Double-blind, placebo-controlled study of intravenous prostacyclin on hemodynamics in severe Raynaud's phenomenon: the acute vasodilatory effect is not sustained

In 12 patients with severe Raynaud's phenomenon (RP: ischemic ulcers or intractable pain despite use of narcotic analgetics), we studied the acute and long-term hemodynamic effects of epoprostenol on systemic and finger skin circulation. Epoprostenol was infused intravenously (i.v., initial infusion rate of 2 ng/kg/min, with a subsequent increase of 2 ng/kg/min every 30 min to the individually tolerated maximal dose of 8 ng/kg/min) in a triple, 5-h, double-blind, placebo-controlled cross-over study. During epoprostenol infusion, systolic blood pressure (SBP) remained stable, while diastolic BP (DBP) decreased (-8 mm Hg, p < 0.02), with a simultaneous increase in heart rate (HR + 14 beats/min, p < 0.001). Forearm blood flow (FBF) increased and forearm vascular resistance (FVR) decreased during epoprostenol as compared with placebo infusion (p < 0.01). Epoprostenol caused a significant increase in fingertip skin temperature (p < 0.01) as well as in laser Doppler flux (p < 0.02) before and after a standardized cooling test of the hand as compared with placebo. The increase in transcutaneous oxygen tension reached significant difference only during recovery (p < 0.02). No long-term improvement was noted during two additional cooling tests performed 1 and 6 weeks after the completed epoprostenol or placebo triple-infusion cycle. Repeated long-lasting epoprostenol infusion immediately improves the microcirculation, but these effects are not sustained after 1 week.     

An experimental model of acute encephalopathy after total body irradiation in the rat: effect of liposome-entrapped Cu/Zn superoxide dismutase

PURPOSE: To develop an experimental model of acute encephalopathy following total body irradiation in rats and to define the therapeutic effect of liposome-entrapped Cu/Zn superoxide dismutase. METHODS AND MATERIALS: A total of 120 4-month-old rats received 4.5 Gy total body irradiation (TBI) while 120 rats received sham irradiation. A behavioral study based on a conditioning test of negative reinforcement, the one-way avoidance test, was performed 5 hours before irradiation and repeated the following days. Subcutaneous treatment was started 1 hour after irradiation and repeated daily for 2 weeks. In both the irradiated and sham group, three subgroups were defined according to the treatment received: liposome-entrapped Cu/Zn superoxide dismutase (0.5 mg/kg), liposomes only, normal saline. RESULTS: This work comprised two consecutive studies. In study A (90 rats) the one-way avoidance test was administered daily from day 0 to day 4 with a recall session at day 14. In study B (validation phase in 150 rats) the behavioral test was performed only from day 0 to day 6. Before irradiation, all rats showed a similar behavioral response. Study A (6 groups of 15 rats): Following TBI, irradiated rats treated with liposomes only or saline demonstrated a significant delay in learning the one-way avoidance test in comparison with sham-irradiated rats (0.05 < p <0.001 depending upon the day of evaluation and the subgroup type). In contrast, irradiated rats treated with liposome-entrapped Cu/Zn superoxide dismutase did not differ from sham-irradiated rats. Study B (6 groups of 25 rats): The results were the same as those in study A, demonstrating a significant delay in the learning of the test in the liposome and saline-treated irradiated rats in comparison with sham-irradiated rats (0.02 < p < 0.001). The irradiated rats, treated with liposome-entrapped Cu/Zn superoxide dismutase did not differ from the sham-irradiated controls. CONCLUSION: This study indicates that a relatively low dose of total body irradiation induces a substantial acute learning dysfunction in the rat. This effect is prevented by the administration of liposome-entrapped Cu/Zn superoxide dismutase.     

Localization of human immunodeficiency virus 1 RNA in thymic tissues from asymptomatic drug addicts

The aim of the present study was to investigate if diabetes negatively influences the skin microvascular reactivity in the toes of patients with peripheral vascular disease (PVD). Twenty healthy subjects, 20 diabetic, and 20 non-diabetic patients with PVD participated. One foot in each subject was investigated. The patient groups were matched for age, sex, and toe pressure. The capillary blood cell velocity in the nailfold of the great toe was investigated by videophotometric capillaroscopy, and the total skin microcirculation within the same area by laser Doppler fluxmetry. Capillary blood cell velocity and laser Doppler flux were studied during rest, and following a 1 min arterial occlusion at the toe base. The skin microvascular reactivity was impaired in both diabetic and non-diabetic patients. In the diabetic patients the disturbances were mainly seen in the capillaries, and the capillary blood flow was severely reduced during reactive hyperaemia (p < 0.01). In contrast, the total skin microcirculation was normal, indicating that sufficient blood reaches the area, but does not come out into the capillaries. The ratio between capillary blood cell velocity and laser Doppler flux, representing the distribution of blood between nutritional and non-nutritional blood compartments, was reduced in the diabetic patients (p < 0.05). These findings may contribute to the higher risk for development of chronic foot ulcers in diabetic patients with PVD.     

Biological activity of C-peptide on the skin microcirculation in patients with insulin-dependent diabetes mellitus

19 insulin-dependent diabetes mellitus (IDDM) patients participated in a randomized double-blind crossover investigation to investigate the impact of human C-peptide on skin microvascular blood flow. The investigation was also carried out with 10 healthy volunteers. Blood pressure, heart rate, blood sugar, and C-peptide levels were monitored during a 60-min intravenous infusion period of C-peptide (8 pmol kg-1 min-1) or saline solution (154 mmol liter-1 NaCl), and 30 min after stopping the infusion. During the same time period, capillary blood cell velocity (CBV), laser Doppler flux (LDF), and skin temperature were assessed in the feet. In the verum arm, C-peptide levels increased after starting infusion to reach a maximum of 2.3+/-0.2 nmol liter-1 after 45 min, but remained below 0. 15 nmol liter-1 during the saline treatment. Baseline CBV was lower in diabetic patients compared with healthy subjects (147+/-3.6 vs. 162+/-4.2 micron s-1; P < 0.01). During C-peptide administration, CBV in IDDM patients increased progressively from 147+/-3.6 to 167+/-3.7 micron s-1; P < 0.001), whereas no significant change occurred during saline infusion or in healthy subjects. In contrast to the CBV measurements, the investigation of LDF, skin temperature, blood pressure, heart rate, or blood sugar did not demonstrate any significant change during the study. Replacement of human C-peptide in IDDM patients leads to a redistribution in skin microvascular blood flow levels comparable to levels in healthy subjects by increasing the nutritive CBV relative to subpapillary arteriovenous shunt flow.     

Effects of positive pressure on both femoral venous and arterial blood velocities and the cutaneous microcirculation of the forefoot

OBJECTIVE: The balance between the apparent beneficial effect and the risk of arterial ischaemia resulting from an external uniform compression is unclear. The purpose of this study was to determine the effects of a positive uniform compression on the lower limb circulation until a critical threshold was reached. METHODS: We used Doppler ultrasound to measure femoral venous and arterial blood velocities. The effects of positive pressure on cutaneous microcirculation were evaluated by laser Doppler flux (LDF), transcutaneous oxygen pressure (tcpO2) and transcutaneous carbon dioxide pressure (tcpCO2) on the forefoot of 17 healthy subjects. RESULTS: The results are expressed as median [lowest observed value-highest observed value]. Whereas the arterial femoral velocity (A.F.V.) decreased from 0.21 [0.08-0.36] to 0.17 [0.08-0.28] m s-1 for an external pressure as low as 10 mmHg (p < 0.001), the venous femoral velocity (V.F.V.) decreased from 0.13 [0.06-0.40] to 0.09 [0.05-0.34] m s-1 at 20 mmHg (p < 0.001). An increase of tcpCO2 from 39.8 [29.9-53.7] to 40.2 [30.0-55.5] mmHg (p < 0.05) and a decrease of LDF from 8.7 [3.1-25.9] to 5.5 [2.3-21.1] A.U. (p < 0.001) occurred at 10 mmHg. However, tcpO2 decreased only from 76.7 [40.2-91.2] to 64.6 [18.9-85.2] mmHg when the splint pressure reached 60 mmHg (p < 0.05). The observed parameters (LDF, tcpO2, V.F.V. and A.F.V.) decreased further (except for tcpCO2 which increased) up to the end of the study as the applied pressure was increased. CONCLUSION: Positive pressure on the full leg provided no significant beneficial effect on femoral venous blood velocity. Whereas we showed that for an external uniform pressure as low as 10 mmHg, significant impairments in both arterial inflow of the lower limb and microcirculation of the forefoot appeared in recumbent healthy young subjects.     

Tyrosine phosphorylation of focal adhesion kinase (p125FAK): regulation by cAMP and thrombin in mesangial cells

This study aimed at evaluating the influence of submaximal isometric contraction on pressure pain thresholds (PPTs) in 14 fibromyalgia (FM) patients and 14 healthy volunteers, before and after skin hypoesthesia. PPTs were determined with pressure algometry over m. quadriceps femoris before, during and following an isometric contraction. Maximum voluntary contraction (MVC) was assessed using a computerized dynamometer. A contraction of 22% MVC on average was held until exhaustion (max. 5 min) and PPTs were assessed every 30 sec. A local anesthetic cream and a control cream were applied following a double-blind design and PPTs were reassessed. In healthy volunteers PPTs increased during contraction (P < 0.001), then decreased after the end of contraction (P < 0.001) but remained above precontraction values during the 5 min of post-contraction assessments (P < 0.001). In FM patients PPTs decreased in the middle of the contraction period (P < 0.05) and remained below precontraction levels during the rest of the contraction period (P < 0.05) and during the 5 min of post-contraction assessment (immediately post-contraction NS; 2.5 min post-contraction P < 0.01; 5 min post-contraction P < 0.05). The normalized PPTs were significantly lower in patients than in controls during contraction (start P < 0.01; middle P < 0.001; end P < 0.001) and at all times during post-contraction assessments (P < 0.001). Anesthetic cream raised PPTs at rest in controls (P < 0.01) but not in FM patients, and did not influence contraction or post-contraction PPTs in either group. Therefore, the increased pressure pain sensibility in FM patients is more pronounced deep to the skin. The observed decrease of PPTs during isometric contraction in FM patients could be due to sensitization of mechanonociceptors caused by muscle ischemia and/or dysfunction in pain modulation during muscle contraction.     

Reflex sympathetic dystrophy: result of autonomic denervation?

1. To investigate the nature of sympathetic dysfunction in the pathogenesis of reflex sympathetic dystrophy, the microcirculatory vasoconstrictive responses to dependency were investigated in the skin of the hand of 76 reflex sympathetic dystrophy patients with unilateral disease by means of laser Doppler flowmetry (in perfusion units) and capillary microscopy. The patients were divided into three stages according to their perception of skin temperature (stage I in the case of a stationary warmth sensation, stage II in the case of an intermittent warmth and cold sensation, and stage III in the case of a stationary cold sensation). The vasoconstrictive responses were induced by lowering of the affected hand. 2. As compared to controls, the mainly sympathetically mediated vasoconstrictive response at thermoregulatory level of the skin microcirculation, as measured by laser Doppler flowmetry, was attenuated at stage I (1.82 versus 1.41, P < 0.05), stage II (1.82 versus 1.09, P < 0.0001) and stage III (1.82 versus 1.14, P < 0.01), suggesting the involvement of sympathetic denervation at all stages of the reflex sympathetic dystrophy syndrome. This sympathetic denervation may also account for the observed increase in thermoregulatory skin blood flow at stage I as compared to controls (152 versus 81, P < 0.01). 3. Since sympathetic denervation has been reported to cause increased sensitivity of vascular structures to catecholamines, the decrease in thermoregulatory skin blood flow at stages II (54 versus 81, P < 0.05) and III (31 versus 81, P < 0.05), both as compared to controls, may result from hypersensitivity to catecholamines of skin microvessels. 4. The sympathetically independent vasoconstrictive response at the nutritive level of skin microcirculation, as measured by capillary microscopy, was impaired only at stage III as compared to controls (1.04 versus 2.06, P < 0.05). This divergence in microvascular reactivity upon dependency of the nutritive and thermoregulatory subsystems also supports the hypothesis of sympathetic dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of surgical sympathectomy on skin blood flow in a rat model of chronic limb ischemia

The role of lumbar sympathectomy in the treatment of limb ischemia secondary to arteriosclerosis obliterans has been controversial. Increased temperature and rubor of the skin, which usually follow sympathectomy, have generally been interpreted as indicative of improved nutritive skin blood flow. However, the existence of a (nonnutritive) thermoregulatory level of skin microcirculation makes such an extrapolation questionable. We investigated the total (mainly thermoregulatory) skin blood flow (TSBF) in the hindlimb of 15 male Lewis rats by means of laser Doppler flowmetry and the nutritive skin blood flow (NSBF) by means of capillary microscopy (red blood cell velocity). Transcutaneous oximetry was used to assess skin oxygenation (SO). Measurements were performed before and 2 and 28 days after ligation of the common iliac and iliolumbar artery. Subsequently, either a surgical resection of the sympathetic chain (L2-L6) was performed or a sham operation. Measurements were repeated 2 and 28 days later. For the group of 15 rats as a whole, TSBF (p < 0.05), NSBF (p < 0.05), and SO (p < 0.05) were found to be drastically reduced at day 2 after litigation compared to preligation values. This reduction partially recovered during the following weeks. TSBF (p < 0.05) and NSBF (p < 0.05), however were still reduced at day 28 after ligation compared to preligation values, whereas the SO at this time tended to be lower (p = 0.11). In the sympathectomy group the TSBF was found to be increased at day 2 (p < 0.05) and day 28 (p < 0.05) after sympathectomy, both compared to values obtained at day 28 after ligation. Sympathectomy did not have an effect on NSFB and SO. The sham procedure had no effect on the TSBF, NSBF, or SO. These results indicate that in case of lower limb ischemia, sympathectomy improves skin blood flow at the thermoregulatory but not the nutritive level of skin microcirculation. This may be related to the fact that the thermoregulatory vessels are mainly sympathetically controlled, whereas the nutritive capillaries are mainly controlled by local (nonneural) factors.     

Reduced skin hyperemia during tap water iontophoresis after intake of acetylsalicylic acid

Skin microcirculation and skin temperature of 10 healthy subjects (6 men and 4 women, 20-44 yr of age) without any vascular diseases were registered when a thermoindifferent tap water iontophoresis was applied. The aim of this controlled study was to evaluate the development of skin hyperemia after the intake of 500 mg of acetylsalicylic acid (ASA). The measurement was conducted by laser-Doppler flowmetry on the proximal forearm. The skin temperature was measured before and after the treatment by an infrared thermometer. In all persons there was an intense erythema on the side of the cathode and only a modest one on the side of the anode. Without ASA preliminary treatment, the cutaneous flow showed an increase of 106% at the anodal side and that of 834% at the cathodal side (P < 0.001). After ending tap water iontophoresis, the skin temperature increased more on the cathode side than on the anode side (P < 0.001). After the intake of 500 mg ASA, the increase of the flow was 78% at the anode and 88% at the cathode. The comparison of the skin microcirculation did not show any differences at the anodal side when acetylsalicylic acid was taken before, but a strong suppression of the galvanic erythema at the cathodal side was observed after the intake of ASA. There is a direct influence of acetylsalicylic acid on the induction of the neurogenic inflammation caused by a galvanic erythema. The intensity of the induced erythema correlates with the analgesic effects of constant current treatment. An attenuation of the electrotherapeutic analgesia is possible.     

Effect of irradiation with a low-intensity diode laser on the metabolism of equine articular cartilage in vitro

OBJECTIVE: To determine whether irradiation with a low-intensity diode laser, which produces radiation at a wavelength of 810 nm, will induce nonthermal enhancement of chondrocyte metabolism. SAMPLE POPULATION: 144 grossly normal articular cartilage explants aseptically harvested from the femoral condyles of 6 adult horses. PROCEDURE: Treated cartilage explants were irradiated with a diode laser at 1 of 7 fluence levels that ranged from 8 to 1,600 J/cm2. Explants were incubated for 24 or 72 hours, labeled for 24 hours with [35S]Na2SO4, and assayed for newly synthesized sulfated glycosaminoglycan (GAG; measured incorporation of 35SO4) and endogenous GAG, chondroitin 6-sulfate (CS), and keratan sulfate (KS) content, using a dimethylmethylene blue assay. Laser-induced temperature changes were measured during irradiation with a diode laser and a neodymium:yttrium aluminum garnet (Nd:YAG) laser, which produces radiation at a wavelength of 1,064 nm, using conditions that were reported in previous studies to increase explant metabolism. RESULTS: After incubation for 24 or 72 hours, rate of 33SO4 uptake or endogenous GAG, CS, or KS content in irradiated explants was not significantly different than in nonirradiated explants. Cartilage temperature increased < 4.75 C during diode laser application. Cartilage temperature increased 5 to 12 C during Nd:YAG laser application. CONCLUSIONS: Minimal thermal increases in cartilage explants with use of a low-intensity diode laser resulted in no change in proteoglycan metabolism of chondrocytes. An increase in tissue temperature over a narrow range with use of a Nd:YAG laser may have contributed to the metabolic alteration of chondrocytes reported in previous studies.     

Right atrial pressure and forearm blood flow during prolonged exercise in a hot environment

Right atrial pressure (RAP) at rest is known to be reduced by an increase in skin blood flow (SkBF) in a hot environment. However, there is no clear evidence that this is so during exercise. To clarify the effect of the increase in SkBF on RAP during exercise, we measured forearm blood flow (FBF) (as an index of SkBF) and RAP continuously using a Swan-Ganz catheter in five male volunteers exercising on a cycle ergometer at 60% of peak aerobic power for 50 min in a hot environment (30 degrees C, relative humidity 20%). Cardiac output increased from 5.5 +/- 0.2 l/min at rest to 17.9 +/- 1.2 l/min (mean +/- SE, P < 0.01) in the first 10 min of exercise and then remained steady until the end of exercise. FBF did not change significantly during the first 5 min, but then increased from 2.7 +/- 0.5 ml/100 ml per min at rest to 10.8 +/- 1.7 ml/100 ml per min (P < 0.001) by 25 min as pulmonary arterial blood temperature (Tb) rose from 37.0 +/- 0.1 degrees C to 38.1 +/- 0.1 degrees C (P < 0.001). FBF then reached a plateau, despite a continuing increase in Tb. RAP increased significantly from 4.3 +/- 0.8 to 7.6 +/- 1.2 mm Hg (P < 0.001) during the first 5 min of exercise and then gradually declined to 6.1 +/- 1.0 mm Hg by 25 min (P < 0.001 vs. 5 min) and further to 5.7 +/- 1.0 mm Hg by 50 min, a value not significantly higher than at rest.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endoneurial localisation of microvascular damage in human diabetic neuropathy

Twenty diabetic patients with neuropathy underwent clinical and neurophysiological evaluation together with a detailed morphometric assessment of capillary pathology in endoneurial and epineurial microvascular beds of the sural nerve. Morphological data were compared with ten non-diabetic control subjects. There were no significant differences in control subjects between basement membrane area, endothelial cell area, endothelial cell profile number or luminal area of endoneurial when compared with epineurial capillaries. In contrast, when compared with epineurial capillaries, endoneurial capillaries from diabetic patients demonstrated a significant increase in basement membrane (p < 0.001) and endothelial cell (p < 0.001) area and a significant reduction in luminal area (p < 0.001). There was no significant difference in endothelial cell profile number between endoneurial and epineurial capillaries amongst diabetic patients. Previous studies have demonstrated a good correlation between the degree of microangiopathy and measures of neuropathic severity. In the present study increased endoneurial capillary basement membrane area was significantly related to reduced peroneal nerve conduction velocity (p < 0.001), myelinated fibre density (p < 0.001) and elevated vibration (p < 0.05) and thermal (p < 0.001) perception. Increased endothelial cell area and reduced luminal size were related to a reduced peroneal nerve conduction (p < 0.05, p < 0.01, respectively), reduced myelinated fibre density (p < 0.05, p < 0.01) and elevated thermal perception (p < 0.05, p < 0.001). Epineurial capillary basement membrane, endothelial cell and luminal area failed to relate to measures of neuropathic severity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Photochemically-induced ischemia of the rat sciatic nerve produces a dose-dependent and highly reproducible mechanical, heat and cold allodynia, and signs of spontaneous pain

Sensory abnormalities and changes in spontaneous behavior were examined after a photochemically induced ischemic lesion of the rat sciatic nerve. Male adult rats were anesthetized and the sciatic nerve was exposed. After the intravenous injection of a photosensitizing dye, erythrosin B, the exposed nerve was irradiated just proximal to the nerve trifurcation with light from an argon laser. Three different irradiation times were used, 30 s, 1 and 2 min. In sham-operated rats, the exposed sciatic nerve was irradiated for 2 min without prior injection of the erythrosin B. Rats were tested for the presence of mechanical, cold and heat allodynia or hyperalgesia. All the animals in the 1- and 2-min irradiation groups developed mechanical, cold and heat allodynia after nerve irradiation. A significant dose-dependent effect of laser exposure time was observed for all modalities tested (2 min > 1 min > 30 s = sham). The maximum effects were observed at 3 and 7 days postirradiation and remained present for up to 10 weeks. No significant contralateral effects were observed in any of the groups. In three separate groups of rats (1, 2 and 4 min of laser exposure), the presence of possible signs of spontaneous pain (paw shaking, paw elevation and freezing behavior) was tested. A significant and exposure time-dependent increase in spontaneous paw elevation and paw shaking was observed which was maximal at week 1, but resolved at 4 weeks (4 min > 2 min > 1 min > sham). In addition, animals in all ischemic groups, but not in the sham group, showed a significant increase in freezing behavior up to 4 weeks after nerve irradiation. Light microscopic evaluation of nerves removed 7 days post-irradiation, i.e. when maximal allodynia was observed, showed clear evidence of demyelination of large myelinated fibers. These data indicate that photochemically-induced peripheral nerve ischemia is associated with abnormal pain-related behaviors, including mechanical, thermal and cold allodynia and signs of spontaneous pain. The incidence and severity of the behavioral changes are clearly dependent on the exposure time and are probably due to, at least in part, a demyelinaton. These results partly confirm previous data using a similar technique and suggest that this may represent a new animal model for peripheral neuropathy of ischemic origin. The advantages of the present model are its good reproducibility and the fact that the nerve injury can be easily quantified and graded.     

Skin flap closure by dermal laser soldering: a wound healing model for sutureless hypospadias repair

OBJECTIVES: Laser tissue soldering (LTS) with the diode laser and human albumin-hyaluronate-indocyanine green solder is a safe and effective method of providing an immediate leak-free closure during hypospadias repair. In this report, we compare the physiology, histology, and immunohistochemistry of wound healing following LTS and suturing in a rat skin flap model. METHODS: A 4 x 5-cm skin flap was raised and bisected (4 cm) on the dorsum of 48 Sprague-Dawley rats. The central wound was either closed from a dermal approach by suturing or LTS or left open, and studied at 0, 3, 5, 7, 10, 14, and 21 days postoperatively. An intraoperative comparison was made between suturing and LTS with respect to operative time. Postoperatively, flaps were excised for tensiometric analysis, and sections were stained with hematoxylin-eosin to define wound architecture. Resting skin temperature, laser exposed temperature without solder, and maximum temperature with solder (one drop) were measured at the level of the deep dermis, superficial striated muscle layer, and within the solder. Mean peak temperatures were recorded during a 1-minute laser activation time. RESULTS: Mean continuous suturing time (4.9 +/- 1.1 minutes) was significantly (P < 0.001) faster than either LTS (7.7 +/- 0.77 minutes) or discontinuous suturing (8.2 +/- 0.62 minutes). Two seromas (sutured) and two instances of partial wound dehiscence (1 sutured, 1 LTS) were noted. Tensile strength was increased significantly (P < 0.001) for up to 5 days in the LTS group, but was equal to suturing at 7 and 10 days. Immediate tensile strength after LTS was equivalent to a 7-day healed wound. At 14 days, wounds initially left open and those closed by LTS were stronger than sutured wounds (P < 0.05). There was no evidence of thermal injury or foreign body reaction in the LTS group. Solder was incorporated within the dermis in all wounds at 21 days. Laser activation of solder resulted in significant increases in temperature at all three tissue levels: 65.0 +/- 5.2 and 69.9 +/- 6.8 degrees C in the deep and superficial skin (no significant difference between the two), and 101 +/- 15.6 degrees C within the solder (P < 0.001 versus superficial and deep skin). CONCLUSIONS: Our results indicate that sutureless dermal LTS of skin flaps provides increased tensile strength for up to 7 days, with relatively greater tensile strength provided within the first 3 days. Our laser technique does not appear to alter the normal wound healing process. Rather, solder-tissue interaction initially, and extracellular matrix infiltration of solder later, provide the basis for improved wound strength. For hypospadias repair using skin flaps, these wound attributes may permit sutureless surgery.     

Distinct P-cadherin expression in cultured normal human keratinocytes and squamous cell carcinoma cell lines

A thermal threshold measurer (TTM) apparatus was developed and tested in 12 dry, nonpregnant, culled cows with the purpose of measuring the thermal nociceptive threshold and of finding the response to morphine sulphate dosages. The cows received a cumulative dose (from 0.00 to 0.40 mg/kg BW) of morphine sulphate through a catheter in the jugular vein. The interval between doses was 20 min, and a nociceptive test was performed 15 min after each injection. The TTM device consisted of a 60 W halogen bulb mounted in a 15 cm PVC tube, with a 0.6 s response time probe attached to its end, connected to a thermocouple. The probe measured the response temperature on the skin over the middle phalanges on the dorsum of the forefoot. The radiating heat stimulus from the bulb was instantaneously terminated with the foot-lift response of the tested animal. The nociceptive response to the 0.00 mg/kg dose was considered the baseline and subsequent measurements were expressed in difference from it. Data were evaluated in a regression analysis using the GLM procedure. A significant elevation (P < 0.0001) in the nociceptive threshold of the cows with cumulative dosing of morphine sulphate was noticed. A high variability (P < 0.0001) in the response among animals was also detected, suggesting that a 2-step dose of morphine sulphate is necessary to achieve a certain degree of induced analgesia in all cows. The nociceptive assay described, using the TTM device, was able to detect an elevation of the thermal threshold of cows due to morphine sulphate induced analgesia. An increase in locomotory behaviour or other side effects due to morphine sulphate were not noticed.     

Elevated concentrations of circulating adhesion molecules and their association with microvascular complications in insulin-dependent diabetes mellitus

To better understand potential associations of circulating adhesion molecules (cAMs) with diabetic microangiopathy, circulating serum concentrations of intercellular adhesion molecule-1 (cICAM-1), vascular cell adhesion molecule-1 (cVCAM-1), and endothelial leukocyte adhesion molecule-1 (cELAM-1) were determined in patients with insulin-dependent diabetes mellitus (IDDM) (n = 70) presenting with varying degree of metabolic control and status of diabetic late complications, and were compared with age-matched healthy subjects (n = 70) in a cross-sectional study. Concentrations of cICAM-1 and cVCAM-1 were elevated in IDDM vs. age-matched controls (cICAM-1: 276 +/- 71 vs. 212 +/- 57 ng/mL; P < 0.0001; cVCAM-1: 781 +/- 245 vs. 615 +/- 151 ng/mL; P < 0.0001), whereas cELAM-1 did not differ between the groups (cELAM-1: 50 +/- 25 vs. 46 +/- 23 ng/mL, P = 0.31). The levels of cVCAM-1 were more markedly elevated in IDDM patients with diabetic retinopathy (n = 32) than in those without (n = 38) (cVCAM-1: 848 +/- 281 vs. 724 +/- 197 ng/mL, P < 0.05), as well as in patients with micro- or macroalbuminuria (n = 10) vs. those without (n = 60) (cVCAM-1: 947 +/- 256 ng/mL vs. 753 +/- 234 ng/mL, P < 0.05), whereas no difference in cICAM-1 and cELAM-1 was apparent regarding the clinical status of diabetic microangiopathy. No correlations were found between hemoglobin A1e and cAMs in the individual subgroups of patients and healthy subjects. Interestingly, however, low density lipoprotein cholesterol correlated with cVCAM-1 (r = 0.38, P = 0.03) in IDDM patients with diabetic microangiopathy (n = 33), but not in healthy controls or patients without microangiopathy (n = 37). Analyzing the pooled data of diabetic patients and healthy subjects (n = 140), concentrations of cICAM-1 were markedly related to cVCAM-1 (r = 0.45, P < 0.0001) and cELAM-1 (r = 0.31, P < 0.0002), whereas cVCAM-1 was related less to cELAM-1 (r = 0.19, P = 0.03), respectively. We conclude that, irrespective of actual metabolic control, serum concentrations of cICAM-1 and cVCAM-1 but not cELAM-1 are elevated in patients with IDDM, reflecting ongoing endothelial cell stimulation and leukocyte activation. More specifically, more marked elevation of cVCAM-1 may even hint at clinically manifest diabetic microangiopathy.     

Role of sham feeding in postprandial changes of gastric myoelectrical activity

The aim of this study was to evaluate the role of sham feeding in postprandial changes of gastric myoelectrical activity. Eighteen asymptomatic healthy volunteers (10 men, 8 women; mean age: 31), with no history of gastrointestinal disease were studied. Gastric myoelectrical activity was recorded for 30 min at baseline, 30 min after sham feeding, and 1 hr after eating, using surface electrogastrography. The electrogastrogram (EGG) was analyzed by spectral analysis. It was found that the changes of postprandial EGG parameters were significantly correlated with those after sham feeding (EGG dominant power: r = 0.6, P < 0.01; dominant frequency: r = 0.8, P < 0.001; percentage of regular slow waves: r = 0.7, P < 0.003). We concluded that intrinsic gastric electrical activity can be altered by sham feeding and the cephalic phase of digestion plays an important role in the postprandial response of gastric myoelectrical activity.     

Improved kidney function with intravenous prostaglandin E1 in patients with terminal heart failure

In end stage congestive heart failure activation of a series of compensatory mechanisms increase renal vascular resistance and impair renal function. Prostaglandin E1 is increasingly used in the treatment of severe heart failure for its vasodilating actions. In various experimental settings prostaglandin E analogues are known to improve renal function by modulating renal filtration pressure and redistribution of renal blood flow. However, prostaglandin E1 decreases systemic blood pressure and thus, also renal perfusion pressure, a fact by which renal function might be further compromized in heart failure patients. The aim of the study was to evaluate the effects of prostaglandin E1 on excretory renal function in patients with end stage heart failure and to prove the hypothesis, that the well known local actions of prostaglandins on renal microcirculation might outweigh the negative impact of an expected decrease in perfusion pressure. 25 patients with terminal congestive heart failure were investigated. 13 patients received prostaglandin E1 at a dose of 13.5 +/- 1.9 ng/kg/min in combination with constant rates of dopamine and dobutamine (group A), 12 patients received prostaglandin E1 at a dose of 10.3 +/- 1.7 ng/kg/min without catecholamines (group B). There was no significant difference in prostaglandin dosages between groups. Kidney function was assessed by measuring plasma creatinine and urea nitrogen, urinary output, creatinine clearance, osmotic and free water clearance at baseline and after 72 h of infusion therapy. Hemodynamic parameters were measured by using a balloon tipped pulmonary arterial catheter. Hemodynamic measurements during infusion showed a significant improvement in all patients. At the same time as expected mean arterial pressure decreased in both groups (p < 0.001). Nevertheless, in both groups a significant increase of creatinine clearance during infusion was observed (in group A from 45 ml/min to 78 ml/min., p < 0.05, in group B from 59 ml/min to 105 ml/min., p < 0.001). Creatinine clearance in group B (without catecholamines) reached higher levels than group A (p < 0.05). Urinary volumes did not change during infusion therapy, whereas free water clearance significantly decreased, as an indication of an improvement of renal concentrations ability. We conclude, that in patients with end stage heart failure continuous infusion of prostaglandin E1 improves excretory kidney function. These findings suggest that the local effects of prostaglandin E1 on renal microcirculation can counterregulate the negative impact of prostaglandins on renal perfusion pressure.     

Characterization of adrenocortical cell lines produced by genetically targeted tumorigenesis in transgenic mice

Microvascular hyperaemia is decreased in subjects at risk of developing non-insulin-dependent diabetes mellitus (NIDDM) who have fasting hyperglycaemia. Such microvascular abnormalities may be involved in the pathogenesis of diabetic microangiopathy. To investigate the relationship of reduced microvascular hyperaemia to metabolic and blood pressure abnormalities associated with the prediabetic state, we studied 24 subjects with fasting hyperglycaemia and 24 age- and sex-matched control subjects. The microvascular hyperaemic response to local heating of the skin on the dorsum of the foot measured by laser Doppler fluximetry was reduced in the subjects with fasting hyperglycaemia (1.18 [0.87-1.83] volts vs 1.51 [1.30-2.14] volts normal subjects; p = 0.0002) and was negatively correlated with fasting plasma insulin concentration (Rs = 0.70; p = 0.001) and positively related to insulin sensitivity determined by continuous infusion of glucose with model assessment (CIGMA) (Rs = 0.52; p = 0.01), but showed no association with fasting plasma glucose, beta-cell function 24 h ambulatory blood pressure profiles or serum lipid concentrations. These results suggests that hyperinsulinaemia, as a result of insulin resistance, may have a detrimental effect on microvascular function in the prediabetic state.     

Effect of skin temperature on multifrequency bioelectrical impedance analysis

This study assessed the effects of changes in skin temperature on multifrequency bioimpedance analysis (MF-BIA) and on the prediction of body water compartments. Skin temperature (baseline 29.3 +/- 2.1 degrees C) of six healthy adults was raised over 50 min to 35.8 +/- 0.6 degrees C, followed by cooling for 20 min to 26.9 +/- 1.3 degrees C, by using an external heating and cooling blanket. MF-BIA was measured at both distal (conventional) and proximal electrode placements. Both distal and proximal impedance varied inversely with a change in skin temperature across all frequencies (5-500 kHz). The change in proximal impedance per degree centigrade change in skin surface temperature was approximately 60% of distal impedance. The change in measured impedance at 50 kHz erroneously increased predicted total body water (TBW) by 2.6 +/- 0.9 liters (P < 0.001) and underpredicted fat mass by 3.3 +/- 1.3 kg (P < 0.0001). Computer modeling of the MF-BIA data indicated changes in predicted water compartments with temperature modifications; however, the ratio of extracellular water (ECW) to TBW did not significantly change (P < 0.4). This change in impedance was not due to a change in the movement of water of the ECW compartment and thus probably represents a change in cutaneous impedance of the skin. Controlled ambient and skin temperatures should be included in the standardization of BIA measurements. The error in predicted TBW is < 1% within an ambient temperature range of 22.3 to 27.7 degrees C (72.1-81.9 degrees F).