V. A. Spence

Increased neutrophil apoptosis in chronic fatigue syndrome

Background/Aims: Many patients with chronic fatigue syndrome (CFS) have symptoms that are consistent with an underlying viral or toxic illness. Because increased neutrophil apoptosis occurs in patients with infection, this study examined whether this phenomenon also occurs in patients with CFS. Methods: Apoptosis was assessed in patients with CFS in conjunction with concentrations of the anti-inflammatory cytokine, transforming growth factor β1 (TGFβ1). Results: The 47 patients with CFS had higher numbers of apoptotic neutrophils, lower numbers of viable neutrophils, increased annexin V binding, and increased expression of the death receptor, tumour necrosis factor receptor-I, on their neutrophils than did the 34 healthy controls. Patients with CFS also had raised concentrations of active TGFβ1 (p < 0.005). Conclusions: These findings provide new evidence that patients with CFS have an underlying detectable abnormality in their immune cells.

Low-grade inflammation and arterial wave reflection in patients with chronic fatigue syndrome

Some of the symptoms reported by people with CFS (chronic fatigue syndrome) are associated with various cardiovascular phenomena. Markers of cardiovascular risk, including inflammation and oxidative stress, have been demonstrated in some patients with CFS, but little is known about the relationship between these and prognostic indicators of cardiovascular risk in this patient group. In the present study, we investigated the relationship between inflammation and oxidative stress and augmentation index, a measure of arterial stiffness, in 41 well-characterized patients with CFS and in 30 healthy subjects. AIx@75 (augmentation index normalized for a heart rate of 75 beats/min) was significantly greater in patients with CFS than in control subjects (22.5+/-1.7 compared with 13.3+/-2.3% respectively; P=0.002). Patients with CFS also had significantly increased levels of CRP (C-reactive protein) (2.58+/-2.91 compared with 1.07+/-2.16 mug/ml respectively; P<0.01) and 8-iso-prostaglandin F(2alpha) isoprostanes (470.7+/-250.9 compared with 331.1+/-97.6 pg/ml respectively; P<0.005). In patients with CFS, AIx@75 correlated significantly with logCRP (r=0.507, P=0.001), isoprostanes (r=0.366, P=0.026), oxidized LDL (low-density lipoprotein) (r=0.333, P=0.039) and systolic blood pressure (r=0.371, P=0.017). In a stepwise multiple regression model, including systolic and diastolic blood pressure, body mass index, CRP, tumour necrosis factor-alpha, interleukin-1, oxidized LDL, high-density lipoprotein-cholesterol levels, isoprostanes, age and gender, AIx@75 was independently associated with logCRP (beta=0.385, P=0.006), age (beta=0.363, P=0.022) and female gender (beta=0.302, P=0.03) in patients with CFS. The combination of increased arterial wave reflection, inflammation and oxidative stress may result in an increased risk of future cardiovascular events. Assessment of arterial wave reflection might be useful for determining cardiovascular risk in this patient group.

Enhanced sensitivity of the peripheral cholinergic vascular response in patients with chronic fatigue syndrome

From the Section of Vascular Medicine and Biology, University Department of Medicine, Ninewells Hospital and Medical School, Dundee, Scotland. Correspondence should be addressed to Faisel Khan, PhD, Section of Vascular Medicine and Biology, University Department of Medicine, Ninewells Hospital and Medical School, Dundee, DD1 9SY Scotland, United Kingdom. Manuscript submitted July 19, 1999, and accepted in revised form March 1, 2000.

FATE OF THE VASCULAR PATIENT AFTER BELOW-KNEE AMPUTATION

50 below-knee amputations were carried out in 45 patients (25 men and 20 women), mean (SD) age 73 (10.5) years. The mean survival time was 22(16) months after the operation. In each patient the healing potential of a below-knee amputation was determined preoperatively by segmental pressure studies and thermographic delineation of skin perfusion. 33 of the stumps healed by first intention, in 14 healing was delayed but occurred without the need for further surgery, and 3 stumps healed after local wedge excision. The initial mobilisation rate was 90%. Thus, there are no grounds for carrying out an initial above-knee amputation to save the patient a further operation.

Peripheral cholinergic function in humans with chronic fatigue syndrome, Gulf War syndrome and with illness following organophosphate exposure

In the present study, we have investigated whether the peripheral cholinergic abnormalities that we have reported previously [Spence, Khan and Belch (2000) Am. J. Med. 108, 736-739] in patients with chronic fatigue syndrome (CFS) are also present in those with Gulf War syndrome (GWS) and agricultural workers exposed to organophosphate pesticides, where cholinesterase inhibition is specifically implicated. We also looked at whether these abnormalities might be due to a reduction in the activity of cholinesterase expressed on the vascular endothelium. We used laser Doppler imaging to measure the forearm skin blood flow responses to iontophoresis of acetylcholine and of methacholine (which is resistant to breakdown by cholinesterase) in patients with CFS, GWS and those with a history of ill health after definite organophosphate exposure, as well as in matched healthy controls. The response to acetylcholine was significantly higher in patients with CFS than in controls ( P =0.029, repeated-measures ANOVA), but was normal in those with GWS and those exposed to organophosphates. The methacholine response was higher than the acetylcholine response in all patient groups except for those with CFS, where there was no difference between the responses. Although there are many clinical similarities between these three illnesses, our results indicate peripheral cholinergic abnormalities in the vascular endothelium of only patients with CFS, suggesting that this syndrome has a different aetiology, which might involve inhibition of vascular cholinesterase.

Prolonged acetylcholine-induced vasodilatation in the peripheral microcirculation of patients with chronic fatigue syndrome.

Although the aetiology of chronic fatigue syndrome (CFS) is unknown, there have been a number of reports of blood flow abnormalities within the cerebral circulation and systemic blood pressure defects manifesting as orthostatic intolerance. Neither of these phenomena has been explained adequately, but recent reports have linked cerebral hypoperfusion to abnormalities in cholinergic metabolism. Our group has previously reported enhanced skin vasodilatation in response to cumulative doses of transdermally applied acetylcholine (ACh), implying an alteration of peripheral cholinergic function. To investigate this further, we studied the time course of ACh‐induced vasodilatation following a single dose of ACh in 30 patients with CFS and 30 age‐ and gender‐matched healthy control subjects. No differences in peak blood flow was seen between patients and controls, but the time taken for the ACh response to recover to baseline was significantly longer in the CFS patients than in control subjects. The time taken to decay to 75% of the peak response in patients and controls was 13·7 ± 11·3 versus 8·9 ± 3·7 min (P = 0·03), respectively, and time taken to decay to 50% of the peak response was 24·5 ± 18·8 versus 15·1 ± 8·9 min (P = 0·03), respectively. Prolongation of ACh‐induced vasodilatation is suggestive of a disturbance to cholinergic pathways, perhaps within the vascular endothelium of patients with CFS, and might be related to some of the unusual vascular symptoms, such as hypotension and orthostatic intolerance, which are characteristic of the condition.

The preparation and stability of radioiodinated antipyrine for use in local blood flow determinations

The accurate assessment of local blood flow by recording the washout of a deposit of radiolabelled 4-iodoantipyrine (4-IAP) requires the use of a stable radiopharmaceutical. This communication shows that it is possible to produce a 125I and 131I-4-IAP compound which fulfills this requirement under simulated conditions of use.

The effect of the transcutaneous electrode on the variability of dermal oxygen tension changes

Transcutaneous oxygen measurements (TCPO2) are being used increasingly for the assessment of tissue viability in the ischaemic limb. The major objective with such a technique is to determine the critical level of TCPO2 which defines the boundary between skin viability and non-viability. To be able to do this, an assumption is made that measurements from different centres using various TCPO2 sensors are comparable. This study shows that static and dynamic changes of TCPO2 (air to oxygen breathing) made with two commercially available instruments are not directly comparable. We suggest that the physical characteristics of present TCPO2 electrodes are not optimal for measurements on adult skin. TCPO2 measurements made in conditions of skin ischaemia should be interpreted with caution because the ratio of local oxygen demand to blood flow is such that the measurement may be underestimated by TCPO2 electrodes with a high oxygen consumption.

A rationale for skew flaps in below-knee amputation surgery

The use of thermography in the assessment of amputation levels has demonstrated a medial to lateral thermal gradient in many cases. In order to see whether this reflected a true medial to lateral skin blood flow gradient, a prospective study was set up to measure blood flow medially and laterally below the knee. Twenty-one patients, presenting for amputation assessment with end-stage peripheral vascular disease, were studied. Skin blood flows were measured using an intradermal radioisotope clearance technique. Results showed a highly significant difference between medial and lateral skin blood flows (t = 4.79; p < 0.001). In view of the significantly higher blood flow in the medial skin of the lower leg, it is suggested that a more medially based posterior below-knee amputation skin flap may be of more value in some patients.

Assessment of tissue viability in relation to the selection of amputation level

Assessment of the optimum level of amputation of an ischaemic limb can be exceptionally difficult. For this reason there has been an intensive effort, particularly in the past 20 years, to find suitable non-invasive ancillary methods to aid in the amputation level selection. This paper reviews three separate research and development areas which have evolved simultaneously in our laboratory: skin partial oxygen pressure, skin blood flow, and infrared thermography. The physiological basis for each of these measurements is discussed along with the merits and demerits of each.