Objective. This case report presents 3-year follow-up of a case of nonsyndromic multiple supernumerary teeth (NSMST) with 11 supernumerary teeth, 2 of which showed subsequent formation. Case Report. A 10-year-old girl was referred to the dental clinic with the chief complaint of delayed eruption. Radiographic examination showed 9 retained supernumerary teeth. The treatment plan consisted of extraction of the supernumerary teeth and associated primary teeth in order to allow the permanent teeth to erupt. After 2 years of follow-up, 2 additional supernumerary teeth were observed. Conclusion. Regular follow-up for late forming supernumeraries is crucial for NSMST cases. Supernumerary teeth refer to teeth in excess of the normal full complement of teeth in primary or permanent dentition. The prevalence of supernumerary teeth ranges from 0.1% to 3.6%, and they are twice as common in permanent compared to in primary dentition [Supernumerary teeth may occur singly, multiply, unilaterally, or bilaterally in the maxilla, mandible, or both. The anterior maxillary region appears to be the site of predilection , 3.Multiple supernumerary teeth are generally associated with cleidocranial dysplasia, Gardner's syndrome, or cleft lip and palate . NonsyndIn general, supernumerary teeth begin to develop before the teeth of the dental series to which they are related; however, some authors have described the subsequent formation of supernumerary teeth , 7–10.This case report presents the treatment and 3-year follow-up of NSMST in a 10-year-old girl with 11 supernumerary teeth, 2 of which showed subsequent formation.A 10-year-old Caucasian girl was referred to the paediatric dentistry clinic with the chief complaint of delayed eruption of the permanent maxillary anterior teeth. There was no significant medical history and no family history of dental anomalies. The patient was a healthy child with no mental retardation, normal facial appearance, and no skeletal or other abnormalities suggestive of a systemic syndrome. She was the first child of a nonconsanguineous marriage, and her parents had no hereditary peculiarities.Intraoral examination revealed the presence of over-retained primary maxillary anterior teeth. The patient was in the mixed dentition stage and had a Class I molar relationship Figures . Oral hyRadiographic examination showed 9 retained supernumerary teeth: 2 mesiodens, 4 in the mandibular left and right premolar regions, 2 in the maxillary right premolar region, and 1 in the maxillary right canine region Figures . PanoramThe proposed treatment plan consisted of extraction of the retained supernumerary teeth and associated primary anterior and molar teeth in order to allow the permanent teeth to erupt. The treatment plan was explained to the patient and her family. With their permission, 20 teeth were extracted under general anesthesia (11 primary teeth and 9 impacted supernumerary teeth) Figures .Figures After 2 years of follow-up, 2 additional supernumerary teeth were observed, 1 in the maxillary left premolar region and 1 in the maxillary anterior region . In all At the end of a 3-year follow-up, orthodontic treatment using fixed mechanics was shown to have achieved good esthetics with an ideal overjet and overbite relation Figures . An EssiPanoramic radiograph of the younger brother of the patients' at age 5 showed an impacted supernumerary tooth in the mandibular left canine region . His folAlthough the exact etiology of supernumerary teeth is unknown, several theories have been postulated to try to explain their presence. Of these, the most acceptable appear to be phylogeny ; autonomic recessive inheritance linked to the X chromosome; an abnormal reaction to a local traumatic episode; environmental factors; dichotomy of the tooth germ; and hyperactivity of the dental lamina , 2, 6. MThe literature points to a familial predisposition to hyperdontia , 3, 4. IYagüe-García et al. reported the majority (76.7%) of supernumerary teeth in NSMST to be located in the upper jaw, with the mesiodens the most frequent supernumerary tooth, representing 35.29% of all supernumerary teeth in NSMST [Late formation of supernumerary teeth has been reported particularly in the premolar region , 7–9. InSupernumerary teeth may erupt normally, stay impacted, appear inverted, or assume an ectopic position or an abnormal path of eruption. The development of supernumeraries may precipitate a variety of complications, including crowding, delayed eruption or impaction, diastema development, cystic lesions, occlusal problems, and resorption of adjacent teeth. Therefore, early diagnosis, proper evaluation, and appropriate treatment are essential , 5, 10. Regular follow-up for late forming supernumeraries is crucial for NSMST cases. Radiographic monitoring of the siblings is also important in such cases.


The present study aimed to quantitatively assess the associations between vitamin D and Parkinson’s Disease (PD) risks, which include: (i) risk of PD in subjects with deficient and insufficient vitamin D levels; (ii) association between vitamin D supplementation and risk of PD; and (iii) association between outdoor work and PD risk, through meta-analyzing available data. An electronic literature search supplemented by hand searching up to March 2015 identified seven eligible studies comprising 5690 PD patients and 21251 matched controls. Odds ratio (OR) and 95% confidence interval (CI) of PD risk were assessed through pooling the collected data from eligible studies using Stata software. Pooled data showed that subjects with deficient and insufficient vitamin D levels had increased PD risks compared with matched-controls according to the corresponding OR: 2.08, 95% CI: 1.63 to 2.65, and 1.29, 95% CI: 1.10 to 1.51. Vitamin D supplementation was associated with significantly reduced risk of PD . Outdoor work was also related to reduced risk of PD . The findings may stimulate larger, well-designed studies to further verify the associations between vitamin D and PD risk. Vitamin D is a fat-soluble steroid hormone, which is essential to maintain human health. In recent years, vitamin D has gained tremendous amount of attention owing to the reported associations between low vitamin D level and a wide range of chronic diseases, as well as the therapeutic potential of vitamin D supplementation for these diseases ,2,3,4,5.et al. in 1997 , a stable marker of vitamin D status, concentrations of <50 nmol/L and <75 nmol/L, respectively . Serum cThe literature selection and identification flow diagram was shown in Three studies covering 966 PD patients and 813 age-matched controls were included in the quantitative analysis of vitamin D level and risk of PD ,16,17. MTwo case-control studies covering 458 patients with PD and 578 cases were included in the assessment of association between vitamin D supplementation and PD risk and the main descriptive data from the studies are shown in There were 4266 PD patients and 19860 controls included in two eligible case-controls studies about the association of outdoor work and risk of PD ,21. TablVitamin D is obtained through the diet and is photosynthesized in the skin upon exposure to solar ultraviolet B radiation. Vitamin D deficiency has been found to be associated with various chronic diseases conditions, such as cancer, cardiovascular diseases, diabetes, stroke, and neurodegenerative diseases, which aroused much interest for the potential of vitamin D in prevention and intervention of these disorders in recent years ,2,3,4,5.The possible biological underpinning underlying the association between vitamin D level and PD risk should be multiple. First, as the primary mediator of vitamin D’s biological actions, the vitamin D receptor (VDR) exhibits multiple genetic polymorphisms, and many studies have reported the association between VDR polymorphisms and risk of PD ,24,25. SPooled results of the meta-analysis should be considered in the context of its limitations. First, the number of the eligible studies and covered participants was relatively small. Second, the vitamin D supplementation and out-door activity are based on self-administered diet history questionnaire and self-report questionnaire. The confounders for which adjustments are made also varied in each study. These factors will potentially affect the results. Third, the potential effects of anti-PD drugs cannot be explicitly considered in the included studies. Fourth, due to the limited eligible studies we cannot perform gender and ethnic subgroup analysis.In conclusion, based on the eligible studies we found that low vitamin D level was associated with increased risk of PD, which is consistent with the hypothesis that low vitamin D status is a risk factor of PD. In addition, it was indicated that vitamin D supplementation and outdoor work may reduce PD risk. Thus, optimizing vitamin D level may represent a potential avenue for the prevention of PD. As only a few studies have investigated the effects of vitamin D supplementation against PD so far, further research on this issue is strongly encouraged.


Recent studies in multiple sclerosis (MS) showed longer survival times from clinical onset than older hospital-based series. However estimated median time ranges widely, from 24 to 45 years, which makes huge difference for patients as this neurological disease mainly starts around age 20 to 40. Precise and up-to-date reference data about mortality in MS are crucial for patients and neurologists, but unavailable yet in France.Estimate survival in MS patients and compare mortality with that of the French general population.We conducted a multicenter observational study involving clinical longitudinal data from 30,413 eligible patients, linked to the national deaths register. Inclusion criteria were definite MS diagnosis and clinical onset prior to January, 1st 2009 in order to get a minimum of 1-year disease duration.After removing between-center duplicates and applying inclusion criteria, the final population comprised 27,603 MS patients . During the follow-up period (mean 15.2 +/- 10.3 years), 1569 deaths (5.7%) were identified; half related to MS. Death rates were significantly higher in men, patients with later clinical onset, and in progressive MS. Overall excess mortality compared with the general population was moderate , but increased considerably after 20 years of disease (2.20 [2.10-2.31]).This study revealed a moderate decrease in life expectancy in MS patients, and showed that the risk of dying is strongly correlated to disease duration and disability, highlighting the need for early actions that can slow disability progression. A number of studies of mortality in multiple sclerosis (MS) have been conducted over the past 20 years, with more or less consistent results. Reported median survival times from MS clinical onset ranged from 24 to 45 years –16, withIn 2004, we carried out a study of 1879 French MS patients  that conWe therefore decided to initiate a large-scale multicenter study of mortality in MS in France, with the aim of measuring death rates and life expectancy in patients, describing causes of death, assessing prognostic factors for death, and comparing mortality in patients with the French general population.st 2009 in order to have a minimum disease duration of 1 year at the end-of-study date, which was set as January 1st 2010.Recruitment took place via the network of French users of EDMUS. Although EDMUS initially was a software dedicated to MS that was developed in France in the 1990s , it now Each EDMUS database has been approved by the French data protection authority . Furthermore, in accordance with French legislation, the present study was approved before its start by both the CNIL  and the French advisory committee for data processing in health research . Those approvals were needed to link our dataset to the national registers containing death information. Then the data were analyzed anonymously.As deaths are not exhaustively registered in the EDMUS databases, the clinical dataset was linked to two national registers. The first register was the national repertory for the identification of physical persons , where each individual born in France after 1890 is identified by sex, surname (maiden name for women), date and place of birth. This allowed us to obtain up-to-date vital status. We also obtained data from the national death register (‘INSERM-CepiDc’), which contains information provided in death certificates from 1968, including the date, place and causes of death, coded according to the International Classification of Diseases . The underlying causes of death were categorized as follows according to ICD codes: MS (ICD-10 code G35), cancer, cardiovascular disease and stroke, infectious disease, respiratory disease, neurological disease except MS, suicide, digestive disease, accidental death, other disease, unspecified (e.g. cardiac arrest) or unknown (i.e. death certificate unavailable) causes.The primary endpoint was death, and the following parameters were considered as potential explanatory variables: age at MS clinical onset, sex, initial MS course, and period of MS onset. The initial MS course was defined as either relapsing onset or progressive onset . The perWe calculated the individual probability of death for every patient during follow-up using life tables for the French general population, by sex and age for the period 1940–2009 . We calculated the number of expected deaths by summing the individual expected probabilities of death. In addition to the overall comparison between MS patients and the French general population, we also ran comparisons for patient subgroups  using standardized mortality ratios (SMRs). The individual expected probability of death was also used to draw the expected survival curve from MS onset. When comparing the expected curve with the observed one, the reduced survival time after MS clinical onset can be estimated approximately.SD), respectively. We calculated overall and subgroup mortality frequencies  and mortality rates (number of deaths divided by number of person-years (PY) of follow-up per 1,000 PY). Sensitivity analysis was performed to estimate number of expected deaths in patients whose vital status was missing. Differences between subgroups were assessed using t, Anova or Fisher’s exact tests when appropriate. Kaplan-Meier estimates with log-rank tests were used to assess prognostic factors for the time between clinical MS onset and death, followed by a multivariate Cox proportional hazards model (backward method). As period of onset was closely linked to disease duration, it was not considered in the multivariate analysis. SMRs were equal to the number of observed deaths divided by the number of expected deaths. The 95% confidence limits of the SMRs were estimated using the Poisson distribution. All statistical tests were two-tailed, and statistical significance was set at the 5% level. Any missing data were excluded from the analyses. Statistical analyses were performed using STATA 11.Qualitative and quantitative variables are provided as numbers (percentage) and means ± standard deviation : 19.9 ± 13.0, 15.8 ± 10.4, and 11.8 ± 7.7 years in the < 20, 20-40, and ≥ 40 years groups respectively. Furthermore, as expected, we found that the earlier the period of MS onset, the longer the disease duration . A total of 4,607 patients (16.7%) had unknown vital status at the end-of-study date because they were not found in the national repertory (‘RNIPP’). These patients were therefore included in the analyses as censored alive at the date of their last clinical information. Their mean follow-up duration was significantly lower than that of the patients with known vital status . Their characteristics compared with those of died and alive patients are presented in Mean follow-up duration was 15.2 ± 10.3 years from MS clinical onset, and the total number of patient-years of follow-up was 420,801. Mean age at last clinical information was 48.0 ± 10.3 years. Mean MS duration differed significantly according to age at MS onset  in 884 women and 685 men, at a median age of 56 years (range: 19-96) and the median disease duration was 20 years (range: 1–88) . Kaplan-The underlying cause of death was known from the death certificates for 1338 dead patients, and were as follows: MS , cancer , cardiovascular disease or stroke , infection , suicide , accident , neurological disease other than MS , digestive disease , respiratory disease , other cause , and unspecified . MS was mentioned as either underlying or contributive cause of death in 1017 death certificates (76.0%). Out of the 231 unavailable death certificates, 2 patients had died abroad and 11 certificates could not be found, while 218 patients were not found in the RNIPP registry  even though their medical files indicated that they were dead.Univariate assessment of the prognostic factors for death revealed that the risk of death was higher among men, patients with later clinical onset, those with primary progressive MS, and those with MS onset in an earlier period. These results were confirmed using a Cox multivariate analysis .The overall SMR was 1.48 (95% CI [1.41-1.55]), resulting in 48% excess mortality in MS patients compared with the French general population. The survival curves  show thaDifferent SMRs were observed across the 15 participating centers. In Rennes, the SMR was 1.99 [1.77-2.25]. In Lyon, which is the original EDMUS center and largest referral center for MS in France, the SMR was 2.15 [1.98-2.34], and up to 2.78 [2.52–3.06] if considering historical cohort only . In LorrAs shown in n = 4,607), a total of 241 deaths may be added, leading to an overall number of 1,810 deaths and an overall SMR of 1.71 [1.63–1.79].If considering the overall death rate  in the subgroup of patients without updated vital status  could not be traced in the French national register, either owing to a missing birthplace or because they were born outside France, or there were suspected mistakes in the maiden name (consistent with the high proportion of women). As this subgroup was older than the group with known vital status, it may lead to under-estimation of mortality, but without changing the key finding of our study. Indeed, if assuming they have the same mortality risk as the 22,996 patients who were identified in the register, the excess mortality compared with the French general population increased from 16% (from 1.48 to 1.71).In the present study, deaths were captured by linking the dataset to two national registers. When the study started, only 500 deaths were notified in the EDMUS databases. This highlights the need for linkage to official national death registers in this kind of epidemiological study, in order to avoid underestimating the event of interest. Even so, a number of patients  than reported in previous studies (SMR up to 3) , 10, 17.We found that excess mortality was strongly correlated with disease duration, as the longer the disease duration, the greater the probability of death. We can assume that the overall SMR was lower than that of other series owing to the shorter disease duration of our MS population mean 15 years). This is consistent with results of the first French EDMUS-user centers. In Rennes, the SMR was 1.99, that is much higher than the SMR (1.3) we had observed in our previous study  years. T, meaningFinally, a selection bias in patients’ enrollment towards a less malign course or an earlier diagnosis cannot be excluded too as the participating centers are considered as MS expert centers, as well as an immortal time bias (patients need to survive a sufficient amount of time to be enrolled in the database) as discussed above.We observed that excess mortality was higher in patients who were young at MS onset and in women, even though these two subgroups had lower mortality rates. The fact that observed mortality may be low and excess mortality high suggests that excess mortality may be due to MS and not attributable to other factors such as demographics. Regarding the 1,338 known causes of death, MS was the underlying cause of death notified in 52.3% of deaths certificates, followed by cancer (14.0%) and cardiovascular disease 9.4%), mostly consistent with the literature. We can assume that the MS category includes complications of MS such as sepsis, aspiration pneumonia, and other events that are seen in individuals with severe disability. If pneumonia (ICD-10 code J690), tetraplegia (G825), and paraplegia (G822) as underlying cause were considered as MS, 18 cases would be added, leading to a proportion of deaths due to MS of 53.7%. Cardiovascular deaths were not so frequent, in accordance with the low mean age of the population at last information. The frequency of suicide (3.5%) was lower than in other series .4%, most, 33, butNext steps will consist of a further analysis of causes of death, not just underlying, but also contributory, and their combination. Moreover, attempts of defining “MS-related” death are ongoing. Cause-specific mortality rates of the French general population will be used and should help us to clarify the relationship between specific causes of death and excess mortality. Moreover, we are currently collecting additional data for suicide cases, in order to look at socioeconomic characteristics , mental health status, and trends over time.To conclude, the results of the SURVIMUS study show that there is a moderate decrease in life expectancy for MS patients, and that the risk of dying is strongly correlated with disease duration, and probably disability progression, highlighting the need for actions that can delay disability progression. Even though excess mortality starts only after 20 years of disease duration, interventions such as DMTs or multidisciplinary care should be started as soon as possible in the disease course in order to maximize their efficacy in slowing down disability progression . We now


Malaria continues to exact a great human toll in tropical settings. Antimalarial resistance is rife and the parasite inexorably develops mechanisms to outwit our best drugs, including the now first-line choice, artesunate. Novel strategies to circumvent resistance are needed. Here we detail drug development focusing on heat shock protein 90 and its central role as a chaperone. A growing body of evidence supports the role for Hsp90 inhibitors as adjunctive drugs able to restore susceptibility to traditionally efficacious compounds like chloroquine. Plasmodium falciparum is responsible for the most severe form of human malaria and causes a tremendous economic burden [P. ovale, P. vivax, P. malariae, and P. knowlesi. The onset of symptoms takes place at 10–15 days after being bitten, resulting in fever of up to 41.5 °C, chills, headaches, and vomiting [The protozoan parasite c burden , leadingc burden ,3. Approvomiting ,7,8. If Naturally acquired immunity to malaria is slow to develop, is not sterile, and is mostly lost in the absence of continual antigenic exposure ,10,11. IThere is no commercially available vaccine to protect against malaria ,10. The Endeavors to eliminate malaria have raised global interest ever since the 1950s, but have failed because of the resistance of mosquito vectors to insecticides, resistance of the parasites to drugs, socioeconomic problems, and the lack of effective vaccines. Transmission control is one of the main goals of global efforts focusing on increased access to insecticide nets, diagnostic tests, vaccines to prevent disease, and novel therapies .P. falciparum malaria in the 1960s. This allowed the United States Army Research and Development Command and the Walter Reed Army Institute of Research to re-assess valuable old leads for their antimalarial effects [Apart from the complexity of the disease, malaria faces a continuous abandonment of drug research and development by the greater part of the pharmaceutical industry due to a lack of profit, which has resulted in a serious shortage in the antimalarial armamentarium ,6. A wak effects .Anopheles mosquito releases anticoagulants into the host blood; simultaneously, the injection of malaria sporozoites takes place [Before taking its blood meal, the es place . The spoes place . This ises place . Merozoies place . in vitro. The stages of the intra-erythrocytic cycle are depicted in P. vivax and P. ovale infections, some of the sporozoites develop into dormant parasites called hypnozoites. Their switch into sporozoites and their replication result in relapses that can occur years after the initial infection [When the merozoites are released from the hepatocytes into the bloodstream, the intra-erythrocytic cycle starts . The erynfection .Plasmodium species have different durations to complete one full asexual replication cycle in the blood, e.g., P. falciparum, P. vivax, and P. ovale cycles last 48 h, the P. malariae life cycle is 72 h, and the P. knowlesi life cycle is 24 h [berghei has a life cycle that is essentially the same as that of the P. falciparum parasite that infects humans, but with differences in the duration of the different stages of the life cycle. The pre-erythrocytic cycle, for example, requires between 42 h and 72 h, while the asexual, intra-erythrocytic cycle lasts between 22 h and 25 h [P. falciparum infection, the addition of the parasite’s erythrocyte membrane binding protein 1 (EMP1) to the surface of the red blood cell (RBC) causes parasitized RBCs to stick to the endothelial cells of blood vessels, avoiding the clearance of these infected cells by the spleen [2 delivery to other organs. The hemolysis leads to anemia and intermittent fever [The different  is 24 h ,21. The P. falciparum has successfully invaded a RBC, it spends the first 20–24 h in what is known as the “ring stage” due to the ring-shape appearance of Giemsa-stained parasites under the microscope. During this stage, the parasite feeds on hemoglobin and plasma nutrients, synthesizes ring-stage molecules, and modifies the RBC membrane [Once membrane ,22. The membrane .P. falciparum [The next stage is the trophozoite stage that appears at 24–36 h after RBC invasion by lciparum . At thislciparum . Trophozlciparum . Knobs alciparum . The trolciparum ,24. As tlciparum ,26.P. falciparum. Synthesized and organized organelles take over the entire area of the RBC. This process of organelle replication continues as the merozoites bud off from the cytoplasm [Trophozoites replicate their DNA to grow into schizonts . In the ytoplasm ,27,28. Once the RBCs infected with schizonts burst, they release as many as 16–32 new merozoites that have the potential to invade fresh RBCs and repeat the intra-erythrocytic cycle . In someMost of the currently available antimalarials have been identified from natural products that exhibit antimalarial activity. The identification of antimalarials such as quinine and artemisinin was serendipitous and involved no rationally identified molecular targets ,29. The In fact, most of the existing antimalarials have similar modes of action: (1) 4-aminoquinolines  and aryl amino alcohols  interfere with the formation of the hemozoin crystal and, therefore, the parasite’s ability to deal with toxic heme by-products ,29; (2) Artemisia annua for the semi-synthetic production of artemisinin derivatives [Antifolates are among the very few antimalarials with well-defined targets and mechanism of action in the folate biosynthesis pathway, but resistance to these inhibitors, including pyrimethamine and cycloguanil, arose soon after their deployment as antimalarials ,29. The ivatives . The conivatives . P. falciparum malaria be treated using artemisinin-based combination therapy (ACT). However, resistance has emerged recently to ACT at the Thai-Cambodia border and may soon be widespread. The two most widely used and cheapest antimalarial drugs, CQ and sulfadoxine-pyrimethamine (SP), have failed at an unprecedented rate in most malaria-endemic regions [Resistance has emerged to all existing drugs in Southeast Asia . Multidr regions . Antimal regions . et al. showed that CQ-resistant (CQR) parasites released pre-accumulated CQ almost 50 times faster than CQ-sensitive (CQS) parasites [et al. identified the CQ resistance transporter (PfCRT) by genetic crosses of Dd2 and HB3 clones  [pfcrt allele [The use of CQ began worldwide in the 1940s. This drug remained the gold standard for the prevention and treatment of uncomplicated malaria for several decades. It was characterized by its rapid parasiticidal action, low cost ($0.2 for a three-day treatment), safety, and widespread availability ,16. CQ iarasites . In the ctively) . The CQRt allele ,37. P.falciparum multidrug resistance transporter (pfmdr1), was amplified in some CQR strains. The PfMDR1 protein is also localized on the membrane of the digestive vacuole [P. falciparum, CQ is still widely used in sub-Saharan Africa for symptom alleviation due to its low cost [Analogous to mammalian cells, the gene for the multidrug transporter,  vacuole ,16. Poin vacuole ,16. In slow cost ,16. P. falciparum susceptibility date back to 1908 in Brazil [pfmdr1 copy number (25-fold 50% inhibitory concentrations (IC50s)) [For quinine, the first reports of decreased n Brazil . In 1984n Brazil . Varianc(IC50s)) . Even th(IC50s)) ,39, poly(IC50s)) . These vet al. [However, the widespread resistance to CQ and SP, the two lowest cost antimalarials, provides a great incentive for the development of new therapeutic approaches with novel mechanisms of action, particularly in this era in which the understanding of the biochemistry and genome of malaria may aid in the identification of new rationales and mechanistic approaches. White et al.  argued tet al. ,41,42. The ideal antimalarial should be cheap, kill the parasite quickly, be safe, and address the problem of resistance ,29. FastHeat shock proteins (HSPs) are a class of highly conserved molecular chaperones that facilitate protein folding ,44. HSPsHsp90 is one of the best-studied members of the HSP family, and it is important for normal eukaryotic growth and development. Cytosolic Hsp90 exists in the form of a multichaperone complex and, together with Hsp70 and Hsp60, helps newly synthesized proteins to fold and to modulate the activities of transcription factors and protein kinases ,46. It iN-terminal ATP-binding domain is an effective approach to inhibit its function and interaction with client proteins [P. falciparum Hsp90 (PfHsp90) [Pharmacologic inhibition of Hsp90 effectively results in lethality or reversal of the abnormal phenotype ,61. Infeproteins ,61. SignPfHsp90) ,63,64,65Human and malaria genomes encode four paralogs of Hsp90 . Hsp90α N-terminal domain, which can be inhibited competitively and selectively by several small molecules [Hsp90 has been exploited as a successful drug target in many cancers, neurodegenerative diseases, and viral and fungal infections due to its activation and mediation of stress-induced interactions in abnormal cells. Hsp90 has a unique Bergerat fold of its ATP binding pocket with an open “lid” domain in the olecules . Since Het al. have shown that Hsp90 inhibitors synergize with known antifungals to which the microbe would otherwise be resistant. In fungi [Saccharomyces cerevisiae strains with mutations in the ergosterol biosynthesis pathway [Cowen In fungi ,67, Hsp9In fungi ,67. CoweIn fungi  Cre-Lox  pathway . Thus, t pathway .C-terminal domains) [P. falciparum Hsp70-Hsp90 organizing protein (PfHop) show distinct sequence variation in their functional domains compared to the human homologue [Crystal structures have revealed paralog-specific conformational differences in response to ATP or geldanamycin (GA) binding in fungi. For example, while the ATP binding pocket is acidic in Grp94 and yeast Hsp82, the neighboring phosphate-binding regions differ ,69,70,71domains) . In addiomologue  presentiN-terminal domain have been developed including natural product inhibitors such as geldanamycin (GA) and radicicol, and synthetic inhibitors comprised of purines, pyrazoles, isoxazoles, and other scaffolds [Brugia pahangi Hsp90 from endogenous protein extracts has shown that Hsp90 is a selective target in parasites and supports the identification of novel chemotypes with enhanced potency and selectivity [A range of Hsp90 inhibitors that target the caffolds ,60,75. Gcaffolds . On inhicaffolds ,77. Degrectivity .in vivo. Due to the toxicity caused by GA and its derivatives in animal and human studies, alternative small molecule inhibitors have been sought [The broad spectrum of Hsp90 interactions and signaling pathways provides a potentially wide range of anti-disease effects and a decreased likelihood for developing resistance. However, Hsp90 inhibition is limited by the compensatory upregulation of Hsp70, which results in counterproductive cytoprotective effects . An addin sought ,70,71,75Efforts in identifying alternative drugs that inhibit Hsp90 have resulted in the discovery of numerous inhibitors from a variety of scaffolds, which take advantage of the unique shape that ATP assumes when it binds to the Hsp90 ATP binding domain and that show specificity for Hsp90 ,80,81. TP. falciparum, one cytosolic Hsp90  is known to be induced by stress [PfHsp90 is essential for the development of the parasite [et al. also implicated Hsp90 as a drug target against malaria and Trypanosoma infections in animal models [P. berghei model at the tested dose (50 mg/kg) [In y stress ,55 and hy stress . PfHsp90parasite ,62,65,85l models . Biochem0 mg/kg) . The crystal structures of the ATP-binding domains of PfHsp90 and human Hsp90 (HsHsp90) reveal a unique Bergerat fold with an open “lid” domain in comparison to other ATPase domains and several unique residues at the drug binding site that can be exploited for drug binding specificity ,71,86,87S. cerevisiae and the human host [PfHsp90 may play a role in the development of drug resistance in the malaria parasite because of its interaction with the CQ resistance-associated protein Cg4 . Hence, man host , highlig50 of 200 nM and cause a transition block at the ring stage, suggesting an important role for PfHsp90 in parasite growth. GA inhibition of PfHsp90 disrupted the PfHsp90 complex consisting of PfHsp70, PfPP5, and tubulin, among other proteins [Heat shock is part of the parasite life cycle when it changes hosts and during the febrile episodes of malaria. Chaperones are very important in responding to this stress and in buffering mechanisms that ensure parasite survival and growth. The increase in temperature activates the PfHsp90 stress response pathway and may facilitate the arousal of new phenotypes by chaperoning mutant client proteins that develop drug resistance, enhance virulence, or cytoadherence properties ,65. GA wproteins . InhibitP. falciparum Hsp90.Taken together, the following key factors suggest that PfHsp90 represents a promising target: (1) the antimalarial activity of known cross-species Hsp90 inhibitors such as GA; (2) the essential and multifaceted chaperone function of Hsp90; (3) its potential cross-talk with pathways involved in drug resistance; and (4) the unique structural features in the ATP-binding domain between human and Because parasite drug resistance is increasing due to widely used monotherapy and since heat shock protein 90 plays a major role during invasion of the host by the malaria parasite, the identification and development of antimalarial compounds that target PfHsp90 has recently attracted the attention of several groups. et al. have characterized the role of GA in malaria. Given that PfHsp90 has the highest ATPase activity of all known Hsp90s and has a 30% higher affinity for ATP than HsHsp90, dissociation constants of GA for PfHsp90 and HsHsp90 are found to be 1.05 and 4.4 μM, respectively [et al. [in vitro at 25 and 160 nm, respectively, after 48 hours [50 value for P. falciparum in culture was comparable with that observed in cancer cell lines. Pallavi ectively . This fi [et al.  who show48 hours . Even thin vitro in the presence of the known antimalarial drug chloroquine. Harmine is a very interesting hit because it belongs to a group of natural metabolites that are the active ingredients of several traditional herbs used to treat malaria in West and Central Africa [in vitro antimalarial activity of pure compounds or methanolic fractions isolated from these plants [Due to the toxicity caused by GA, Rd, and derivatives in animal and human studies, alternative small molecule inhibitors have been sought. To this end, our group performed a robotic high throughput screen (HTS) using 4000 small molecules from a natural compound (Spectrum), pharmacologically active (Lopac), and Food and Drug Administration (FDA) approved drug library (Prestwick) for competitive inhibition of the ATP-binding (GHKL) domain of PfHsp90 . Hits wel Africa ,92. A sye plants . We evale plants , suggestin vitro have incited evaluation of antimalarial activity in vivo with mouse models of malaria infection. Using Peter's four-day suppressive test, Pallavi et al. showed that mice treated with 50 mg/kg 17-AAG significantly reduced parasitemia and had a two-fold prolonged survival time than vehicle-treated control mice [et al., i.e., 50–100 mg/kg [These encouraging results of PfHsp90 inhibition rol mice . In orde00 mg/kg . For malin vivo. However, harmine potentiates the activity of chloroquine in vivo. This type of synergy known as potentiation occurs when a compound possesses little or no activity on its own, but it enhances the activity of another active compound [in vivo is encouraging for circumventing antimalarial resistance and potentiating the activity of existing antimalarials at subtherapeutic doses. Administration of harmine alone (75 mg/kg and 100 mg/kg daily) resulted in a modest effect on parasitemia compound . This efcompound . The synin vitro and in vivo data support the role for the Hsp90 inhibitors such as GA, 17-AAG, PU-H71 and harmine, which have a high affinity for the PfHsp90 ATP-binding domain, as being able to act synergistically with CQ. From the study of the PfHsp90 inhibitors synergistic activity with CQ, a complex putative model emerges for both CQS and CQR P. falciparum  that permits the transport of charged CQ molecules to the cytosol ,98,99. Thotspots , suggestcaveat in mind, there are significant implications of the Hsp90 inhibitors synergistic activity with conventional antimicrobials when used in combination. Targeting PfHsp90 affords the possibility of developing a synergistic adjunctive therapy with the potential of reversing resistance to existing antimalarials such as CQ. One could envision the development of a chemical genomic catalog of PfHsp90 interactions weighted by the average FIC ratios of the dual targets. The broad spectrum of Hsp90 interactions provides extensive possibilities for adjunctive therapies that decrease the likelihood of developing resistance. A catalog of these interactions will allow for rational selection and circulation of alternative combinations to avoid the prolonged exposure of the parasites to a single therapy. However, with this Ideally, combination regimens incorporate two novel agents with potent efficacy and similar pharmacokinetic profiles; however, this is not met by any existing combination in use or in development ,29. The P. falciparum gametocytes produced in vitro [Drug development is a laborious and time-consuming process. It is important to start with drugs that have already been investigated for absorption, distribution, and excretion in rodents and humans. Successful candidate drugs need to be easy to manufacture, stable, readily formulated, bioavailable, have an acceptable half-life, and should be safe to administer . For antin vitro ,6. Preliin vitro screens and culturing methods that select for the fittest isolate under laboratory conditions. Multiple drug-resistant and drug-sensitive isolates from around the world have now been culture-adapted and can be obtained from the Malaria Research and Reference Reagent Resource Center. However, all of these isolates have been passaged in multiple laboratories over many years. As such, the biology of these strains has changed and adapted to laboratory life. Therefore, the evaluation of compound activity in these strains can only be predictive. The evaluation of the PfHsp90 inhibitors in vivo is encouraging in potentiating the effect of CQ, but their assessment in an endemic malaria site would be paramount for their further clinical evaluation. The attractive research interface with these inhibitors will provide the motivation for their further development. One limitation of preliminary antimalarial evaluations in general is the use of


Objective: Toxic shock syndrome is a rare but life-threatening complication after plastic surgery procedures. Methods: We experienced 2 cases of toxic shock syndrome after expander-based breast reconstruction caused by methicillin-resistant Staphylococcus aureus. Results: The first patient took a severe clinical course due to the delayed diagnosis and treatment, and the second patient recovered rapidly after the early diagnosis and treatment based on our experience of the first case. Fever, rash, and gastrointestinal symptoms (diarrhea and/or vomiting) were characteristic and important for the early diagnosis of toxic shock syndrome. Conclusions: Considering the increased prevalence of methicillin-resistant Staphylococcus aureus, we should suspect methicillin-resistant Staphylococcus aureus in cases of toxic shock syndrome that occur postoperatively, and the empiric administration of vancomycin should be initiated in such cases. Staphylococcus aureus and Streptococcus pyogenes. Since its first report by Todd et al,4,6-Staphylococcus aureus (MRSA).Toxic shock syndrome (TSS) is an acute, multisystem, toxin-mediated illness, often resulting in multiorgan failure.Case 1 was a 40-year-old woman, and she underwent a mastectomy and sentinel node biopsy for left breast cancer. Immediately after the surgery, a tissue expander was implanted under the pectoralis major muscle for breast reconstruction. Prophylactic antibiotics  were administered for 9 days following the surgery, until all drains were removed. On postoperative day 10, the patient presented with a fever of 39.3°C, a diffuse rash on her upper extremities, hypotension, and diarrhea . The sitCase 2 was a 54-year-old woman, and she underwent a mastectomy and sentinel node biopsy for left breast cancer. Immediately after the surgery, a tissue expander was implanted under the pectoralis major muscle for breast reconstruction. Prophylactic antibiotics  were administered for 7 days following the surgery, until all drains were removed. On postoperative day 8, the patient presented with a fever of 40.0°C, a diffuse rash on the upper part of her body, hypotension, and vomiting .3  and a C-reactive protein (CRP) level at 15.5 mg/dL . The data showed renal dysfunction, with 33.9 mg/dL of blood urea nitrogen  and creatinine at 3.11 mg/dL . The data also showed liver dysfunction, with total bilirubin at 3.0 mg/dL , lactate dehydrogenase at 272 IU/L , aspartate transaminase at 84 IU/L , and alanine transaminase at 212 IU/L . Dopamine and noradrenaline were administered to maintain the patient's blood pressure. Late at night on the day of onset, we diagnosed the patient's condition as TSS and removed the tissue expander under local anesthesia. The patient was cared for in the intensive care unit for 4 days, and dopamine and noradrenaline were continued during that period. Broad-spectrum antibiotics  were first administered for 2 days and were changed to vancomycin (2 g per day) when intraoperative wound cultures revealed MRSA. On the fifth day after the onset of TSS, the patient presented with desquamation of the hands  count of 18,100/mmhe hands . Her conhe hands .3  and CRP level at 6.5 mg/dL . The data showed liver dysfunction with lactate dehydrogenase at 336 IU/L , aspartate transaminase at 189 IU/L , and alanine transaminase at 81 IU/L . On the basis of our experience with case 1, we immediately diagnosed this patient's condition as TSS. The tissue expander was removed 3 hours after the onset of TSS. Vancomycin (2 g per day) was started on the first day of onset in addition to a broad-spectrum antibiotic . The patient's condition rapidly improved, and she was discharged home on the ninth day after the onset of TSS  were attributed to a viral infection or allergic reaction. Vancomycin was not used until the intraoperative wound cultures revealed MRSA. We believe that the delay of diagnosis and treatment in case 1 caused the delayed recovery of the patient even after the removal of the tissue expander. In case 2, an early diagnosis of TSS was made on the basis of our experience with case 1. The tissue expander was removed soon after the onset, and vancomycin was started on the first day. The early diagnosis and treatment in case 2 led to her rapid recovery.-The case definition of TSS according to the criteria of the US Centers for Disease Control and Prevention includes fever, rash, desquamation, and hypotension, in addition to the presentation of specific abnormalities in at least 3 specified organ systems .5MRSA strains have increased in prevalence during the last decade, and MRSA has been reported as a cause of TSS.In conclusion, although it is a rare postoperative complication, all plastic surgeons should be aware of TSS. The early diagnosis of TSS based on its characteristic symptoms of fever, rash, and gastrointestinal abnormalities and its prompt treatment are crucial.


Solid tumors following myelodysplastic syndrome (MDS) are rare and have no uniform treatment guidelines. The current study presents a rare case of a 47-year-old female diagnosed with cervical cancer  with an eight-year history of MDS. A multidisciplinary treatment discussion was organized and a rigorous treatment plan was developed. With injection of granulocyte colony-stimulating factor and interleukin-11 factor, transfusion of red blood cell suspension and close monitoring of the blood count, the patient was administered radiotherapy, specifically intensity modulated radiation therapy. However, a degree IV bone marrow suppression repeatedly assaulted, leading to interruption of the radiotherapy treatment. Eventually, the total dose received by point A  was 51 Gy. One month later, a gynecological examination and magnetic resonance imaging of the pelvis revealed that the treatment resulted in a complete remission. In conclusion, radiation therapy can still be implemented to obtain satisfactory local control when the hematopoietic function of the bone marrow is weakened due to long-term MDS. Laboratory studies revealed normal urine, feces, blood coagulation and liver and kidney function.The initial complete blood cell count was as follows: White blood cell (WBC) count, 0.9×10No abnormality was found on the computed tomography scan of the chest and abdomen. Magnetic resonance imaging (MRI) of the pelvis  showed aA multidisciplinary treatment (MDT) discussion was conducted and a rigorous treatment plan was created. The peripheral blood count of the patient was improved. A total of 250 μg of granulocyte colony-stimulating factor (G-CSF) and 2 mg of interleukin-11 (IL-11) were subcutaneously injected twice a day to stimulate granulocyte and megakaryocyte proliferation and differentiation, respectively. RBC suspensions were transfused to correct the anemia. Hematopoietic materials, including vitamin B12 and folic acid, were also supplied to correct the anemia. External body radiation therapy (EBRT) was prescribed to the whole pelvic region in 25 fractions totaling 50 Gy, followed by intracavitary brachytherapy. The total dose of brachytherapy prescribed was 20 Gy/4 fractions  to point A . In order to protect the bone marrow, the EBRT was applied through intensity-modulated radiation therapy (IMRT) techniques and the volume of the pelvic bone receiving 20 Gy (V20) was controlled to <70% . Due to 9 cells/l, ≥50×109 cells/l and ≥50 g/l, respectively. During the radiotherapy, the patient continued to have injections of G-CSF and IL-11 along with the intermittent transfusion of the RBC suspension. However, the patient experienced a IV degree myelosuppression following 16 Gy/8 fractions of EBRT. The EBRT was halted and brachytherapy, with a potential to produce weaker bone marrow suppression, was initiated. Following 20 Gy/4f of brachytherapy , the EBRT was continued. Subsequently, the amount of EBRT was pushed to 26 Gy/13 fractions. However, the WBC count, PLT count and HGB decreased to 0.35×109 cells/l, 17×109 cells/l and 29 g/l, respectively. The radiotherapy was withheld due to the recurrent IV degree myelosuppression and the failure of supportive care for the bone marrow hematopoietic function. Therefore, the total dose of point A was 51 Gy . The patient was then discharged from the hospital, as no further treatment was accepted. One month later, a gynecological examination and pelvic MRI  13 months after radiotherapy.Seven months later, however, lung and liver metastasis occurred. The patient succumbed to an acute intracranial hemorrhage due to thrombocytopenia  is likely to cause bone marrow damage, resulting in blood disease and a poor prognosis. However, the patient in the present case would have had a poor prognosis if the cancer was ignored. On the premise of elevating blood count and protecting the bone marrow, the patient in the present study accepted reduced-dose radiotherapy without chemotherapy. Finally, the total dose accepted by point A was 51 Gy. The treatment effect achieved CR. Therefore, for these patients to achieve the optimal therapeutic effect and the longest survival time, the dose of radiotherapy should be appropriately reduced on the premise of elevating blood count and protecting the bone marrow.Anemia has a negative impact on local control, disease-free survival and overall survival rate of cervical cancer ,10. In t


Postpolio syndrome (PPS) is characterized by progressive disabilities that develop decades after prior paralytic poliomyelitis. Because chronic inflammation may be the process underlying the development of PPS, immunomodulatory management, such as intravenous immunoglobulin (IVIg) administration, may be beneficial.We performed a systematic review and meta-analysis of published randomized controlled trials (RCTs) and prospective studies that evaluated the efficacy of IVIg in managing PPS. Electronic databases, including PubMed, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials, were searched for articles on PPS published before December 2014. The primary outcomes were pain severity, fatigue scores, and muscle strength. The secondary outcomes were physical performance, quality of life (QoL), and cytokine expression levels.We identified 3 RCTs involving 241 patients and 5 prospective studies involving 267 patients. The meta-analysis of pain severity , fatigue scores , and muscle strength revealed no significant differences between the IVIg and the placebo group. Regarding QoL, the RCTs yielded controversial outcomes, with improvement in only certain domains of the Short Form 36 (SF-36). Moreover, one prospective study reported significant improvement on SF-36, particularly in patients aged younger than 65 years, those with paresis of the lower limbs, and high pain intensity.The present review indicated that IVIg is unlikely to produce significant improvements in pain, fatigue, or muscle strength. Thus, routinely administering IVIg to patients with PPS is not recommended based on RCTs. However, a potential effect in younger patients with lower limbs weakness and intense pain requires confirmation from further well-structured trials. Postpolio syndrome (PPS) may develop from prior paralytic poliomyelitis after an interval  of stable neurological function. It is characterized by a gradual onset of persistent and progressive, new or further muscle weakness or decreased endurance. Muscle atrophy, pain, and fatigue are common, whereas hypoventilation, dysphagia, or dysphonia may develop as well ,3. The WTo date, no curative or specific treatment exists for PPS. Potential management approaches include pharmacological  and nonpharmacological interventions . However, the evidence available from randomized controlled studies is inadequate for formulating a definite conclusion regarding the alleviation of activity limitations, fatigue, and pain as well as the improvement of muscle strength .The most widely accepted pathogenesis for the muscle-related effects of PPS is uncompensated reinnervation through collateral sprouting that increases the motor unit areas in response to denervation from prior acute poliomyelitis. Thus, progressive muscle weakness occurs years after prior acute poliomyelitis. The cause of the ongoing denervation remains unclear and is probably multifactorial, including factors such as stress or the overuse of motor units, normal aging, the persistence of poliovirus fragments, a patient’s genetic background, and chronic inflammation . In addiWe reviewed RCTs or prospective trials that evaluated the outcomes of IVIg in PPS treatment. For inclusion in our study, the trials were required to describe the following: (1) inclusion and exclusion criteria used for patient selection, (2) IVIg dosing strategies, and (3) evaluations of clinical outcomes. We excluded trials that met as least one of the following criteria: (1) the clinical outcomes stated were unclear or (2) duplicate reporting of patient cohorts.http://clinicaltrials.gov/). The following terms and Boolean operator were used in MeSH and free-text searches: postpolio syndrome OR poliomyelitis OR postpoliomyelitis, intravenous immunoglobulin OR IVIg. The “related articles” facility in PubMed was used to broaden the search. No language restrictions were applied. The final search was performed in December 2014. We attempted to identify additional studies by searching the reference sections of relevant papers and contacting known experts in the field. The systematic review described here was accepted by the online PROSPERO international prospective register of systematic reviews of the National Institute for Health Research (CRD42014013305).The studies were identified by performing keyword searches of electronic databases, namely PubMed, EMBASE, CINAHL, the Physiotherapy Evidence Database (PEDro), SCOPUS, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov registry , and changes in cytokine expression at 1, 2, and 12 months. The pain intensity was assessed using visual analog scales (VASs) . The fatI2 test, with I2 quantifying the proportion of total outcome variability that was attributable to the variability among the studies.Statistical analysis was conducted using the Review Manager (Version 5.3) computer software . The meta-analysis of RCTs was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines . When neThe flow chart in Figure Table Table I2 value was 76%, indicating heterogeneity among the studies.Pain was assessed using a 10-cm VAS . We compared the outcome measures during the initial 2 to 3 months following IVIg treatment. The pooled mean difference in the pain scores of the 3 included RCTs was −1.02 (95% CI: −2.51 to 0.47), and no significant differences were observed in the pain scores between the treatment and the control groups ,14 .Two of the 3 RCTs that reported reduction of fatigue scores 2 and 3 months after treatment, respectively ,14, wereP = 0.029) [Muscle strength was measured using a dynamometer in the 3 RCTs ,12,14. D= 0.029) . However= 0.029) .Figure 4To evaluate physical performance, 2 RCTs and 2 prospective studies used the 6-MWT, whereas one RCT and one prospective study used PASE. One RCT reported significant improvements in PASE results , and onlThe PCS, including the physical functioning, role physical, BP, and perception of general health scores, and mental component score (MCS), comprising the vitality (VT), social functioning (SF), role limitations because of emotional problems (RE), and mental health scores, of the SF-36, were assessed in 2 RCTs ,14 and 3Among the eligible prospective studies, Gonzales et al.  and KapoOne RCT (compared with data from the placebo groups)  and 2 prAlthough Gonzalez et al. reported several adverse effects of IVIg treatment, it was well tolerated by most patients; no anaphylactic reactions or severe adverse events related to IVIg treatment were reported in the studies. The incidence of gastrointestinal disorders, general disorders, adverse reactions at the administration site, nervous system disorders, and skin and subcutaneous tissue disorders was higher in the active treatment group than in the control group, with headache being the most common side effect .The present review showed that pain, a major outcome in all studies, improved after IVIg treatment, particularly in patients with PPS who exhibited high VAS scores before intervention, in younger patients, and in those with paresis of the lower limbs. However, when the overall data were subjected to meta-analysis, no significant differences were observed between the intervention and the placebo groups. The meta-analysis of the reduction of fatigue scores revealed no significant improvement after IVIg treatment. Regarding QoL, some prospective studies observed significant improvements in the overall PCS after IVIg treatment, but the RCTs revealed more controversial outcomes. Only scores in certain SF-36 subdomains significantly improved, particularly in patients aged older than 65 years and those with paresis of the lower limbs and high pain intensity. Moreover, only one RCT reported improvements in muscle strength and physical performance.A study postulated that new-onset muscle weakness and decreased endurance of previously polio-affected muscles, cardinal symptoms of PPS, result from an uncompensated denervation–reinnervation process that leads to the loss of motor units . All 3 RRegarding the cytokine expression levels, 2 studies reported that both serum and CSF IFN-γ and TNF-α levels were higher in patients with PPS than in the control group patients with ONDs. Although the OND patient cohort was heterogeneous, the patients with ONDs exhibited decreased cytokine expression levels in the blood and CSF . ContrarFurthermore, the studies used various intervention schemes. Gonzalez et al. administered a fixed IVIg dosage, which was repeated at 3-month intervals. By contrast, in Norwegian and Italian study groups, IVIg was administered according to the patients’ body weight during a single treatment period. In addition to PPS, numerous trials have investigated the clinical benefits of IVIg in immune-mediated diseases of the central and peripheral nervous systems, such as Guillain–Barré syndrome (GBS) and myasthenia gravis (MG). The EFNS guidelines recommend IVIg regimens of 0.4 g/kg/day for 5 days for GBS. For patients with MG, 2 g/kg of IVIg administered over 2 days was compared with 1 g/kg of IVIg administered in a single day, and a trend toward superior outcomes was observed at the higher dose .Variability in the clinical factors and nonuniform reporting of the clinical parameters contributed to the heterogeneity among the reviewed studies. First, the characteristics of the participants varied considerably; for example, one study recruited 9 patients with weakness involving one or 2 limbs and 11 with more widespread weakness . Second,Our review had several strengths; specifically, a comprehensive search for relevant studies was conducted, the eligibility criteria were applied systematically and explicitly, study quality was considered carefully, and a rigorous analytical approach was used. However, our review was limited by the methodological quality of the original studies Table . First, Although we observed statistically significant differences in the pain scores in each individual prospective trial, our meta-analysis of the RCTs indicated that the administration of IVIg treatment for PPS is unlikely to produce a significant reduction in the pain and fatigue severity, and improvement of muscle strength. Overall, the methodological quality of the reviewed studies was not adequate. Regarding the cost benefit, we cannot recommend the routine administration of IVIg for patients with PPS, but it could serve as a supportive treatment option for patient subgroups with moderate to severe PPS. Additional large, long-term RCTs are required to further evaluate the responding subgroups, long-term effects, and dosing schedules.


Abdominal surgical site infections are among the most common complications of inpatient admissions and have serious consequences for outcomes and costs. Different risk factors may be involved, including age, sex, nutrition and immunity, prophylactic antibiotics, operation type and duration, type of shaving, and secondary infections. This study aimed to determine the risk factors affecting abdominal surgical site infections and their incidence at Imam Khomeini, a major referral teaching hospital in Iran.Patients (n = 802) who had undergone abdominal surgery were studied and the relationships among variables were analyzed by Student's t and Chi-square tests. The subjects were followed for 30 days and by a 20-item questionnaire. Data were collected through pre- and post-operative examinations and telephone follow-ups.Of the 802 patients, 139 suffered from SSI (17.4%). In 40.8% of the cases, the wound was dirty infected. The average age for the patients was 46.7 years. The operations were elective in 75.7% of the cases and 24.7% were urgent. The average duration of the operation was 2.24 hours, the average duration of pre-operative hospital stay 4.31 days and the average length of (pre- and post-operation) hospital stay 11.2 days. Three quarters of the cases were shaved 12 hours before the operation. The increased operation time, increased bed stay, electivity of the operation, septicity of the wound, type of incision, the administration of prophylactic antibiotic, type of operation, background disease, and the increased time lapse between shaving and operation all significantly associated with SSI with a p-value less than 0.001.In view of the high rate of SSI reported here (17.4% compared with the 14% quoted in literature), this study suggests that by reducing the average operation time to less than 2 hours, the average preoperative stay to 4 days and the overall stay to less than 11 days, and approximating the timing of shaving to the operation and substituting cefazolin for cefaluthin when prophylactic antibiotic is to be administered, the SSI may be reduced to a more acceptable level. SSIs are among the most common hospital acquired infections comprising 14–16 percent of inpatient infections. Such inClean wounds (1.5–3.7%); clean-contaminated wounds 3–4%); contaminated wounds (8.5%); dirty-infected wounds (28–40%); in laparoscopy (10%) umbilical hernia (2–5%); in the cancer of the colon without taking antimicrobial drugs (30–60%); or with antibiotic and proper intestine wash (10%); in colostomy (above 50%); in colon perforation (20%); in stomach cancer and surgery (20%); in hernionite (50%); in adult appendectomy (10–20%); in children's appendicitis (2–5%); in aged appendicitis and in pregnant women (10–50%); and in AIDS victims (above 50%); in liver abscess (20%); in hydatid cyst (2–5%); in acute and chronic cholecystectomy without stones (10%); in acute septic cholangitis (10–20%); in laparoscopic cholecystectomy (2–5%); and in splenectomy (2–5%) [%; contamSSI is identified with redness, inflammation, heat, pain, a temperature of 38°C, and septic drainage from the surgical site during the 30 days following operation. SeveralWhile we could not find any significant correlation between sex and SSI rate, age proved to be an important factor; the rate of wound infection for 15 to 24-year-old patients was only10% but increased significantly for those over 65 years of age. The extent of SSI was doubled for obese patients. The duration of surgical operation also proved to be a significant factor: only 3% of operations lasting 30 minutes or less led to infection, while for operations lasting more than 6 hours this rate leapt to 18%. SSI rate increased with longer durations of preoperative bed stay, but preoperative showers with a disinfecting soap such as chlorhexidine or Betadine decreased the cutaneous bacterial load. According to Kruise, the rate of infection was reduced to 1.3% among patients who showered with disinfecting soap containing hexachlorophene. In those who showered with ordinary soap the corresponding figure was 2.1%, and for patients who did not shower at all it increased to 2.3%. However, another study on 5536 subjects showed no decrease in SSI in patients who showered with chlorhexidine preoperatively; the rate was 4% [In this study, 802 patients in a teaching hospital during the 15 months from April 2002 to July 2003 underwent abdominal surgery and were studied for SSI and the factors affecting it. Initially, 884 patients were recruited for the study but 82 were excluded on the basis of the following criteria: deficient medical records; patients operated at a different hospital and subsequently transferred to Imam's Hospital: or patients deceased during the operation or within the following 30 days.The dependent variable in this study was abdominal surgical site infection, defined as redness, swelling, pain, temperature above 38°C, during the 30 days after operation. The independent variables were: age, sex, site operated, body mass index, time of shaving the site of incision, administration of prophylactic antibiotics, type of surgical operation, duration of operation, duration of preoperative bed stay; preoperative shower, type of shaving, and accompanying conditions.The data were collected through a 20-item questionnaire. The stages for data collection and information completion were as follows: identification of patients; preoperative interview; postoperative interview; record completion; weekly examinations and telephone follow-ups for 30 days following operation; and pre-discharge examinations. The collected data were analyzed by the SPSS 10 package, using Student's t-test for continuous variables and chi-square test.for categorical variables.To the best of our ability, this study was conducted with due attention to research ethics.however, problems met in the follow-ups the patient's discharge imposed limitations on the studyOf the 802 patients studied who had undergone abdominal surgery 139 (17.4%) suffered from SSI as defined in Table The body mass index for 73 patients (9.1%) was above 30, indicating obesity. Over half the patients (403 cases) suffered from accompanying conditions such as diabetes, high arterial blood pressure, kidney or liver failure, malignancy, febrile condition, cardiac disorders, thyroid disorders, blood disease, chronic obstructive pulmonary disease, convulsion, hyperlipidemia, or immunological disorders; or had previously undergone surgical operations. The rest were free of accompanying conditions Table .We found no significant correlations between SSI incidence and sex or preoperative shower. However, correlations with duration of operation, duration of preoperative bed stay, electivity of surgery, lengthening of preoperative shaving time, increasing age, wound infection, site of surgery, type of incision, accompanying disorders, and type of prophylactic antibiotic administered before operation were all significant at p < 0.001. Although differences in SSI rates were not significantly related to BMI, a trend was apparent: SSI rate was higher with low and high BMI.The following prophylactic antibiotics were used: ampicillin, gentamicine, cephalothin, metronidazole, ceftriaxone and cefazoline table .For the 802 participants in this study, the SSI reported was 17.4%, which is well above the 14–16% reported in other studies [SSI is not correlated with sex , in agreThe findings supported the literature by showing that administration of prophylactic antibiotic half an hour before the operation would bring about the best results and the lowest SSI . This waThe literature shows that with the duration of above 2 hours, the risk of SSI increases . The aveThe time of shaving when it approaches the operation and if done by clippers, reduces the SSI risk. In this study the two times: one hour before surgical operations and 12 hours before that were contrasted which supported previous findings with p = 0.001. This is one area where we can lower the risk by approximating the time of shaving as much as possible to that of operation.Other such factors quoted in the literature as the conditions of the operating theatre, personal hygiene, acompanying diseases, immunological disorders, smoking, techniques of surgery, the surgeon's expertise, duration of surgical scrub, preoperative skin preparation, poor hemostasis, failure to obliterate dead space, tissue trauma, and inadequate sterilization of instruments, which were not included in this study might be considered as confounding factors.Considering the relatively higher rate of SSI in this study (17.4% compared with the 14% quoted in the literature), especially in such cases as stomach cancers and umbilical hernia, where the rate is considerablly higher, we should carefully reconsider the whole operation procedure. In general, we should do our best to reduce the average operation duration to less than 2 hours and the average preoperative bed stay to less than 4 days. Thus, the present average of 11.2 days for the total bed stay would be reduced to less than 11 days. The time of shaving should approximate the operation time as much as possible. Finally, when the administration of prophylactic antibiotics is required, cefazoline is recommended to substitute cephalothin.Razavy: main researcher Ibrahimpour: Sabouri Kashani: Jafarian: (counsult)The author(s) declare that they have no competing interests.The pre-publication history for this paper can be accessed here:


Urechis caupo.Mitochondria contain small genomes that are physically separate from those of nuclei. Their comparison serves as a model system for understanding the processes of genome evolution. Although hundreds of these genome sequences have been reported, the taxonomic sampling is highly biased toward vertebrates and arthropods, with many whole phyla remaining unstudied. This is the first description of a complete mitochondrial genome sequence of a representative of the phylum Echiura, that of the fat innkeeper worm, This mtDNA is 15,113 nts in length and 62% A+T. It contains the 37 genes that are typical for animal mtDNAs in an arrangement somewhat similar to that of annelid worms. All genes are encoded by the same DNA strand which is rich in A and C relative to the opposite strand. Codons ending with the dinucleotide GG are more frequent than would be expected from apparent mutational biases. The largest non-coding region is only 282 nts long, is 71% A+T, and has potential for secondary structures.Urechis caupo mtDNA shares many features with those of the few studied annelids, including the common usage of ATG start codons, unusual among animal mtDNAs, as well as gene arrangements, tRNA structures, and codon usage biases. Mitochondrial genomes are physically separate from the nuclear genome. For animals, they are typically circular with a compact arrangement of an identical set of 37 genes . For somUrechis caupo, the first example from the phylum Echiura. Echiurans comprise about 150 species and are commonly called spoon worms because of the shape of their extensible proboscis. Unlike annelids, they have no overt segmentation, but they develop via trochophore larvae, very similar to those of annelids. U. caupo is a pink, sausage shaped worm that lives in U-shaped burrows in the mud or sand of the intertidal or subtidal zones. Unlike other echiurans, it feeds on plankton by filtering using an elaborate mucus net.Toward this end, this article describes the complete mtDNA sequence of the fat innkeeper worm, Urechis caupo is 15,113 nts in length (GenBank accession number AY619711) and contains the same 37 genes found for nearly all animal mtDNAs /[G+C]) is – 0.24 and T-skew ([T-A]/[T+A]) is – 0.016 [Terebratalia transversa [The  – 0.016 . These vansversa .U. caupo mtDNA use ATG. The only exceptions are cox1, which uses GTG and nad3 which uses ATC. In the case of cox1, there is an in frame stop only three codons upstream and neither of the intervening codons is ATG. Also, this inference of starting on GTG specifies a set of amino acids well matched to those at the beginning of other Cox1 proteins. The situation for nad3 is nearly identical, with an in frame stop only four codons upstream and no intervening ATG codons. However, downstream of the inferred start are several ATA codons that can not be ruled out as alternatives. The commonality of using ATG as a start codon has also been noted for mitochondrial genes of four annelids, Platynereis dumerilii [Lumbricus terrestris [Helobdella robusta and Galathealinum brachiosum (previously considered to be of the phylum Pogonophora) [Phascolopsis gouldii [Mitochondrial genes commonly use several alternatives to ATG as start codons. However, 11 of the 13 proteins coding genes of umerilii , Lumbricrrestris , Helobdenophora)  and a sicox2, nad1, nad2, cob, and nad5 , a complete stop codon could be formed by including only the next two nucleotides, and two other cases (nad1 and cox2), there is an in frame stop codon just one or two codons downstream, respectively. It is not clear how gene overlaps could be resolved from a polycistronic transcript (assuming that the genes of this mtDNA are expressed in this way), but the presence of these stop codons seems beyond coincidence. It could be that they serve as a "back up" in case translation should begin in the absence of transcript cleavage.A complete stop codon without overlap of the downstream gene is found for all except Twenty-two regions can be folded into the typical cloverleaf structures of the expected set of tRNAs Fig. . There arrnS is 903 nucleotides and rrnL is 1266 nucleotides in length. These genes are arranged sequentially, but without an intervening tRNA gene as is otherwise commonly found.As has been the case for all studied animal mtDNAs to date, two rRNA genes are identified, one for each of the small and large mitochondrial ribosomal subunits. Determining the precise ends of the rRNA transcript requires experimentation, but if it's assumed that they extend to the boundaries of the adjacent genes, then trnS1 and cox3. This has no repeat elements and the base composition is unremarkable. What role, if any, these sequences have in the regulation of transcription and/or replication awaits further study.The largest non-coding region is only 282 nts long. The region is 71% A+T and contains one palindrome of an 11 nt sequence , but otherwise no large repeat elements. Obviously, this has potential for forming a stem-loop structure, and it may be significant that a short sequence a few nucleotides upstream, TCAAAA, has the potential for competing with this to form a short hairpin with the TTTTGA at the end of the palindrome. There has been previous speculation that regions with potential for competing, mutually exclusive hairpins may play a role in regulating transcription and/or replication [e.g. ref. [Aside from these 282 and 43 nt regions, there are only 36 total intergenic nucleotides scattered among 14 regions. In seven cases these are 2–6 nts long . For the other seven cases, genes are separated by a single nucleotide, and in six of these, that nucleotide is a C. (The remaining case is a T.) The prevalence of C is consistent with the measured G-skew between the strands, although it is possible that this otherwise indicates some function of these nucleotides.This is the first description of a complete mitochondrial genome sequence of a representative of the phylum Echiura. The genome contains the same 37 genes most commonly found in animal mtDNAs. Many features are most similar to those found for annelid mtDNAs, including A+T content, use of protein initiation codons, size and potential secondary structures of the largest non-coding region, and the relative arrangement of many genes. As in annelids examined to date, all genes are found on the same DNA strand. As noted for brachiopod mtDNA, there is a preference for G nucleotides to appear in tandem, without obvious explanation. Further description and comparison of complete mtDNA sequences will continue to produce a picture of genome evolution, particularly once sampling includes representatives of each animal phylum.Urechis caupo total DNA was the kind gift of Eric Rosenthal. The entire mtDNA sequence was obtained using techniques detailed in [cox1, cob, and rrnS using primer pairs HCO 2198/LCO 1490 [A preparation of ailed in . BrieflyLCO 1490 , CytbF/CLCO 1490 , and 16SLCO 1490 , respectLumbricus terrestris mtDNA [Genes encoding rRNAs and proteins were identified by matching nucleotide or inferred amino acid sequences to those of is mtDNA . Since icox1, cox2, cox3, cytochrome oxidase subunit I, II, and III protein genes; cob, cytochrome b gene; atp6, atp8, ATP synthase subunit 6 and 8 genes; nad1, nad2, nad3, nad4, nad4L, nad5, nad6, NADH dehydrogenase subunit 1–6, 4L genes; trnA, trnC, trnD, trnE, trnF, trnG, trnH, trnI, trnK, trnL1, trnL2, trnM, trnN, trnP, trnQ, trnR, trnS1, trnS2, trnT, trnV, trnW, trnY, transfer RNA genes designated by the one-letter code for the specified amino acid, with numerals differentiating cases where there are two tRNAs for the same amino acid.


We compared the effect of a novel NO-releasing derivate, NCX 4040, with that of aspirin and its denitrated analog, NCX 4042, in In vitro cytotoxicity was evaluated on a panel of colon cancer lines  by sulforhodamine B assay. Cell cycle perturbations and apoptosis were evaluated by flow cytometry. Protein expression was detected by Western blot. In the in vivo experiments, tumor-bearing mice were treated with NCX 4040, five times a week, for six consecutive weeks.in vitro studies, aspirin and NCX 4042 did not induce an effect on any of the cell lines, whereas NCX 4040 produced a marked cytostatic dose-related effect, indicating a pivotal role of the -NO2 group. Furthermore, in LoVo and LRWZ cell lines, we observed caspase-9 and -3-mediated apoptosis, whereas no apoptotic effect was observed after drug exposure in WiDr or LoVo Dx cell lines. In in vivo studies, both NCX 4040 and its parental compound were administered per os. NCX 4040 induced a 40% reduction in tumor weight. Conversely, aspirin did not influence tumor growth at all.In the in vitro and in vivo antiproliferative activity, indicating its potential usefulness to treat colon cancer.NCX 4040, but not its parental compound, aspirin, showed an  One of the most important approaches for reducing cancer incidence is chemoprevention. This is especially relevant for colon cancer, which represents the third leading cause of cancer mortality in developing countries and for which diagnostic tests and clinical treatments are not satisfactory .Recently published reviews -4 underlDespite a multiplicity of studies conducted on this compound family of drugs, little is known about the molecular targets that are responsible for their tumor-preventing properties and which are important, not only from a mechanistic point of view, but also because of their clinical implications in identifying individuals or subsets of patients who are sensitive to these drugs. Originally, it was believed that the regular use of these compounds acted exclusively through the inhibition of COX-1 and COX-2 activity involved in the production of prostaglandins . There iIn an attempt to reduce gastrointestinal toxicity, conventional NSAIDs have been coupled with a nitric oxide (NO)-releasing moiety ,16. The in vitro [Interestingly, the activity of some NO-NSAIDs is considerably higher than that of the parental drugs. For example, NCX 4016 has been found to be much more effective than the parent aspirin in reducing aberrant crypt foci, a precancerous lesion, in a rat model of colorectal cancer  and in iin vitro . Similarin vitro ,23, in ain vitro and in vivo human colon cancer models and investigated the mechanisms of action underlying its antitumor activity.In the present work, we compared the effect of a novel NO-releasing derivate, NCX 4040, with that of aspirin and its denitrated analog in The studies were performed on colon adenocarcinoma cell lines: 2 (LoVo and WiDr) were obtained from the American Type Culture Collection , 1 (LRWZ) was isolated in our laboratory and derived from a patient with a confirmed diagnosis of colon adenocarcinoma, and 1 was doxorubicin-resistant (LoVo Dx) derived from the above-mentioned LoVo cells. Cell lines were maintained as a monolayer at 37°C and subcultured weekly. Culture medium was composed of DMEM/HAM F12 (1:1) supplemented with fetal calf serum (10%), glutamine (2 mM), non-essential aminoacids (1%) , and insulin (10 μg/ml) . Cells were used in the exponential growth phase in all the experiments.Aspirin, NCX 4040 (NO-releasing aspirin), NCX 4042  Fig. ,  assay was used according to the method by Skehan et al . BrieflyThe cells were treated according to the previously described Western blot procedure.  COX-1 anTotal RNA was isolated from cells by direct lysis and quantified spectrophotometrically. After quantification, RT reaction was performed with 1 μg of each sample using Gene Amp Gold RNA PCR Core Kit . The same cDNA was used for RT-PCR amplification of COX-1 and COX-2. PCR reactions were carried out in a final volume of 25 μl containing 2 μl of cDNA template, 1 unit of Klen Taq, 0.2 mM dNTP and 0.4-μM amounts of each forward and reverse primer, using a thermal cycler . 5-μl aliquots of the amplified DNA fragments were separated on an ethidium bromide-stained 2% agarose gel.After a 24-h exposure to 10 μM of NCX 4040, cells were harvested and stained in a solution containing RNase  and NP40 . After 30–60 min, samples were analyzed by flow cytometry using a FACS Vantage flow cytometer. Data acquisition  was performed using CELLQuest software. Data were elaborated using Modfit (DNA Modelling System) software and expressed as fractions of cells in the different cycle phases. Samples were run in triplicate, and each experiment was repeated three times.Apoptosis was evaluated by flow cytometric analysis according to the previously described TUNEL assay procedure . BrieflyIn situ cell death detection kit, fluorescein; Roche Diagnostic GmbH, Mannheim, Germany).In LoVo cells, positivity to TUNEL assay was also evaluated by fluorescence photomicroscope  according to the manufacturer's instructions  were used to visualize chromatin condensation and/or fragmentation typical of apoptotic cells.Antitumor efficacy was evaluated on 6–8-week old CD-1 male nude (nu/nu) mice weighing 22–24 g . All procedures involving animals and their care were conducted in conformity with institutional guidelines, which are in compliance with national  and international laws .NCX 4040 and aspirin were homogeneously suspended in 0.5% carboxymethyl cellulose (CMC) containing 10% of DMSO for antitumor efficacy studies. All the drugs were administered orally.in vivo experiments were performed on WiDr, LoVo and LoVo Dx lines. Tumor cells were resuspended (5 × 106 viable cells) in 0.2 ml of serum-free medium and injected into the hind leg muscles of mice.Since LRWZ line showed a low tumorigenicity when cells were injected into nude mice, th day after the tumor cell implant, when a tumor mass of about 300 mg was evident in all the animals. The dose of aspirin and NCX 4040 was chosen on the basis of previous observations obtained using the parental NCX 4016 compound [T – C, where T and C are the median times for treated and control tumors, respectively, to achieve equivalent size.Each experimental group included at least 6 mice. 10 mg/kg of aspirin and NCX 4040 were administered orally five days a week for 6 consecutive weeks starting on the 6compound . Toxicitcompound . The antThe significance of results was analyzed by the Mann-Whitney non parametric test. Differences were considered significant at P values < 0.05 (two-sided).50) ranging from 5.4 μM in LoVo cells to 24 μM in LoVo Dx. The same treatment scheme also induced the highest cytocidal effect, with a modulation for the different cell lines and a 50% lethal concentration (LC50) in LoVo cells (9.6 μM) about four- and threefold lower than that observed in WiDr and LRWZ, respectively. In LoVo Dx, no cytocidal effect was observed at any of the concentrations tested.The effect of aspirin, NCX 4040, and its structural analog, NCX 4042, on cell growth was determined after different exposure schemes and using various concentrations. Aspirin and NCX 4042 did not exhibit an effect on any of the cell lines Fig. . In partFlow cytometric analysis of apoptosis performed after exposure to various concentrations of NCX 4040 showed 90% of apoptotic cells at 24 h starting from a 10-μM concentration in LoVo line, whereas apoptosis was not detected at the same time in any other cell line at any of the concentrations tested , these proteases were activated only in LoVo and in LRWZ cells, where apoptosis was found. In particular, in LoVo cells caspase-3 and -9 activation was already evident after 3 h, whereas in LWRZ, activation took a longer time to occur (at least 10 h for caspase-9 and 12 h for caspase-3). The temporal activation in these 2 cell lines corresponds to the early or late induction of apoptosis Fig. .in vitro data, which demonstrated that LoVo line is the most sensitive to NCX 4040 exposure.The administration of aspirin in mice bearing all 3 cell lines did not influence the growth of tumors Fig. . In contin vitro on a panel of human colon cancer lines with different genetic profiles representing clinical tumor heterogeneity, and in vivo on xenografted immunosuppressed mice.Our study evaluated the antitumor activity of the novel NO-aspirin NCX 4040 2 group in the mechanism of action underlying its in vitro activity. Extensive evidence indicates that nitric oxide is capable of initiating apoptotic cell death in some cell types as a consequence of DNA-induced damage [Neither aspirin nor the denitrated analog, NCX 4042, influenced the growth of any of the cell lines studied, whereas NCX 4040 produced an important cytocidal effect. These findings suggest a pivotal role of the -NOd damage ,30, but In LRWZ cells, a relevant apoptosis was also observed but after a longer exposure time and at higher NCX 4040 concentrations, after which the irreversibly damaged cells underwent apoptotic death through the activation of caspases-9 and -3.Moreover, two NO donors were used to better clarify the role of the aspirin component. These compounds, at concentrations similar to those utilized for NCX 4040, showed a very modest cytotoxic activity (data not shown), confirming the importance of the aspirin component for the antineoplastic effectiveness of the NCX 4040 molelcule.In addition, WiDr and LoVo Dx cell lines, which proved to be resistant to NCX 4040-induced apoptosis, were characterized by baseline expression of COX-2 protein. This finding, which is consistent with data recently published for breast and colorectal cancer cells, would seem to support the hypothesis that a high level of COX-2 protein protects cells from apoptosis, especially that induced by NO-compounds ,32.in vitro studies showed a high tumorigenic capacity, making it possible to evaluate in vivo the antitumor efficacy of NCX 4040. The long-term administration of this drug was well tolerated by the mice and reduced the tumor mass of LoVo, LoVo Dx and WiDr lines compared to untreated mice. Analysis of growth curves highlighted differences in the degree of drug sensitivity between cell lines. NCX 4040 was very effective in delaying tumor growth in LoVo tumors, whereas WiDr, and especially LoVo Dx lines, regrew after the end of treatment. These results confirm the in vitro data and seem to indicate that, as observed in vitro, the ability of NCX 4040 to induce apoptosis has a key role in the antitumor efficacy of this drug.With the exception of LRWZ, all the lines evaluated in in vitro and in vivo, whereas the parental compound aspirin showed no activity, which suggests that the NO-releasing derivate could prove useful in the clinical management of colon cancer, possibly in combination with conventional antineoplastic drugs.In conclusion, NCX 4040 was effective in reducing the growth of several human colon cancer cell lines both COX, cyclooxygenase; NO, nitric oxide; NO-NSAID, nitric oxide-releasing nonsteroidal antiinflammatory drug releasing; NSAID, nonsteroidal antiinflammatory drug; SRB, sulforhodamine B; TUNEL, terminal uridine nick end labeling.Manlio Bolla is an employee of NicOx SA.in vitro experiments. CL, MS and GZ also participated in the study design and carried out the in vivo experiments. All authors read and approved the final manuscript.AT was responsible for study design, data analysis, and drafting the manuscript. WZ, DA and MB participated in the study design and acted as scientific advisors. AT, PU, FF and MR performed the