Central opioidergic neurotransmission in complex regional pain syndrome.

OBJECTIVE: Complex regional pain syndrome (CRPS) is a chronic pain condition characterized by sensory, motor, and autonomic symptoms. It develops after limb trauma and may be associated with relevant psychiatric comorbidity. As there is evidence for central pathophysiology which might be related to an altered opioidergic neurotransmission, we investigated the cerebral opioid receptor status under resting conditions in this patient population. METHODS: In this case-control study, 10 patients with CRPS and 10 age- and gender-matched healthy subjects underwent a PET scan using the subtype-nonselective opioidergic radioligand [(18)F]fluoroethyl-diprenorphine. As a surrogate for regional cerebral opioid receptor availability, the opioid receptor binding potential (OR-BP) was assessed by means of the modified Logan plot with reference region input for categorical group comparison and correlation with clinical data in the patient group. RESULTS: Patients with CRPS showed reduced OR-BP in contralateral amygdala and parahippocampal gyri and increased OR-BP in contralateral prefrontal cortical areas. When OR-BP in the midcingulate cortex and the ipsilateral temporal cortex was low, the McGill pain rating index was high. In general, when anxiety and depression scales were high, contralateral temporal OR-BP was high as well. In addition, the anxiety scale decreased with increasing OR-BP in the contralateral parahippocampal cortex. CONCLUSIONS: These results demonstrate altered central opioidergic neurotransmission in CRPS. The correlation of regional opioid receptor availability to measures of pain, anxiety, and depression underlines the clinical importance of these findings.

Evaluation of hemodynamic and regional tissue perfusion effects of minimized extracorporeal circulation (MECC).

Minimized extracorporeal circulation (MECC, Maquet, Cardiopulmonary AG, Hirrlingen, Germany) is an established procedure to perform coronary revascularization. Studies showed positive effects of MECC compared to conventional cardiopulmonary bypass (CCPB) procedures in terms of transfusion requirements, less inflammation reactions, and neurological impairments. Recent retrospective studies showed higher mean arterial pressure (MAP) and a lower frequency of vasoactive drug use. We addressed this issue in this study. The hypothesis was to find a higher MAP during coronary bypass grafting surgery in patients treated with MECC systems. We performed a prospective, controlled, randomized trial with 40 patients either assigned to MECC (n = 18) or CCPB (n = 22) undergoing coronary bypass grafting. Primary endpoints were the perioperative course of mean arterial pressure, and the consumption of norepinephrine. Secondary endpoints were the regional cerebral and renal oxygen saturation (rSO2) as an indicator of area perfusion and the course of hematocrit. Clinical and demographic characteristics did not significantly differ between both groups. Thirty-day mortality was 0%. At four of five time points during extracorporeal circulation (ECC) MAP values were significantly higher in the MECC group compared to CCPB patients (after starting the ECC 60 +/- 11 mmHg vs. 49 +/- 10 mmHg, p = .002). MECC patients received significantly less norepinephrine (MECC 22.5 +/- 35 microg vs. CCPB 60.5 +/- 75 microg, p = .045). The rSO2 measured at right and left forehead and the renal area was similar for both groups during ECC and significantly higher at CCPB group 1 and 4 hours after termination of CPB. Minimized extracorporeal circulation provides a higher mean arterial pressure during ECC and we found a lower consumption of vasoactive drugs in the MECC group. There was a decrease in regional tissue saturation at 1 and 4 hours post bypass in the MECC group possibly due to increased systemic inflammation and extravascular fluid shift in the CCPB group.

Mechanical but not painful electrical stimuli trigger TNF alpha release in human skin.

Pro-inflammatory cytokines-in particular tumor necrosis factor (TNF)-alpha-play an important role in pain and hyperalgesia. The stimuli inducing TNF-alpha release in humans and the time course of this release are largely unknown. We performed dermal microdialysis in healthy subjects (n=36) during three experimental conditions: The first condition (control) was microdialysis without stimulation, the second condition was 30 min of electrical current stimulation (1 Hz, 20 mA, moderately painful), the third condition was 30 min of repetitive mechanical stimulation via an impact stimulator (bullet 0.5 g; velocity 11 m/s, minimally painful). TNF-alpha was quantified in the samples collected at the end of the baseline perfusion (about 1 h of saline perfusion), at the end of stimulation period (exactly 30 min after stimulation commenced) and at the end of the experiment (exactly 90 min after stimulation commenced) using a commercial enzyme-linked immunosorbent assay. The C-fiber-related flare was quantified with a laser-Doppler imager. ANOVA revealed that TNF-alpha levels increased during the eluate sampling period. At 90 min TNF-alpha in the eluate of the mechanical stimulation condition was significantly increased as compared to electrical current or control condition. Flare intensity was highest in the electrical current stimulation condition and only marginally different from control in mechanical stimulation. Our results show that minimal mechanical trauma is sufficient to induce significant TNF-alpha release in the skin. These results may be relevant to the treatment of posttraumatic pain disorders.

Warm and cold complex regional pain syndromes: differences beyond skin temperature?

OBJECTIVE: To investigate clinical differences in warm and cold complex regional pain syndrome (CRPS) phenotypes. BACKGROUND: CRPS represents inhomogeneous chronic pain conditions; approximately 70% patients with CRPS have "warm" affected limbs and 30% have "cold" affected limbs. METHODS: We examined 50 patients with "cold" and "warm" CRPS (n = 25 in each group). Both groups were matched regarding age, sex, affected limb, duration of CRPS, and CRPS I and II to assure comparability. Detailed medical history and neurologic status were assessed. Moreover, quantitative sensory testing (QST) was performed on the affected ipsilateral and clinically unaffected contralateral limbs. RESULTS: Compared with patients who had warm CRPS, patients who had cold CRPS more often reported a history of serious life events (p < 0.05) and chronic pain disorders (p < 0.05). In cold CRPS, the incidence of CRPS-related dystonia was increased (p < 0.05), and cold-induced pain had a higher prevalence (p < 0.01). Furthermore, QST revealed a predominant sensory loss in patients with cold CRPS (p < 0.05). In contrast, patients with warm CRPS were characterized by mechanical hyperalgesia (p < 0.05) in the QST of affected limbs. CONCLUSION: Our results indicate that warm and cold complex regional pain syndromes (CRPS) are associated with different clinical findings, beyond skin temperature changes. This might have implications for the understanding of CRPS pathophysiology.

Stress and thermoregulation: different sympathetic responses and different effects on experimental pain.

Stress and thermoregulation both activate the sympathetic nervous system (SNS) but might differently affect pain. Studies investigating possible interactions in patients are problematic because of the high prevalence of SNS disturbances in patients. We therefore analyzed the influence of these different sympathetic challenges on experimentally-induced pain in healthy subjects. SNS was activated in two different ways: by mental stress (Stroop task, mental arithmetic task), and by thermoregulatory stimulation using a water-perfused thermal suit (7 degrees C, 32 degrees C, or 50 degrees C). Attentional effects of the mental stress tasks were controlled by using easy control tasks. Both, stress and thermoregulatory stimuli, robustly activated SNS parameters. However, the patterns of activation were different. While stress co-activated heart rate, blood pressure, peripheral vasoconstriction and sweating, thermal stimulation either increased blood pressure (cold) or heart rate and sweating (warm). Only stress was able to induce a significant reduction of pain. The control tasks neither activated the SNS nor altered pain perception. Our results suggest that (1) different patterns of sympathetic activation can be recorded after stress and thermoregulatory challenges and (2) that only stress is able to interfere with sensation of experimental pain. Whether SNS activation is causally responsible for analgesia needs to be further investigated.

Patterns of sympathetic responses induced by different stress tasks.

Stress tasks are used to induce sympathetic nervous system (SNS) arousal. However, the efficacy and the patterns of SNS activation have not been systematically compared between different tasks. Therefore, we analyzed SNS activation during the following stress tasks: Presentation of negative, positive, and - as a control - neutral affective pictures, Color-Word interference test (CWT), mental arithmetic under time limit, singing a song aloud, and giving a spontaneous talk. We examined 11 healthy subjects and recorded the following SNS parameters: Activation of emotional sweating by quantitative sudometry, skin vasoconstriction by laser-Doppler flowmetry, heart rate by ECG, blood pressure by determination of pulse wave transit time (PWTT), and electromyographic (EMG) activity of the trapezius muscle. Moreover, subjective stress ratings were acquired for each task using a visual analog scale. All tasks were felt significantly stressful when compared to viewing neutral pictures. However, SNS activation was not reliable: Affective pictures did not induce a significant SNS response; singing, giving a talk and mental arithmetic selectively increased heart rate and emotional sweating. Only the CWT globally activated the SNS. Regarding all tasks, induction of emotional sweating, increase of heart rate and blood pressure significantly correlated with subjective stress ratings, in contrast to EMG and skin vasoconstriction.Our results show that the activation of the SNS widely varies depending on the stress task. Different stress tasks differently activate the SNS, which is an important finding when considering sympathetic reactions - in clinical situations and in research.

A chamber for determining the conventionally true value of Hp(10) and H*(10) needed by calibration laboratories.

A secondary standard chamber for photon radiation developed for measuring directly the conventionally true value of the personal dose equivalent, Hp(10), in a slab phantom is now commercially available. In addition, this chamber can be used for determining the true value of the ambient dose equivalent, H*(10), in monodirectional radiation fields; for example, photon fields generated by X ray facilities. Once the chamber has been calibrated at the facility of the calibration laboratory, the true value of Hp(10) or H*(10) can be measured at other facilities without applying any conversion coefficients. For low energy photon fields the conversion coefficients are strongly dependent on the spectral distribution. For nominally the same radiation quality small spectral differences, caused, for example, by use of different X ray facilities, may lead to differences between the spectrum-averaged conversion coefficients from Ka to Hp(10) and H*(10), respectively, of up to several tens per cent. For this reason, tabulated conversion coefficients for low energy radiation fields cannot be used for calibration purposes, if the standard uncertainty is to be 2-5%. Direct measurement by the secondary standard chamber overcomes this problem.

T-wave alternans in LQTS: repolarization-rate dynamics from digital 12-lead Holter data.

T-wave alternans (TWA) is a harbinger of ventricular vulnerability and an important prognostic indicator for torsade de pointes and likely sudden death in patients with LQTS. We analyzed the occurrence of TWA in 18 patients with LQTS (7 males, 11 females, ages ranging from 6 months to 32 years--median 8.4 years). Analysis was performed with software to investigate dynamics of cycle length mediated repolarization changes. Digital Holter ECG analysis revealed macroscopic, true TWA in 3 of 18 patients. TWA showed a variable morphological expression. One patient had continuous changes of T wave polarity, but not on a periodic beat-to-beat basis. Onsets of macroscopic TWA were preceded by long/short cycle length sequences and tachycardic rates above 130 to 140 bpm. Impact of ventricular premature beats on TWA onset was insignificant. Two of the identified patients with TWA had sudden cardiac death during follow-up (one refused PM therapy). At present, TWA cannot be detected automatically from Holter ECGs and therefore may be missed, despite the potential danger for the individuals. The observation that predominantly high beat rates and not beat rate changes, per se, triggered episodes of TWA renders difficult general therapeutic recommendations for the identified patients at risk.

Expression of cancer testis genes in human brain tumors.

Cancer-testis (CT) genes are expressed in a variety of human cancers but not in normal tissues, except for testis tissue, and represent promising targets for immunotherapeutic and gene therapeutic approaches. Because little is known about their composite expression in human brain tumors, we investigated the expression of seven CT genes (MAGE-3, NY-ESO-1, HOM-MEL-40/SSX-2, SSX-1, SSX-4,HOM-TES-14/SCP-1, and HOM-TES-85) in 88 human brain tumor specimens. Meningiomas expressed only HOM-TES-14/SCP-1 (18% of meningiomas were HOM-TES-14/SCP-1 positive) and did not express any other CT genes. One ependymoma was negative for all CT genes tested. SSX-4 was the only CT gene expressed in oligodendrogliomas (2 of 5 cases), and it was also expressed in oligoastrocytomas (3 of 4 cases) and astrocytomas (10 of 37 cases). Astrocytomas were most frequently positive for HOM-TES-14/SCP-1 (40%) and SSX-4 (27%), followed by HOM-TES-85 (13%), SSX-2 (11%), and MAGE-3 (7%). Whereas MAGE-3 was detected only in grade IV astrocytomas, the expression of the other CT genes showed no clear correlation with histological grade. Of 39 astrocytomas, 60% expressed at least one CT gene, 21% expressed two CT genes, and 8% coexpressed three CT genes of the seven CT genes investigated. We conclude that a majority of oligoastrocytomas and astrocytomas might be amenable to specific immunotherapeutic interventions. However, the identification of additional tu-mor-specific antigens with a frequent expression in gliomas is warranted to allow for the development of widely applicable polyvalent glioma vaccines.

Clinical and economic outcomes in the hypertension and COPD arms of a multicenter outcomes study.

OBJECTIVE: To evaluate the impact of pharmaceutical care on selected clinical and economic outcomes in patients with hypertension or chronic obstructive pulmonary disease (COPD) in ambulatory care settings. DESIGN: Clinic patients with hypertension or COPD were randomly assigned to a treatment group (pharmaceutical care) or a control group (traditional pharmacy care) over a six-month period. Clinical pharmacists and pharmacy residents conducted the protocols. There were 133 evaluable patients (63 treatment and 70 control) in the hypertension study arm and 98 evaluable patients (43 treatment and 55 control) in the COPD study arm. SETTING: 10 Departments of Veterans Affairs medical centers and 1 academic medical center. INTERVENTIONS: Patient-centered pharmaceutical care model (employing standardized care) implemented by clinical pharmacy residents. MAIN OUTCOME MEASURES: Patient knowledge, medication compliance, and health resource use. RESULTS: The hypertension treatment group had a significantly greater reduction in systolic blood pressure from visit 1 to visit 5 than did the control group. In the COPD study arm, trends were positive in the treatment group for patients ratings of symptom interference with activities and dyspnea measures. There was a significant difference between the hypertension treatment and control group for compliance. There were no significant changes in compliance scores in the COPD study arm. Mean number of hospitalizations and other health care provider visits was higher for the hypertension control group. For patients with COPD, hospitalizations increased in the control group, and the number of other health care provider visits was higher in the control group. CONCLUSION: Pharmacists' participation in a pharmaceutical care program resulted in disease state improvement in ambulatory patients with hypertension and COPD.

Prediction of normal QT intervals in children.

Measuring QT intervals in individual children is of great importance, particularly in view of increasing evidence linking long QT syndrome to subsequent risk for sudden death. Three hundred seventy-three healthy subjects, 185 women and 188 men, aged 5.2 to 16.5 years, were investigated with a 12-lead-standard electrocardiogram (ECG). Values for predicted QTp50 and QTp95 (percentiles) were calculated by using the cycle length (RR interval [RRI]) and the measured QT interval. We used multiple regression analysis to test the influence of possible important variables and the resulting data were used to generate tables. Additionally, predicted QTp values were compared to QTc values after Bazett's correction. RRI, body height, age, and sex turned out to influence the QTp values most. For clinical use, data are presented in tabular form by RRI and age for both genders. The tables are of great clinical value in predicting the upper limits of normal QTp95 for individual children. Bazett's correction tends to underestimate the values found in our data when heart rate increases.

Impact of pulmonary rehabilitation team effort for ambulatory patients with chronic lung disease.

The pulmonary rehabilitation program at the Veterans Affairs Medical Center in Memphis, Tennessee, is a program consisting of an interdisciplinary team effort that is coordinated by a clinical pharmacist and focuses intensively on educating patients with chronic lung disease about their disease, the basics of care, and life style changes that may prevent acute illnesses and help the patient remain as functional as possible. Implementation of this program, including information and data on proposal and development of this preventive care program are included. The success has been measured in the accomplishment of its goals of decreasing inpatient acute care needs through patient and family education, increasing functional status of patients handicapped with lung disease, and increasing patients' satisfaction with their care.

Conjugation to antifibrin Fab' enhances fibrinolytic potency of single-chain urokinase plasminogen activator.

Single-chain urokinase plasminogen activator (scu-PA) that had been modified with N-succinimidyl-3-(2-pyridyldithio)propionate was covalently linked by disulfide bonds to the Fab' of a monoclonal antibody specific for the beta-chain of fibrin (antibody 59D8). scu-PA-59D8 Fab' conjugate was separated from free scu-PA and two-chain urokinase coupled to 59D8 Fab' by two-step affinity chromatography. First, the reaction mixture was chromatographed on a column containing Sepharose linked to the peptide that had been used as immunogen for antibody 59D8; scu-PA-59D8 Fab' conjugate and unconjugated 59D8 Fab' were retained but not unconjugated scu-PA. Then, the eluate from the peptide-Sepharose column was chromatographed on a column containing Sepharose linked to benzamidine, which acts as a ligand for two-chain urokinase. The molecular weight of the scu-PA-59D8 Fab' conjugate was approximately 100 kDa when electrophoresed on a nonreducing sodium dodecylsulfate-polyacrylamide gel. Enzymatic assay after purification revealed that more than 97% of the scu-PA present in the conjugate retained the single-chain form. The Fab' portion of the conjugate functioned in a manner indistinguishable from that of native antibody 59D8. In an in vitro assay for lysis of fibrin monomer, the fibrinolytic potency of scu-PA-59D8 Fab' was 33-fold more than that of tissue plasminogen activator (p less than 0.001), 230-fold more than that of unconjugated scu-PA (p less than 0.0001), and 420-fold more than that of urokinase (p less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)