Differential effects of lidocaine and mexiletine on relaxations to ATP-sensitive K+ channel openers in rat aortas

BACKGROUND: In cardiac myocytes, lidocaine reduces but mexiletine increases adenosine triphosphate (ATP)-sensitive K+ currents, suggesting that these class Ib antiarrhythmic drugs may differentially modify the activity of ATP-sensitive K+ channels. The effects of lidocaine and mexiletine on arterial relaxations induced by K+ channel openers have not been studied. Therefore, the current study was designed to evaluate whether lidocaine and mexiletine may produce changes in relaxations to the ATP-sensitive K+ channel openers cromakalim and pinacidil in isolated rat thoracic aortas. METHODS: Rings of rat thoracic aortas without endothelia were suspended for isometric force recording. Concentration-response curves were obtained in a cumulative fashion. During submaximal contractions to phenylephrine (3 x 10(-7) M), relaxations to cromakalim (10(-7) to 3 x 10(-5) M), pinacidil (10(-7) to 3 x 10(-5) M), or diltiazem (10(-7) to 3 x 10(-4) M) were obtained. Lidocaine (10(-5) to 3 x 10(-4) M), mexiletine (10(-5) to 10(-4) M) or glibenclamide (5 x 10(-6) M) was applied 15 min before addition of phenylephrine. RESULTS: During contractions to phenylephrine, cromakalim and pinacidil induced concentration-dependent relaxations. A selective ATP-sensitive K+ channel antagonist, glibenclamide (5 x 10(-6) M), abolished these relaxations, whereas it did not alter relaxations to a voltage-dependent Ca2+ channel inhibitor, diltiazem (10(-7) to 3 x 10(-4) M). Lidocaine (more than 10(-5) M) significantly reduced relaxations to cromakalim or pinacidil in a concentration-dependent fashion, whereas lidocaine (3 x 10(-4) M) did not affect relaxations to diltiazem. In contrast, mexiletine (more than 10(-5) M) significantly augmented relaxations to cromakalim or pinacidil. Glibenclamide (5 x 10(-6) M) abolished relaxations to cromakalim or pinacidil in arteries treated with mexiletine (10(-4) M). CONCLUSIONS: These results suggest that lidocaine impairs but mexiletine augments vasodilation mediated by ATP-sensitive K+ channels in smooth muscle cells.     

The effect of beta-subunit assembly on function and localization of the colonic H+,K+-ATPase alpha-subunit

BACKGROUND: Previous experiments from our laboratory have demonstrated that HKalpha(2) coimmunoprecipitated with beta(1)-Na(+),K(+)-ATPase. Although HKalpha(2) is expressed abundantly in the apical membrane of distal colon, the demonstration that beta(1) localizes to this same membrane in distal colon has not been demonstrated previously. METHODS: Immunolocalization was performed in distal colon using a polyclonal antibody against HKalpha(2) and a monoclonal antibody against beta(1). RESULTS: The results demonstrate that HKalpha(2) localizes to the apical membrane. Two pools of beta(1)-Na(+),K(+)-ATPase were detected. The first localized to the apical membrane. The second pool was detected in the basolateral membrane when distal colon sections were deglycosylated with glycosidase F. Therefore, our results demonstrate that beta(1) localizes to the apical membrane with HKalpha(2), and supports the view that beta(1) is the physiologic beta-subunit for HKalpha(2). We tested, therefore, the efficiency of the two beta-subunits expressed in distal colon (beta(1) and beta(3)) to support the activity of HKalpha(2). Human embryonic kidney HEK-293 cells were transiently cotransfected with HKalpha(2) plus beta(1) or HKalpha(2) plus beta(3). Subsequently, (86)Rb(+)-uptake and plasma membrane localization were evaluated. The results demonstrate that both HKalpha(2)/beta(1) and HKalpha(2)/beta(3) support (86)Rb(+)-uptake. However, (86)Rb(+)-uptake measured in the cells cotransfected with HKalpha(2) plus beta(1) exceeded that measured in cells expressing HKalpha(2)/beta(3). Fluorescence microscopy using enhanced green fluorescent protein cloned at the amino-terminus of HKalpha(2) demonstrated protein migration to the plasma membrane in cells cotransfected with EGFP-HKalpha(2) plus beta(1). In contrast, in cells cotransfected with EGFP-HKalpha(2) plus beta(3), the vast majority of the protein remained confined to intracellular compartments. The significantly higher (86)Rb(+)-uptake corresponded to additional localization of HKalpha(2) to the plasma membrane when coexpressed with beta(1) compared to beta(3). CONCLUSION: Taken together, these and previous results from our laboratory indicate that beta(1)-Na(+),K(+)-ATPase is likely to represent the most physiologic and efficient subunit for HKalpha(2) assembly in distal colon.     

Factors predictive of mortality in pediatric extremity rhabdomyosarcoma

In order to examine factors predictive of fatal outcome in children presenting with histologically confirmed extremity rhabdomyosarcoma, we performed a retrospective analysis of our institutional experience from 1970 to 1985. Thirty-five patients were identified and staged according to international criteria (TNM). Variables evaluated for their predictive effect on fatal outcome included (1) tumor invasiveness, (2) tumor size, (3) anatomic location of the primary, (4) regional lymph node involvement, (5) distant metastases at presentation, (6) complete surgical resection, (7) use of amputation, and (8) alveolar histologic subtype. Significant predictors of mortality included (1) tumor invasiveness (P less than or equal to .0001), (2) regional node involvement (P less than or equal to .0002), (3) distant metastases at the time of presentation (P less than or equal to .001), (4) alveolar histology (P less than or equal to .001), (5) size of primary (P less than or equal to .007), and (6) completeness of surgical resection (P less than or equal to .05). In multivariate analysis, local tumor invasiveness was the most important predictor of fatal outcome with an associated relative risk of 18. We conclude that local tumor invasiveness is the most important determinant of clinical stage.     

Ophthalmic artery blood flow velocity increases during hypocapnia

PURPOSE: The effects of anesthetic management on blood flow to the optic nerve have not been well-studied. The ophthalmic artery provides the majority of the blood supply to the optic nerve via several smaller branches. Retinal blood flow has been shown to react to carbon dioxide (CO(2)) similar to intracranial vessels, but insufficient data exist for the ophthalmic artery. The purpose of this study is to examine the CO(2)-reactivity of the ophthalmic artery. METHODS: Eight healthy awake subjects aged 28 to 50 yr were tested for CO(2)-reactivity in the ophthalmic artery using transcranial Doppler (TCD) insonation of blood flow velocity (V(op)), while simultaneously recording the V(op) of the middle cerebral artery (V(mca)) as an internal control. V(op) and V(mca) recordings were made under hypocapnic, normocapnic and hypercapnic conditions. RESULTS: The CO(2)-reactivity slope of V(mca) was 3.27% per mmHg PaCO(2). From normocapnia to hypercapnia, V(op) did not change significantly (mean +/- SD, 18 +/- 4 cm*sec(-1) to 18 +/- 6 cm*sec(-1)), (end-tidal CO(2), etCO(2), = 43 +/- 5 mmHg to 53 +/- 4 mmHg, respectively). In contrast, V(op) increased significantly under hypocapnic conditions (etCO(2) = 26 +/- 4 mmHg) to 25 +/- 5 cm*sec(-1) (P < 0.05). The CO(2)-reactivity slope of V(op) from normocapnia to hypocapnia was 2.57% per mmHg. CONCLUSIONS: This study demonstrates that V(op) increases with hypocapnia, but is unaffected by hypercapnia. The anastomoses of the ophthalmic artery with the external carotid artery, which displays a relatively fixed resistance, may account for these findings.     

Interaction of arousal states and low dose halothane on the acute hypercapnic ventilatory response in humans

The purpose of this study was to examine the effect of low dose halothane on the acute ventilatory response to hypercapnia, and to assess whether arousal (due to audiovisual (AV) stimulation or pain) modulates the response to halothane. Single step increases in end-tidal Pco(2) using dynamic end-tidal forcing were performed from eucapnia (end-tidal Pco(2) held 1 mmHg (0.13 kPa) above ambient) to hypercapnia (end-tidal Pco(2) 6 mmHg (0.79 kPa) above ambient) in eight healthy volunteers, with end-tidal PO(2) held at 100 mmHg (13.2 kPa), in six protocols: 1) control conditions (darkened, quiet room, eyes closed) without halothane; 2) control conditions with 0.1 MAC halothane; 3) AV stimulation (bright room, loud television) without halothane; 4) AV stimulation with 0.1 MAC halothane; 5) pain (electrical stimulation of skin over tibia to produce visual analogue pain score 5-6/10) without halothane; 6) pain with 0.1 MAC halothane. Both AV stimulation (p = 0.014) and pain (p = 0.0003) significantly increased the baseline eucapnic minute ventilation modestly (by approximately 1.5-4 l.min(-1)). Halothane did not influence the baseline minute ventilation in any arousal state (p = 0.572), nor did it affect the hypercapnic ventilatory response in any arousal state (p = 0.208). Arousal (either AV stimulation or pain) did not affect the ventilatory response to CO(2), regardless of the presence or absence of halothane (p = 0.585). We conclude that halothane affects neither baseline minute ventilation nor the response to CO(2). Arousal can increase baseline ventilation but has no influence on the ventilatory response to CO(2).     

Pharmacokinetics of doxercalciferol, a new vitamin D analogue that lowers parathyroid hormone.

BACKGROUND: This is the first detailed pharmacokinetic report published on the administration of doxercalciferol [1alpha(OH)D(2)] recently introduced to treat secondary hyperparathyroidism. METHODS: 1alpha(OH)D(2) was administered in a range of single and multiple doses to volunteers with and without normal renal and/or hepatic function. Subsequent serial blood samples were assayed by HPLC/radioimmunoassay for the metabolite 1,25-dihydroxyvitamin D(2) [1,25(OH)(2)D(2)], the major active species. RESULTS: Bioavailability of 1,25(OH)(2)D(2) from a single 5 micro g 1alpha(OH)D(2) oral-capsule dose was estimated to be normally approximately 42% of that from a 5 micro g intravenous injection. Steady-state serum concentrations of 1,25(OH)(2)D(2) were attainable within 8 day, and fluctuated approximately 2.5-fold from peak to trough when oral 1alpha(OH)D(2) doses were taken every second day, and the terminal half-life was 34+/-14 h. Mean steady-state serum concentrations rose less than proportionally (from 20 to 45 pg/ml) on increasing oral 1alpha(OH)D(2) doses from 5 to 15 micro g every 48 h. Renal patients showed 39+/-37% increase in serum 1,25(OH)(2)D(2) concentration during 3-4 h haemodialysis sessions, but no other difference in steady-state pharmacokinetics was found between these or hepatically impaired patients and normal subjects. CONCLUSIONS: Given the sensitivity limits of current assays, the pharmacokinetics of this and other vitamin-D compounds is best elucidated from steady-state studies. The pharmacokinetics of 1,25(OH)(2)D(2) from 1alpha(OH)D(2) doses appears to be similar to that of 1,25(OH)(2)D(3) from 1alpha(OH)D(3) doses, albeit D(3) data have to date largely derived from single-dose studies. Deviation of 1,25(OH)(2)D(2) pharmacokinetics from linearity appears to be marginal enough to be clinically manageable with adequate precaution.     

Isoflurane does not further impair microvascular vasomotion in a rat model of subarachnoid hemorrhage

PURPOSE: Since isoflurane is known to attenuate endothelium-dependent dilation (EDD) in normal cerebral arterioles, we examined whether the anesthetic has a similar effect and further impairs EDD in vessels exposed to SAH. METHODS: Autologous blood was introduced in the subarachnoid space and the parietal lobe harvested. Control animals were sacrificed without introduction of blood. The response of microvessles to the endothelium-dependent dilator adenosine diphosphate (ADP) 10(-9)-10(-4) M, the endothelium-independent dilator nitroprusside 10(-9)-10(-4) M, and ET-1 10(-13)-10(-8) M was measured by videomicroscopy in the presence of 0-2 minimum alveolar concentration (MAC) of isoflurane. RESULTS: Isoflurane attenuated EDD to ADP in control vessels [66 +/- 5% (control) vs 27 +/- 11% (2 MAC) dilation to ADP 10(-4) M, P < 0.05]. Although SAH was associated with reduced dilation to ADP, exposure to isoflurane did not further impair dilation to ADP after SAH [26 +/- 3% (SAH) vs 21 +/- 5% (SAH/2 MAC) dilation to ADP 10(-4) M, P = NS]. Dilation to nitroprusside was not affected by isoflurane or SAH. Constriction to ET-1 was reduced by 2 MAC of isoflurane [21 +/- 1% (control) vs 13 +/- 5% (2 MAC) constriction to ET-1 10(-8) M, P < 0.05], but not by 1 MAC of isoflurane in control vessels. Constriction to ET-1 was greatly attenuated by 1 or 2 MAC of isoflurane after SAH [32 +/- 5% (SAH) vs 18 +/- 4% (SAH/2 MAC) constriction to ET-1 10(-8) M, P < 0.05]. CONCLUSION: In rats, isoflurane does not further impair EDD after SAH and modulates the constrictive response to ET-1. Such an effect of isoflurane would not predispose the SAH-exposed vessels to vasospasm.     

Nitrous oxide fraction in the carbon dioxide pneumoperitoneum during laparoscopy under general inhaled anesthesia in pigs

During prolonged laparoscopy, the diffusion of other gases in the carbon dioxide (CO(2)) pneumoperitoneum may lessen its safety. Nitrous oxide (N(2)O)/CO(2) gas mixtures may become hazardous with regard to gas embolization and fire risk. We therefore evaluated the kinetics of pneumoperitoneal intrusion of N(2)O. In five anesthetized domestic pigs, controlled ventilation, with an initial fraction of inspired oxygen = 1.0, was adjusted to keep ETCO(2) pressure between 35 and 45 mm Hg. The peritoneum was insufflated with CO(2) to a pressure of 12 mm Hg, which was maintained throughout the procedure. T0 was defined as the time when N(2)O was introduced in the breathing circuit (N(2)O end-tidal fraction = 66%). Gas samples (10 mL) from the pneumoperitoneum were analyzed every 10 min after T0. The N(2)O concentration was measured by using capillary gas chromatography coupled with mass spectrometry. Percentages of N(2)O in the CO(2) increased with time (t) according to the ideal equation: N(2)O((t)) = 66 (1 - exp(-0.005t)). In the peritoneal cavity, <2 h were required for the N(2)O to reach the concentration of 29%, which can support combustion. Eight hours to 10 h after T0, the intraperitoneal N(2)O fraction approaches the level of the N(2)O end-tidal fraction. Options to prevent accumulation of N(2)O are suggested. IMPLICATIONS: Pig models were used to evaluate the time course of nitrous oxide (N(2)O) diffusion in the pneumoperitoneum during nitrous oxide/oxygen anesthesia. Although peritoneal N(2)O concentration approaches the end-expiratory value after 8-10 h, it reaches 29% within 2 h. At this level, N(2)O is known to support combustion. This N(2)O pollution should be prevented.     

The in vitro reversal of histamine-induced vasodilation in the human internal mammary artery.

Anaphylactic shock therapy includes the use of catecholamines but they may not always be effective. Because vasodilation during anaphylaxis is a result of the endothelial release of multiple mediators, we investigated the effects of epinephrine, vasopressin, and inhibitors of nitric oxide and prostanoid pathways on histamine-induced relaxation in human internal mammary artery. The vessel segments were obtained intraoperatively and were suspended in organ chambers to record isometric tension. Norepinephrine (10(-6) M) was used to precontract the rings followed by histamine (10(-6.5) M) to relax the vessels and mimic vascular collapse. Epinephrine, vasopressin, methylene blue, N(G)-monomethyl-L-arginine (L-NMA) and indomethacin were added in a cumulative fashion to reverse the histamine-induced vasodilation. The internal mammary artery segments exhibited greater contraction in the presence of the epinephrine (4.9 +/- 0.7 g) compared with vasopressin (2.6 +/- 0.7 g). Vasopressin (10(-11) to 10(-7) M), methylene blue (10(-7) to 10(-5) M), L-NMA (10(-6) to 10(-4) M), and indomethacin (10(-7) to 10(-5) M) were only partially effective. These findings suggest that vasopressin and methylene blue may offer a potential therapeutic option in the treatment of histamine-induced vasodilatory shock. IMPLICATIONS: Epinephrine only partially reverses histamine-induced vasodilation in human internal mammary arteries, whereas vasopressin, methylene blue, and drugs involved in the inhibition of nitric oxide and prostaglandin generation lead to a complete reversal of the vascular relaxation.     

Investigation of serotonin receptors in the isolated penile bulb of rats

The aim of this study was to investigate serotonin (5-HT) receptors in the penile bulb, which have been suggested to play a role in penile erection. Serotonin (10(-7)-3 x 10(-4) M) contracted penile bulbs in a concentration-dependent manner. Ketanserin (5-HT(2A) antagonist, 10(-9)-10(-7) M) and prazosin (alpha(1)-adrenergic receptor blocker, 10(-9)-10(-7) M) suppressed the lower and upper parts of concentration-response curves to 5-HT, respectively. Guanethidine (adrenergic neuron blocker, 5 x 10(-5) M) reduced the responses to 5-HT at only 10(-4) and 3 x 10(-4) M concentrations. NAN-190 (5-HT(1A) antagonist, 10(-8), 10(-7) M) shifted the concentration-response curve to the right with a reduction in the maximum response to 5-HT. While ondansetron (5-HT(3) antagonist, 10(-6)-10(-5) M) and GR55562 (5-HT(1B/1D) antagonist, 10(-6)-10(-5) M) had no effect on the concentration-response curve to 5-HT. The 5-HT(1A) agonist 8-OH-DPAT (10(-7)-3 x 10(-4) M) contracted penile bulbs in a concentration-dependent manner with a lower pD(2) value than that of 5-HT. Sumatriptan (5-HT(1B/1D) agonist, 10(-8)-10(-4) M) did not produce any contractile response in the penile bulbs. Prucalopride, a selective 5-HT(4) agonist (R093877, 10(-7)-3 x 10(-4) M) produced concentration-dependent relaxation in penile bulbs contracted by phenylephrine (10(-5) M). 5-HT(4) agonists cisapride (10(-7)-10(-4) M) and metoclopramide (10(-7)-3 x 10(-4) M) also relaxed the tissue, concentration-dependently. Selective 5-HT(4) antagonists GR125487 (10(-6)-10(-5) M) and GR113808 (10(-6)-10(-5) M) slightly, but not significantly, decreased prucalopride- and cisapride-induced relaxation. Propranolol (beta-adrenergic receptor blocker, 10(-6)-10(-5) M) and L-NOARG (nitric oxide synthase inhibitor, 10(-4) M) had no effect on prucalopride-induced relaxation. These results suggest the existence of alpha(1)-adrenergic, 5-HT(1A) and 5-HT(2A) serotonergic receptors in the penile bulb of rats, which are responsible for 5-HT-induced contraction. Additionally, a serotonergic receptor resembling a 5-HT(4)-type plays a role in the relaxation. The latter receptor is activated by 5-HT(4) agonists, but is not antagonized by 5-HT(4) antagonists.     

Is ultrasound more accurate than axial computed tomography for determination of maximal abdominal aortic aneurysm diameter?

OBJECTIVE(S): Clinical assessment of maximal abdominal aortic aneurysm (AAA) diameter assumes clinical equivalency between ultrasound (US) and axial computed tomography (CT). Three-dimensional (3D) CT reconstruction allows for the assessment of AAA in the orthogonal plane and avoids oblique cuts due to AAA angulation. This study was undertaken to compare maximal AAA diameter by US, axial CT, and orthogonal CT, and to assess the effect that AAA angulation has on each measurement. METHODS: Maximal AAA diameter by US (US(max)), axial CT (axial(max)), and orthogonal CT (orthogonal(max)) along with aortic angulation and minor axis diameters were measured prospectively. Spiral CT data was processed by Medical Media Systems (West Lebanon, NH) to produce computerized axial CT and reformatted orthogonal CT images. The US technologists were blinded to all CT results and vice versa. RESULTS: Thirty-eight patients were analyzed. Mean axial(max) (58.0 mm) was significantly larger (P<0.05) than US(max) (53.9 mm) or orthogonal(max) (54.7 mm). The difference between US(max) and orthogonal(max) (0.8 mm) was insignificant (P>0.05). When aortic angulation was <==25 degrees, axial(max) (55.3 mm), US(max) (54.3 mm), and orthogonal(max) (54.1 mm) were similar (P>0.05); however, when aortic angulation was >25 degrees, axial(max) (60.1 mm) was significantly larger (P<0.001) than US(max) (53.8 mm) and orthogonal(max) (55.0 mm). The limits of agreement (LOA) between axial(max) and both US(max) and orthogonal(max) was poor and exceeded clinical acceptability (+/-5 mm). The variation between US(max) and orthogonal(max) was minimal with an acceptable LOA of -2.7 to 4.5 mm. CONCLUSION: Compared to axial CT, US is a better approximation of true perpendicular AAA diameter as determined by orthogonal CT. When aortic angulation is greater than 25 degrees axial CT becomes unreliable. However, US measurements are not affected by angulation and agree strongly with orthogonal CT measurements.     

Current Status of Palliative and Terminal Care for Patients with Primary Malignant Brain Tumors in Japan

Palliative care and advance care planning (ACP) from the first diagnosis of glioblastoma are important. This questionnaire survey was conducted to understand the current status of palliative care for brain tumors in Japan. Representative characteristics of Japan in comparison with Western countries (P <0.01) are described below: (1) Gender ratio of male in physicians who treat brain tumors in Europe and the United States/Canada are about 70%, but 94% in Japan. (2) The specialty is predominantly neurosurgeon (93%) in Japan. The ratio of neurologists is predominantly 40% in Europe. In the United States/Canada, neurologist (27%) and neurosurgeon (29%) are main parts. (3) Years of medical experience over 15 in physicians is 73% in Japan. Proportions of those with over 15 years are 45% in Europe and 30% in the United States/Canada. (4) In practicing setting, the rate of academic medical centers is about 80% in Europe and the United States/Canada, and ~60% in Japan. Representative differences compared with past domestic data (2007) (P <0.01): (1) In glioblastoma, the rate of explaining about median survival time increases from 39% (2007) to 80% (2018). Explanation about medical conditions to the patient himself with his family increases from 20% (2007) to 39% (2018). (2) Place of death: The rate at hospital is decreasing from 96% (2007) to 79% (2018) and at home is increasing from 3% (2007) to 10% (2018) (3) The rate of ventilator in adult has decreased from 74% (2007) to 54% (2018), but nasal tube feeding has remained unchanged from 62% (2007) to 60% (2018). These results will be shared with physicians to make better care systems for patients with brain tumors.     

Nutrition in children with CRF and on dialysis

The objectives of this study are: (1) to understand the importance of nutrition in normal growth; (2) to review the methods of assessing nutritional status; (3) to review the dietary requirements of normal children throughout childhood, including protein, energy, vitamins and minerals; (4) to review recommendations for the nutritional requirements of children with chronic renal failure (CRF) and on dialysis; (5) to review reports of spontaneous nutritional intake in children with CRF and on dialysis; (6) to review the epidemiology of nutritional disturbances in renal disease, including height, weight and body composition; (7) to review the pathological mechanisms underlying poor appetite, abnormal metabolic rate and endocrine disturbances in renal disease; (8) to review the evidence for the benefit of dietetic input, dietary supplementation, nasogastric and gastrostomy feeds and intradialytic nutrition; (9) to review the effect of dialysis adequacy on nutrition; (10) to review the effect of nutrition on outcome. An erratum to this article can be found at     

Evaluation of a progressive treatment program for erectile dysfunction in patients with diabetes mellitus

The aim was to evaluate the effectiveness of a progressive program, starting with simple methods and, when not effective, moving to more complex methods, to treat erectile dysfunction (ED) in patients with diabetes mellitus. A total of 284 diabetic patients with ED entered into a 6-phase program starting with sildenafil citrate (Viagra). Those with contraindications, side effects, or negative response (erection insufficient for vaginal penetration) were switched to the vacuum erection device (VED), and then progressively (for failures) to intracavernous injection (ICI), sildenafil citrate+ICI, ICI+VED, and penile prosthesis. Patients were followed for 2 y. Of the 284 patients 276 patients were eligible for sildenafil citrate and 147 (53.3%) responded positively, but 25 (9.1%) patients stopped it soon due to adverse effects. Of 162 patients (129 nonresponders, eight noneligible for the sildenafil and 25 patients who dropped out due to adverse effects), treated with VED, 114 (70.4%) responded well, however, only 19 (11.7%) patients agreed to continue its use. Of the remaining 143 patients (nonresponders, noneligible for the previously mentioned treatments and patients who dropped out due to adverse effects), 103/143 (72%) responded to ICI, 27/40 (67.5%) to sildenafil+ICI, and 9/13 (69.2%) to ICI+VED. Four patients received a penile implant. At the 2 y follow-up, 81 of 284 patients who entered the study (28.5%) were still responding to sildenafil, seven (2.5%) to VED, 113 (39.8%) to ICI, 24 (8.5%) to sildenafil+ICI, two (0.7%) to ICI+VED; 15 (5.3%) had a penile implant. In all 17 (6%) patients reported spontaneous erections, 11 (3.9%) stopped the treatment due to family reasons and 14 (4.9%) failed the treatment. In conclusion, the progressive treatment program for ED seems to be very effective for diabetic patients, yielded a complete response for short-term and 91.2% rate of success at the end of 2 y follow-up.     

MANAGEMENT DEFICIENCIES AND DEATH PREVENTABILITY IN 120 VICTORIAN ROAD FATALITIES (1993–1994)

Background : In 1992 a multidisciplinary committee was established to identify problems in the management of road fatalities in Victoria, Australia, to assess their contribution to death, and to identify preventable deaths (preventable: survival probability more than 75%; potentially preventable: survival probability between 25 and 75%). Methods : For 1993–94, 120 consecutive fatality cases surviving until arrival of ambulance services were evaluated by analysis and discussion of their complete pre-hospital, hospital and autopsy records. Results : A total of 1175 problems were identified in 455 admissions to the various areas of care. A total of 949 problems (81%) were found to be management errors and 123 (11%) were found to be system inadequacies. Technique errors (35 (3%)), diagnosis delays (27 (2%)) and diagnosis errors (41 (4%)) were less frequent. The emergency department (ED) accounted for 662 (56%) problems, followed by 191 (16%) pre-hospital problems and 140 (12%) intensive care unit (ICU) problems. There were 598 (51%) problems that were assessed as contributing to death. A total of 308 (52%) problems occurred in the ED, 106 (18%) were pre-hospital problems and 71 (12%) occurred in ICU. Management errors comprised 465 (78%) problems contributing to death, and system inadequacies comprised 76 (13%) problems. Resuscitation problems accounted for 101 (40%) of the 254 ED management errors contributing to death. A total of 79 (66%) deaths were assessed as non-preventable, five (4%) were assessed as preventable and 36 (30%) were assessed as potentially preventable. Conclusions : Organizational and educational countermeasures are required to reduce the high frequency of problems in emergency services and clinical management.     

Contrasting effects of allergen challenge on airway responsiveness to cysteinyl leukotriene D(4) and methacholine in mild asthma

BACKGROUND: Cysteinyl leukotrienes (cysteinyl-LTs) have been implicated in the pathogenesis of allergen induced airway responses. Airway responsiveness (AR) to inhaled cysteinyl-LTs is dramatically increased following allergen challenge in animal studies. The effect in man has not been evaluated. METHODS: Ten mild steroid-na?ve asthmatic subjects with an isolated early asthmatic response (EAR) and 21 with an additional late asthmatic response (LAR) took part in a randomised controlled crossover study to assess AR to inhaled methacholine (MCh) and cysteinyl-LT D(4) (LTD(4)) 22 and 24 hours, respectively, after allergen challenge. Eight subjects had two further LTD(4) challenges separated by a 2 week washout period to assess the reproducibility of inhaled LTD(4) challenge. RESULTS: In subjects with an isolated EAR, non-significant mean (SE) increases in AR of 0.4 (0.4) doubling doses (DD) for MCh and 0.4 (0.5) DD for LTD(4) followed allergen challenge compared with control. A significant correlation between AR to MCh and LTD(4) followed both control (r=0.91, 95% CI 0.67 to 0.98; p=0.0002) and allergen challenge (r=0.79, 95% CI 0.32 to 0.95; p=0.0063). In subjects with an additional LAR there was a significant increase in AR to MCh (1.2 (0.3) DD, p=0.0005) following allergen challenge but no overall effect on AR to LTD(4) (0.69 (0.4) DD, p=0.11). A significant correlation between AR to MCh and LTD(4) was again observed (r=0.70; 95% CI 0.38 to 0.87; p=0.0004) following control, although it was reduced following allergen challenge (r=0.48; 95% CI 0.063 to 0.76; p=0.027). LTD(4) challenge was highly reproducible with a mean difference of 0.2 (0.3) DD between challenges. CONCLUSIONS: Allergen challenge significantly increases AR to inhaled MCh but not to LTD(4) in subjects with LAR. The lack of a comparable increase in AR to LTD(4) is surprising. Endogenous cysteinyl-LTs are produced in abundance following allergen challenge and may enhance AR to MCh or induce a degree of tachyphylaxis to LTD(4).     

Ketamine and Sympathetic Mechanisms in Cardiac and Smooth Muscle

The effects of ketamine on the response of rat isolated cardiac and smooth muscle to electrical stimulation of intramural sympathetic nerves and to exogenous norepinephrine are reported. Low concentrations of ketamine (1 x 10(-5) to 5 x 10(-5) mol l-1) significantly potentiated, whilst high concentrations (2 x 10(-4) and 4 x 10(-4) mol l-1) significantly depressed the positive inotropic response of left atria to sympathetic nerve stimulation. Ketamine 5 x 10(-5) mol l-1 caused a leftward shift of the concentration-response curves of left atria to norepinephrine (threefold increase in potency) and isoproterenol (twofold increase in potency). Spontaneously beating right atria were slowed in a concentration-dependent manner by ketamine (5 x 10(-5) to 4 x 10(-4) mol l-1). Ketamine 1 x 10(-4) mol l-1 potentiated the positive chronotropic response of right atria to low frequency (2 and 5 Hz) sympathetic nerve stimulation, whilst ketamine 4 x 10(-4) mol l-1 depressed the response to all stimulation frequencies. Ketamine 3 x 10(-5) mol l-1 significantly potentiated the amplitude of the response of both hepatic portal vein and vas deferens to field stimulation of sympathetic nerves, and to exogenous norepinephrine. In the presence of reuptake blockade of norepinephrine by pancuronium 1 x 10(-4) mol l-1, ketamine caused no further potentiation of the response of the vas to nerve stimulation.     

Bacterial adherence in a rat bladder augmentation model: ileocystoplasty versus colocystoplasty

PURPOSE: Various intestinal segments are used to reconstruct the urinary tract. For unclear reasons asymptomatic chronic bacteriuria is common in patients treated with reconstruction. We compared bacterial adherence in ileum, colon and bladder in rats with ileal and colonic bladder augmentation. MATERIALS AND METHODS: Bladder augmentation using ileum or colon was performed in 8-week-old rats. After 3 months urinary pH was measured and urine was cultured. Urovirulence factors of Escherichia coli aspirated from the augmented bladders were detected by polymerase chain reaction. In rats with negative urine culture after augmentation experimental cystitis was induced by the transurethral inoculation of E. coli C5, with type I pili and aerobactin or E. coli C92 with type I pili, P fimbriae and aerobactin at a concentration of 10(5) colony forming units per 0.3 ml. After 14 days we counted the colony forming units per cm.(2) of bladder and cm.(2) of intestinal augmentation tissue. RESULTS: When cultures were negative, mean urinary pH plus or minus standard deviation for ileocystoplasty (7.35 +/- 0.33) was significantly higher than that for colocystoplasty (6.80 +/- 0.45) or in controls (6.67 +/- 0.30). Bacterial colonization occurred in 60 of 96 ileocystoplasties (62.5%) and 36 of 68 colocystoplasties (52.9%). All 32 E. coli strains aspirated from ileocystoplasties had type I pili. In colocystoplasties 14 strains had type I pili, 4 had P fimbriae and type I pili, and 1 had no virulence factor. In experimental cystitis in the ileal patch and bladder there were 10(3.2) to 10(6.2) (log mean 4.9) and 10(1.1) to 10(5.1) (log mean 3.5) colony forming units of E. coli C5, respectively. In the colonic patch and bladder there were 10(2.2) to 10(6.2) (log mean 3.9) and 10(2.1) to 10(5.1) (log mean 3.7) colony forming units of E. coli C5, respectively. In the ileal patch and bladder versus the colonic patch and bladder there were 10(3.2) to 10(6.2) (log mean 5.0) and 10(3.1) to 10(6.1) (log mean 4.5) versus 10(3.2) to 10(6.2) (log mean 4.3) and 10(2.1) to 10(6.1) (log mean 3.8) colony forming units of E. coli C92, respectively. E. coli C5 adhered to more ileum than bladder, while bacterial adherence did not differ for colon and bladder. Adherence of E. coli C92 did not differ significantly in bladder and implanted ileum or colon. CONCLUSIONS: The colonic segment offers more resistance to E. coli than the ileal segment in urinary diversion.     

Prolonged exposure of canine coronary arteries to a nitric oxide donor desensitizes soluble guanylate cyclase

BACKGROUND: This study investigated the role of soluble guanylate cyclase desensitization in the development of tolerance to organic nitrates. MATERIALS AND METHODS: In organ baths, canine coronary arteries were exposed to either sodium nitroprusside (SNP) (experimental group) or papaverine (control group) at various concentrations (10(-9), 10(-7), or 10(-5) M) for 3 h. Arteries were then compared for response to vascular agonists and for inducible cyclic guanine monophosphate (cGMP) formation. RESULTS: KCl (5 to 50 mM) and prostaglandin F(2alpha) (10(-9) to 10(-5) M) induced similar vascular contractions (n = 7, P > 0.05). Vascular relaxation in response to calcium ionophore A23187 (10(-9) to 10(-6) M) and to authentic nitric oxide (NO) (3 x 10(-9) to 10(-5) M) was attenuated in arteries exposed to SNP at 10(-7) and 10(-5) M concentrations but not at a 10(-9) M concentration (n = 7 each, P < 0.05 versus the respective papaverine group). Pretreatment of arteries with methylene blue (10(-5) M) abolished the responses to authentic NO (n = 4). In cGMP determinations, control arteries demonstrated an increase in cGMP from 364 +/- 89 to 778 +/- 175 pg/mg of protein with A23187 (3 x 10(-5) M) stimulation (n = 5). Conversely, arteries exposed to SNP (10(-5) M) demonstrated similar levels of cGMP before (562 +/- 126 pg/mg of protein) and after (641 +/- 98 pg/mg of protein) A23187 stimulation. CONCLUSIONS: Prolonged exposure of coronary arteries to SNP did not alter vascular smooth muscle function, but it markedly attenuated the relaxation in response to both A23187 and authentic NO at concentrations above 10(-9) M in a concentration-dependent fashion. The constant levels of cGMP in response to an NO donor suggest that the attenuation of relaxation is due to desensitization of soluble guanylate cyclase. Thus, this study supports the role of soluble guanylate cyclase desensitization in the development of tolerance to organic nitrates.