Likewise, irradiation with carbon ions was performed with single carbon doses of 0.125, 0.5, 2 and 3 Gy. Four chemotherapeutic substances, camptothecin, gemcitabine, paclitaxel and cisplatinum, were used for single and combination experiments. The assessment of the effect of single and double treatment on cell viability was performed using the clonogenic growth assay representing the radiobiological gold standard.The RBE of carbon ions ranges between 3.3 and 3.9 depending on survival level and dose. All chemotherapeutic substances showed a clear does-response relationhips. in their characteristic concentrations. For subsequent combination experiments, two dose levels leading to low and medium reduction of cell survival were chosen. Combination experiments showed additive effects independently of the drugs' mechanisms of action. Paclitaxel and campthothecin demonstrated the most prominent cytotoxic effect in combination with carbon ion radiotherapy.In conclusion, combination of carbon ion radiotherapy with chemotherapies of different mechanisms of action demonstrates additive effects. The most dominant effect was produced by paclitaxel, followed by camptothecin, as espected from previously published work. The present data serve as an important radiobiological basis for further combination experiments, as well as clinical studies on combination treatments. Novel radiotherapeutic treatment approaches for patients with glioblastoma (GBM) may enable the radiation oncologist to increase local control, and thus impact on progression-free survival and overall survival times; this includes the application of novel radiation qualities, technical advances, dose and fractionation concepts, as well as combined treatment modalities. In spite of extensive research, current outcome after the standard treatment, consisting of postoperative photon radiotherapy in combination with the alkylating substance temozolomide (TMZ) is around 15 months [Particle radiotherapy, such as proton or carbon ion radiation, offers distinct physical characteristics leading to a more conformal dose distribution: Due to the inverted dose profile with low dose deposition in the entry channel of the beam, and high local doses in the so called Bragg Peak, normal tissue surrounding the tumor area can be spared, and the integral dose to the patient can be reduced. Additionally, carbon ions, offer a higher relative biological effeciveness (RBE) due to the severe radiation damage produced within the beam track -4. Most in vitro studies including our own work have shown that, for GBM, the RBE of carbon ions is between 3 and 5, depending on the cell line and the endpoint [Several endpoint -9. Compaendpoint .Several studies have evaluated the combination of chemotherapy with radiation using X-rays, however, only few data is available on the effect of chemotherapy and carbon ion radiotherapy. It has been hypothesized that, due to the different radiobiological effects of high-LET particle beams with special respect to impact on cell cycle control, combination effects known from photon radiotherapy in combination with chemotherapeutic substances of different working mechanisms might be different for carbon ions. A study by Kitabayashi and colleagues evaluated carbon ion radiotherapy and different chemotherapies in esophagenal cell lines, showing that combination with docetaxel was the strongest of 4 combinations revealing promising combination effects . However2 and 95% humidity.The human glioblastoma (GBM) cell line U87 was obtained from the American Type Culture Collection . The cells were cultured in DMEM supplemented with 10% fetal calf serum (FCS); they were maintained in culture at 37°C with 5% COCells were irradiated at room temperature. RT was performed as single exposure to doses of photon RT of 2 Gy, 4 Gy and 6 Gy delivered by a linear accelerator .Irradiation with carbon ion was performed at the Heidelberg ion Therapy Center (HIT) with the horizontal beamline using the rasterscanning technique. To treat cell cultures with clinically relevant parameters we delivered the dose as an extended Bragg peak with 103 keV/μm (dose averaged LET). The position of the Breagg peak was adjusted using a 1 cm acrylic shield, and cell monolyers were placed in the middle ot the extended Bragg peak. Single carbon doses of 0.125, 0.5, 2 and 3 Gy were applied.U87 cells were treated with chemotherapy at various concentrations 4 hours prior to radiation treatment followed by a medium change to discontinue drug exposition. Four chemotherapeutic substances, camptothecin, gemcitabine, paclitaxel and cisplatinum, were used for single and combination experiments using differenct substance-specific concentrations.For all substances, dose-response-relationships were generated for single-agent treatment. For combination experiments, low, i.e. ~70-80% survival, and medium, i.e. ~ 50-60% cell survival, toxicity concentrations were chosen: For paclitaxel, 5 nM and 20 nM, 10 nM and 30 nM for gemcitabine, 0.5 μM and 1 μM for cisplatinum, and 10 nM and 30 nM for camptothecin.For combination experiments, glioma cells were irradiated immediately after drug wash-out by medium change.2 to 5 × 104) were plated in 25 cm2 flasks  as described previously [The assessment of the effect of single and double treatment on cell viability was performed using the clonogenic growth assay representing the radiobiological gold standard. Clonogenic survival is an important criterion of cell survival in repsonse to antitumor agents because the final cell death may occur only after additional cell divisions. For these analyses, the GBM cell lines were grown under standard conditions. To investigate the effect of photon and carbon ion irradiation alone, chemotherapy alone, or the combination of both, on clonogenic survival, increasing numbers of cells  integrating various parameters has been established in clinical routine ,18,19. SIn conclusion, combination of carbon ion radiotherapy with chemotherapies of different mechanisms of action demonstrates additive effects. The most dominant effect was produced by paclitaxel, followed by camptothecin, as espected from previously published work. The present data serve as an important radiobiological basis for further combination experiments, as well as clinical studies on combination treatments.


Point-of-sale advertising provides an opportunity for the tobacco industry to communicate with current and potential smokers. The US Family Smoking Prevention and Tobacco Control Act allows states to implement policies requiring that tobacco products be placed out of sight, and the Food and Drug Administration is considering banning point-of-sale advertising within 1,000 feet of schools. Our objective was to compare cigarette point-of-sale advertising near schools with grades prekindergarten through 12 and by store type.All registered cigarette retailers  and schools (n = 581) in the city of St Louis and St Louis County were geocoded and mapped by using ArcGIS. Retailers were divided into 2 groups, those within 1,000 feet and those within 1,001 to 2,000 feet of a school; 200 retailers from each group were randomly selected. We assessed tobacco interior and exterior advertising, brands advertised, discounts, gifts with purchase, “no sales to minors” signage, and cigarette functional items . Analyses were done by distance from a school and store type.P = .20). Convenience stores had the highest number of interior ads. In multivariable models, distance from school explained 0.2% of the variance in total advertising.We analyzed 340 retailers. Most retailers within 1,000 feet (91.2%) and from 1,001 to 2,000 feet (94.2%) of a school displayed cigarette advertising (Cigarette point-of-sale advertising is highly prevalent in St Louis within 1,000 feet of schools. A ban based on distance from a school might decrease advertising exposure, but its effect on smoking prevalence is yet to be determined because advertising farther from schools would still prevail. Tobacco industry marketing campaigns have been instrumental in spreading the tobacco use epidemic worldwide. The industry has used several channels to market tobacco products, including television, magazines, billboards, radio, and sponsorships  . As restIn 2009, the Family Smoking Prevention and Tobacco Control Act (FSPTCA) was passed in the United States. This act grants the Food and Drug Administration (FDA) specific regulatory authority to restrict the sale, distribution, accessibility, advertising, and promotion of tobacco products “consistent with and to the full extent permitted by the first amendment to the Constitution” . As of OAmong the 50 states, Missouri ranks 38th in adolescent (aged 12–17 years old) smoking prevalence   from the Missouri Department of Education. Tobacco retailers  and schools (n = 581) in St Louis City and County were then mapped in ArcGIS 10 . This is a suite of geographic information system software for working with maps and geographic information. Following geocoding of the retailers and school street addresses, we conducted a proximity analysis using ArcGIS to determine which retailers were within 1,000 feet of a school and which were within 1,001 to 2,000 feet of a school. Euclidean distance (straight line), as opposed to network distance (using the road network), was used to calculate distance between a school and a tobacco retailer. We chose the former, given that the latter will measure vehicular travel distance rather than walking distance, because a significant proportion of students walk to school . The disTo assess the prevalence and characteristics of point-of-sale advertising in stores, we trained auditors to use a checklist developed by Feighery et al . The che2 and Mann–Whitney U test), and parametric statistics . Multiple linear regression was used to estimate total (exterior plus interior) and interior number of ads as continuous dependent variables. Predictor variables  were chosen based on the previously identified predictors of point-of-sale advertising , nonparametric . Several retailers displayed advertisements (12.3%) or cigarette products (1.5%) near (within 50 cm of) candy. Most retailers (72.8%) had a promotional sale price, and 21.1% offered multi-pack discounts. A gift with cigarette purchase was found in 2.3% of the stores. Most (88.6%) stores posted a “no sales to minors” sign.Of the 340 stores sampled , most were convenience stores with gas stations, followed by small, independently owned grocery stores  . Nearly P = .50) different between stores within 1,000 feet (64%) and those within 1,001 to 2,000 feet (60%). In a sensitivity analysis we used 350 feet as the distance cutoff point; however, results remained unchanged (no difference in interior and exterior advertising). The total number of stores that had 13  or more ads was not significantly (P = .50) different from the number of stores within 1,000 feet  and those within 1,001 to 2,000 feet  of a school. Furthermore, multiple regression models showed that distance from a school is not a significant predictor (P > .05) of point-of-sale advertising and explained 0.2% of the variance of total number of ads and 0.6% of the variance of total number of interior ads. When number of cash registers and store type were included in the analyses, the model explained 11.3% of the variance in the total number of ads and 6.6% of the variance of interior ads. Excluding supermarkets and liquor stores, where youth might likely spend less time, yielded the same results.When analyzed by distance from a school , there wP < .001) by store type. Most convenience stores with (86%) and without (67%) a gas station, liquor stores (85%), and small markets (77%) had exterior ads. Exterior ads were less likely to be found in other store types (37%), supermarkets (11%), and drugstores. Promotional sales pricing were most frequently found in convenience stores with no gas station, followed by convenience stores with gas stations, drugstores, small markets, liquor stores, and supermarkets  and convenience stores with (15.1 [9.1] ads) and without (14.9 [7.8] ads) a gas station compared with other store types . More thrmarkets .Tobacco point-of-sale advertising is highly prevalent in St Louis. The prevalence of advertising in stores is independent of distance from a school but dependent on store type. Furthermore, prominent pack display and multi-pack and promotional discounts are also highly prevalent.Point-of-sale advertising (including prominent pack display) has been for the most part ignored in tobacco control programs worldwide. For example, except for Scotland and Ireland, none of the advertising bans implemented in the world’s largest cigarette markets  include a comprehensive ban at the point of sale ,20. In HAmong adolescents, cigarette point-of-sale advertising increases students’ perception of the ease of purchasing cigarettes and decreases their likelihood for showing proof of age . AlthougOur finding of promotional sales prices and multi-pack discounts is in agreement with the reported priorities of cigarette industry spending on promotional advertising ,5,20. SiOur data suggest that banning advertising based on distance from schools may decrease exposure of school-aged children and adolescents to point-of-sale cigarette advertising. However, even if we assume that it is near their schools where adolescents spend most of their spare time, it would ignore other issues with cigarette advertising. First, adolescents attending schools are not the only people influenced by point-of-sale advertising. Former and current smokers attempting to remain or become committed to quitting smoking are also negatively impacted by point-of-sale advertising . Second,Our data have several strengths and limitations. This is the first study to document cigarette point-of-sale advertising in St Louis and to assess its relationship with distance from a school (as proposed by the FSPTCA). However, the FDA includes both schools and playgrounds in their proposal. Our study does not include information on distance from a playground because we were not able to obtain playground location data. One solution was to use park location data; however, not all parks contain playgrounds. Although we did not include playgrounds in our analysis, our study is still relevant in that it focuses on schools, a place where children spend a large portion of their day. Furthermore, cigarette point-of-sale advertising has been found to be more prevalent in neighborhoods with a higher percentage of African Americans and of residents of low socioeconomic status ,30. TherTo achieve its goal to decrease exposure to cigarette advertising overall (not only among adolescents around schools), the FSPTCA in the United States (and any other legislative body with the same objective) should include a ban at the point of sale in retail stores regardless of location and type. Furthermore, other advertising strategies implemented at the point of sale  should also be included in a comprehensive ban. Because point-of-sale advertising is widely integrated throughout the society, a comprehensive ban is needed to decrease adolescents’ exposure to tobacco advertising and other tobacco industry marketing strategies  that lead to smoking initiation and uptake. More than free speech, point-of-sale advertising represents a clear marketing strategy aimed at maintaining the public visibility and social acceptability of tobacco products, encouraging brand loyalty and further consumption among current smokers, and recruiting new smokers or former smokers. Despite what we know about the effects of point-of-sale advertising on adolescents, young adults, adults, and former smokers, further research is likely to support the notion that this type of advertising is inherently harmful to public health because it encourages smoking in several ways. Therefore, our data should aid tobacco control advocates to argue for a comprehensive advertising ban and serve as baseline to track FSPTCA implementation.


Plasmodium falciparum strains is a major concern and novel anti-malarial drugs are, therefore, needed. Ferroquine is a ferrocenic derivative of chloroquine with proven anti-malarial activity against chloroquine-resistant and -sensitive P. falciparum laboratory strains.The development and spread of drug resistant P. falciparum, were included in two-dose escalation, double-blind, randomized, placebo-controlled Phase I trials, a single dose study and a multiple dose study aiming to evaluate oral doses of ferroquine from 400 to 1,600 mg.Adult young male aged 18 to 45 years, asymptomatic carriers of Overall, 54/66 patients  experienced at least one adverse event, 15 were under placebo. Adverse events were mainly gastrointestinal symptoms such as abdominal pain (16), diarrhoea (5), nausea (13), and vomiting (9), but also headache (11), and dizziness (5). A few patients had slightly elevated liver parameters (10/66) including two patients under placebo. Moderate changes in QTc and morphological changes in T waves were observed in the course of the study. However, no adverse cardiac effects with clinical relevance were observed.P. falciparum infection. Further clinical development of ferroquine, either alone or in combination with another anti-malarial, is highly warranted and currently underway.These phase I trials showed that clinically, ferroquine was generally well-tolerated up to 1,600 mg as single dose and up to 800 mg as repeated dose in asymptomatic young male with  Plasmodium falciparum has become resistant to several commonly used anti-malarial drugs. As a consequence new anti-malarial compounds are urgently needed. Despite a considerable increase in international efforts in anti-malarial drug development, there is at present a shortage of truly novel drugs which do not share the same mechanisms of action and drug resistance with those that are failing today. The entire reliance on artemisinin derivatives in the drug development over the past decade might be deceptive in the light of first reports of artemisinin resistant P. falciparum . However, no increases in QT, QTc were noted in the 13-week oral toxicity study in dogs at 0.2/25, 1/25 and 5/25 mg/kg of ferroquine/artesunate combination and at 5 mg/kg of ferroquine alone.First, in human studies of ferroquine were conducted in a double-blind, randomized, placebo controlled, and sequential dose escalation study in 42 healthy male subjects in Germany [unpublished data]. Single oral doses up to 800 mg were clinically well tolerated and no drug-related clinically relevant adverse event was observed. One serious adverse event occurred which was unrelated to the study drug and all other adverse events were mild to moderate and no relevant electrocardiogram abnormalities, such as QT prolongation or repolarisation abnormalities were described.P. falciparum infection and to determine the maximum tolerated dose after oral administration of ferroquine.This is a report on two clinical phase I trials, which aimed to assess the clinical, and laboratory safety and tolerability profile of ferroquine. These studies were designed to evaluate ascending oral doses in young male volunteers with asymptomatic Both clinical trials were designed as phase I, randomized, double blind, placebo-controlled, sequential dose escalation studies. The first study TDU5967 ("Single Dose Study") was designed as a dose escalation trial of a single oral dose, whereas the second study TDR5969 ("3 Day Repeated Dose Study") aimed to evaluate a three-day treatment course.Clinical work was carried out from April 2005 to June 2006 at the Medical Research Unit of the Albert Schweitzer Hospital in Lambaréné, Gabon, a semi-urban town of about 30,000 inhabitants where malaria transmission is perennial with moderate seasonal variation ,10.P. falciparum infection were enrolled into the study if they fulfilled the following criteria: (1) weight between 50 and 90 kg, (2) BMI of 18 to 28 kg/m2, (3) normal vital signs after 10 minutes resting in supine position, i.e. systolic blood pressure between 95 and 140 mmHg, and diastolic blood pressure between 50 and 90 mmHg, and heart rate between 45 and 90 beats per minute, (4) normal 12-lead automatic ECG, (5) and no fever or history of fever in the last 72 hours. Exclusion criteria were (1) presence of any clinical signs of malaria, (2) previous anti-malarial treatment, (3) significant co-morbidities or other conditions impeding compliance with the study, (4) presence or history of drug allergy, (5) evidence for hepatitis B, C, or HIV infection .Male volunteers aged between 18 and 45 years residing in Lambaréné and its surrounding areas were invited to participate. Individuals having provided written informed consent and harbouring asymptomatic th World Health Congress  and all applicable amendments, also with laws, regulations, and any applicable guideline of Gabon, the country where the studies were conducted in compliance with the International Harmonized Conference on Good Clinical Practices guidelines. Informed consent was obtained prior to the conduct of any study-related procedures.The studies were granted ethical clearance by the Ethics Committee of the International Foundation of the Albert Schweitzer Hospital. The study protocols complied with recommendations of the 18Study treatments were prepared by dose level for each patient according to the study randomization list. The following doses of ferroquine were to be explored, 400 mg, 800 mg, 1,200 mg, 1,400 mg, and 1,600 mg for the single dose study and 400 mg, 600 mg, 800 mg, and 1,000 mg for the three-day repeated dose study.Treatment allocation was performed in sequential groups of eight participants per dose group. Six participants were to receive ferroquine and two participants were to receive placebo. All ferroquine dose strengths and placebo capsules were identically matched. The first patients were assigned to the lowest dose level of the study.The treatment allocation was double-blinded and was done according to the randomization list which was computer-generated. The allocation code was concealed at site and procedures were put in place to have the option for code breaking in case of urgent clinical need. Decision for dose escalation was based on a thorough review of clinical and laboratory data, including ECG and pharmacokinetic data of the preceding dose level.P. falciparum infection status by blood smear, Rapid Test and PCR [Recruitment of volunteers was started with a pre-screening visit to determine the  and PCR . If infeAdverse events were defined as any clinical change from baseline or previous visit spontaneously reported by the patient or observed by the investigator. All adverse events regardless of seriousness or relationship to the investigational product were recorded. Adverse events were coded according to Medical Dictionary for regulatory Activities .Due to the very long half-life of the product, around 20 days, the rule applied for the emergence of adverse event was 5 half-lives after administration. Thus, an adverse event was considered as emergent until the end-of-study visit. Abnormalities of vital signs, laboratory parameters or ECG readings were recorded as adverse events only if they were medically relevant by being symptomatic, requiring corrective treatment, leading to discontinuation and/or fulfilling a seriousness criterion.A standard 12-lead ECG was performed hourly up to six hours post-dosing, two-hourly up to 12 hours post-dose, and weekly until the end of follow-up. ECG measures were obtained from measurement of three consecutive QRS complexes and averaged. Heart rates, QTc (Bazett and Fridericia) were derived from the mean values of the measured parameters. In addition, a 24-hr ECG was recorded in the repeated dose study for five days to detect cardiac rhythm abnormalities.Primary outcomes (endpoints) for these randomized clinical trials were defined as the clinical and laboratory adverse event profile and the effect of ferroquine on the cardiovascular system.Sample size for these studies was based upon empirical considerations from clinical phase I studies and no formal sample size calculation was performed. Safety analysis was based on participants who were administered at least one dose of study drug (exposed population) including participants who withdrew consent prematurely. If a participant had received the study drug and prematurely stopped study participation he was replaced, unless if follow up data were available up to day 15.P. falciparum infections were further screened for eligibility. Eighty-four were excluded because of abnormal chemistry or haematology results, abnormal ECGs, or other health problems. Seventeen volunteers could not be enrolled due to logistical reasons and further eight volunteers were not enrolled because the predefined number of participants for each of the two studies was already reached. Recruitment and participant flow are depicted in Figure Out of a total of 498 volunteers pre-screened, 158 persons with P. falciparum were enrolled, randomized, and treated. In the single dose study, a total of 30 volunteers were exposed to single oral doses of ferroquine over a range from 400 mg to 1,600 mg and 10 received placebo. In the three-day multiple dose study, 19 volunteers were treated for three days with daily doses from 400 mg to 1,000 mg and seven received placebo. Only one participant was administered the 1,000 mg dose. Enrolment was discontinued at 1,000 mg dose because of morphologic changes in T waves and a moderate QT prolongation observed in patients treated with 800 mg and 1,000 mg. Seven participants stopped the study prematurely for reasons unrelated to adverse events, three in the single dose study and four in the three-day repeated dose study . The adverse events reported were mainly in the gastrointestinal tract, abdominal pain (16), diarrhoea (5), nausea (13), vomiting (9) and toothache (6), and in the nervous system disorders, headache (11) and dizziness (5), but also those that appeared during the follow-up period, in the musculoskeletal and connective tissue disorders (9), such as arthralgia and back pain, the injury, poisoning and procedural complications (10) .Other symptoms such as mild, transient eye disorders , mild skin rash (ECGs electrode application sites dermatitis or pruritis), infections and infestations, and fatigue were infrequent and were single occurrences across all dose groups in either study. All adverse events were considered mild to moderate in intensity and were transient. There were no deaths, serious adverse events, or adverse events leading to withdrawal reported during the trials.Because of the small numbers of volunteers studied at each dose, no significant conclusions can be drawn from comparisons of adverse events between dose groups at the individual dose levels.The clinical laboratory evaluation was performed through clinical chemistry and haematology tests of samples taken at different time points of scheduled visits until the end-of-study visit 60 days). The majority of the clinical chemistry potentially clinically significant abnormalities observed on patients treated with concerned elevations of creatine phosphokinase . In most cases, creatine phosphokinase was elevated at baseline and was related to intense farming activities prior to inclusion  at any time point of the study with a possible association to changes of other liver functions. Among them were four patients treated with ferroquine and one patient treated with placebo. These changes were asymptomatic and, therefore, were not reported as adverse events. One patient under placebo experienced an increased level of alanine transaminase, with a maximum value of 59 IU on Day 21. The increase was associated to a parallel and moderate increase of total bilirubin  and a moderate increase of aspartate transaminase and gamma glutamyl transferase. In the 800 mg dose-group, one patient had an increased level of alanine transaminase with a maximum value of 148 IU on Day 15, with associated increases in total bilirubin (24 μmol/L), aspartate transaminases, alkaline phosphatases, and gamma glutamyl transferase. In the 1,200 mg dose-group, at one patient an increased level of alanine transaminase with a maximum value of 52 IU was observed on Day 7, whereas, alkaline phosphatase and total bilirubin (5 μmol/L) remained within normal ranges. At one patient treated with 1,400 mg, an increased level of alanine transaminase with a maximum value of 47 IU was observed on Day 15, associated to parallel changes in other liver function parameters at the exception of the bilirubin level (8 μmol/L). Finally, one patient was one of the 1,600 mg dose-group experienced an increase of alanine transaminase values with a maximum value of 48 IU on Day 2 with parallel increase in total bilirubin (25 μmol/L) on Day 15. The respective parameters of this patient were already slightly elevated at baseline (Day -1).In the three-day repeated dose study, elevated alanine transaminases (>2 ULN) was observed in one placebo-treated patient and in four patients in the ferroquine groups. One patient in the 400 mg group  had an alanine transaminase >10 ULN starting at Day 12 with a maximum magnitude of 16.55 ULN, which was associated to abdominal pain and headache. Over the course of the following week, alkaline phosphatases and bilirubin increased and picked at about 2 ULN and 1.7 ULN, respectively. Infectious causes were ruled out. However, the patient reported intake of an herbal tea against abdominal pain, which might have contributed to the enzyme abnormalities. Alanine transaminases returned to normal by Day 37 (0.71 ULN). A patient of the 600 mg group, who had a slightly elevated alanine transaminase value at screening (1.22 ULN), but within normal ranges at baseline (0.91 ULN), presented again an elevated value on Day 3 (1.71 ULN) and reached the potentially clinically significant abnormality level (2.18 ULN) on Day 5, subsequently followed by a decrease to normal rangeby Day 12. In this same 600 mg dose group, another patient with normal baseline value of 0.42 ULN, presented an elevated alanine transaminase values on Day 3 that reached the potentially clinically significant abnormality level on Day 23 (2.56 ULN). His values were still elevated at the end-of-study visit (1.78 ULN). Finally, one patient of the 800 mg dose group, with normal baseline value of 0.38 ULN, had a peak alanine transaminases value of 6.37 ULN and a bilirubin value of 1.48 ULN at Day 12 without clinical symptoms. Alkaline phosphatases peaked at 1.77 ULN on Day 17. Liver parameter values decreased toward the normal range by the end-of-study visit. The most frequently observed haematology, potencially clinically significant abnormalities were related to eosinophils that were likely to be related to concomitant parasitic infections existing at baseline.In the single dose study, no QTcF values >450 ms, or delta QTcF >60 ms were observed in any treatment group. One patient in the 1,200 mg dose group experienced a delta QTcF value between 30 and 60 ms, while a moderate change in mean increases from baseline of + 8.2 ms was observed for the 1,600 mg dose level coinciding with the time of maximal plasma concentrations. In the three-day repeated dose study, continuous monitoring did not show any clinically significant arrhythmic episode developing after drug administration in any patient. A deviation in the repolarization pattern (inversion of T wave), visible from T5 upwards and lasting for several hours, was observed in four patients of the 800 mg dose group, especially in one patient who showed a clear and long-lasting T inversion each day of investigational product administration. According to previous experiences and the known influence of aminoquinolines on ECGs, these episodes were considered to be related to the investigational product, but remained without any clinical significance. In the 800 mg dose group, there were 12.6 ms, 16.8 ms, and 19.2 ms mean increases in QTcF intervals on Day 3 at 6, 8, and 12 hours, respectively. Additionally, in the 800 mg dose group, there was a 19.6 ± 6.8 ms (mean ± SEM) maximum mean increase in QTcF intervals, compared to maximum mean increases of 9.9 ± 5.5, 5.2 ± 3.6, and 16.5 ± 6.8 ms for the placebo, 400 mg, and 600 mg groups, respectively. There were no delta QTcF intervals >60 ms and no QTcF intervals >450 ms.Despite an increase in international investment in anti-malarial drug development in the past decade only a few novel drugs have been developed -19. FerrGastrointestinal side effects and central nervous disorders appear to be the most common clinical adverse events following treatment with ferroquine. These symptoms were however self-limiting and mild to moderate in intensity. Most important the frequency of these events was similar in patients treated with ferroquine and those receiving placebo and overall compared well to currently used anti-malarials. However, these side effects are well described for other 4-aminoquinoline anti-malarials and need, therefore, further investigation in the case of ferroquine -26. OtheOne limitation of the assessment of adverse events in this study may be the potential progression of asymptomatic infection to malaria. However, the inclusion of a control group with placebo treatment helped to minimize this factor in the absence of knowledge on the efficacy of ferroquine in humans. Similarly, the apparent dose dependent increase in gastrointestinal adverse events may be either due to pharmacodynamic properties of the drug or alternatively to the high number of capsules that had to be swallowed (up to 16 capsules per participant). In summary, ferroquine may lead to gastrointestinal side effects comparable to other anti-malarials. However, the number of participants in this study does not permit to make a final judgement on a potential dose dependent increase of gastrointestinal toxicity of ferroquine.At eight weeks follow-up, there was no evidence for cardiac, ocular, hepatic, haemotologic, renal, dermatologic, or other end-organ adverse events. Although adverse events involving these and other organs have been reported with aminoquinolines previously ,23-25, tThe finding of abnormal liver function tests in the course of the study. These observations are consistent with data from toxicology studies on rats and dogs which showed small increases of alanine transaminase and aspartate aminotransferase (unpublished data). These changes were minor and not considered to be of toxicological significance. In our clinical trials the laboratory changes were not clinically significant and most of the abnormal test results normalized during the course of the study without further intervention. Important is that no linear dose depending relationship between the administration of ferroquine and increase of liver parameters was observed in this study.Based on previous animal and human studies showing prolongation of the QT interval for chloroquine a special emphasis was laid on the assessment of cardiac effects -32. FerrIn conclusion, ferroquine showed a favourable tolerability and safety profile up to 1,600 mg when administered as single dose, and appears to be well tolerated up to 800 mg once daily for three days. Although gastrointestinal disorders (including nausea and vomiting) and nervous system disorders (including dizziness and headache) appear to be the prevalent clinical adverse events, the liver is the potential target organ and it should be carefully monitored via liver function tests. Ferroquine has the potential to prolong the QTc interval and affect T wave morphology. Subjects should undergo careful ECG monitoring while taking this investigational product.Authors declare no conflict of interest. This study was funded by the Department of Research of Sanofi-Aventis as part of the developing programme of ferroquine. Part of this work was presented as dissertation by GMN for his medical degree's thesis at the Faculty of Medicine in Libreville, Gabon, MK, PGK and BL were co-directors of the thesis (Université des Sciences de la Santé (USS), Thesis n°524, 2006)GMN carried out the safety study and drafted the manuscript. CS, MDB, MAM, PBM, COS, BL carried out the study. MK, MR, PGK participated in the design of the study and performed the statistical analysis. DTM and BL conceived of the study, and participated in its design and coordination. All authors read and approved the final manuscript.


Inflammatory bowel diseases, ulcerative colitis and Crohn’s disease are considered to be of autoimmune origin, but the etiology of irritable bowel syndrome remains elusive. Furthermore, classifying patients into irritable bowel syndrome and inflammatory bowel diseases can be difficult without invasive testing and holds important treatment implications. Our aim was to assess the ability of gene expression profiling in blood to differentiate among these subject groups.Transcript levels of a total of 45 genes in blood were determined by quantitative real-time polymerase chain reaction (RT-PCR). We applied three separate analytic approaches; one utilized a scoring system derived from combinations of ratios of expression levels of two genes and two different support vector machines.All methods discriminated different subject cohorts, irritable bowel syndrome from control, inflammatory bowel disease from control, irritable bowel syndrome from inflammatory bowel disease, and ulcerative colitis from Crohn’s disease, with high degrees of sensitivity and specificity.These results suggest these approaches may provide clinically useful prediction of the presence of these gastro-intestinal diseases and syndromes. CD is me colitis. When the colitis.(p-ANCA) and anti-Saccharomyces cerevisiae antibody (ASCA) have been reported to be markers for UC and CD, respectively. However, p-ANCA is also detected in 10–40% of patients with CD and ASCA is detected in 6–14% of patients with UC[a) Escherichia coli outer membrane porin C (Omp-C), (b) protein from Pseudomonas fluorescens[c) flagellin c-BIR1 (anti-CBIR1)[ANCA, ASCA, I2 (antibody to Pseudomonas fluorescens), and Omp-C, have significantly higher post-operative complications[Developing biomarkers that can be easily obtained and allow for the correct diagnosis early into evaluation can avoid costly interventions that expose patients to multiple unnecessary procedures. Blood markers for both IBD and IBS have been sought for decades. For IBD, perinuclear antineutrophil cytoplasmic antibody uorescens and (c) ications. Other iications, but tesications.e.g., heirarchical clustering, K-means clustering, which depend upon the general ability to find common features across a sample population or forms of linear discriminate analysis, which depend upon the ability to find linear combinations of features that have the ability to separate two or more classes. The former method is a common method to analyze large numbers of features, such as microarray data whereas the latter is a more common method for analysis of smaller numbers of features. Both methods are suitable for further analyses using machine learning methods such as support vector machines, logistic regression, principal components analysis or prediction analysis for microarrays. Using a form of linear discriminant analysis, we have attempted to employ mRNA transcript profiles to distinguish between subjects with multiple sclerosis and other comparator groups[Additional biomarker candidates include DNA variants, differences in RNA transcript abundances, including mRNAs, microRNAs, long intergenic non-coding RNAs, proteins, or metabolites. A general view is that different profiles of biomarkers could provide useful information to guide clinical decision-making; from diagnosis to choice of optimal therapies and in some cases these biomarker profiles are being implemented in clinical practice,12-24. Sr groups,26. Our Blood samples collected in PAXgene tubes were obtained from CTRL, IBS, CeD, CD or UC subjects. Diagnosis of IBD, both CD and UC, was made by colonoscopy or sigmoidoscopy and tissue biopsy to localize inflammation to all layers of the intestinal wall (CD) or only the inner lining layer (UC). Diagnosis of IBS was made by the absence of pathologic damage in the colon after examination by colonoscopy or sigmoidoscopy. Inclusion criteria were diagnosis by a gastro-intestinal specialist using these methods. Age, race and gender were not statistically different among the different study groups. Time of blood draw, for example, morning/afternoon clinics, was also not statistically significant among the different study groups. Relevant institutional review board  approval was obtained from all participating sites. Informed consent was obtained from all subjects.housekeeping genes in 300 ng cDNA. The gene probes on the TLDA plate were: ABR, ACTB, ACTR1A, ADAMTSL4, ANAPC1, APOBEC3F, ASL, B2M, BRCA1, CD55, CDH1, CDKN1B, CHEK2, CSF3R, CTSS, EPHX2, EXT2, FOS, FOSL1, GAPDH, GATA3, GNB5-1, GNB5-1, GSTM4, HLA-DRA, HRAS, IFI27, IL11RA, JUN, KRAS, LEPREL4, LLGL2, NRAS, OAS1, ORC1L, PGK1, PMAIP1, POU6F1, RANGAP1, SC65, SPIB, TAF11, TBP, TGFBR2, TP53-1 TP53-2, TXK. GNB5-1 and −2 and TP53-1 and −2 interrogate different exon-intron junctions[a) previous studies demonstrating differential expression among control and multiple autoimmune diseases, (b) protein products possess known inflammatory functions, (c) expression levels change in response to pro-inflammatory stimuli (cytokines), and/or (d) protein products have known roles in cell cycle progression and/or apoptosis. Patient diagnosis was blinded for all experimental procedures. Relative expression levels were determined directly from the observed threshold cycle (CT).Total RNA was purified using Qiagen’s RNA isolation kits using standard protocols and was reverse-transcribed using poly-A primers uisng Superscript III . A TaqMan Low Density Array (TLDA) was designed to analyze expression levels of 44 target genes and of four unctions. InclusiBioinformatics Toolkit  and other techniques to identify a lower dimensional space of gene expressions that could be used to classify controls from cases. The results were disappointing and we concluded that looking at ratios of the gene expression data may be a more productive approach. The computational algorithm and permutation testing strategy employed to identify discriminatory combinations of ratios to create the ratioscore (our terminology) have been previously described[D denote the set of gene-expression levels associated with the disease group and C denote the set of gene-expression levels associated with the control group. The algorithm searches for the “best” set of gene ratios that partitions D and C:Principal Component Analysis (PCA) was applied directly to the normalized gene expression data using MATLAB’s escribed. For comD and C. For each ratio, the number of elements in the disease group that are larger than the largest ratio in the control group is computed. The top 500 ratios that separate elements in D and C are saved. This calculation is repeated 200 times resulting in a set of 200 subsets of ratios (each subset having 500 ratios).• 80% of the control and disease groups are randomly selected. Gene-expression level ratios are formed for elements in R={r1, r2, …, rn}, that produce the maximum of separation of D and C. Associate with each of the ratios in R, there are threshold values, T={t1, t2, …, tn}, which correspond to the highest value in the control group for each of the ratios in R.• The 500 subsets are then processed looking for the smallest number of ratios, D, the ratios in R are computed, {α1, α2, …, αn}. If αi ≥ ti, then we assign the ratio a 1; otherwise, it is assigned a 0. In this way, we generate an n-tuple of 1’s and 0’s for each member of D. For example, if n = 6, then a typical 6-tuple would be {1,1,0,0,1,0}. This would mean that this individual in the disease group would have 3 ratios that exceed the corresponding ratios in the control group.• For each member of the disease group n-tuples is calculated. The larger the percentage, the better the separation of D and C.• Lastly, the percentage of members in the disease group that have nonzero The algorithm alllows one to identify the smallest number of ratios that partitions the case and control groups.Mathematica  and the second SVM employed LS-SVMLab software (http://www.esat.kuleuven.be/sista/lssvmab). We decided to use the two independently developed SVM since the choice of kernels, optimization algorithms, and the training algorithms can produce differing results. There was little difference in the performance of the two machines when classifying the different case–control combinations. To confirm the results of the Ratioscore Method and the SVM approaches, logistic regression was employed to separate to the case and control sets using the gene ratios. Its performance was in line with the other two approaches and hence, we have chosen not to report these results.Two support vector machines (SVM) were independently created and trained using ratios identified by the Ratioscore Method. The first SVM was coded in The Welch’s-corrected T-test not assuming equal variances was employed to calculate p-values in two-way comparisons. Fisher’s exact test was employed to calculate p-values in 2 by 2 comparisons. The Bonferroni’s method was employed to correct for multiple testing.GAPDH transcript levels. We employed a heatmap to depict those genes differentially expressed in individual subject cohorts relative to the CTRL cohort, p-value < 0.05 , IBS subjects were recruited from multiple sites within the United States. Demographic characteristics of the different gastrointestinal disease cohorts were not statistically different from the CTRL cohort Table. We measGAPDH, gene expression data from IBD samples or IBS samples and CTRL samples were analyzed using unsupervised and supervised heirarchical clustering using all genes or only those genes whose expression was statistically significant using the supervised T-test. We found that unsupervised heirarchical clustering segregated 72% of IBD samples in one major branch and 28% of IBD samples in the second major branch. Similarly, 36% of CTRL samples were segregated into the branch with most of the IBD samples while 64% of CTRL samples were segregated into the alternate branch. Comparison of IBS and CTRL using unsupervised heirarchical clustering also did not produce the desired level of discrimination between case and control cohorts. Supervised heirarchical clustering and principal components analysis produced a similar low level of overall accuracy.Initially, we employed standard methods of microarray analyses including unsupervised heirarchical clustering, supervised heirarchical clustering, and principal components analysis using the TIGR microarray software Multiexperiment Viewer to segregate patient groups. After normalization to housekeeping genes in the analysis and the assumption that expression levels of housekeeping genes did not vary among different subject populations. Third, comparisons of ratios or combinations of ratios may more accurately identify cellular phenotypes that may contribute to disease. For example, a ratio containing one gene in the numerator that is over-expressed in the case cohort relative to the control cohort and one gene in the denominator that is under-expressed in the case cohort relative to the control cohort should produce a greater ratio value difference between individuals in the two cohorts than a single expression value. Fourth, ANAPC1, RANGAP1, and LEPREL4 genes encode unique proteins and each participates in mitosis[ANAPC1 while a second individual with the same disease may exhibit a deficiency in expression of RANGAP1 and a third with the same disease may exhibit a defect in LEPREL4 expression levels. Any of these defects has the potential to produce a common cellular phenotype. Our approach makes it possible to capture each subject as positive for a given disease. We refer to this as the Ratioscore Method.For these reasons, we turned to a type of linear discriminant analysis classifier (Ratioscore Method) that we employed previously to discriminate subjects with multiple sclerosis from different control cohorts. We employed a search algorithm to identify those ratios of gene-expression levels in which the greatest number of subjects in the test group possessed a ratio value greater than the highest ratio value in the comparator group. We employed a second algorithm to perform permutation testing of one subject group to identify the optimum set of discriminatory ratios. CeD was excluded from this analysis due to the low number of cases in this cohort. Examination of expression levels of ratios of genes rather than individual genes offered the following advantages. First, ratios normalized for differences in mRNA or cDNA template quantity and quality among different samples. Second, ratios obviated the need for inclusion of a  mitosis-33. ThusPGK1/POU6F1 . This introduced a second fitting parameter C. Programs written in Mathematica  were created and random training subsets of the two groups were chosen to find the parameters, β and C. Each training subset consisted of 60% of the total dataset. The values of the two fitting parameters that produced the smallest number of incorrect cases and controls were used to define the SVM. This SVM analysis also accurately discriminated the different subject groups: (i) IBD and CTRL, (ii) IBS and CTRL, (iii) IBD and IBS, and (iv) CD and UC (TableSupport Vector Machines (SVM) were also employed to classify the data into two distinct groups. The inputs for the SVM were the same ratios used to calculate the ratioscores. For example, when separating IBS patients from CTRL subjects, the same 19 ratios of normalized gene-expression ratios employed to compute the ratioscore were used as input to the SVM. In the SVM calculations, we chose the radial basis kernel (RBK) to perform the UC Table.LS-SVMLab software (http://www.esat.kuleuven.ac.be/sista/lssvmlab) to validate the SVM created with Mathematica. The procedure for training the SVM followed the following algorithm:A second SVM was also employed using X  was randomly selected from the total set of data and used to train the SVM.• L-fold cross-validation was performed. In this type of training a certain fraction of the training set was omitted from training and the remaining portion of the partial training set was used to estimate the parameters of the SVM. This was repeated L times. We used L = 10. At the completion of the training, a composite estimate for the parameters was obtained.• On the selected training set, X% of the total data, the SVM was applied to the total data set.• Once the SVM was trained on Numbers of correct and incorrect classifications were tabulated for total sets , training sets and validation sets Table. OverallThis second SVM was used to discriminate between the different subject groups, IBD and CTRL, IBS and CTRL, IBD and IBS, and CD and UC producing levels of sensitivity and specificity comparable to the Ratioscore Method or the first SVM method Table. We detee.g., the union of the set from CTRL vs. CD, CTRL vs. UC, and CD vs. UC. In this case, the SVM identified 99.1% of CTRL, 100% of UC, and 84.8% of CD. One factor that may contribute to this increased accuracy is that the number of gene ratios used in the training of the SVM was increased from 23 ratios to 49 thus introducing additional parameters into the SVM structure.In the above discussion, two support vector machines were independently created and trained using the ratios identified by the Ratioscore Method. There was little difference in the performance of the two machines when used to classify the different case–control combinations. One advantage of the SVM-based approach is that it can be used to classify more than two groups. As an example of classification into three groups, we considered data for UC (N = 40), CD (N = 46), and CTRL (N = 113). Using gene ratios determined by comparing CTRL (controls) to UC+CD (cases), the SVM identified 99.8% of CTRL, 72.5% of UC, and 56.5% of the CD. Hence, the performance of the tertiary classification was not as accurate as the binary classifications. However, the tertiary classification was improved by using a different set of gene ratios, ASCA and p-ANCA have clinical utility in diagnosing IBD. ASCA IgA is found in 35-50% of patients with CD but < 1% of patients with UC. ASCA IgG is found in 50-80% of patients with CD but only 20% of patients with UC. In contrast, atypical p-ANCA is found in 70% of UC patients but only 20% of CD patients[a) IBS and IBD, and (b) the two forms of IBD, UC and CD, using three independent methods based upon transcript levels in blood of a discrete set of genes. Each method employs the same input, which are multiple ratios of expression levels of two genes. The analytic methods, ratioscore, two SVM methods, and logistic regression, produce similar levels of overall accuracy determined by ROC curves which exceed 95%. We have summarized the overall process of going from the raw samples to classification in FigureIBS and IBD can exhibit overlapping clinical symptoms making diagnosis difficult without invasive procedures,12,34. Tpatients. Here, wIn contrast, biomarkers for IBS are non-existent and diagnosis largely depends upon the absence of pathological findings in the colon. Previously identified experimental biomarkers to distinguish UC and CD clearly do not perform with the same degree of accuracy as experimental approaches described here. Thus, we propose these gene expression ratio tests using the Ratioscore Method, SVM, or logistic regression for analysis represent simple non-invasive tests that could accurately classify patients to IBS or IBD categories and IBD patients to UC or CD categories even without colonoscopy or sigmoidoscopy and tissue biopsy.PGK1 is associated with IBS, CeD, CD, and UC and PGK1 is known to be induced by hypoxia and may be induced by other forms of stress, inflammation or generalized mucosal irritation[ABR, ACTR1A, EXT2, HRAS, and KRAS are over-expressed in both IBS and CeD but not CD and UC. In contrast, APOBEC3F, ASL and SPIB are under-expressed in CD and UC, but not IBS and CeD. Thus, the IBS gene-expression signature is more similar to the CeD gene-expression signature and the UC signature is more similar to the CD signature. It is uncertain if this suggests that IBS may bear additional relationships to CeD. An improved understanding of mechanisms producing differences in levels of specific gene transcripts in IBS may further our understanding of the pathogenesis of IBS.UC and CD are chronic inflammatory autoimmune diseases. Using various strategies, numerous studies have identified unique gene-expression signatures in blood or peripheral blood mononuclear cells (PBMC) associated with different autoimmune diseases. Some arritation. FurtherLimitations to our study include selection of patients with pre-existing diagnoses of IBS and IBD, as this may not completely represent patients in the general population in whom these tests may be performed. However, in other studies we have shown that subjects with clinically isolated syndrome, a precursor of multiple sclerosis, who progress to a diagnosis of multiple sclerosis score positive in ratioscore- or SVM-based analyses, similar to those described here. This may suggest that subjects with initial clinical symptoms associated with IBD or IBS, CD or UC, may be discriminated by this approach. Future longitudinal approaches are planned to evaluate utility of these tests. Additional methods, such as analysis of gene-expression ratios in multi-dimensional space rather than binary space may improve the diagnostic capabilities of these tests. We employed three independent approaches to evaluate the ability of gene-expression ratios to discriminate subjects with gastro-intestinal diseases with overlapping clinical symptoms and each produced high degrees of specificity and sensitivity. Thus, these minimally invasive tests may assist in excluding or establishing a diagnosis of IBS or IBD, CD or UC.IBD: Inflammatory bowl disease; IBS: Irritable bowel syndrome; CD: Crohn’s disease; UC: Ulcerative colitis; CeD: Celiac’s disease; CTRL: ConTRoL ; PBMC: Peripheral blood mononuclear cell; SVM: Support vector machine; RBF: Radial basis function; RBK: Radial basis kernel.NJO and TMA are co-owners of ArthroChip, LLC. No conflicts exist for other authors.SNH, DAS and DBB were responsible for the collection and cataloging of the patient data. JTT and MAH performed the processing of the patient data. PSC, JLT, NJO and TMA developed the modeling and computational processing of the laboratory data.


Physical activity decreases deaths from cardiovascular disease and other causes; however, it is unclear whether physical activity is associated with cancer incidence and death in Asian populations.Data from 59 636 Koreans aged 30 to 93 years were collected using a questionnaire and medical examination at the Severance Hospital Health Promotion Center between 1994 and 2004. Study participants were followed for a mean duration of 10.3 years.In the exercising group, the multivariate Cox proportional hazards model showed a lower risk of cancer death  in men but not in women. Those who exercised, as compared with those who did not, had lower risks of all-cause death  and noncancer death . Physical activity was inversely associated with risk of noncancer death among men and women.Physical activity was associated with lower risks of cancer death and noncancer death. Studies have found a dose–response relationship,8 as well as reverse J-shape,9 L-shape,10 J-shape, and U-shape11 associations, between physical activity and all-cause death. Cancer is now the leading cause of death in South Korea. Between 1999 and 2009, cancer deaths increased from 114.2 to 140.5 deaths per 100 000 person-years in Korean adults.12 According to recent reports, physical activity has beneficial effects on cancer risk.13 However, most studies of the benefits of exercise have focused on death from CVD5,6,10,14–17 rather than cancer risk13,15–17 or cancer mortality,5,6,10,14–16 and most studies have investigated Western populations. Large-scale follow-up studies have been conducted in only 2 Asian countries.13,18Regular physical activity prevents obesity,19 is a relatively accurate measure of physical activity.20 However, it would be more useful for predicting individual health status if simple MET-min/week values were calculated based on a few types of common physical activities. Therefore, the purpose of this study was to use simple MET-min/week calculations from 9 common physical activities to determine the association of physical activity with cancer incidence and mortality, using data collected from participants enrolled from 1994 through 2004 at the Severance Hospital Health Promotion Center.Metabolic equivalent of task (MET)-min/week calculated from walking, moderate physical activity, and vigorous physical activityThe cohort consisted of 70 862 Korean men and women who ranged in age from 20 to 93 years and participated in at least 1 medical evaluation at the Severance Hospital Health Promotion Center between 1994 and 2004. To avoid the confounding effect of a pre-existing condition on the association of physical activity with death, we excluded 4323 participants younger than 30 years, 119 participants who reported having any cancer, 687 participants who reported having cardiovascular disease, and 327 participants who reported having lung disease or asthma. In addition, we excluded 4695 participants with missing information on smoking status or alcohol intake and 95 participants with missing exercise information. The final study sample included 59 636 participants. Written consent was not obtained from participants before 2005. However, after 2004 such consent was obtained from all participants after nurses explained the purpose of the study. The Yonsei University Institutional Review Board on Human Research approved this study.Participants were asked to describe their smoking habit , alcohol consumption , and demographic characteristics such as age, sex, and past history of diabetes or hypertension. Body weight and height were measured while participants were wearing light clothing. A registered nurse or technician measured blood pressure (BP) using a standard mercury sphygmomanometer while participants were in a seated position. Systolic and diastolic BP was measured after a minimum 5-minute rest period.For the clinical chemistry assay, serum was separated from peripheral venous blood samples that were obtained from each participant after a minimum of 12 hours of fasting and stored at −70°C. Biomarkers of metabolic syndrome such as fasting blood glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride levels were measured using a Hitachi 7600 analyzer . All measurements were performed by the central laboratory at Severance Hospital, Yonsei University Health System, Seoul, Korea. Data quality was maintained in accordance with the procedures of the Korean Association of Laboratory Quality Control.21 which was calculated based on the energy expended by sitting quietly. Next, we multiplied the MET value of each activity by the average amount of time spent exercising (minutes per exercise) and by frequency of exercise per week. Finally, we calculated MET-min/week to estimate physical activity levels.The main parameter in the present study was physical activity level. In our survey, 4 questions on physical activity were asked during the baseline evaluation. The first question was “Do you exercise regularly?”. The possible responses were “yes” and “no”. If participants answered “yes”, they went on to the next question, which was “If you exercise, which of the following 9 types of physical activity do you do: jogging, rope jumping, walking, mountain climbing, calisthenics, swimming, yoga, aerobics, or golf?”. The next question asked the average amount of time spent (minutes per exercise) exercising and what physical activity (of 9 options) was frequently done during the week. Each activity on the questionnaire was assigned a MET value,Participants were followed from their starting point until 31 December 2010. Cancer incidence was identified via notification from the National Cancer Center until 31 December 2008. We calculated total cancer incidence after identifying participants who received a diagnosis of any cancer according to data from the Korean National Cancer Center. Computerized searches for death certificates were performed until 31 December 2009, using the identification number assigned at birth by the National Statistical Office. Because cause of death was not included in our data, we used the category noncancer death, which was defined as the difference between all-cause deaths and cancer deaths.We divided our study samples into 3 groups based on physical activity level . Additionally, we created a category for diabetes by combining participants with self-reported antidiabetic treatment or a fasting serum glucose level of 126 mg/dL or higher. Hypertension was defined as a systolic BP of at least 140 mm Hg, a diastolic BP of at least 90 mm Hg, or self-reported antihypertensive treatment.P value less than 0.05.Multiple regression analyses were used to examine the association between physical activity level and cardiovascular risk factors at baseline. Also, we examined the association of physical activity level with cancer incidence, all-cause death, cancer death, and noncancer death. Cox proportional hazards models were examined after adjusting for age and other potential confounding factors, including smoking status, alcohol consumption, body mass index, hypertension, diabetes, and dyslipidemia. To avoid the possible confounding effects of health status on physical activity, we excluded participants who received a cancer diagnosis or died within 3 years of the starting point. Cox proportional hazards models were used to estimate the risk of cancer and death from all causes, cancer, and noncancer, after these exclusions. All analyses were performed separately for men and women, using SAS statistical software version 9.1 . All statistical tests were 2-sided, and statistical significance was defined as a The characteristics of the participants by MET-min/week are shown in Table As physical activity increased, the β-coefficient for diastolic BP and ALT significantly decreased, and that for HDL cholesterol significantly increased, in men and women .Table Table In this cohort study, physical activity was associated with cancer incidence, all-cause death, cancer death, and noncancer death. Greater physical activity had a positive effect on noncancer deaths and all-cause deaths among both men and women.In this study, men who were more physically active were more likely to have hypertension and type 2 diabetes, which suggests that highly physically active men have a greater chance of having a diagnosis of hypertension and type 2 diabetes. This could be the result of reverse causality in this cross-sectional study, ie, men newly diagnosed as having hypertension or type 2 diabetes might increase their physical activity, while women already exercise and have a low chance of being diagnosed as having hypertension or type 2 diabetes before menopause.22 and decrease BP.23 Also, physical activity is inversely associated with ALT level.24 Elevated ALT is associated with metabolic syndrome, independent of insulin resistance,25 and predicts CVD.26We found that physical activity was associated with diastolic BP, HDL, and ALT . Regular8–11 and reported an inverse dose–response relationship between them8; however, some studies have shown a reverse J-shaped,9 L-shaped,10 J-shaped, or U-shaped11 curve. We found that physical activity was associated with a slight inverse dose–response relationship. The findings were similar after excluding deaths and cases of new cancer within 3 years of the starting point.We found that physical activity was inversely associated with all-cause death. Many studies have examined the association between physical activity and all-cause death27 Therefore, our results may not be related to total cancer incidence. Those who regularly exercised had a lower risk of cancer death as compared with those who did not exercise. Only a few studies have explored the association between cancer risk and physical activity.13,28,29Physical activity was associated with cancer death only among men. However, the relationship between physical activity and cancer incidence was not significant. The effect of physical activity on cancer differs by cancer site.13 The insulin/insulin-like growth factor (IGF) axis influences cell proliferation, differentiation, and apoptosis,30 and IGF-1 has an important role in carcinogenesis.31 Physical activity increases insulin sensitivity and decreases C-peptide levels, which improves insulin resistance.32 Thus, regular physical activity may influence cancer incidence and death via the IGF axis.The mechanisms by which physical activity affects cancer development at different sites are similar.12 Therefore, our results may be related to the number of CVD deaths and can be explained by the fact that physical activity was positively correlated with HDL and inversely correlated with DBP and ALT in this study. The association between physical activity and CVD is well-known. However, the intensity of physical activity that is needed to prevent CVD is unclear. In some studies, only vigorous physical activity reduced CVD risk,33,34 while other studies suggested that non-vigorous physical activity was sufficient to reduce CVD risk.35,36 The present study found that physical activity was inversely associated with noncancer death. After exclusion of early deaths (those within 3 years of the study start), the results were unchanged. Previous studies have suggested that physical activity had an effect on CVD risk factors such as total, HDL, and LDL cholesterol and triglyceride levels.37,38We found a significant inverse association between physical activity and risk of noncancer death. In Korea, cancer is the leading cause of death, followed by CVD.13 That study assessed various activity categories, such as leisure-time and non-leisure time activity . In the present study, we assessed physical activity by asking participants to choose only among leisure activities. Although the methods of assessment differed between the 2 studies, both found that physical activity was inversely associated with cancer risk.There have been few follow-up studies of large Asian populations. One such study found an association between cancer incidence and physical activity in Japan.39The present study design was prospective, and the large study population was selected from the general population of Korea. An important limitation of the present study was that assessment of physical activity was based on self-reports; therefore, some misclassification was unavoidable. Also, on our questionnaire, only 1 response was checked for type of physical activity, which may have led to an underestimation of the associations. We do not have validation data for our calculation of MET-min/week. This is relevant because participants tend to over-report their physical activity, including duration and frequency of physical activity performed on a given day, which might have resulted in overestimation of the true relationship.In conclusion, physical activity affects cancer incidence, all-cause death, cancer death, and noncancer death. Physical activity was inversely associated with noncancer death and all-cause death in both men and women. There is a need for further research on the association of physical activity with the risks of specific cancers and death in the general population. In addition, optimal activity levels should be determined in mechanistic studies of physical activity intensity.


To investigate CT characteristics of Castleman and their pathologic basis.Thirteen cases of pathologically proved Castleman, encountered in our hospital during a period of five years, were collected in this study. The diagnoses were confirmed by surgery in all patients. The surgical, histopathologic records, and CT images were reviewed.The lesion was localized in 5 and diffusely distributed in 3 cases. Pathologically, 5 cases belonged to hyaline vascular type and 3 cases belonged to plasma cell type, which 1 had retroperitoneal, 2 had mesentery and 5 had chest lesions. On CT scan, all cases showed round or ellipse soft tissue masses, with satellite nodules in 3 cases, and calcification in 3 cases. Enhanced scanning revealed obvious enhancement in the arterial phase and continuous enhancement in the vein and delayed phase in all the lesions, enlarged blood vessels within or around the mass were displayed in 3 case. In 3 cases, the intra-tumoral radial or fissured non-enhanced areas in early stage of enhancement were gradually filled up as the scan time was delayed.Castleman’s disease is rare and liable to misdiagnosis, a mass with benign characters, with calcification, especially delayed enhancement, can help in the diagnosis and differential diagnosis.


Objective: Because cholinergic deficits are prominent in dementia with Lewy bodies (DLB), we investigated the effects of a cholinesterase inhibitor, donepezil, in such patients in a randomized, double-bilnd- placebo-controlled exploratory phase 2 trial.Methods: One-hundred forty patients with DLB, recruited from 48 specialty centers in Japan, were randomly assigned to receive placebo or 3, 5, or 10mg of donepezil hydrochloride daily for 12 weeks . Effects on cognitive function were assessed using the Mini-Mental State Examination (MMSE) and several domain-specific neuropsychological tests. Changes in behavior were evaluated using the Neuropsychiatric Inventory, caregiver burden using the Zarit Caregiver Burden Interview, and global function using the Clinician’s Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus). Safety measures included the Unified Parkinson’s Disease Rating Scale part III.Results: Donepezil at 5 and 10mg/day was significantly superior to placebo on both the MMSE  and CIBIC-plus (p < 0.001 for each); 3mg/day was significantly superior to placebo on CIBIC-plus (p < 0.001), but not on the MMSE (p = 0.017). Significant improvements were found also in behavioral measures (p < 0.001) at 5 and 10mg/day and caregiver burden (p = 0.004) at 10 mg/day. The safety results were consistent with the known profile of donepezil and similar among groups.Interpretation: Donepezil at 5 and 10mg/day produces significant cognitive, behavioral, and global improvements that last at least 12 weeks in DLB patients, reducing caregiver burden at the highest dose. Donepezil is safe and well tolerated. Dementia with Lewy bodies (DLB) is a common form of dementia in the elderly, and constitutes the second largest group of patients with dementia after Alzheimer disease (AD).D-aspartate receptor antagonist, was also tested in 2 RCTs including DLB patients; however, the results were equivocal.Cholinergic loss in DLB is associated with deficits in attention and cognition, and also with neuropsychiatric symptoms.Patients who met the consensus diagnostic criteria−1); sick sinus syndrome; atrial or atrioventricular conduction block; QT interval prolongation (≥450 milliseconds); hypersensitivity to donepezil or piperidine derivatives; severe parkinsonism (Hoehn and Yahr score ≥ IV)Exclusion criteria included Parkinson disease diagnosed at least 1 year prior to the onset of dementia; focal vascular lesions on magnetic resonance imaging or computed tomography that might cause cognitive impairment; other neurological or psychiatric diseases; clinically significant systemic disease; complications or history of severe gastrointestinal ulcer, severe asthma, or obstructive pulmonary disease; systolic hypotension (<90mmHg); bradycardia  and his/her caregiver before initiating the study procedures. The study was conducted in accordance with the principles of the Declaration of Helsinki. The protocol was approved by the institutional review board at each center.This was a multicenter, randomized, double-blind, parallel-group, placebo-controlled study. Treatment lasted 14 weeks, including a 2-week prerandomization period followed by a 12-week randomization period. All participants were given placebo tablets during the prerandomization period, after which the patients were randomly assigned in a 1:1:1:1 ratio to placebo, 3, 5, or 10mg of donepezil. The randomization list was computer-generated using a randomized block design to allocate several blocks (size 4) to each center. Patients were sequentially assigned to the lowest randomization number available at the time of each enrollment at each center. The randomization list was securely managed by an allocation officer, who was independent of all parties concerned with the study, at Bellsystem24, Tokyo, Japan, until study completion. Access to the list was not allowed except in emergency. Study personnel and participants were unaware of the treatment assignment. During the study period, the code was broken for 2 patients: 1 each in the placebo and 3mg arms because of serious adverse events .Patients received 2 study drug tablets, which were composed of a combination of 3mg, 5mg, or matched placebo tablets with the same physical appearance, once daily in the morning. Dosage was titrated at the beginning of the randomization period in the 5 and 10mg groups. In the 5mg group, treatment began with 3mg for 2 weeks, and then the dose was increased to 5mg. The 10mg group started with 3mg for 2 weeks, followed by 5mg for 4 weeks, after which the 10mg dose was provided for 6 weeks. The dose was escalated after patient safety was confirmed by telephone interview.This study had no formal predefined primary endpoint. However, cognition, behavior, global function, and caregiver burden were determined as core efficacy outcomes prior to the study initiation.Efficacy was assessed at baseline and weeks 4, 8, and 12. Cognition was assessed using the MMSE.Behavior was assessed using the NPI-plus .Changes in global clinical status were assessed by an experienced clinician who was not involved in patient management or other assessments, using the Clinician’s Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus), with 7 grades ranging from Marked Improvement to Marked Worsening.Caregiver burden was assessed using the Zarit Caregiver Burden Interview (ZBI), which evaluates the physical, psychological, and social consequences of caring activities.Motor function was assessed as a safety measure using the Unified Parkinson’s Disease Rating Scale (UPDRS) part III at baseline and week 12.The sample size was originally defined as 160 patients (40 in each arm) on the basis of feasibility considerations. However, because of recruitment difficulties, the sample size was reduced to 140. Although no formal calculation of power was performed, this number of patients should have provided a roughly 80% power to detect a 40% difference in responder rates (see definition below) between the active and placebo arms with a 2-sided significance level of 0.0167.The safety analysis set comprised all patients who received at least 1 dose and had a postbaseline safety assessment. Efficacy analyses were performed on the full analysis set, which consisted of all patients who had at least 1 valid postbaseline assessment on any of the efficacy scales, with the last observation carried forward (LOCF).Imbalances in baseline demographics and background characteristics were assessed by analysis of variance (ANOVA), Kruskal-Wallis test, or chi-square test, with a 2-sided significance level of 0.15.t test and analysis of covariance (ANCOVA), with baseline values  as covariates. In addition to the LOCF analysis, the mixed-effect model for repeated measures was applied to analyze data with dropouts as the secondary approach. For CIBIC-plus, the Wilcoxon rank sum test was used to compare the grade distributions between each active group and placebo. In addition, the MMSE and CIBIC-plus were analyzed by number of responders, defined as a ≥3 point improvement on the MMSE and as -minimal improvement- or better on the CIBIC-plus. Fisher exact probability test was used to compare each active group to placebo. The dose-response relationship (linear or 5mg saturation) across the 3 doses was also analyzed, as a secondary analysis, by ANOVA with contrasts for the MMSE and NPI, and by Cochran-Armitage test with contrasts for the CIBIC-plus. Significance levels were set at 2-sided 0.0167 for comparison with placebo (multiplicity adjustment by Bonferroni method) and 2-sided 0.05 for trend analysis.For efficacy, mean changes from the baseline in each outcome measure other than CIBIC-plus were compared between each active group and placebo by both Student t test and ANCOVA, with baseline values as covariates. Significance level was set at 2-sided 0.05 for safety analysis.The incidence of AEs was calculated, and group differences were examined by Fisher exact probability test. For laboratory parameters and vital signs, descriptive statistics and frequency distributions were calculated. UPDRS part III scores were compared between each active group and placebo by both Student All analyses were made on SAS version 9.1.3 .Of the 167 patients screened in the prerandomization period, 140 were randomized to the 4 groups . In the randomization period, 1 patient in the placebo group was withdrawn before receiving the study drug due to refusal, and was excluded from the safety analysis set. Two patients (1 each in the placebo and 10mg groups) who did not meet probable DLB criteria and 2 patients (1 each in the placebo and 5mg groups) with no postbaseline efficacy assessments were excluded from the full analysis set. Thus, the safety analysis set included 139 patients , and full analysis set included 135 patients . Sixteen patients  withdrew during the study; LOCF was applied to them . In the Baseline patient characteristics are summarized in Table p < 0.001; 10mg, 2.0, p = 0.001) than in the placebo group  compared to placebo (12.9%). No dose dependency was demonstrated on trend analysis. On the WMS-R attention/concentration and WAIS-III symbol digit tests, significant improvements were also noted in each dose group compared to placebo. No significant improvement was detected on the verbal fluency and visuoperceptual tests.Mean changes in MMSE scores were significantly higher at the final evaluation (LOCF) in the 5 and 10mg groups  but not for NPI-4 and NPI-10.Scores for NPI-2 and NPI-4 were significantly more improved at the final evaluation (LOCF) in the 5mg (except NPI-4) and 10mg groups than in the placebo group .The NPI-plus domains Delusion, Hallucination, and Cognitive Fluctuation improved in all active groups, whereas they deteriorated in the placebo group Fig . The difp < 0.001 for each group; Table p = 0.010; 5mg, p = 0.004; 10mg, p = 0.034). No dose dependency was demonstrated on trend analysis.The distributions of CIBIC-plus at the final evaluation (LOCF) in all active groups were significantly superior to that of placebo (p = 0.004), although the difference did not reach the significance level after baseline value adjustment .Also noteworthy was the improvement of neuropsychiatric features and reduction of caregiver burden in the donepezil groups. The beneficial effect of donepezil was evident on each symptom domain characteristic of DLB , as generally consistent with the previous rivastigmine studyPatients who received donepezil also demonstrated improved global function, as measured by CIBIC-plus. A higher percentage of patients showed improvement, and fewer patients worsened in each donepezil group than in placebo. The beneficial effect seemed greater than those of ChEIs reported for patients with AD and PDD.AEs were not rare; however, only approximately 8% of the study population withdrew due to AEs, and the prevalence of withdrawal or AEs, including typical cholinergic side effects, did not differ among treatment groups. Although symptoms of parkinsonism were reported as AEs somewhat more frequently in the 3 and 5mg groups than in the placebo group, the difference was not reflected in the mean UPDRS part III score. Indeed, the score demonstrated numerical, although nonsignificant, improvement in the highest dose group. Cholinergic treatment theoretically exacerbates parkinsonism. However, the possible beneficial effects of donepezil observed in this study suggest that the use of ChEIs should not necessarily be avoided in the treatment of DLB due to concern of possible parkinsonism. These unexpected effects, despite not being confirmed, might be explained by a complicated neuronal network for motor control.As the discontinuation rate was relatively low, and there was no significant difference among groups, it is unlikely that exclusion bias caused by early termination affected the efficacy results. Both the LOCF analysis and the mixed-effect model analysis consistently showed favorable results.As an aim of this study was to explore targetable clinical presentations of DLB, we did not set a specific primary endpoint despite assigning multiple efficacy outcome measures, which could be a major limitation. In addition, cognitive fluctuation was measured by an unestablished tool, which is well equipped but not yet validated. Another limitation is that nearly half of the centers enrolled only 1 or 2 patients, which may have caused an inter-rater discordance of the clinical ratings, although a training and certification course was mandatory for the investigators. Also, the small sample, short duration of treatment, and lack of formal dose-response comparison are evident limitations. Nevertheless, the results of this study strongly suggest that donepezil is safe in patients with DLB, and provide a preliminary indication of its clinical effectiveness in terms of cognitive function, behavioral symptoms, and global function of DLB, and consequently in effecting a reduction of caregiver burden. The findings of the present study with donepezil should be verified in a confirmatory clinical trial. In addition, long-term effects should be examined. Although both 5mg/day and 10mg/day seemed to be beneficial, 10mg/day was somewhat more beneficial in terms of behavioral symptoms. The optimum dose should be determined in a follow-up trial, in which dose titration with patients unable to tolerate 10mg/day being allowed to take 5mg/day would be a sensible design.


We report a case series of successful treatment of intractable renal colic using parenteral lidocaine.Because of inconsistent responses to standard treatment with opioids and non-steroidal anti-inflammatory drugs in patients with renal colic pain, we decided to begin a trial of a single intravenous dose of lidocaine (approximately 1.5 mg/kg) slowly in eight patients with intractable renal colic who were referred to our emergency medicine department. The patients were six men and two women with a mean age at diagnosis of 34.62 years . The patients were of Iranian ethnic origin. The patients' degree of pain, based on Visual Analog Scale score upon entering our emergency medicine department, was recorded 10, 20, and 30 minutes after lidocaine injection. The patients' degree of pain decreased from a mean Visual Analog Scale score (±SD) of 8.87 ± 0.99  8.04 to 9.70) to a mean Visual Analog Scale score (±SD) of 1 ± 2.82 (95% CI -1.36 to 3.36) before and 30 minutes after lidocaine treatment, respectively. Two of eight patients experienced transient mild dizziness, and three of eight patients experienced minimal slurring of speech. No patient experienced serious adverse events.Parenteral lidocaine treatment can reduce pain dramatically or subtly. Numerous medications have been utilized for pain relief in patients with renal colic; however, no medication has yet been found to relieve pain quickly and completely. A variety of drugs are used to treat this condition, including anti-spasmodics, non-steroidal anti-inflammatory drugs (NSAIDs), and opioids . ParenteEight patients (mean age (±SD) 34.62 ± 4.34 years, six men and two women) with intractable renal colic who presented to our emergency department were enrolled into this study. All included patients previously underwent therapy with morphine and NSAIDs previously but were resistant to treatment. Adults with acute flank pain radiating to the groin, vomiting, and urinary symptoms were eligible for inclusion in the study. Every aspect of the present study was explained to the patients, and we obtained their written consent for participation in the study. The diagnosis of renal stone was confimed by ultrasonsgraphy and by the presence of red blood cells (RBCs) revealed by urinalysis . BecauseCase 1 was a 31-year-old Iranian woman who was referred to our emergency department because of refractory renal colic (resistant to morphine and NSAIDs). The patient had a history of renal colic, and, in spite of receiving morphine and NSAIDS previously, she mentioned no decrease in her degree of pain (VAS score 10 of 10). Her clinical examination revealed tenderness in her left costovertebral angle (CVA) radiating to the genitalia, which was associated with dysuria, urination frequency, and nausea. Abundant RBCs were detected by urinalysis, and moderate hydronephrosis of the left kidney was visualized by ultrasonography. After obtaining written consent from the patient, lidocaine 1.5 mg/kg was administered intravenously. Ten, twenty, and thirty minutes after lidocaine treatment, the patient's VAS scores decreased to 3 of 10, 0 of 10, and 0 of 10, respectively. After lidocaine administration, the patient experienced transient dizziness for less than one minute. The patient was followed up in the hospital until she was discharged. Follow-up was carried out by telephone for more than 24 hours after discharge. The patient experienced no colic pain during the follow-up period. On a planned KUB X-ray requested the day after her discharge from the emergency ward, a radiopaque stone was observed.Case 2 was a 32-year-old Iranian man who was referred to our emergency department because of refractory renal colic (resistant to morphine and NSAIDs). Despite the fact that he had previously received treatment with morphine and NSAIDs, he mentioned no regression in pain degree (VAS score 9 of 10). His clinical examination revealed tenderness in his right CVA radiating to the genitalia, which was associated with dysuria, hematuria, nausea, and vomiting. Abundant RBCs were revealed by urinalysis, and moderate hydronephrosis of his right kidney was visualized by ultrasonography. After obtaining written consent from the patient, lidocaine 1.5 mg/kg was administered intravenously. Ten, twenty, and thirty minutes after lidocaine treatment, the patient's VAS scores decreased to 2 of 10, 0 of 10, and 0 of 10, respectively. The patient experienced transient dizziness and slurring of speech lasting less than one minute after lidocaine administration. He was followed up in the hospital until he was discharged. The follow-up procedure was continued by telephone for more than 24 hours after discharge. The patient did not report any colic pain during the follow-up period. On a planned KUB X-ray requested the day after his discharge from the emergency ward, a radiopaque stone was observed.Case 3 was a 38-year-old Iranian man who was referred to our emergency department because of refractory renal colic (resistant to morphine and NSAIDS). The patient had a history of renal colic, and, in spite of receiving treatment with morphine and NSAIDs previously, he had no regression in pain degree (VAS score 10 of 10). His clinical examination revealed tenderness in the left CVA radiating to the genitalia, which was associated with dysuria, urination frequency, and nausea. Abundant RBCs were revealed by urinalysis, and mild hydronephrosis of the left kidney was visualized by ultrasonography. With the patient's written consent, lidocaine 1.5 mg/kg was administered intravenously. Ten, twenty, and thirty minutes after treatment, the patient's VAS scores decreased to 0 of 10, 0 of 10, and 0 of 10, respectively. After lidocaine administration, he experienced no adverse events. The patient was followed up in the hospital until he was discharged. His follow-up was extended until the day after discharge and was carried out by telephone. During the follow-up period, the patient reported no colic pain. On a planned KUB X-ray requested the day after his discharge from emergency ward, a radiopaque stone was observed.Case 4 was a 28-year-old Iranian woman who was referred to our emergency department because of refractory renal colic (resistant to morphine and NSAIDs). In spite of her previous treatment with morphine and NSAIDs, she had no regression in pain degree (VAS score 9 of 10). Her clinical examination revealed tenderness in her right CVA radiating to the genitalia, which was associated with dysuria, urination frequency, and nausea. Abundant RBCs were revealed by urinalysis, and mild hydronephrosis of the right kidney was visualized by ultrasonography. The patient's written consent was obtained, and lidocaine 1.5 mg/kg was administered intravenously. Ten, twenty, and thirty minutes after treatment, the patient's VAS scores decreased to 0 of 10, 0 of 10, and 0 of 10, respectively. After lidocaine administration, she experienced transient dizziness and slurring of speech for less than one minute. The patient was followed up in the hospital until she was discharged. Follow-up was extended and carried out by telephone for more than 24 hours after her discharge. She reported no colic pain during the follow-up period. On a planned KUB X-ray requested the day after her discharge from our emergency ward, a radiolucent stone was observed.Case 5 was a 42-year-old Iranian man who was referred to our emergency department because of refractory renal colic (resistant to morphine and NSAIDs). Although he had previously received morphine and NSAIDs, he had no regression in pain degree (VAS score 9 of 10). His clinical examination revealed tenderness in the left CVA radiating to the genitalia, which was associated with dysuria, urination frequency, nausea, and vomiting. Abundant RBCs were revealed by urinalysis, and moderate hydronephrosis of the left kidney was visualized by ultrasonography. Once the patient's written consent was obtained, lidocaine 1.5 mg/kg was administered intravenously. Ten, twenty, and thirty minutes after lidocaine treatment, the patient's VAS scores decreased to 3 of 10, 2 of 10, and 0 of 10, respectively. After lidocaine administration, the patient did not experience any adverse events. The patient was followed up in the hospital until he was discharged. Follow-up was continued by telephone for more than 24 hours after discharge. The patient reported no colic pain during the follow-up period. On a planned KUB X-ray requested the day after his discharge from our emergency ward, a radiopaque stone was observed.Case 6 was a 35-year-old Iranian man who was referred to our emergency department because of refractory renal colic (resistant to morphine and NSAIDs). In spite of receiving previous treatment with morphine and NSAIDs, he had no regression in pain degree (VAS score 7 of 10). His clinical examination revealed tenderness in the left CVA radiating to the genitalia, which was associated with dysuria, urination frequency, nausea, and vomiting. Abundant RBCs were detected by urinalysis, and moderate hydronephrosis of the left kidney was visualized by ultrasonography. After obtaining written consent from the patient, lidocaine 1.5 mg/kg was administered intravenously. Ten, twenty, and thirty minutes after treatment, the patient's VAS scores decreased to 0 of 10, 0 of 10, and 0 of 10, respectively. After lidocaine administration, the patient experienced no adverse events. The patient was followed up in the hospital until he was discharged. Follow-up was carried out by telephone for more than 24 hours after he was discharged. The patient reported no colic pain during the follow-up period. On a planned KUB X-ray requested the day after his discharge from our emergency ward, a radiopaque stone was observed.Case 7 was a 36-year-old Iranian man who was referred to our emergency department because of refractory renal colic (resistant to morphine and NSAIDs). He had previously been treated with morphine and NSAIDs, but he had no regression in pain degree (VAS score 9 of 10). His clinical examination revealed tenderness in his right CVA radiating to the genitalia, which was associated with hematuria, dysuria, and urination frequency. Abundant RBCs were revealed by urinalysis, and moderate hydronephrosis of the right kidney was visualized by ultrasonography. After obtaining the patient's written consent, lidocaine 1.5 mg/kg was administered intravenously. Ten, twenty, and thirty minutes after treatment, the patient's VAS scores decreased to 6 of 10, 8 of 10, and 8 of 10, respectively. After lidocaine administration, the patient did not experience any adverse events. Because of his inconsistent response to lidocaine, this patient needed additional anodyne treatment. A KUB X-ray was requested immediately for this patient for further study, and a number of radiopaque stones were observed.Case 8 was a 35-year-old Iranian man who was referred to our emergency department because of refractory renal colic (resistant to morphine and NSAIDs). The patient had a history of renal colic, and, in spite of receiving previous treatment with morphine and NSAIDs, he had no regression in pain degree (VAS score 8 of 10). His clinical examination revealed tenderness in the right CVA radiating to the genitalia, which was associated with dysuria, urination frequency, nausea, and vomiting. Abundant RBCs were revealed by urinalysis, and moderate hydronephrosis of the right kidney was visualized by ultrasonography. Once his written consent was obtained, lidocaine 1.5 mg/kg was administered intravenously. Ten, twenty, and thirty minutes after treatment, the patient's VAS scores decreased to 0 of 10, 0 of 10, and 0 of 10, respectively. After lidocaine administration, the patient experienced transient slurring of speech for less than one minute. The patient was followed up in the hospital until he was discharged. Follow-up was carried out for more than 24 hours by telephone while he was resting at home after discharge. This patient experienced renal colic and rated his pain as 3 of 10 on the VAS scale. His pain was relieved by administration of NSAIDs. On a planned KUB X-ray requested the day after his discharge from our emergency ward, a radiolucent stone was observed.We have presented a short-lived but simple, inexpensive, low-risk, and effective technique for treating pain associated with intractable renal colic. Lidocaine is effective for treating patients with visceral or central pain . LidocaiKUB: kidney, ureter, and bladder X-ray; NSAIDs: non-steroidal anti-inflammatory drugs; RBC: red blood cell; RS: recurrent stone; VAS: Visual Analog Scale; FS: first stone.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.HS, KH, DA, and HV collected clinical data, reviewed the literature on the topic, and drafted the manuscript. RME analyzed and interpreted the patient data. All of the authors were involved in patient management or the writing of the manuscript. All authors read and approved the final manuscript.