Long-term antinociception by electroacupuncture is mediated via peripheral opioid receptors in free-moving rats with inflammatory hyperalgesia.

BACKGROUND: Electroacupuncture (EA) has been widely accepted and applied as an important acupuncture-related technique for acupuncture analgesia (AA) research. The involvement of opioid peptides and receptors in acute AA has been shown via pre-EA application of opioid receptor/peptide antagonists. In this study, we intended to reproducibly institute acupoint position and needling excluding influences from anaesthesia or restrainers on rats with complete Freund's adjuvant (CFA) hind paw inflammatory pain, as well as to explore opioid-dependency and anti-inflammatory effects in sustained acupuncture analgesia. METHODS: Accurate position and needling approach on acupoint GB30 was modelled by computer-based three-dimensional (3D) images and followed by an optimal EA treatment protocol (100 Hz, 2-3 mA, 20 min) at 0 and 24 h post-CFA in conscious free-moving rats. Opioid receptor antagonists, naloxone (NLX) and naltrindole (NTI) were applied intraplantarly post-EA at late phase (96 h) of CFA. Nociceptive thresholds were assessed by paw pressure threshold (Randall-Sellito) or paw withdrawal latency (Hargreaves), and anti-inflammatory effects were evaluated by measurement of plantar temperature and paw volume. RESULTS: EA elicited significant sustained mechanical and thermal antinociception up to 144 h. Mechanical antinociception of EA was suppressed by peripheral intraplantar application of NLX and NTI. EA also reduced paw temperature and volume during the same time frame indicating anti-inflammatory effects. CONCLUSIONS: By employing a reproducible EA treatment model on GB30 in free-moving rats, we demonstrated the involvement of peripheral opioid receptors mediated EA-induced long-term antinociception. Future studies should examine the specific neuroimmunological connection of EA-induced sustained antinociception in inflammation.

Modulation of tight junction proteins in the perineurium for regional pain control.

Peripheral neurons are surrounded by the perineurium that forms the blood-nerve barrier and protects the nerve. Although the barrier serves as protection, it also hampers drug delivery of analgesic drugs to the peripheral nerve. We previously showed that opening of the barrier using hypertonic solutions facilitates drug delivery, for example, of hydrophilic opioids, which selectively target nociceptors. The perineurial barrier is formed by tight junction proteins, including claudin-1, claudin-5, and occludin. Under pathophysiological conditions such as nerve crush injury, the perineurial barrier is opened and tight junction proteins are no longer present. After several days, tight junction proteins reappear and the barrier reseals. Similarly, perineurial injection of hypertonic saline transiently opens the barrier, claudin-1 disappears, and hydrophilic analgesic drugs are effective. In the future, these findings could be used to reseal the barrier breakdown and could be applied to other barriers like the blood-brain or the intestinal mucosal barrier.

Recruitment of opioid peptide-containing neutrophils is independent of formyl peptide receptors.

In complete Freund's adjuvants (CFA) inflammation opioid containing neutrophils release opioid peptides upon stimulation and mediate peripheral analgesia. Neutrophil migration is regulated partially by chemokines, but other mediators e.g. formyl peptides could also contribute. In vitro, formyl peptides but not Mycobacterium butyricum (CFA component) induced migration of neutrophils. In contrast, local formyl peptide injection did not induce leukocyte recruitment in vivo due to insufficient up-regulation of adhesion molecule expression. Furthermore, leukocyte recruitment and peripheral opioid-mediated analgesia were unaffected by systemic formyl peptide receptor blockade in CFA inflammation. Thus, while formyl peptides do not regulate migration they directly stimulate opioid peptide release.

Antinociception by neutrophil-derived opioid peptides in noninflamed tissue--role of hypertonicity and the perineurium.

Inflammatory pain can be controlled by intraplantar opioid injection or by secretion of endogenous opioid peptides from leukocytes in inflamed rat paws. Antinociception requires binding of opioid peptides to opioid receptors on peripheral sensory nerve terminals. In the absence of inflammation, hydrophilic opioid peptides do not penetrate the perineurial barrier and, thus, do not elicit antinociception. This study was designed to examine the conditions under which endogenous, neutrophil-derived hydrophilic opioid peptides (i.e. Met-Enkephalin and beta-endorphin) can raise nociceptive thresholds in noninflamed tissue in rats. Intraplantar injection of the chemokine CXCL2/3 (macrophage inflammatory protein-2) induced selective neutrophil recruitment without overt signs of inflammation or changes in mechanical nociceptive thresholds (paw pressure threshold). Following intraplantar injection of hypertonic saline, the perineurial barrier was permeable for hours and intraplantar injection of opioid peptides increased mechanical nociceptive thresholds. While formyl-Met-Leu-Phe (fMLP) triggered opioid peptide release from neutrophils in vitro, nociceptive thresholds were unchanged in vivo. In vitro, hypertonicity interfered with fMLP-induced p38 mitogen activated kinase (MAPK) phosphorylation and opioid peptide release from neutrophils. These inhibitory effects were fully reversible by washout. In vivo, return to normotonicity occurred within 30min while the perineurium remained permeable for hours. Under these conditions, fMLP triggered MAPK phosphorylation and induced opioid peptide-mediated increases in nociceptive thresholds in the noninflamed paw. Taken together, antinociception mediated by endogenous opioids in noninflamed tissue has two important requirements: (i) opening of the perineurial barrier for opioid peptide access and (ii) opioid peptide release from neutrophils involving p38 MAPK.

[Treatment of euthyroid struma. Comparable volume reduction with 400 micrograms iodine, 100 micrograms levothyroxine combined with 100 micrograms iodine or individually dosed levothyroxine]. / Behandlung der euthyreoten Struma. Vergleichbare Volumenreduktion mit 400 micrograms Jodid, 100 micrograms Levothyroxin kombiniert mit 100 micrograms Jodid oder individuell dosiertem Levothyroxin.

AIM: In patients with euthyroid goitre, the efficacy of treatment with 400 micrograms iodine and 100 micrograms levothyroxine combined with 100 micrograms iodine was compared to that of the previous standard of therapy, individually dosed levothyroxine. PATIENTS AND METHODS: A total of 78 patients presenting with euthyroid diffuse goitre (> or = 25 ml) were prospectively enrolled, randomised and treated for 6 months. The course of thyroid volume was followed using thyroid volumetry. RESULTS: Data of 69 patients were included in the final evaluation (57 women, 12 men, age 31 +/- 1 years, thyroid volume 31.5 +/- 1.4 ml, 23 per treatment group). In the patients treated with individually dosed levothyroxine, the thyroid volume decreased by about 39% (95%-confidence limit [CL]-31% to -41%). However, the volume reductions achieved in the patients treated with 400 micrograms iodine or 100 micrograms levothyroxine/100 micrograms iodine were not significantly different (p = 0.35, variance analysis, mono-iodine -34%, 95%-CL -29% to -43%, 100 micrograms levothyroxine/100 micrograms iodine -39%, 95%-CL -32% to -45%). CONCLUSIONS: In patients with euthyroid diffuse goitre, treatment with mono-iodine or combination of levothyroxine with iodine should have principally the same status as the previous standard of therapy, individually dosed levothyroxine. In the view of the authors, its preferential treatment with mono-iodine appears most reasonable.

[The prevention of the recurrence of endemic goiter. The efficacy of a once-a-week dose of 1.53 mg iodide]. / Rezidivprophylaxe der endemischen Struma. Effektivität der einmal wöchentlichen Gabe von 1,53 mg Jodid.

OBJECTIVE: To investigate the efficacy of 1.53 mg iodide administered once weekly in the prophylaxis of goitre recurrence in patients with endemic euthyroid goitre after initial treatment to reduce the goitre size. PATIENTS AND METHODS: 46 consecutive patients who had undergone initial L-thyroxine, iodide or combined treatment were included in the prospective study. Thyroid volume was measured sonographically at the beginning as well as 6 and 18 months later. An increase in thyroid volume of more than 15% was taken as recurrence. RESULTS: The study was concluded in 41 patients. During the prophylaxis mean thyroid volume increased from initially 21.7 +/- 9.9 ml to 22 +/- 10.9 ml after 6 months and to 24.5 +/- 12.1 ml after 18 months (P < 0.01). While thyroid volume remained unchanged in at least two thirds of patients, a recurrence occurred in 32% (n = 13; from initially 22.7 +/- 9.7 ml, to 26.3 +/- 11.3 ml at 6 months and to 29.7 +/- 12.3 ml at 18 months). In all patients with a recurrence a doubling of the iodide dosage to twice weekly 1.53 mg for 6 months reduced thyroid volume again (mean of 25.7 +/- 10.0 ml; P < 0.01). CONCLUSIONS: In at least two third of patients a once-weekly dose of 1.53 mg iodide is a reliable means of preventing a recurrence of endemic euthyroid goitre, but in the remainder the same dose must be increased to twice weekly.

Amyloid disease of the heart.

A 70-year-old woman with a history of hypertension had been well until 3 years before when she developed atrial fibrillation and subsequently congestive heart failure. The heart failure became worse and she had three fainting spells. Low voltage on electrocardiogram and global hypokinesis on echocardiography were suggestive of cardiac amyloidosis. The patient died suddenly of intractable ventricular fibrillation. Autopsy confirmed heavy infiltration of the myocardium by amyloid.

Idiopathic dilated cardiomyopathy.

A 43-year-old man had a 9-year history of congestive heart failure manifested by an enlarged heart and symptoms of shortness of breath and chest discomfort. Heart failure had been preceded by a "viral illness" and he had been a heavy alcohol user until that time. Autopsy showed congestion and edema characteristic of heart failure and cardiomegaly with biventricular dilatation. Either viral or alcoholic disease, or both, could have been the cause of the cardiac problems.

Cor pulmonale caused by recurrent pulmonary emboli.

A 53-year-old black man developed femoral thrombophlebitis in 1983 following a Harrington nail implantation in his first lumbar vertebral region. There was evidence of pulmonary embolization at that time and recurrently until he developed ventricular fibrillation and died in 1987. The terminal event followed a hypotensive episode during the course of a right ventricular catheterization. Autopsy confirmed the clinical impression that he had multiple recurrent thromboemboli to his lungs. After several years of embolization, the pulmonary arterial circulation was sufficiently occluded to result in pulmonary hypertension. Cor pulmonale was produced, with congestive heart failure leading to a progressively downhill course in the 4 months before his death.

Congestive heart failure in a patient with systemic hypertension.

A 70-year-old man developed hypertension many years previously and had a bout with severe congestive heart failure 4 to 5 years before his death. Autopsy showed congestion and edema characteristic of heart failure, and enlarged heart, and slight focal interstitial left ventricular fibrosis, but only slight to moderate coronary atherosclerosis.

Acute myocardial infarction with ventricular septal rupture.

The interventricular septum is one of the three main sites at which the myocardium can rupture. The features of the interventricular septal rupture that occurred in a 72-year-old woman are characteristic of interventricular septal ruptures in general: (1) they occur most commonly in elderly women; (2) the most common site is the mid-portion of an acute, transmural anteroseptal apical infarct; (3) they are also most common during the patient's first heart attack; (4) the clinical diagnosis of acute myocardial infarct is confirmed by both ECG and by serum enzyme levels; (5) the usual time of the rupture is 3-10 days after the onset of the infarction (it occurred after 3 days in our patient); (6) a new cardiac murmur usually is heard and the patient frequently goes into shock; (7) the diagnosis can be confirmed by a step-up in pO2 levels from right atrium to right ventricle; (8) the usual cause is severe old coronary atherosclerosis with a recent thrombotic occlusion as the final precipitating event.

Acute myocardial infarction with papillary muscle rupture.

The subject of this report is a 57-year-old obese, hypertensive woman who had been well until the onset of severe chest pain and hypotension. She had to be defibrillated four times on her way to the hospital. The diagnosis of acute inferior-posterior infarction was made by electrocardiogram (ECG) and there was a markedly elevated serum creatine kinase (CK) (including the MB fraction). The patient had a very low cardiac output and ejection fraction. A lung scan revealed possible pulmonary embolism for which she was anticoagulated. She remained hypotensive and hypoxemic and, on Day 17 of her hospital stay, she had a bout of severe dyspnea. A new systolic murmur was heard and the clinical diagnosis of ruptured papillary muscle was made and confirmed by echocardiography, and later at autopsy. All three coronary arteries were severely atherosclerotic and, in addition, the right coronary artery was completely closed by a thrombus. This case clearly illustrates the major pathological changes in the heart that correlate with the clinical findings in patients with a myocardial infarct that is complicated by left ventricular papillary muscle rupture. The pathophysiological effects of this condition, as illustrated in this case report, include the following:1. The posterior papillary muscle wa s almost completely separated from its base, with only a thin strip of muscle intact. The mistral valve thus was insufficient (a "flail valve''); this markedly reduced the ejection fraction of the left ventricle, increased its end-diastolic volume and pressure, produced a damming of blood in the pulmonary circulation, and this resulted in the pulmonary edema seen on the chest x-ray.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute circumferential subendocardial infarction.

A 48-year-old black man had his first attack of chest pain on exertion, radiating to both arms, in December 1982 (angina pectoris). It was undoubtedly preceded by a period of asymptomatic coronary atherosclerosis of unknown duration. The first anginal attack was followed by three to four similar episodes over the next four months. The attacks became more prolonged, frequent, and severe thereafter (so-called "pre-infarct" angina), and six days later the patient showed signs of having developed actual myocardial necrosis. The patient underwent saphenous vein coronary artery bypass surgery but could not be weaned from the pump. He died late on the day of surgery. He was found at autopsy to have severe old three-vessel coronary artery disease with the myocardial changes that would be expected from the severe global ischemia to which this heart was undoubtedly subjected. Several basic and important differences between this sort of a circumferential subendocardial infarct and a transmural infarct are discussed, as is the basis for the striking subendocardial hemorrhage.

Very early acute myocardial infarct treated with streptokinase and balloon angioplasty.

A 57-year-old man developed anginalike chest pain for the first time but there was no objective evidence of an infarct (i.e., EKG and serum enzymes were normal). After 12 days the pain increased, but EKG and serum enzymes remained normal ("preinfarct," crescendo, unstable, or accelerated angina). At this time a cardiac catheterization showed 90% occlusion of the left anterior descending (LAD) coronary artery. On the 17th day after the onset of pain, severe pain recurred together with an abnormal EKG and the patient was taken immediately to the laboratory where a total occlusion of the LAD was now found and he was treated with intracoronary streptokinase. The artery remained open for only a short time, and balloon angioplasty was performed. However, the patient died 12 hours after onset of the last episode of severe pain. A very early acute myocardial infarct was diagnosed at autopsy together with severe coronary atherosclerosis especially of the LAD which had disruption of atherosclerotic plaques and microscopic evidence of embolization.

Correlation of the complete version of the Selvester QRS scoring system with quantitative anatomic findings for multiple left ventricular myocardial infarcts.

The correlation between myocardial infarct size estimated by the complete version of the Selvester QRS scoring system and that documented by pathoanatomic studies has been reported for single anterior, inferior and posterolateral infarcts. Although previous studies described electrocardiographic changes in patients with multiple infarcts, no quantitative documentation of the ability of such changes to estimate the total amount of left ventricular infarction has been reported. This study of 32 patients with anatomically documented multiple infarcts shows a significant correlation between QRS-estimated and anatomically documented sizes (r = 0.44; p = 0.01), which is less than that previously reported for single infarcts in the anterior, inferior and posterolateral locations. Several of the 54 electrocardiographic criteria were never satisfied. Criteria for posterior infarction were seldom present, suggesting "cancellation effect" of coexisting anterior infarction. These results will be the basis for future modification of QRS criteria for estimating myocardial infarct size.

Sensitivity of a set of myocardial infarction screening criteria in patients with anatomically documented single and multiple infarcts.

A subset of 3 screening criteria (Q wave greater than or equal to 30 ms in lead aVF, any Q or R wave less than or equal to 10 ms and less than or equal to 0.1 mV in lead V2, and R wave greater than or equal to 40 ms in V1) has been proposed to identify single nonacute myocardial infarcts. Cumulatively, these 3 criteria achieved 95% specificity, and 84 and 77% sensitivities for inferior and anterior myocardial infarcts, respectively, among patients identified by coronary angiography and left ventriculography. This study establishes the true sensitivities of the set of screening criteria in 71 patients with anatomically proven single myocardial infarcts and 32 patients with multiple myocardial infarcts. In the single inferior infarct group, the aVF criterion was 90% sensitive. The V2 criterion (any Q or R wave less than or equal to 10 ms and less than or equal to 0.1 mV) was 67% sensitive in the single anterior infarct group. No single criterion proved sensitive in identifying a posterolateral infarct. The set of screening criteria performed just as well for multiple infarcts as it did for single infarcts, with a cumulative sensitivity of 72%. The overall sensitivity of the screening set in the 103 patients in all groups was 71%.

Anatomic validation of electrocardiographic estimation of the size of acute or healed myocardial infarcts.

Seventeen new criteria added to the simplified version of the Selvester QRS scoring system to comprise the complete version were evaluated to determine their value in estimating the size of single infarcts. These non-Q-wave criteria might be particularly useful regarding posterolateral infarcts in the distribution of the left circumflex artery. The study population was made up of 21 anterior, 30 inferior and 20 posterolateral single myocardial infarction (MI) patients with no evidences of bundle branch or fascicular blocks, ventricular hypertrophy or previous MI on their final stable electrocardiogram. The complete system's maximum 32 points is capable of indicating MI in 96% of the left ventricle and it estimated a mean electrocardiographic MI size that better approximated the anatomic size compared with the simplified version in all MI locations. The correlation between anatomic and electrocardiographic MI size using the complete system was better and statistically significant for the posterolateral MI group (simplified r = 0.55, p less than 0.01 vs complete r = 0.70, p less than 0.0006). Criteria such as Q and S amplitude less than or equal to 0.3 mV in V1 and less than or equal to 0.4 mV in V2 were particularly helpful. This study documents the improved ability provided by the 17 additional non-Q-wave criteria which have been added in the complete version of this scoring system regarding the sizing of infarcts in the region of the left ventricle supplied by the left circumflex artery.

Correlation of clinical history with quantitative histology of lower extremity atheroma biopsies obtained with the Simpson atherectomy catheter.

The purpose of this study was to compare the histologic variability of atheromas resected from patients with various risk factors for vascular disease. Twenty-seven plaques obtained using the Simpson atherectomy catheter were studied. The results of this light and electron microscopic study indicate that patients with diabetes mellitus had increased numbers of smooth muscle cells in their plaques (P less than 0.05) and a trend toward denser, less fatty connective tissue matrix (P less than 0.07) when compared with non-diabetics, and that female diabetics had more smooth muscle cells in their plaques than male diabetics (P less than 0.05). The female patients, regardless of risk factors, had more smooth muscle cells in their plaques than male patients (P less than 0.004). Patients with poor distal runoff had more neovascularization of plaque (P less than 0.001). Tobacco use and age did not have statistically significant correlations with histologic patterns.