Transient Receptor Potential Channel Opening Releases Endogenous Acetylcholine, which Contributes to Endothelium-Dependent Relaxation Induced by Mild Hypothermia in Spontaneously Hypertensive Rat but Not Wistar-Kyoto Rat Arteries.

Mild hypothermia causes endothelium-dependent relaxations, which are reduced by the muscarinic receptor antagonist atropine. The present study investigated whether endothelial endogenous acetylcholine contributes to these relaxations. Aortic rings of spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats were contracted with prostaglandin F2 α and exposed to progressive mild hypothermia (from 37 to 31°C). Hypothermia induced endothelium-dependent, Nω-nitro-l-arginine methyl ester-sensitive relaxations, which were reduced by atropine, but not by mecamylamine, in SHR but not in WKY rat aortae. The responses in SHR aortae were also reduced by acetylcholinesterase (the enzyme responsible for acetylcholine degradation), bromoacetylcholine (inhibitor of acetylcholine synthesis), hemicholinium-3 (inhibitor of choline uptake), and vesamicol (inhibitor of acetylcholine release). The mild hypothermia-induced relaxations in both SHR and WKY rat aortae were inhibited by AMTB [N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide; the transient receptor potential (TRP) M8 inhibitor]; only those in SHR aortae were inhibited by HC-067047 [2-methyl-1-[3-(4-morpholinyl)propyl]-5-phenyl-N-[3-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide; TRPV4 antagonist] while those in WKY rat aortae were reduced by HC-030031 [2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; TRPA1 antagonist]. The endothelial uptake of extracellular choline and release of cyclic guanosine monophosphate was enhanced by mild hypothermia and inhibited by HC-067047 in SHR but not in WKY rat aortae. Compared with WKY rats, the SHR preparations expressed similar levels of acetylcholinesterase and choline acetyltransferase, but a lesser amount of vesicular acetylcholine transporter, located mainly in the endothelium. Thus, mild hypothermia causes nitric oxide-dependent relaxations by opening TRPA1 channels in WKY rat aortae. By contrast, in SHR aortae, TRPV4 channels are opened, resulting in endothelial production of acetylcholine, which, in an autocrine manner, activates muscarinic receptors on neighboring cells to elicit endothelium-dependent relaxations in response to mild hypothermia.

Low-dose desmopressin improves hypothermia-induced impairment of primary haemostasis in healthy volunteers.

Mild hypothermia (34-35 °C) increases peri-operative blood loss. We have previously demonstrated the beneficial effect of in vitro desmopressin on impairment of primary haemostasis associated with hypothermia. This study evaluated subcutaneous desmopressin in 52 healthy volunteers, randomly assigned to receive either normal saline or desmopressin 1.5, 5 or 15 µg (with 13 in each group). Blood samples were collected before and 2 h after drug administration and incubated at 32 and 37 °C. Platelet function analyser PFA-100(®) closure times were measured. Hypothermia at 32 °C prolonged mean (95% CI) closure times (for adenosine diphosphate/collagen by 11.3% (7.5-15.2%) and for adrenaline/collagen by 16.2% (11.3-21.2%); these changes were reversed by desmopressin. A very small dose was found to be effective (1.5 µg); this dose did not significantly change closure times at 37 °C, but fully prevented its prolongation at 32 °C. Subcutaneous desmopressin prevents the development of hypothermia-induced impairment of primary haemostasis.

Effects of the aqueous extract of Salvia Miltiorrhiza (danshen) and its magnesium tanshinoate B-enriched form on blood pressure.

Danshen is the dried root and rhizome of the Chinese medicinal plant Salvia miltiorrhiza Bunge (Labiatae), which has been used to treat hypertension and myocardial infarction. One of its water-soluble active components is magnesium tanshinoate B (MTB). The present study examined and compared the cardiovascular effects of the water-soluble extract of danshen (SME) and its MTB-enriched form (containing 70% of MTB (MTB70)). Anaesthetized rats were infused intravenously with saline or phenylephrine to achieve a normal or elevated blood pressure, respectively. Different doses of SME, MTB70 or vehicle were then injected intravenously and their effect on blood pressure was monitored. The results indicate that SME and MTB70 reduce blood pressure dose-dependently. Independently of the initial blood pressure, SME caused a smaller reduction in blood pressure than MTB70. In rats infused with phenylephrine, MTB70 caused greater decreases in blood pressure than in rats infused with saline, while the responses to SME did not differ between the two groups. From these findings, it appears that MTB is one of the major components responsible for the cardiovascular effects of danshen, and that the beneficial cardiovascular effect of the extract is more prominent under conditions of elevated blood pressure.

Is metformin still the most efficacious first-line oral hypoglycaemic drug in treating type 2 diabetes? A network meta-analysis of randomized controlled trials.

OBJECTIVES: The objective of the study is to compare the efficacy of hypoglycaemic drugs for type 2 diabetes mellitus (T2DM) by network meta-analysis of randomized controlled trials (RCTs). METHODS: We compared 11 major oral hypoglycaemic drugs under five categories evaluated by RCTs as drug monotherapy for the patients with T2DM, measuring glycosylated haemoglobin (%) or fasting plasma glucose (mmol L-1 ) as outcomes. RCT quality was assessed with the Cochrane risk of bias tool. Network meta-analysis estimated the mean differences and 95% credible intervals. Subgroup and sensitivity analyses were performed to determine the results robustness. The Grading of Recommendation, Assessment, Development, and Evaluation evidence strength was assessed. RESULTS: Seventy-five RCTs including 33,830 patients were identified. Their study quality was high. Regarding glycosylated haemoglobin, top three anti-diabetics were repaglinide (mean differences -1.39 [95% credible intervals -1.75 to -1.03]), gliclazide (-1.37 [-2.04 to -0.71]) and metformin (-1.13 [-1.37 to -0.90]), against placebo. Regarding fasting plasma glucose, top three anti-diabetics were repaglinide (-2.01 [-2.75 to -0.97]), metformin (-1.72 [-2.16 to -1.27]) and glipizide (-1.57 [-2.44 to -0.64]), against placebo. There was no difference between metformin and repaglinide. Subgroup and sensitivity analyses found the results to be robust. The evidence strength was moderate to high. CONCLUSION: This meta-analysis showed that repaglinide and metformin would be the most efficacious oral drugs for first-line monotherapy of T2DM.

Structure-activity relationships of flavonoids for vascular relaxation in porcine coronary artery.

Flavonoids are polyphenolic compounds that are widespread in the plant kingdom, and structure-activity relationships (SAR) for vascular relaxation effects were examined for 17 of them using porcine coronary arteries. Density functional theory was employed to calculate the chemical parameters of these compounds. The order of potency for vascular relaxation was as follows: flavones (apigenin and luteolin) >or= flavonols (kaempferol and quercetin)>isoflavones (genistein and daidzein)>flavanon(ol)es (naringenin)>chalcones (phloretin)>anthocyanidins (pelargonidin)>flavan(ol)es ((+)-catechin and (-)-epicatechin). SAR analysis revealed that for good relaxation activity, the 5-OH, 7-OH, 4'-OH, C2=C3 and C4=O functionalities were essential. Comparison of rutin with quercetin, genistin with genistein, and puerarin with daidzein demonstrated that the presence of a glycosylation group greatly reduced relaxation effect. Total energy and molecular volume were also predictive of their relaxation activities. Our findings indicated that the most effective relaxing agents are apigenin, luteolin, kaempferol and genistein. These flavonoids possess the key chemical structures demonstrated in our SAR analysis.

Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.

Expression of vascular endothelial growth factor (VEGF) is induced in cells exposed to hypoxia or ischemia. Neovascularization stimulated by VEGF occurs in several important clinical contexts, including myocardial ischemia, retinal disease, and tumor growth. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix protein that activates transcription of the human erythropoietin gene in hypoxic cells. Here we demonstrate the involvement of HIF-1 in the activation of VEGF transcription. VEGF 5'-flanking sequences mediated transcriptional activation of reporter gene expression in hypoxic Hep3B cells. A 47-bp sequence located 985 to 939 bp 5' to the VEGF transcription initiation site mediated hypoxia-inducible reporter gene expression directed by a simian virus 40 promoter element that was otherwise minimally responsive to hypoxia. When reporters containing VEGF sequences, in the context of the native VEGF or heterologous simian virus 40 promoter, were cotransfected with expression vectors encoding HIF-1alpha and HIF-1beta (ARNT [aryl hydrocarbon receptor nuclear translocator]), reporter gene transcription was much greater in both hypoxic and nonhypoxic cells than in cells transfected with the reporter alone. A HIF-1 binding site was demonstrated in the 47-bp hypoxia response element, and a 3-bp substitution eliminated the ability of the element to bind HIF-1 and to activate transcription in response to hypoxia and/or recombinant HIF-1. Cotransfection of cells with an expression vector encoding a dominant negative form of HIF-1alpha inhibited the activation of reporter transcription in hypoxic cells in a dose-dependent manner. VEGF mRNA was not induced by hypoxia in mutant cells that do not express the HIF-1beta (ARNT) subunit. These findings implicate HIF-1 in the activation of VEGF transcription in hypoxic cells.

Prosthetic devices: challenges and implications of robotic implants and biological interfaces.

Although among designs of prosthetics there have been some successes in the design of functional robotic implants, there remain many issues and challenges concerned with the failure to meet the 'ideal' requirements of a satisfactory prosthetic. These 'ideals' require the device to be easy to control, comfortable to wear, and cosmetically pleasing. Because the literature on prosthetics and robotic implants are voluminous, this review focuses on four topics to determine key challenges and opportunities underlying these interdisciplinary research areas: firstly, an artificial hand as a biomimetic; secondly, prosthetic implants (electromyography signals and control); thirdly, prosthetic implants and tissue reactions to the material(s) of implants; fourthly, how inflammatory responses of cells and tissues surrounding implanted sensors interfere with the signal transmission of such sensors. This review also notes the importance of the biological interfaces that robotic implants and other prosthetic devices are in contact with and how an improved knowledge of pathophysiological changes at such biological interfaces will lead to improved and more biocompatible designs of prosthetics. This review concludes with the vision that, to develop a design that satisfies the above 'ideals', an interdisciplinary team of biomedical and tissue engineers, and biomaterial and biomedical scientists is needed to work together holistically and synergistically.

Endothelium-dependent hyperpolarization: age, gender and blood pressure, do they matter?

Under physiological conditions, the endothelium generates vasodilator signals [prostacyclin, nitric oxide NO and endothelium-dependent hyperpolarization (EDH)], for the regulation of vascular tone. The relative importance of these two signals depends on the diameter of the blood vessels: as the diameter of the arteries decreases, the contribution of EDH to the regulation of vascular tone increases. The mechanism involved in EDH varies with species and blood vessel types; nevertheless, activation of endothelial intermediate- and small-conductance calcium-activated potassium channels (IKCa and SKCa , respectively) is characteristic of the EDH pathway. IKCa - and SKCa -mediated EDH are reduced with endothelial dysfunction, which develops with ageing and hypertension, and is less pronounced in female than in age-matched male until after menopause. Impaired EDH-mediated relaxation is related to a reduced involvement of SKCa , so that the response becomes more dependent on IKCa . The latter depends on the activation of adenosine monophosphate-activated protein kinase (AMPK) and silent information regulator T1 (SIRT1), proteins associated with the process of cellular senescence and vascular signalling in response to the female hormone. An understanding of the role of AMPK and/or SIRT1 in EDH-like responses may help identifying effective pharmacological strategies to prevent the development of vascular complications of different aetiologies.

Equivalent magnetic vector potential model for low-frequency magnetic exposure assessment.

In this paper, a novel source model based on a magnetic vector potential for the assessment of induced electric field strength in a human body exposed to the low-frequency (LF) magnetic field of an electrical appliance is presented. The construction of the vector potential model requires only a single-component magnetic field to be measured close to the appliance under test, hence relieving considerable practical measurement effort-the radial basis functions (RBFs) are adopted for the interpolation of discrete measurements; the magnetic vector potential model can then be directly constructed by summing a set of simple algebraic functions of RBF parameters. The vector potentials are then incorporated into numerical calculations as the equivalent source for evaluations of the induced electric field in the human body model. The accuracy and effectiveness of the proposed model are demonstrated by comparing the induced electric field in a human model to that of the full-wave simulation. This study presents a simple and effective approach for modelling the LF magnetic source. The result of this study could simplify the compliance test procedure for assessing an electrical appliance regarding LF magnetic exposure.

Prostaglandin E2 regulates renal function in C57/BL6 mouse with 5/6 nephrectomy.

AIMS: To investigate the roles of cyclooxygenases (COX) and their metabolites in C57/BL6 mice with 5/6 nephrectomy, an animal model of chronic renal failure. MAIN METHODS: C57/BL6 mice were grouped into sham-operated (2K), one kidney removal (1K) and 5/6 nephrectomy groups (5/6Nx). Renal resistive index was measured by ultrasonography. Blood, aortae, renal arteries and renal cortex were collected for measurement of kidney function, assessment of vascular responsiveness, Western blotting, immuohistochemistry and enzyme-linked immunosorbent assays. KEY FINDINGS: After four weeks, acetylcholine-induced relaxations were blunted in renal arteries of 1K and 5/6Nx mice; indomethacin, a non-selective COX inhibitor, improved the response in 5/6Nx, but not in 1K renal arteries. In 5/6Nx renal arteries, but not in 1K preparations, the protein presence of endothelial nitric oxide synthase (eNOS) was decreased, while that of COX-2 and its products [prostacyclin and thromboxane A2] were increased. The renal resistive index was lower in 5/6Nx mice, suggesting a lower resistance in the renal microvasculature. In the renal cortex of 5/6Nx mice, eNOS protein presence was increased; while the presence of COX-2 was not detectable. The prostaglandin E2 level was lower in the 5/6Nx cortex than in the other two groups. SIGNIFICANCE: The early stage of renal mass removal is associated with increased renal arterial constriction and reduced microvascular resistance. The former is due to downregulation of eNOS and upregulation of COX-2, leading to an increased production of prostacyclin and thromboxane A2. A reduced production of PGE2 in the renal cortex is important for maintaining normal renal function.

Molecular epidemiology of the novel coronavirus that causes severe acute respiratory syndrome.

BACKGROUND: Severe acute respiratory syndrome (SARS) is a newly emerged disease caused by a novel coronavirus (SARS-CoV), which spread globally in early 2003, affecting over 30 countries. We have used molecular epidemiology to define the patterns of spread of the virus in Hong Kong and beyond. METHODS: The case definition of SARS was based on that recommended by WHO. We genetically sequenced the gene for the S1 unit of the viral spike protein of viruses from patients with SARS in Hong Kong (138) and Guangdong (three) in February to April, 2003. We undertook phylogenetic comparisons with 27 other sequences available from public databases (Genbank). FINDINGS: Most of the Hong Kong viruses (139/142), including those from a large outbreak in an apartment block, clustered closely together with the isolate from a single index case (HKU-33) who came from Guangdong to Hong Kong in late February. Three other isolates were genetically distinct from HKU-33 in Hong Kong during February, but none of these contributed substantially to the subsequent local outbreak. Viruses identified in Guangdong and Beijing were genetically more diverse. INTERPRETATION: The molecular epidemiological evidence suggests that most SARS-CoV from the outbreak in Hong Kong, as well as the viruses from Canada, Vietnam, and Singapore, are genetically closely linked. Three viruses found in Hong Kong in February were phylogenetically distinct from the major cluster, which suggests that several introductions of the virus had occurred, but that only one was associated with the subsequent outbreak in Hong Kong, which in turn spread globally.

Role of lipid A of endotoxin in the production of tumour necrosis factor.

Bacterial lipopolysaccharide (LPS) induces the release of tumour necrosis factor (TNF) into serum of mice previously infected with Listeria monocytogenes or immunized with formalin-killed Corynebacterium parvum. This release is greatly reduced by neutralisation of lipid A of LPS with the antibiotic polymyxin B sulfate. The effect is dose-dependent. Base-hydrolysed LPS, which is devoid of lipid A, cannot induce TNF release. Crude lipid A still retains its ability to induce TNF release but is significantly less effective than native LPS molecules. LPS neutralised by polymyxin B also loses its ability to cause high mortality in C. parvum primed mice. These results suggest that lipid A of LPS molecule is important in causing lethality and TNF release in vivo while the polysaccharide portion may be involved in delivering the lipid A moiety to TNF-producing cells.

Short-term exposure to physiological levels of 17 beta-estradiol enhances endothelium-independent relaxation in porcine coronary artery.

OBJECTIVES: While alterations in cholesterol and lipoprotein profiles partly account for menopause being a risk factor for coronary heart disease, recent studies have suggested that 17 beta-estradiol may have vascular effects. Our aims were to study the short-term effects of 17 beta-estradiol on vascular function in isolated porcine coronary artery rings. Concomitantly, we sought to determine if physiological concentrations of 17 beta-estradiol could acutely potentiate relaxation RESULTS: 17 alpha- and 17 beta-estradiol at pharmacological (> 1 microM) concentrations produced relaxation in U46619-pre-contracted porcine coronary artery rings. Relaxation evoked by 17 beta-estradiol was not reversed by the estrogen receptor antagonists tamoxifen and ICI 182780. Following 20 min exposure to a physiological concentration of 17 beta-estradiol (1 nM), which on its own had no effect, relaxation elicited by cromakalim, levcromakalim and sodium nitroprusside, but not bradykinin or calcium ionophore A23187, were significantly enhanced. This potentiating action was also insensitive to tamoxifen and ICI 182780. Our data provide evidence for an acute indirect relaxant action of 17 beta-estradiol and suggest that it may be via a tamoxifen- and ICI 182780-insensitive estrogen receptor. While this response was only observed at pharmacological concentrations, the potentiation of cromakalim, levcromakalim and sodium nitroprusside relaxation was evident in the presence of a physiological concentration (1 nM) of 17 beta-estradiol. CONCLUSIONS: These results demonstrate that short-term exposure to 17 beta-estradiol, at concentrations that have no effect on their own, can enhance vasorelaxation. These vascular effects may partly account for some of the acute effects of 17 beta-estradiol on blood flow.

Kaempferol enhances endothelium-dependent relaxation in the porcine coronary artery through activation of large-conductance Ca(2+) -activated K(+) channels.

BACKGROUND AND PURPOSE: Kaempferol, a plant flavonoid present in normal human diet, can modulate vasomotor tone. The present study aimed to elucidate the signalling pathway through which this flavonoid enhanced relaxation of vascular smooth muscle. EXPERIMENTAL APPROACH: The effect of kaempferol on the relaxation of porcine coronary arteries to endothelium-dependent (bradykinin) and -independent (sodium nitroprusside) relaxing agents was studied in an in vitro organ chamber setup. The whole-cell patch-clamp technique was used to determine the effect of kaempferol on potassium channels in porcine coronary artery smooth muscle cells (PCASMCs). KEY RESULTS: At a concentration without direct effect on vascular tone, kaempferol (3 × 10(-6) M) enhanced relaxations produced by bradykinin and sodium nitroprusside. The potentiation by kaempferol of the bradykinin-induced relaxation was not affected by N(ω)-nitro-L-arginine methyl ester, an inhibitor of NO synthase (10(-4) M) or TRAM-34 plus UCL 1684, inhibitors of intermediate- and small-conductance calcium-activated potassium channels, respectively (10(-6) M each), but was abolished by tetraethylammonium chloride, a non-selective inhibitor of calcium-activated potassium channels (10(-3) M), and iberiotoxin, a selective inhibitor of large-conductance calcium-activated potassium channel (KCa 1.1; 10(-7) M). Iberiotoxin also inhibited the potentiation by kaempferol of sodium nitroprusside-induced relaxations. Kaempferol stimulated an outward-rectifying current in PCASMCs, which was abolished by iberiotoxin. CONCLUSIONS AND IMPLICATIONS: The present results suggest that, in smooth muscle cells of the porcine coronary artery, kaempferol enhanced relaxations caused by endothelium-derived and exogenous NO as well as those due to endothelium-dependent hyperpolarization. This vascular effect of kaempferol involved the activation of KCa 1.1 channels.

Cardiac L-type calcium channel alpha 1-subunit is increased by cyclic adenosine monophosphate: messenger RNA and protein expression in intact bone.

L-type calcium channels have been identified previously in both osteoblast-like osteosarcoma cell lines and primary cultures of osteoblasts using numerous techniques such as patch clamp recording, drug inhibited 45Ca2+ uptake, and Fura-2 measurements, but intact bone has not been investigated. Using reverse-transcription polymerase chain reaction (RT-PCR) we found that the three major isoforms of the alpha 1-subunit of L-type calcium channels, (alpha 1C, alpha 1D, and alpha 1S) are present in RNA extracted from ROS 17/2.8 osteosarcoma cells, rat femur, and rat skull. Sequencing of most of the alpha 1C-subunit from rat femur and ROS cells revealed that the splice variants in osteosarcoma cells and intact bone differ, but there are no unique sequence variations compared with those found in other tissues. Northern blot analysis of ROS cell RNA indicated that cyclic adenosine monophosphate (cAMP), but not 1 alpha, 25-dihydroxyvitamin D3, increased the messenger RNA (mRNA) of the alpha 1C-subunit. Western blot of ROS cell lysates revealed a band of more then 220 kDa, the amount of which increased in cells treated with cAMP. Using confocal microscopy combined with immunohistochemistry in ROS cells, intact bone, and cartilage, we found that the alpha 1C-subunit of this channel is expressed in osteoblasts and chondrocytes suggesting this channel may be a pathway for signal transduction in intact tissue, because it is in osteosarcoma cell lines and primary osteoblasts grown in tissue culture.

Lying-on position of total skin electron therapy.

PURPOSE: A technique for whole-body electron therapy with the patient in a lying position has been developed. This technique allows Total Skin Electron Therapy (TSET) for those patients who were previously unable to be treated in a conventional standing position. METHODS AND MATERIALS: This study was carried out on a Varian 2100C linear accelerator with a 6 MeV high dose rate electron beam. The collimator was open to a width of 36 x 36 cm. There were two main procedures, with six dual-field techniques: 1) two static AP/PA vertical dual fields (VDF): the patient laid on the floor transversely under the collimator when the gantry was in a vertical position. A 0.6 cm acrylic board was placed 15 cm away from the patient, then the gantry was rotated 25 degrees clockwise and counterclockwise to treat the patient in the supine and prone positions, respectively. 2) Four oblique junction fields (OJF): the patient laid on the floor in a prone and supine position parallel to the wave guide at (227 - body thickness x tan 60 degrees) cm away from the vertical axis of the gantry, then the gantry was rotated 60 degrees toward the patient. A 0.6 cm acrylic board was placed 15 cm away from the patient perpendicular to the beam. The patient was move along the field central axis. It allowed the patient's body to be within the 160 cm effective treatment profile. When the patient's body axis move 5 degrees toward the lateral side of the field central axis, we could obtain a better dose distribution in the vertex of the scalp and the soles of the feet. The angle of the VDF was measured by chamber detectors to obtain the effective treatment profile. Likewise, the optimal profile for the OJF was determined by the same procedures. The Rando phantom was used to measure the superficial dose of the body. RESULTS: The dimension of effective treatment profile for the VDF was 188 x 72 cm at 87% dose level For the OJF, we had to move the patient along the field central axis to obtain the effective treatment profile in a 180 x 85 cm dimension at a 87% dose level. The vertex and sole dose measured in this setup was in the range of 80-88%. CONCLUSIONS: The empirical data showed that the lying-on position for TSET was technically feasible. The dose distribution in the body surface was also compatible with the Stanford standing technique. The nonambulatory skin malignancy patient can be treated in a comfortable and reproducible position.

Local vaginal anesthesia during high-dose-rate intracavitary brachytherapy for cervical cancer.

PURPOSE: To evaluate the clinical efficacy of local vaginal lidocaine application for pain relief during high-dose-rate (HDR) intracavitary brachytherapy for patients with cervical cancer, and to investigate sequential changes in serum levels of lidocaine during the procedures. METHODS AND MATERIALS: This prospective study was designed to examine the analgesic effect, physical response, and side effects of local anesthesia during HDR intracavitary brachytherapy. Forty patients were enrolled. All patients received 10-15 MV X-rays to the pelvis with a total dose of 45-59.4 Gy 5-6 weeks before undergoing HDR intracavitary brachytherapy. All patients underwent first intracavitary brachytherapy under general anesthesia. These patients were randomly allocated to receive one of two different treatment protocols as follows: (1) treatment session - control session - treatment session - control session; or (2) control session - treatment session- control session - treatment session. In the treatment sessions, topical anesthesia was administered using 4 ml of 10% lidocaine solution sprayed liberally on the cervix and vagina during intracavitary brachytherapy. In the control sessions, a placebo was administered in the same manner during brachytherapy. The Hensche's applicators for brachytherapy were inserted into the cervix and vagina 5 min after lidocaine application. The visual analogue scale (VAS) was used to assess pain and discomfort during brachytherapy. Blood pressure and heart rates were measured to evaluate the physiological response. Another prospective study was then performed to investigate the sequential changes of serum lidocaine levels during the anesthetic procedure. Eleven additional patients with similar disease state and demographic characteristics were enrolled and blood samples were obtained before, and 5, 15, 30, and 45 min after the initiation of lidocaine application. RESULTS: The mean VAS values recorded during the treatment sessions and control sessions were 49.9 +/- 24.1 versus 60.1 +/- 24.8, respectively. The value of VAS in the treatment session was significantly lower than that of the control session (p < 0.001). No statistically significant differences were found in the changes of blood pressure and heart rate and in the incidence of side effects during these two types of sessions (p > 0.05). In the drug-level study, serum levels of lidocaine reached a peak 5 min after the initiation of local anesthesia. The mean peak concentrations (Cmax) of lidocaine were 0.50 +/- 0.45 microg/ml. CONCLUSION: Local vaginal anesthesia with 10% lidocaine solution can significantly decrease the degree of painful sensation during HDR intracavitary brachytherapy, and is safe to administer for the procedure for cervical cancer.

Impact of the extent of parametrial involvement in patients with carcinoma of the uterine cervix.

PURPOSE: A scoring system is proposed to measure the extent of parametrial involvement and predict treatment outcome in patients with carcinoma of the uterine cervix. METHODS AND MATERIALS: 244 patients with FIGO Stage IIB (n = 146) or IIIB (n = 98) carcinoma of the uterine cervix were treated by radical radiotherapy from October 1987 to June 1992. Impact of the extent of parametrial involvement on outcome was studied. All patients were scored by the newly introduced scoring system described as follows: score 1, tumor extending <1/2 the distance to the pelvic side wall; score 2, tumor extending >1/2 the distance to the pelvic side wall but not to pelvic side wall; score 3, tumor extending to the pelvic side wall. The score in each patient was defined as the sum of the scores of both the left and right parametrial tumor extent. RESULTS: There were 53, 47, 61, 34, 25, and 24 patients in score 1, 2, 3, 4, 5, and 6, respectively. All 244 patients were subdivided into three groups described as follows: score 1 and 2, group I; score 3 and 4, group II; score 5 and 6, group III. In univariate analysis, lower score groups had better overall survival rate (OS), disease-free survival rate (DFS), local control rate (LC), and distant metastasis-free rate (DMF) than higher score groups including groups I vs. II, II vs. III, or I vs. III. The differences were all statistically significant except for the difference of the DMF in group I vs. II. In multivariate analysis, score (range 1-6) was also statistically significant in OS (p < 0.0001), DFS (p = 0.0015), LC (p = 0.0032), and DMF (p = 0.0141). CONCLUSIONS: The data suggested that the new scoring system defined by pelvic examination is a convenient, simple, and reliable method of measuring the degree of parametrial extension and predicting the outcome of patients with parametrial disease.

The correlation of acute toxicity and late rectal injury in radiotherapy for cervical carcinoma: evidence suggestive of consequential late effect (CQLE).

PURPOSE: To correlate the acute toxicity during pelvic irradiation and the development of late rectal injury following radiation therapy for cervical carcinoma. METHODS AND MATERIALS: Two hundred and twenty patients treated with curative-intent radiation therapy between November 1987 and January 1992 were analyzed. Patients were treated initially with external beam irradiation, 40-44 Gy/20-22 fractions to whole pelvis, followed by high dose rate intracavitary brachytherapy, 7.2 Gy to point A for 3 fractions. Severity of diarrhea during radiation therapy was scored according to six criteria: fecal characteristics, frequency, onset, prescription of antidiarrheal agents, body weight loss during irradiation, and extramedical care needed. Patients were categorized as group ND (no obvious diarrhea), group MD (moderate diarrhea), and group SD (severe diarrhea) for sum score 0-1, 2-5, and > or = 6, respectively. The rate of radiation proctitis was expressed, analyzed, and compared with actuarial proctitis-free rate and prevalence. RESULTS: 1) According to the score, 76 (35%), 89 (40%), and 55 (25%) patients were categorized as group ND, group MD, and group SD, respectively. Distribution of patients and treatment characteristics among the three groups appeared similar. Patients treated with a larger field size, > or = 16.5 cm2, tended to have increased severity of diarrhea. 2) Overall, 103 patients (47%, 103 of 220) developed radiation proctitis. Twenty-one patients were in group ND (28%, 21 of 76), 43 in group MD (48%, 43 of 89), and 39 in group SD (71%, 39 of 55). 3) The five-year actuarial proctitis-free rate was 72, 52, and 29% for group ND, MD, and SD, respectively (p < 0.005). 4) Taking time evolution and recoverability into account, the effect of diarrhea on the prevalence of radiation proctitis remained statistically significant at the first through the fourth year after irradiation. 5) Severity of radiation proctitis and severity of diarrhea were not correlated (Spearman's rank correlation coefficient r(s) = 0.229, p = 0.098). 6) Cox's multivariate analysis revealed that severity of diarrhea was the only factor that significantly correlated with the development of radiation proctitis. CONCLUSION: Patients with increased acute toxicity and diarrhea during radiation therapy of cervical carcinoma significantly increased the risk of late rectal injury. This result suggested that early excessive damage of acute-responding component of rectal wall may play an important role in the initiation of late rectal injury. Radiation proctitis can be accounted, in part, as a consequential late effect.

Topographic distribution of inguinal lymph nodes metastasis: significance in determination of treatment margin for elective inguinal lymph nodes irradiation of low pelvic tumors.

PURPOSE: To study the distribution of gross inguinal lymph node metastasis and, in particular, its correlation with major pelvic bony structures on a simulation film. METHODS AND MATERIALS: Thirty-seven cases of low pelvic tumors having gross inguinal lymph node metastasis that were treated with radiation therapy between November 1987 and December 1992 were segregated for study. The patient's nodes were palpated and marked with lead wire before the simulation film was assumed to be the origin of the previously uninfested node. A total of 84 such labeled nodes was taken. The geometric center of the usually round or elliptical node on the film was obtained from these 37 cases. These centers were transferred to and mapped collectively on a new simulation film showing major pelvic bony structures of left hemipelvis and upper femur. RESULTS: Distribution of gross inguinal lymph nodes was found confined to the following area, as related to major pelvic bony structure: laterally, just abutting the tangential line that passes through lateral border of the femoral head; medially: 3 cm away from the body's midline axis; superiorly: 1 cm below the line that joins both upper borders of the femoral head; inferiorly: 2.5 cm below the low borders of ischial tuberosity. According to this rectangular boundary, three nodes were out of the field, nine nodes near the border less than 1 cm margin. This area adequately covered 86% (72 of 84) of the studied nodes. CONCLUSION: Distribution study is important in determining the treatment margin. In general, an additional 1-2 cm beyond the area described above is the recommended treatment margin for elective inguinal lymph nodes irradiation with high confidence level of coverage.