Skin microvascular function in patients with type 1 diabetes: An observational study from the onset of diabetes.

BACKGROUND: The development of disturbances in skin microcirculation in type 1 diabetes is not well characterised. We assessed skin microcirculation longitudinally from the onset of diabetes up to 29 years of duration to investigate when such disturbances start. MATERIAL AND METHODS: Seventeen adult patients with type 1 diabetes participated. Skin microvascular function in digit IV of the left hand was investigated by laser Doppler fluxmetry (LDF, arbitrary units [AU]). LDF was carried out at rest and following one-min arterial occlusion. Time to peak LDF (s) and percentage increase of LDF (post-occlusive reactive hyperaemia, PRH%) were determined. Retinopathy was assessed from fundus photographs or ophthalmoscopic recordings. RESULTS: Skin microvascular function remained normal during the first five years. Compared with baseline and a non-diabetic reference group, time to peak LDF was prolonged after 7-9 years of diabetes ( p < 0.01). PRH% was lower than in the reference group after 7-9 years ( p < 0.01), and lower than baseline after 24-29 years of diabetes ( p < 0.05). All but one patient developed retinopathy and the first signs were found after 10 years of diabetes. CONCLUSIONS: Functional disturbances in total skin microcirculation were observed after seven years in patients with type 1 diabetes and preceded diabetic complications such as retinopathy.

Setae from larvae of the northern processionary moth (Thaumetopoea pinivora, TP) stimulate proliferation of human blood lymphocytes in vitro.

Larvae of the Northern pine processionary moth (Thaumetopoea pinivora, TP) carry microscopic needles (setae), which by penetrating skin and mucous membranes, may cause inflammatory/immune derived symptoms in man. In the present study the stimulatory effects of setae on human blood lymphocytes in vitro was investigated. Blood mononuclear cells were separated from venous blood or buffy coat of ten healthy individuals, six previously exposed to setae and four with no known exposure. Lymphoproliferation was measured as uptake of 3H-thymidine. Setae were prepared from TP larvae. Setae and saline setae extracts stimulated proliferation of T-lymphocytes in the presence of monocytic cells. Stimulation was pronounced in cells from persons who had been exposed to setae, and weak in cells from non-exposed donors. Chitin also induced lymphocyte proliferation in most donors, but to a lesser extent and independently of donor's previous exposure to setae. In conclusion, setae contain molecules that in the presence of monocytes activate human T-lymphocytes to proliferation. The antigenic nature of stimulatory molecules was supported by the significantly stronger lymphocyte response in persons previously exposed to setae than in non-exposed donors. The nature of such molecules remains to be defined.

Evaluation of MP4OX for prevention of perioperative hypotension in patients undergoing primary hip arthroplasty with spinal anesthesia: a randomized, double-blind, multicenter study.

BACKGROUND: MP4OX (oxygenated polyethylene glycol-modified hemoglobin) is an oxygen therapeutic agent with potential applications in clinical settings where targeted delivery of oxygen to ischemic tissues is required. The primary goal of this study was to investigate MP4OX for preventing hypotensive episodes. An additional goal was to establish the safety profile of MP4OX in a large surgical population. METHODS: Patients (n = 367) from 18 active study sites in six countries, undergoing elective primary hip arthroplasty with spinal anesthesia, were randomized to receive MP4OX or hydroxyethyl starch 130/0.4. Patients received a 250-ml dose at induction of spinal anesthesia and a second 250-ml dose if the protocol-specified trigger (predefined decrease in systolic blood pressure) was reached. The primary end point was the proportion of patients who developed one or more hypotensive episodes. RESULTS: The proportion of patients with one or more hypotensive episodes was significantly lower (P < 0.0001) in the MP4OX group (66.1%) versus controls receiving hydroxyethyl starch 130/0.4 (90.2%). More MP4OX-treated patients experienced adverse events compared with controls (72.7% vs. 61.4%; P = 0.026). Transient elevations in laboratory values (e.g., alanine aminotransferase, aspartate aminotransferase, lipase, and troponin concentrations) occurred more frequently in the MP4OX group. There were no significant differences in the incidence of serious adverse events or in the composite morbidity and ischemia outcome end points, but nausea and hypertension were reported more often in MP4OX-treated patients. CONCLUSION: MP4OX significantly reduced the incidence of hypotensive episodes in patients undergoing hip arthroplasty, but the adverse event profile does not support use in routine low-risk surgical patients for the indication evaluated in this study.

A double-blind, randomized, multicenter study of MP4OX for treatment of perioperative hypotension in patients undergoing primary hip arthroplasty under spinal anesthesia.

BACKGROUND: MP4OX (oxygenated polyethylene glycol-modified hemoglobin) is a novel oxygen therapeutic agent specifically developed to perfuse and oxygenate tissue at risk for ischemia and hypoxia. In this study, we investigated the ability of MP4OX to treat hypotensive episodes. In addition, the tolerability profile of MP4OX in a large surgical population was established. METHODS: Patients from 21 study sites in 5 countries, scheduled to undergo primary hip arthroplasty under spinal anesthesia, were randomized in a double-blind manner to receive MP4OX or hydroxyethyl starch (HES) solution (Voluven®; HES 130/0.4). Patients received the first 250-mL dose of investigational product when systolic blood pressure decreased to the predefined dosing trigger. A second 250-mL dose was given only if the systolic blood pressure decreased to the same trigger level after administration of the first dose. The primary efficacy outcome was total duration of all hypotensive episodes during surgery and the first 6 hours after skin closure. RESULTS: Of the 474 patients randomized, 405 reached the dosing trigger and received at least 1 dose. The mean total duration of all hypotensive episodes was significantly shorter (P < 0.0001) in the MP4OX group (52.4 ± 71.50 minutes; range, 3-442 minutes) compared with the HES group (137.6 ± 120.21 minutes; range, 5-435 minutes). The overall incidence of adverse events (AEs) in the intent-to-treat population was similar between the MP4OX and HES groups (75.2% vs 73.4%; P = 0.733). Transient increases in laboratory values were reported in more patients in the MP4OX group versus HES controls for aspartate aminotransferase (13.4% vs 7.4%; P = 0.052), alanine aminotransferase (6.9% vs 4.9%; P = 0.409), lipase (9.7% vs 3.6%; P = 0.015), and troponin (8.1% vs 2.0%; P = 0.006). There was no significant difference in the incidence of serious AEs reported (6.4% in MP4OX group vs 3.0% in HES controls; P = 0.106). Certain AEs did occur more frequently in the MP4OX group, including nausea (23.8% vs 14.3%; P = 0.016), bradycardia (14.9% vs 5.9%; P = 0.003), hypertension (8.4% vs 2.5%; P = 0.009), and oliguria (5.9% vs 1.5%; P = 0.019). The composite morbidity and ischemia end points did not reveal any differences between the 2 treatment groups. CONCLUSIONS: Administration of MP4OX achieved the end point of treating perioperative hypotension in patients undergoing primary hip arthroplasty under spinal anesthesia. The study was not powered to demonstrate clinical benefit based on the composite morbidity or ischemia outcomes. Although efficacy end points with sufficient power were met, MP4OX is not being proposed for use in routine surgery where the risk-benefit profile would not be favorable based on the safety profile demonstrated in this study.

Urticating hairs in arthropods: their nature and medical significance.

The ecological phenomenon of arthropods with defensive hairs is widespread. These urticating hairs can be divided into three categories: true setae, which are detachable hairs in Lepidoptera and in New World tarantula spiders; modified setae, which are stiff hairs in lepidopteran larvae; and spines, which are complex and secretion-filled structures in lepidopteran larvae. This review focuses on the true setae because their high density on a large number of common arthropod species has great implications for human and animal health. Morphology and function, interactions with human tissues, epidemiology, and medical impact, including inflammation and allergy in relation to true setae, are addressed. Because data from epidemiological and other clinical studies are ambiguous with regard to frequencies of setae-caused allergic reactions, other mechanisms for setae-mediated disease are suggested. Finally, we briefly discuss current evidence for the adaptive and ecological significance of true setae.

Hematocrit and mean arterial blood pressure in pre- and postmenopause women.

The relationship between mean arterial blood pressure (MAP) and hematocrit (Hct) was studied in pre- and postmenopause women in the city of Durango, Mexico. Premenopause women show a negative trend between parameters that is not statistically significant. MAP and Hct are directly related in postmenopause women (p < 0.01). It is proposed that that this MAP/Hct relationship is in part due to differences in endothelial function where menopause decreases the capacity of the endothelium to respond to increased blood viscosity and shears stress, leading to the increased production of vasodilator mediators to compensate for changes in blood viscosity due to changes in Hct. Comparison with a large group of postmenopause women in the city of Stockholm showed identical trends.

Skin reactions induced by experimental exposure to setae from larvae of the northern pine processionary moth (Thaumetopoea pinivora).

BACKGROUND: Moth larvae that carry noxious hairs (setae) are spread worldwide. A population of the northern pine processionary moth (Thaumetopoea pinivora, TP) is present on the island of Gotland in the Baltic Sea. This study aimed to evaluate the local skin reactions following experimental exposure to TP setae. SUBJECTS AND METHODS: A drop of setae suspension was applied on the volar forearm of six volunteers. The local skin reactions were studied by microscopy and skin perfusion using laser Doppler (LD) scanning. RESULTS: Setae penetrated into the skin, and LD scanning showed marked increase in blood perfusion in all subjects. In two, with a history of severe symptoms, microscopic vacuoles developed around setae, followed by desquamation and severe symptoms. Remaining individuals, with only light symptoms during previous exposure, exhibited only mild reactions that disappeared within 3 weeks. In none of the volunteers, immunoglobulin (Ig) E or IgG4 antibodies to larval antigens were found. CONCLUSION: Experimental skin exposure to TP setae induces local inflammatory reactions independent of earlier exposure to TP. The degree of reaction correlated well with the magnitude of symptoms during natural exposure. The initial reaction mimics a 'foreign body reaction' that varies depending on individual predisposition.

Beneficial effects of dalteparin on haemostatic function and local tissue oxygenation in patients with diabetes, severe vascular disease and foot ulcers.

INTRODUCTION: A state of hypercoagulation and fibrinolytic dysfunction is present in individuals with diabetes, which may contribute to disturbed skin microcirculation and impaired ulcer healing. We have previously reported an improved outcome of chronic diabetic foot ulcers during treatment with dalteparin. In the present study we investigated the effects of dalteparin on skin microcirculation and haemostatic function. MATERIALS AND METHODS: 87 patients with diabetes, peripheral arterial obliterative disease and chronic foot ulcers were investigated in a prospective, randomised, double-blind and placebo-controlled study. They were randomised to treatment with subcutaneous injections of 5000 U dalteparin (n=44) or placebo (n=43), once daily until ulcer healing or for a maximum of six months. Plasma fibrinogen, fibrin gel structure [permeability coefficient (Ks) and fiber mass/length ratio (mu)], prothrombin fragment 1+2 (F1+2) antigen, plasminogen activator inhibitor-1 (PAI-1) activity and tissue plasminogen activator (tPA) antigen were analysed before randomization (baseline value), and at the end of the treatment period. The skin microcirculation of the foot was investigated by transcutaneous oxygen tension (TcPO(2)) and laser Doppler fluxmetry (LDF). RESULTS: The changes (Delta-values) of Ks, mu, tPA and TcPO(2) were higher (p<0.05) during treatment with dalteparin, as compared to the changes during treatment with placebo. At baseline, plasma fibrinogen and Ks were significantly correlated to TcPO(2). CONCLUSIONS: Local skin oxygenation improved and a less thrombogenic fibrin gel structure was formed in patients treated with dalteparin. Beneficial effects on haemostatic function are likely to contribute to the improved skin oxygenation observed during treatment with dalteparin.

A multicenter clinical study of the safety and activity of maleimide-polyethylene glycol-modified Hemoglobin (Hemospan) in patients undergoing major orthopedic surgery.

BACKGROUND: Hemospan (Sangart Inc., San Diego, CA), a polyethylene glycol-modified hemoglobin with unique oxygen transport properties, has successfully completed a phase I trial in healthy volunteers. Because adverse events are expected to increase with age, the authors conducted a phase II safety study of Hemospan in elderly patients undergoing elective hip arthroplasty during spinal anesthesia. METHODS: Ninety male and female patients, American Society of Anesthesiologists physical status I-III, aged 50-89 yr, in six Swedish academic hospitals were randomly assigned to receive either 250 or 500 ml Hemospan or Ringer's acetate (30 patients/group) before induction of spinal anesthesia. Safety assessment included vital signs and Holter monitoring from infusion to 24 h, evaluation of laboratory values, and fluid balance. The hypothesis to be tested was that the incidence of adverse events would be no more frequent in patients who received Hemospan compared with standard of care (Ringer's acetate). RESULTS: Three serious adverse events were noted, none of which was deemed related to study treatment. Liver enzymes, amylase, and lipase increased transiently in patients in all three groups. There were no significant differences in electrocardiogram or Holter parameters, but there was a suggestion of more bradycardic events in the treated groups. Hypotension was less frequent in the treated patients compared with controls. CONCLUSIONS: In comparison with Ringer's acetate, Hemospan mildly elevates hepatic enzymes and lipase and is associated with less hypotension and more bradycardic events. The absence of a high frequency of serious adverse events suggests that further clinical trials should be undertaken.

A phase I single blind clinical trial of a new oxygen transport agent (MP4), human hemoglobin modified with maleimide-activated polyethylene glycol.

BACKGROUND AND OBJECTIVES: MP4 (Hemospan), a hemoglobin-based oxygen carrier, has been designed to deliver oxygen to hypoxic tissues without causing vasoconstriction. A phase I clinical trial of MP4 was undertaken to evaluate whether MP4 elicits the clinical side effects associated with previous hemoglobin-based solutions. DESIGN AND METHODS: Twelve volunteers were studied. One cohort (n=4) received 50 mg/kg of MP4, a second (n=4) received 100 mg/kg of MP4, and the third (n=4) received lactated Ringer's solution. Single blind infusions were given at 5 mL/min. Vital signs and symptoms, hematologic parameters, serum chemistry, renal and electrocardiographic measurements were monitored for 15 days after dosing. RESULTS: Five mild adverse events occurred in the controls and 2 each in the 50 mg/kg and 100 mg/kg MP4 groups. None was severe or judged related to MP4 administration by the principal investigator. There were no clinically significant alterations in blood pressure or heart rate, and there were no gastrointestinal symptoms, abdominal or flank pain, loss of appetite or clinically significant alterations of liver or pancreatic enzymes. In one subject (100 mg/kg of MP4), amylase and lipase were slightly above the upper limit of normal 4 hours after dosing, but without associated symptoms or signs. Pharmacokinetic analysis of plasma hemoglobin (assuming no hemolysis) yielded an estimated half-life (T1/2) of 43 hours in the 100 mg/kg MP4 subjects. INTERPRETATION AND CONCLUSIONS: MP4 appears to have a favorable safety profile. Subjects in both study groups survived and did no less well than those in the control group.