IgM in human immunity to Plasmodium falciparum malaria.

Most studies on human immunity to malaria have focused on the roles of immunoglobulin G (IgG), whereas the roles of IgM remain undefined. Analyzing multiple human cohorts to assess the dynamics of malaria-specific IgM during experimentally induced and naturally acquired malaria, we identified IgM activity against blood-stage parasites. We found that merozoite-specific IgM appears rapidly in Plasmodium falciparum infection and is prominent during malaria in children and adults with lifetime exposure, together with IgG. Unexpectedly, IgM persisted for extended periods of time; we found no difference in decay of merozoite-specific IgM over time compared to that of IgG. IgM blocked merozoite invasion of red blood cells in a complement-dependent manner. IgM was also associated with significantly reduced risk of clinical malaria in a longitudinal cohort of children. These findings suggest that merozoite-specific IgM is an important functional and long-lived antibody response targeting blood-stage malaria parasites that contributes to malaria immunity.

A study protocol for a randomised open-label clinical trial of artesunate-mefloquine versus chloroquine in patients with non-severe Plasmodium knowlesi malaria in Sabah, Malaysia (ACT KNOW trial).

INTRODUCTION: Malaria due to Plasmodium knowlesi is reported throughout South-East Asia, and is the commonest cause of it in Malaysia. P. knowlesi replicates every 24 h and can cause severe disease and death. Current 2010 WHO Malaria Treatment Guidelines have no recommendations for the optimal treatment of non-severe knowlesi malaria. Artemisinin-combination therapies (ACT) and chloroquine have each been successfully used to treat knowlesi malaria; however, the rapidity of parasite clearance has not been prospectively compared. Malaysia's national policy for malaria pre-elimination involves mandatory hospital admission for confirmed malaria cases with discharge only after two negative blood films; use of a more rapidly acting antimalarial agent would have health cost benefits. P. knowlesi is commonly microscopically misreported as P. malariae, P. falciparum or P. vivax, with a high proportion of the latter two species being chloroquine-resistant in Malaysia. A unified ACT-treatment protocol would provide effective blood stage malaria treatment for all Plasmodium species. METHODS AND ANALYSIS: ACT KNOW, the first randomised controlled trial ever performed in knowlesi malaria, is a two-arm open-label trial with enrolments over a 2-year period at three district sites in Sabah, powered to show a difference in proportion of patients negative for malaria by microscopy at 24 h between treatment arms (clinicaltrials.gov #NCT01708876). Enrolments started in December 2012, with completion expected by September 2014. A total sample size of 228 is required to give 90% power (α 0.05) to determine the primary end point using intention-to-treat analysis. Secondary end points include parasite clearance time, rates of recurrent infection/treatment failure to day 42, gametocyte carriage throughout follow-up and rates of anaemia at day 28, as determined by survival analysis. ETHICS AND DISSEMINATION: This study has been approved by relevant institutional ethics committees in Malaysia and Australia. Results will be disseminated to inform knowlesi malaria treatment policy in this region through peer-reviewed publications and academic presentations. TRIAL REGISTRATION NUMBER: NCT01708876.

Factors that are associated with the risk of acquiring Plasmodium knowlesi malaria in Sabah, Malaysia: a case-control study protocol.

INTRODUCTION: Plasmodium knowlesi has long been present in Malaysia, and is now an emerging cause of zoonotic human malaria. Cases have been confirmed throughout South-East Asia where the ranges of its natural macaque hosts and Anopheles leucosphyrus group vectors overlap. The majority of cases are from Eastern Malaysia, with increasing total public health notifications despite a concurrent reduction in Plasmodium falciparum and P. vivax malaria. The public health implications are concerning given P. knowlesi has the highest risk of severe and fatal disease of all Plasmodium spp in Malaysia. Current patterns of risk and disease vary based on vector type and competence, with individual exposure risks related to forest and forest-edge activities still poorly defined. Clustering of cases has not yet been systematically evaluated despite reports of peri-domestic transmission and known vector competence for human-to-human transmission. METHODS AND ANALYSIS: A population-based case-control study will be conducted over a 2-year period at two adjacent districts in north-west Sabah, Malaysia. Confirmed malaria cases presenting to the district hospital sites meeting relevant inclusion criteria will be requested to enrol. Three community controls matched to the same village as the case will be selected randomly. Study procedures will include blood sampling and administration of household and individual questionnaires to evaluate potential exposure risks associated with acquisition of P. knowlesi malaria. Secondary outcomes will include differences in exposure variables between P. knowlesi and other Plasmodium spp, risk of severe P. knowlesi malaria, and evaluation of P. knowlesi case clustering. Primary analysis will be per protocol, with adjusted ORs for exposure risks between cases and controls calculated using conditional multiple logistic regression models. ETHICS: This study has been approved by the human research ethics committees of Malaysia, the Menzies School of Health Research, Australia, and the London School of Hygiene and Tropical Medicine, UK.

Arterial homografts--a possible solution to an infective dilemma.

Seven patients with infected arterial conduits (six with prosthetic bypass grafts and one autogenous vein anastomosis) with ten limbs at risk (three patients with bilateral groin infection) are reported. The most common site for infection was the groin and the most frequent organism cultured was Staphylococcus aureus. These patients were selected for arterial homograft implantation through infected fields as they were unsuitable for extra-anatomical prosthetic bypass or had inadequate autogenous tissue available for use as a bypass conduit, i.e. the alternative to homograft insertion was arterial ligation and potential limb sacrifice. The arterial homografts were obtained form brain-dead organ donors (human immunodeficiency virus, hepatitis B- and hepatitis C-negative) and stored at -80 degrees C until ready for use. All seven patients had initial success with their homograft procedures in terms of graft patency, limb salvage and control of infection, although two required early reoperation for haemorrhage. During the follow-up period (mean 24.5, range 6-52 months) three homografts have occluded at 6, 13 and 29 months resulting in limb loss. Two patients have died at 48 and 52 months from causes unrelated to their homograft procedures with functioning homografts and limb salvage. Two further patients remain alive with patent homografts at 7 and 20 months. The authors' experience suggests that arterial homografts have a role in overcoming arterial bypass infection, achieving wound healing and maintaining limb viability rather than resorting to arterial ligation and accepting major limb amputation.

Predicting healing of lower limb ulcers.

Management of ischaemic ulcers in patients with compromised peripheral arterial circulations relies on the physical examination and the simple, non-invasive assessment of arterial supply. This study aims to determine if transcutaneous oxygen pressure (tcPO2) measurement can improve management decisions based on ankle or toe systolic blood pressure measurement. Twenty-two consecutive patients with ischaemic ulcers had tcPO2 measured and the ankle/brachial (ABI) and toe/brachial (TBI) indices calculated. Two months after surgery 12 of 22 (55%) ulcers were healing and 10 (45%) were indolent. Postoperative tcPO2 values were predictive of wound outcome (P < 0.001). A tcPO2 > 31 mmHg was invariably associated with healing whilst a tcPO2 < 28 mmHg was associated with indolence. Ankle/brachial indices and TBI were unable to be calculated in all patients due to falsely elevated pressures and hallux amputations, respectively, and neither was predictive of outcome (ABI P = 0.152, TBI P = 0.069). The response to revascularization was less in diabetic patients with a mean tcPO2 increase of 18 mmHg compared to non-diabetic patients with a mean tcPO2 increase of 37 mmHg. TcPO2 measurement appears to be a reliable technique that can influence ischaemic ulcer management.

The response of peri-aneurysmal fibrosis--the "inflammatory" aneurysm--to surgery and steroid therapy.

It is generally thought that the fibrotic process associated with an "inflammatory" aneurysm abates with operative repair. This paper reports a patient in whom the inflammatory process was accelerated after surgery leading to the development of subacute small bowel obstruction and worsening urinary tract obstruction in the postoperative period. Graft sepsis was suspected but all cultures were negative and his condition deteriorated on broad-spectrum antibiotics. Steroid therapy, however, resulted in a prompt reversal of symptoms, signs and objective evidence of obstruction. The problems of investigation of peri-aneurysmal fibrosis and graft sepsis are discussed. Possible aetiological factors and the relationship between the "inflammatory" aneurysm and idiopathic retroperitoneal fibrosis are considered.

Intraperitoneal placement of gentamicin beads in the management of prosthetic graft sepsis.

A simple and non-hazardous technique for intraperitoneal placement of gentamicin beads after excision of an infected prosthetic aortic graft is presented. It has been used successfully in six cases of aortic graft sepsis.

Vascular graft infection: the role of indium scanning.

Infection of a prosthetic graft is one of the most feared complications of vascular surgery. The difficulties of accurate, objective diagnosis are well recognised. We have used III Indium labelled white blood cell scans (InWBC) in two groups: 9 control patients who underwent uncomplicated aortic aneurysm surgery, and 23 patients with suspected graft sepsis. In the control group there was one positive scan in a patient with an inflammatory aneurysm. In the suspected sepsis group, 11 patients subsequently has proven graft sepsis. Nine were correctly predicted by Indium scanning. Ten of 12 patients who did not have proven graft sepsis had negative scans. There was a total of 5 inflammatory aneurysms in the control and suspected sepsis groups, of whom two had positive scans. False positive scans were not present in the early postoperative period i patients without inflammatory aneurysms. In our experience Indium labelled WBC scanning for suspected graft sepsis has a accuracy of 83% a negative predictive value of 83% and a positive predictive value of 82%. These results suggest that Indium white cell labelling techniques which do not involve substantial cross-labelling of platelets are the best objective methods of establishing the presence or absence of graft sepsis.

Is arterial reconstruction to the ankle worthwhile in the absence of autologous vein?

Autologous vein from either the arm or the leg is the preferred conduit for femoro-crural grafting. Limb salvage rates using prosthetic grafts have been sufficiently disappointing for many surgeons to consider primary amputation in the absence of suitable vein. We have attempted to improve prosthetic graft patency by the creation of a compliant, wide diameter vein collar at the distal anastomosis. Thirty patients with critical ischaemia (i.e.: rest pain with distal tissue loss or doppler ankle pressure less than 40 mmHg2.3) have undergone grafting to a crural vessel in the lower third of the calf using 6 mm externally supported PTFE (IMPRA) with a vein collar (17% of all lower calf grafts, 9% of all femoro-distal procedures). Five of the grafts occluded in the peri-operative period, resulting in major amputations. Another 4 grafts occluded within 12 months of operation resulting in amputation. A further 7 grafts have occluded but not required amputation. Fourteen (47%) grafts remain patent at a mean follow-up of 13.9 months (range 1-49) with a mean graft patency of 10 months. The aim of salvage surgery is to maintain independence until death supervenes. In this series 6 (20%) patients have died during follow-up and the best possible result in the 30 patients would have been a total of 417 "amputation avoided" months. In fact 300 "amputation avoided" months were achieved. Moreover, 21 legs (70%) have avoided amputation during the patient's lifetime, or at the most recent follow-up. These results suggest that femorocrural grafting using PTFE with a vein collar is worthwhile and preferable to primary amputation in the elderly patient.

The efficacy of thymoxamine in primary Raynaud's phenomenon.

A randomised double-blind, three-way cross-over trial comparing oral thymoxamine 40 mg, oral thymoxamine 80 mg with a matched placebo was performed in 24 patients with primary Raynaud's phenomenon. The response to treatment was objectively assessed by monitoring digital skin temperature response for 7 min after exposure to a mild cold stimulus (20 C for 1 min). Thymoxamine treatment "normalised" rewarming responses in a statistically significant number of patients (P less than 0.01). Absolute digital temperatures and maximum rewarming rates were increased and the length of the latent period reduced (P less than 0.001). These effects were more pronounced with thymoxamine 80 mg than with thymoxamine 40 mg.

A perioperative technique for detection of retained valve cusps in the in situ vein graft.

A problem of the in situ vein bypass technique is the retained value cusp. To ensure that maximum flow has been obtained through the vein graft after valvotomy, a simple perioperative technique has been developed. This consists of infusing normal saline solution into the vein and comparing the distal to proximal (antegrade) flow with the proximal to distal (retrograde) flow under the same conditions. Twelve consecutive in situ vein grafts have been assessed. Antegrade and retrograde flow measurements were similar in four of the grafts but different in eight (40% to 80% reduced retrograde flow). Valvotomy was repeated and subsequent measurements of retrograde flow were similar or greater than the antegrade. The technique described is simple, reproducible, inexpensive, and may prove useful for routine intraoperative evaluation of valvotomy of in situ vein grafts.

Detection and grading of femorodistal vein graft stenoses: duplex velocity measurements compared with angiography.

Increasing recognition of the importance of vein graft stenoses in precipitating failure of femorodistal bypass procedures has stimulated an increasing interest in noninvasive postoperative surveillance. We have used duplex scanning, measuring relative changes in velocity throughout the entire length of the graft, to detect nonhemodynamic stenoses (i.e., stenoses without a significant change in ankle-brachial pressure indexes) as well as more severe lesions during the postoperative period. Seventy-five in situ vein grafts were assessed at three monthly intervals from operation with duplex scanning and intravenous digital subtraction angiography. Nineteen grafts (25%) had angiographically documented stenoses at a mean follow-up of 12 months. All 19 stenoses were detected independently by duplex velocity ratio criteria and 15 were correctly graded as mild, moderate, or severe. The results suggest that duplex-derived velocity ratio criteria are appropriate for graft surveillance and for determining the natural history of even minor stenoses to identify the optimal time of surgical intervention.

Femorodistal vein bypass graft stenoses.

Eighty femorodistal in situ vein bypass grafts have been evaluated at 3-monthly intervals clinically, with ankle:brachial pressure indices (ABI), by intravenous digital subtraction angiography (IV DSA) and by Duplex scanning. Five grafts (6 per cent) failed in the perioperative period. Nineteen (25 per cent) of the remaining 75 grafts subsequently developed stenoses on IV DSA during the first 12 months. All angiographic stenoses were detected by Duplex scanning using velocity ratio criteria before the development of symptoms or a measurable decline in ABI, i.e. while non-haemodynamically significant. This technique involves scanning the entire length of the graft but allows even minor stenoses to be detected and progression of stenoses can be determined. At a mean follow-up of 12 months (3-18 months), four (7 per cent) of the fifty-six grafts without stenoses occluded. Eight (42 per cent) of the nineteen stenosed grafts either occluded or developed symptoms. None of the occluded grafts in this series could be salvaged. Non-haemodynamically significant vein stenoses can be detected non-invasively, occur frequently and are associated with graft failure.

The reliability of duplex derived haemodynamic measurements in the assessment of femoro-distal grafts.

The aim of this study was to assess the reliability of flow and velocity measurements obtained in the postoperative period by duplex scan monitoring of femoro-distal bypass grafts. Three points along each of 24 grafts were studied by 2 independent observers using a Diasonics 300 DRF duplex scanner. Results obtained for diameter, peak systolic velocity (PSV) and flow were compared. The mean PSV for all points studied was 70 cm/s (S.D. = 14.5): comparing observers the calculated experimental error (EE) for all points was 11 cm/s (coefficient of EE = 15%). In contrast, the experimental error for flow was 44.5 ml/min (coefficient of EE = 31). The mean flow for all grafts was 142 ml/min (S.D. = 66.5). Flow at the different points of individual grafts could also be compared since routine postoperative intravenous angiography showed all grafts to be devoid of branches. The coefficient of experimental error for flow was 58%. Four of the grafts studied were found to have asymptomatic stenoses. These 4 grafts had low flows (mean = 42 ml/min) but so did 7 other non-stenotic grafts. Although PSV measurements entailed a 15% error, the mean change in PSV in relation to the stenoses was 350%. These data suggest that flow is an unreliable measurement. PSV is more reliable, changes exponentially with luminal diameter and can detect, and perhaps grade, asymptomatic stenoses.

Combination reversed and non-reversed upper arm vein for femoro-distal grafting.

Arm veins are the "second choice" conduit for femoro-distal grafting when the long saphenous vein is either not available or is unsuitable. However, obtaining a graft of sufficient length may be difficult if the forearm veins have been damaged by previous intra-venous cannulation. The harvesting of the upper arm veins separately may overcome the problem of insufficient length but entails a veno-venous anastomosis which is a potential source of both early and late problems. We have harvested both the upper arm cephalic and basilic veins in continuity and created a vein graft which is non-reversed proximally and reversed distally.

The significance of cerebral infarction and atrophy in patients with amaurosis fugax and transient ischemic attacks in relation to internal carotid artery stenosis: a preliminary report.

There is a growing appreciation for the high incidence of silent cerebral infarction and cerebral atrophy on CT scans in patients with amaurosis fugax (AF) and hemispheric transient ischemic attacks (TIAs). Seventy patients with AF only (no TIAs), 104 patients with hemispheric TIAs (no AF), 185 patients without focal carotid territory symptoms (i.e., vertebrobasilar TIAs or asymptomatic carotid bruit only), and 129 patients with stroke and good recovery were studied with CT scan and duplex scanning to grade the degree of stenosis of the internal carotid artery (grades: A = normal, B = 0% to 15% stenosis, C = 16% to 49%, D = 50% to 99%, and E = occlusion). In patients with AF, the incidence of infarction increased from 20% in grades A, B, and C to 40% in grade D and 58% in grade E. The incidence of atrophy increased in parallel from 10% in grade A to 30% in grade E. The increased incidence of atrophy with increasing degrees of stenosis was not the result of increasing degrees of stenosis per se, but the associated increase in the incidence of infarction (patients without CT infarcts in grades D and E had 5% and 0% incidence of atrophy). In patients with hemispheric TIAs, the incidence of CT infarction increased from 25% in grades A and B to 48% in grades D and E. The incidence of atrophy did not show a parallel increase. Our findings support the hypothesis that atrophy is associated not only with cerebral infarction but may be causally related.(ABSTRACT TRUNCATED AT 250 WORDS)

The assessment of Raynaud's phenomenon using a radiation thermometer and a mild cold (20 degrees C) stress test.

Digital skin temperature was monitored using a radiation thermometer in 27 normal volunteers and in 24 patients with Raynaud's phenomenon before and after the application of a mild cold stress (20 degrees C for 1 minute). The test was performed in standardized environmental conditions and repeated after the ingestion of alcohol (30 mls of 25% ethyl alcohol). Three types of response were identified: "Normal" rewarming curves before alcohol in 25 of 27 volunteers and in one patient. "Abnormal" rewarming curves unaffected by alcohol in 18 patients. "Abnormal" rewarming curves normalized by alcohol in the 2 remaining volunteers and in 5 patients. This simple, practical, painless and noninvasive test may be of value in the objective assessment of the severity of Raynaud's phenomenon and in the evaluation of the effect of therapy.

Experience with diagnostic peritoneal lavage in blunt abdominal trauma.

Fifty-one patients who had suffered blunt abdominal trauma were assessed clinically and with diagnostic peritoneal lavage. The latter has been shown to be a safe, accurate means of determining the presence or absence of haemoperitoneum. Furthermore, in patients with disturbed conscious states, the initial clinical assessment has been found to be inaccurate and the performance of diagnostic peritoneal lavage has resulted in a statistically significant increase in diagnostic accuracy (P = 0.006). However, in patients with a normal conscious state, the improvement in diagnostic accuracy achieved by the performance of diagnostic peritoneal lavage was not statistically significant. The technique of diagnostic peritoneal lavage is discussed in detail.