Biofeedback as therapy in Raynaud's disease.

The following dimensions of Raynaud's disease are reviewed: (a) etiological factors, particularly those of a psychological nature, (b) proposed biological mechanisms of vasospastic episodes, (c) efficacy of pharmaceutical and surgical interventions, and (d) use of biofeedback as therapy. Emotional stress appears to be wholly sufficient to induce vasopastic episodes in victims. Some authors further hypothesize that suppressed anger may be involved in the phenomenon. Vehicles proposed to account for the symptoms include local vascular pathology, sympathetic discharge, and biochemical phenomena. Sympathectomy does not produce permanent remission and vasodilator medications tend to have undesirable side effects even when successful. Documented success with feedback techniques is sparse but encouraging. Published outcome studies are often confounded by the use of additional treatment modes such as relaxation training and hypnosis. The study of Raynaud's disease has enormous potential for the understanding of psychosomatic illness in a holistic fashion. Stresses induce immediate physiological responses, and corrective conditioning is easily implemented and monitored.     

Training to vasodilate in a cooling environment: a valid treatment for Raynaud's phenomenon?

While many reports indicate that voluntary modification of skin temperature is possible and may be useful in the treatment of Raynaud's phenomenon, little attention has been paid to the ecological validity of training skin temperature increases when a considerable amount of vasodilation of digital vessels may already exist (room temperature, 22-24 degrees C). Patients with Raynaud's vasospastic attacks may benefit from learning to avoid attacks when they are impending by voluntarily vasodilating the vessels of their digits under conditions when vasoconstriction has begun. The results in 14 patients with primary and secondary Raynaud's phenomenon indicated that (a) patients learned to voluntarily increase digital skin temperatures in a "cooling" environment during documented vasoconstriction, and (b) there was a 31% decrease in the occurrence of vasospastic attacks following such learning. These data suggest that a new methodology may be useful in the biofeedback treatment of Raynaud's phenomenon, but further research is needed to determine the specific mechanism(s) involved, and the limits to its usefulness.     

Biofeedback treatment of Raynaud's disease and phenomenon

Six Raynaud's disease and four Raynaud's phenomenon patients were treated with 12 sessions of finger temperature biofeedback. The mean frequency of vasospastic attacks was reduced to 7.5% of that reported during the pretreatment baseline and was maintained for a 1 year follow-up period. Significant control of digital temperature was demonstrated during laboratory training sessions. Raynaud's phenomenon patients showed significantly greater temperature increases during feedback periods than Raynaud's disease patients. Correlations between finger temperature and other physiological measures suggested that results could not be attributed to general physical relaxation. The role of imagery in self-control of digital temperature is considered.Portions of this paper were presented at the annual meeting of the Biofeedback Society of America, Albuquerque, March 1978.     

Training to vasodilate in a cooling environment: A valid treatment for Raynaud's phenomenon?

While many reports indicate that voluntary modification of skin temperature is possible and may be useful in the treatment of Raynaud's phenomenon, little attention has been paid to the ecological validity of training skin temperature increases when a considerable amount of vasodilation of digital vessels may already exist (room temperature, 22–24° C). Patients with Raynaud's vasospastic attacks may benefit from learning to avoid attacks when they are impending by voluntarily vasodilating the vessels of their digits under conditions when vasoconstriction has begun. The results in 14 patients with primary and secondary Raynaud's phenomenon indicated that (a) patients learned to voluntarily increase digital skin temperatures in a cooling environment during documented vasoconstriction, and (b) there was a 31% decrease in the occurrence of vasospastic attacks following such learning. These data suggest that a new methodology may be useful in the biofeedback treatment of Raynaud's phenomenon, but further research is needed to determine the specific mechanism(s) involved, and the limits to its usefulness.This research was supported by grants from the Manitoba Heart and St. Boniface General Hospital Research Foundations. We gratefully acknowledge John Arnett, Garry Hawryluk, and Charles Weinstein for their critical reading of a draft of this paper. Portions of this paper were presented at the Canadian Psychological Association meeting, Winnipeg, 1983.     

The behavioral treatment of Raynaud's disease: A review

Raynaud's disease is a peripheral vascular system disorder characterized by episodes of vasoconstriction in the hands and feet resulting in a lowering of skin temperature and pain. Recent studies are reviewed that focus on the behavioral treatment of Raynaud's disease—in particular, biofeedback and autogenic training. Methodological problems and other difficulties include the measurement of skin temperature, schedules of reinforcement/feedback, and characteristics of the experimenter and subject. Studies in this area indicate some promise for certain behavioral interventions, especially finger temperature biofeedback under cold stress conditions. On the other hand, further research is needed to clarify the mechanisms, especially that of vasodilation, and the applications of temperature biofeedback, as well as the role of attitudinal, interpersonal, and cognitive factors.     

The behavioral treatment of Raynaud's disease: a review

Raynaud's disease is a peripheral vascular system disorder characterized by episodes of vasoconstriction in the hands and feet resulting in a lowering of skin temperature and pain. Recent studies are reviewed that focus on the behavioral treatment of Raynaud's disease--in particular, biofeedback and autogenic training. Methodological problems and other difficulties include the measurement of skin temperature, schedules of reinforcement/feedback, and characteristics of the experimenter and subject. Studies in this area indicate some promise for certain behavioral interventions, especially finger temperature biofeedback under cold stress conditions. On the other hand, further research is needed to clarify the mechanisms, especially that of vasodilation, and the applications of temperature biofeedback, as well as the role of attitudinal, interpersonal, and cognitive factors.     

Skin temperature biofeedback for Raynaud's disease: A double-blind study

The lack of control procedures inherent in most of the experiments conducted to assess the effectiveness of skin temperature biofeedback in the treatment of Raynaud's disease renders the results inconclusive. In this study, control groups and a double-blind approach are adopted. Thirty-six patients, carefully screened for a diagnosis of primary Raynaud's disease, were assigned to a skin temperature increase group (N=12), to an EMG relaxation control group (N=12), or to a notreatment control group (N=12). All patients kept records of their symptoms for the duration of the study. Each subject in the two training groups received 20 sessions, the last 2 conducted under cold stress. Data analysis according to original group assignment, as well as following regrouping of subjects according to several learning criteria, showed that while all patients reported a marked decrease in the number of vasospastic attacks, no significant differences were found among the three groups on the clinical measures used to assess symptomatic relief. The general improvement reported must therefore be attributed to nonspecific factors.This study was supported in part by Rehabilitation Services Administration Grant No. 16-P-56810/5–17 to the University of Minnesota Medical Rehabilitation Research and Training Center. We are grateful to Gail Gaebe, Carla Grossman, Steve Janousek, Linda Rubbelke, and Scott Williamson, who served as blind assistants, and to Steve Sheffield for his technical support.     

Rebound of vasospastic angina after cessation of long-term treatment with nifedipine.

The beneficial effect of calcium antagonists in the treatment of vasospastic angina is now well recognized. Although withdrawal symptoms have been reported following abrupt cessation of therapy with some cardiovascular drugs, there is no detailed report on similar complications of the cessation of therapy with calcium antagonists. In a 4-month period eight patients with well documented and well controlled vasospastic angina experienced a marked increase in the frequency and duration of anginal episodes at rest following the involuntary cessation of treatment with nifedipine, 10 to 20 mg four times a day. The increase began within 2 to 5 days after the cessation of treatment. Substitute therapy with isosorbide dinitrate, 30 mg, and verapamil, 80 to 120 mg, each four times a day, was effective in all cases. Although the mechanism responsible for this rebound phenomenon is not known, awareness of its existence is essential considering the widespread use of calcium antagonists.     

Ketanserin in the treatment of traumatic vasospastic disease.

The specific serotonin receptor blocker ketanserin was given orally to 12 patients with traumatic vasospastic disease in a double blind crossover study. The effect of treatment was assessed by measuring finger systolic pressure and rewarming time after cold provocation and by medical interview and diaries. Median (range) percentage change in finger systolic pressure after cooling was 50 (0-100)% after treatment with ketanserin compared with 0 (0-90)% after placebo. Median (range) rewarming time after cooling decreased from 320 (236-972)s with placebo to 160 (88-404)s after treatment with ketanserin. These changes were not significant. Ninety five percent confidence intervals for difference between the treatments, however, showed that finger systolic pressure may be 80% better and rewarming time 256 seconds faster after treatment with ketanserin than after placebo. The number of attacks did not differ significantly between the two treatments. Two patients had a feeling of warmth in their hands during treatment with ketanserin. The results suggest that orally administered ketanserin may improve digital circulation in patients with traumatic vasospastic disease, but larger numbers of patients are required to assess the true effect of treatment with ketanserin in this disease.     

Cold pressor test and retinal capillary perfusion in vasospastic subjects with and without capsular glaucoma (a preliminary study)

PURPOSE: Using the cold pressor test the authors investigated the change in retinal and neuroretinal capillary perfusion in vasospastic patients suffering from capsular glaucoma (CG) and in vasospastic control subjects. METHODS: Changes in retinal and optic nerve head capillary perfusion induced by the cold pressor test (one hand immersed in 4 degrees C water for 30 seconds, then in 30 degrees C water for 2 minutes) was measured using the Heidelberg Retina Flowmeter in 4 patients with CG and in 5 healthy control subjects. Previously all subjects showed a reduction of cutaneous capillary flow higher than 70% in the cold pressor test (vasospastic reaction). One eye per subject was investigated. Two images were obtained for each phase (baseline, cold phase and warm phase), and the better quality image from each phase was selected for the measurements. One location on the temporal neuroretinal rim and one location on the temporal retina outside the peripapillary area were selected for the HRF measurements. RESULTS: In the CG group neuroretinal rim "Volume" decreased by 26.05%, "Flow" by 25.82% and "Velocity" by 23.91% (p<0.05), retinal "Volume" decreased by 12.30% (p=0.051), and retinal "Flow" by 22.36% (p=0.01) in the cold phase. All these parameters returned to the corresponding baseline values in the warm phase. In the control group a significant decrease was observed in retinal "Volume" (15.96%), "Flow" (17.81%), and "Velocity" (16.11%) in the cold phase (p<0.05), which diminished in the warm phase but remained still significant for "Flow" and "Velocity". CONCLUSION: Cutaneous cold provocation can induce an immediate decrease in retinal and optic nerve head capillary perfusion at least in a part of the vasospastic subjects with or without capsular glaucoma. This decrease diminishes or disappears quickly when the hand is immersed in warm water. To evaluate the potential role of cold-induced retinal and optic nerve head vasoconstriction in the pathogenesis of capsular glaucoma further investigations are necessary since this reaction was also present in the vasospastic control subjects.     

A case of primary pulmonary hypertension in a patient with Raynaud's disease

A case of a 50-year female patient with Raynaud's disease is presented. The primary pulmonary hypertension accompanying the underlying condition suggests that the excessive contractibility of the vessels, typical for the Raynaud's disease, may play a role in the etiology of the primary pulmonary hypertension.     

Rapid-onset, linezolid-induced lactic acidosis in MELAS

Due to their prokaryotic origins, mitochondria are susceptible to a number of antibiotics that target the bacterial ribosome, and this vulnerability is exacerbated by certain mutations of the mitochondrial genome.MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) syndrome is characterised by biochemical and structural abnormalities of the muscle mitochondria, in which episodes of lactic acidosis stem from dysfunction of assembled respiratory complex I.Linezolid is an oxazolidinone antibiotic that has been reported to induce lactic acidosis, especially after prolonged administration, through inhibition of the mitochondrially synthesised components of oxidative phosphorylation.We report a patient with longstanding MELAS who suffered a severe lactic acidosis of rapid onset, with associated features of mitochondrial failure, shortly after the commencement of linezolid therapy and in the context of an otherwise improving clinical picture.This case emphasises the importance of circumspection when utilising drugs known to be toxic to the mitochondrion in patients with mitochondrial disease. In particular, given the biochemically plausible interaction, it would seem prudent to avoid the use of linezolid in patients with MELAS whenever possible.     

131I]metaiodobenzylguanidine therapy of malignant pheochromocytoma: interference of medication

Malignant pheochromocytoma may present as a widespread metastatic disease, which is little or non-responsive to external beam radiotherapy and chemotherapy. The prognosis of these patients is bad due to both the progressive metastasis and the secretion of excess catecholamines which may cause hypertensive episodes. For these conditions [131I]metaiodobenzylguanidine (131I-MIBG) therapy may be an alternative treatment modality to induce both tumor remission and reduction of hormonal activity of the disease. The experience with 131I-MIBG therapy in four patients with metastatic malignant pheochromocytoma at The Netherlands Cancer Institute is reviewed. One patient with abdominal tumor recurrence and metastases to the lymph nodes and lungs had a partial remission of disease for 3 years; a second had a mixed response together with palliation and two other patients had stable disease, but were relieved of bone pain and severe hypertension, respectively. It is essential to be aware of the medication the patient is using, as many drugs are known or may be expected to interfere with the uptake and/or retention of 131I-MIBG by the tumor cells. The case of a significant reduction of 131I-MIBG uptake and retention by Labetalol in one of the patients is discussed. It is concluded that 131I-MIBG therapy may induce objective remission in patients with malignant pheochromocytoma and is certainly meaningful in the reduction of hormonal activity, the control of hypertension and the relief of pain from metastases.     

Eicosanoid biosynthesis and action: novel opportunities for pharmacological intervention

Novel eicosanoid biosynthetic pathways and receptors are reviewed as potential targets for pharmacological intervention. In addition to the cyclooxygenase and lipoxygenase pathways of arachidonate metabolism, a cytochrome P450-dependent monooxygenase has been identified in corneal and renal epithelial cells. Elucidation of the enzymatic pathways of thromboxane (TX) disposition and development of analytical techniques for measuring urinary metabolites have allowed a reliable assessment of TXA2 biosynthesis in health and disease, and provide a rationale for the combined use of TX-synthase inhibitors and TXA2-receptor antagonists in the setting of platelet activation. Recent evidence for a transcellular metabolism of neutrophil-derived leukotriene (LT) A4 by other human blood cells might link platelet and neutrophil activation to the occurrence of vasospastic phenomena. Prostacyclin (PG1(2)), PGE2, PGD2, TXA2/PGH2, and sulfidopeptide-LT receptors are being characterized in terms of distribution, signal-transduction mechanisms, and agonist-mediated regulation. Development of relatively selective agonists and antagonists of these receptors is providing novel therapeutic strategies for several human diseases.     

Epoprostenol in patients with Raynaud's disease

Prostaglandin metabolism and the clinical effect of epoprostenol (prostacyclin, PGI2) infusions were studied in thirteen patients with Raynaud's disease. Epoprostenol was infused at 5 ng/kg/min for six hours daily for two consecutive five day periods, separated by a two day interval. No beneficial effects either during or after infusion could be detected in terms of frequency of severity of attacks or on skin temperature measurement. Raynaud's patients had significantly lower serum thromboxane B2 levels than normal controls though plasma levels of thromboxane B2, 6-oxo-PGF1 and the bicyclic metabolite of PGE2 did not differ between the two groups. Platelets from Raynaud's patients had a significantly lower conversion rate of arachidonic acid into thromboxane B2 and HHT and a significantly higher rate of HETE production than platelets from controls.     

Investigation of sialic acids and sialyltransferase activity in blood of patients with systemic scleroderma.

Systemic scleroderma (SSd) is a connective tissue disorder accompanied by generalized fibrosis. A disturbance of the synthesis and production of matrix glycoproteins, such as collagens, fibronectin, and proteoglycans, by connective tissue cells is typical for this disease. We previously demonstrated a decrease in the ganglioside content of cultured skin fibroblasts from patients with SSd. In this work the contents of sialoglycoproteins and sialoglycolipids in blood sera of patients with SSd were estimated. Simultaneously, the level of asialofetuin-sialyltransferase activity in blood plasma of three groups of patients--those with SSd, Raynaud's phenomenon, and with localized scleroderma--was investigated. CMP-5-acetamido-9-deoxy-9-fluoresceinylthioureidoneuraminic acid was used as a substrate for the enzyme assay. It was shown that the concentration of total sialic acid was increased and the concentration of lipid-bound sialic acid was slightly decreased in the blood sera of patients with SSd. A correlation between the lipid-bound sialic acid level and the severity of disease was observed; there was no correlation between severity of disease and total sialic acid. Sialyltransferase assay showed a decrease in the activity level in all three groups of patients. The greatest decrease (2-fold) of this activity was observed in patients with Raynaud's phenomenon. Our data suggest that in SSd and similar diseases the process of glycoconjugate sialylation is disturbed. These changes may considerably affect the mechanisms of regulation of metabolism and cellular interactions.     

Oxidative stress in Systemic Sclerosis

In 63 patients affected by Systemic Sclerosis (SSc) (limited subset., 40; diffuse subset: 23; early: 30; advanced: 33) the peroxidation product diene-conjugates (DC) and antibodies against oxidised low density lipoproteins (Ab oxLDL) were tested in serum by a spectrophotometer (absorbance 234 mn) and by a standard ELISA respectively. The data were compared with those obtained by 21 healthy subjects. DC was significantly higher in patients (73.3 ± 37.2 M/l; p < 0.0001) than in controls (48.4 ± 16.7) as well as in the limited (80 ± 48.8; p < 0.05) than in the diffuse subset (64.5 ± 36.4); and in early (84.1 ± 31.4; p < 0.05) than in advanced stage of the disease (67.9 ± 42.5). The levels Ab oxLDL were significantly higher in SSc patients (309.5 ± 367.2 mU/ml; p < 0.0001) in all its subsets (limited: 351.9 ± 351.1, p < 0.0001; diffuse: 207.7 ± 316. 1, p < 0.05; early: 428.9 ± 417.1, p < 0.001; advanced: 302.7 ± 89.9, p < 0.0001) than in controls (89.3 ± 29.1). These antibodies levels were higher in limited subset than in diffuse (p < 0.05) and in early SSc than in advanced SSc (p < 0.05). The highest values of parameters of oxidative stress are found in the early stages, when the episodes of reperfusion after ischemic episodes (Raynaud's phenomenon) are very ferequent. Moreover, the damage is higher in the early stages of SSc, with intact microvessels, than in late stages, when microvessels are very reduced in number, destroyed by the worsening of the disease. These radicals products works as well in other diseases such as myocardial ischemia and pulmonary fibrosis.These data show that the respiratory burst deduced their lipoperoxidation is higher in SSe than in controls, may be an important pathogenetic factors involved in tissue changes in SSe.     

Rheographic evaluation of the changes in blood flow after superficial electric stimulation in patients with Raynaud's disease or syndrome

An effect of the superficial electrostimulation on skin microcirculation in the patients with both Raynaud's disease and syndrome was assessed with electro-impedance rheography. Significant increase of blood flow through the stimulated region was seen (mean value 42%). It was also shown that electro-impedance rheography is of value in both quantitative and qualitative investigation comparing Raynaud's disease and syndrome.     

Acquired immunity and postnatal clinical protection in childhood cerebral malaria

By analysing data on the age distribution of cerebral malaria among sites of different transmission intensities, we conclude that the most plausible explanation for the epidemiological patterns seen is that (i) cerebral malaria is caused by a distinct set of Plasmodium falciparum antigenic types; (ii) these antigenic types or 'CM strains' are very common and induce strong strain-specific immunity; and (iii) the postnatal period of protection against cerebral malaria is much longer than the period of protection against other forms of severe disease. The alternative hypothesis that cerebral malaria may be caused by any 'strain' of P. falciparum is compatible with the data only if a single exposure is sufficient to protect against further episodes. This is not consistent with observations on the history of exposure of patients with cerebral malaria. Finally, it is clear that although the delayed peak in incidence of cerebral malaria (with age) can be generated by assuming that subsequent exposures carry a higher risk of disease, such an explanation is not compatible with the observation that severe disease rates are low among infants and young children in areas of high transmissibility.     

High-temperature GC-MS-based serum cholesterol signatures may reveal sex differences in vasospastic angina

Alterations of cholesterol metabolism are responsible for vasospastic angina and atherosclerosis. To comprehensively evaluate cholesterol metabolism, 18 sterols, including cholesterol, 6 cholesteryl esters (CEs), 3 cholesterol precursors, and 8 hydroxycholesterols (OHCs), were simultaneously analyzed using hybrid solid-phase extraction (SPE) purification coupled to high-temperature gas chromatography-mass spectrometry (HTGC-MS). Methanol-based hybrid SPE increased the selective extraction, and HTGC resulted in a good chromatographic resolution for the separation of lipophilic compounds. The limits of quantification of cholesterol and CEs ranged from 0.2 to 10.0 μg/ml, while OHCs and cholesterol precursors ranged from 0.01 to 0.10 μg/ml. Linearity as the correlation coefficient was higher than 0.99 with the exception of cholesteryl laurate, myristate, oleate, and linoleate (r² > 0.98). The precision (% coefficient of variation) and accuracy (% bias) ranged from 1.1 to 9.8% and from 75.9 to 125.1%, respectively. The overall recoveries of CEs ranged from 26.1 to 64.0%, and the recoveries of other sterols ranged from 83.8 to 129.3%. The cholesterol signatures showed sex differences in patients with vasospastic angina and may associate with 24-reductases. This technique can be useful for making clinical diagnoses and for an increased understanding of the pathophysiology of vasospastic angina.