). 4. The response characteristics of MRAs change to those of typical RAs after a systemic injection of phentolamine, an alpha-adrenergic receptor blocker. 5. We conclude that many RAs become abnormal under the influence of sympathetic efferents in neuropathic pain, so that their response patterns change to those of MRAs. We propose that this abnormality is responsible for signaling the mechanical allodynia that can be seen in neuropathic pain states such as causalgia.     

Development of shock-induced analgesia: A search for hyperalgesia.

With the use of parameters intended to maximize the potential to observe hyperalgesia, the possibility was examined that hyperalgesia might be the immediate response to aversive stimulation, whereas analgesia is delayed (L. D. Matzel and R. R. Miller; see record 1987-33731-001). Consistent with the later prediction, analgesia in rats, as assessed by latency to paw lick in response to thermal stimulation, increased as a function of the delay between a tailshock (Exp 1) or footshock (Exp 3) and the test of pain sensitivity. However, in neither case was a hyperalgesic response observed at shock offset. In Exp 2, the strength of the analgesic response was found to increase as a direct function of both the time since the tailshock and tailshock intensity over the limited ranges examined, but no hyperalgesia was observed immediately after either low- or high-intensity shock. In Exp 4, the opiate antagonist naloxone was found to attenuate both a weak immediate and stronger delayed analgesia, suggesting a common underlying mechanism. Data show that opioid analgesia mediates a compensatory process that increases over time. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Peer review of the quality of care. Reliability and sources of variability for outcome and process assessments

CONTEXT: Peer assessments have traditionally been used to judge the quality of care, but a major drawback has been poor interrater reliability. OBJECTIVES: To compare the interrater reliability for outcome and process assessments in a population of frail older adults and to identify systematic sources of variability that contribute to poor reliability. SETTING: Eight sites participating in a managed care program that integrates acute and long-term care for frail older adults. PATIENTS: A total of 313 frail older adults. DESIGN: Retrospective review of the medical record with 180 charts randomly assigned to 2 geriatricians, 2 geriatric nurse practitioners, or 1 geriatrician and 1 geriatric nurse practitioner and 133 charts randomly assigned to either a geriatrician or a geriatric nurse practitioner. MAIN OUTCOME MEASURES: Interrater reliabilities for structured implicit judgments about process and outcomes for overall care and care for each of 8 tracer conditions (eg, arthritis). RESULTS: Outcome measures had higher interrater reliability than process measures. Five outcome measures achieved fair to good reliability (more than 0.40), while none of the process measures achieved reliabilities more than 0.40. Three factors contributed to poorer reliabilities for process measures: (1) an inability of reviewers to differentiate among cases with respect to the quality of management, (2) systematic bias from individual reviewers, and (3) systematic bias related to the professional training of the reviewer (ie, physician or nurse practitioner). CONCLUSIONS: Peer assessments can play an important role in characterizing the quality of care for complex patients with multiple interrelated chronic conditions, but reliability can be poor. Strategies to achieve adequate reliability for these assessments should be applied. These strategies include emphasizing outcomes measurement, providing more structured assessments to identify true differences in patient management, adjusting systematic bias resulting from the individual reviewer and their professional background, and averaging scores from multiple reviewers. Future research on the reliability of peer assessments should focus on improving the ability of process measures to differentiate among cases with respect to the quality of management and on identifying additional sources of systematic bias for both process and outcome measures. Explicit recognition of factors influencing reliability will strengthen efforts to develop sound measures for quality assurance.     

Bacterial antigen detection in body fluids: methods for rapid antigen concentration and reduction of nonspecific reactions

We sought procedures which would allow a rapid concentration in high yield of bacterial antigens from tissue fluids of patients and which could be applied also to protein-rich fluids like serum. Ethanol precipitation at a subzero temperature with albumin added as an antigen coprecipitant made it possible to achieve a more than 20-fold concentration of antigen in 15 min and a 200-fold concentration in 45 min. Heat-stable antigens could be concentrated from protein-rich fluids (like serum) after the sample had been deproteinized by boiling. Such heating (100 degrees C, 3 min) also liberated bacterial polysaccharides from antibody complexes and elminated the nonspecific interference of serum in enzyme-linked immunosorbent assay.     

Testosterone sulphation and glucuronidation in the human liver: interindividual variability

We present a case with the traumatic extracranial internal carotid artery dissecting aneurysm. A 21-year-old man was involved in a motorcycle accident, resulting in multiple injuries but no apparent head and neck injuries. Head CT was normal on his admission. He was discharged from his local hospital 3 weeks after the accident without any neurological deficits. Five weeks after the accident, he suddenly presented with a motor aphasia and a right hemiparesis. CT and MRI showed infarctions in the left para-Sylvian and the left angular areas. Angiography showed a left extracranial carotid artery dissecting aneurysm at the level of C1 vertebral arch. The patient was initially managed by an anticoagulant agent, but he suffered from another transient ischemic attack due to distal embolism from the aneurysm. Balloon occlusion test of the left ICA was performed under monitoring EEG, SEP. Mean stump pressure (MSP) revealed 60 mmHg. and MSP/Mean systematic blood pressure revealed 67%. We judged that the left ICA ligation was a safe method to treat this patient, however, considering the patient's age and the side of the lesion, left STA-MICA bypass and ligation of the left ICA were carried out in one stage. Postoperatively, the patient did not show any cerebral ischemic complications and angiography showed disappearance of the aneurysm and patency of the bypass. The left MCA territories were filled well by cross circulation and the bypass.     

The NCI-H295 cell line: a pluripotent model for human adrenocortical studies

The human adrenal cortex is a complex endocrine organ that secretes mineralocorticoids, glucocorticoids and adrenal androgens. These steroids arise from morphologically and biochemically distinct zones of the adrenal gland. Studying secretion of these distinct steroid hormones has, in the past, required the isolation of cells from each of the adrenocortical zones. Indeed, the lack of a human adrenocortical cell line retaining the ability to produce any of the major adrenal steroid products has slowed studies on normal and abnormal adrenal function. This obstacle has now been largely overcome with the availability of H295 cells, which represents the first adrenocortical cell line to maintain the ability, under specified conditions, to produce all the adrenocortical steroids (i.e., mineralocorticoids, glucocorticoids, and adrenal androgens). Thus, H295 cells appear to act as pluripotent adrenocortical cells capable of being directed to produce each of the zone-specific steroids. The H295 cell line should prove to be of value in studying the molecular and biochemical mechanisms controlling adrenal steroidogenesis.     

Possible reasons for the variability of human responses to IAC-CPR

OBJECTIVE: To propose reasons for the variability of the hemodynamic responses and survival data observed when interposed abdominal compression cardiopulmonary resuscitation (IAC-CPR) is performed on humans in cardiac arrest. METHODS: Critical content review of all studies performed in the United States examining IAC-CPR in humans and of selected animal studies addressing hemodynamic mechanisms of CPR. Articles in the English language dealing with human IAC-CPR studies from 1970-1993 were retrieved using the MEDLINE database of the National Library of Medicine. RESULTS: IAC-CPR does not consistently improve coronary perfusion pressure (CPP) over standard CPR in humans and is capable of decreasing as well as increasing CPP. This variability does not seem dependent on the manner in which abdominal compressions are performed. Because of the limited response to standard CPR, significant increases in return of spontaneous circulation would be expected with IAC-CPR if a large percentage of patients were to have favorable increases in CPP. However, other patients may be adversely affected by decreases in CPP during IAC-CPR, with unsuccessful resuscitation of those individuals. Return of spontaneous circulation also may be enhanced using IAC-CPR due to other factors reflected in the initial arrest rhythm and in arrest-population demographics. CONCLUSION: IAC-CPR should not be recommended for routine use until the mechanism of its beneficial effects is known and until those patients who are likely to benefit from the technique can be better identified.