Background. This study was conducted to investigate the clinical characteristics and treatment results of osteosarcoma in pediatric patients during the past 30 years. Trends in survival rates and long-term toxicity were analyzed. Procedure. 130 pediatric patients under the age of 20 years with primary localized or metastatic high-grade osteosarcoma were analyzed regarding demographic, treatment-related variables, long-term toxicity, and survival data. Results. Comparison of the different time periods of treatment showed that the 5-year OS improved from 58.6% for children diagnosed during 1979–1983 to 78.6% for those diagnosed during 2003–2008 (P = 0.13). Interestingly, the basic treatment agents including cisplatin, doxorubicin, and methotrexate remained the same. Treatment reduction due to acute toxicity was less frequent in patients treated in the last era . Furthermore, late cardiac effects and secondary malignancies can become evident many years after treatment. Conclusion. We elucidate the prevalence of toxicity to therapy of patients with osteosarcoma over the past 30 years. The overall improvement in survival may in part be attributed to improved supportive care allowing regimens to be administered to best advantage with higher tolerance of chemotherapy and therefore less chemotherapy-related toxicity. Osteosarcoma comprises 5% of all pediatric malignancies and is the most common primary bone cancer in children and adolescents. It is a highly aggressive tumor that usually involves the metaphysis of long bones and metastasizes primarily to the lung. Before the 1970s, the prognosis for patients with high-grade osteosarcoma was poor, with long-term survival rates of less than 20% –6. Furth To gain more insight in the young patients, as osteosarcoma is predominantly being a disease that affects young patients, we investigate survival trends in this patient group and subsequently analyze the occurrence of long term toxicity over the last three decades. In total 130 pediatric patients were consecutively treated between 1979 and 2008 in two different centers: Radboud University Nijmegen Medical Centre and University Medical Centre Groningen. All patients under the age of 20 years with newly diagnosed, primary localized, or metastatic high-grade osteosarcoma were evaluated. Complete clinical and pathologic records and appropriate data regarding followup were present. Informed consent was obtained for all patients. 2 daily for 2-3 consecutive days, six cycles of cisplatin 120 mg/m2 administered by repeated 6 hours infusions, 8–12 cycles of high-dose methotrexate 8–12 mg/m2 with appropriate folinic acid rescue, and 1-2 cycles of BCD was used. From 1984 to 2002 trials with control arm treatment of six cycles of doxorubicin 25 mg/m2 daily for 3 days in combination with cisplatin 100 mg/m2 as a continuous infusion were used. The comparison arm consisted of only four doxorubicin/cisplatin courses and additionally 12 courses of high-dose methotrexate 12 mg/m2 with appropriate folinic acid rescue. In the last era from 2003 to 2008 patients was treated with six cycles of doxorubicine 25 mg/m2 daily for 3 days, four cycles of cisplatin 120 mg/m2 as a continuous infusion, and 12 cycles of high-dose methotrexate 8–12 g/m2 with appropriate folinic acid rescue. Information from the patients' medical charts about cumulative dosage of treatment, treatment response , reduction of chemotherapy (defined as >15% reduction of planned chemotherapy), and surgical approach was collected. The overall period was split into subperiods relating to the major changes in protocol . In the first era from 1979–1983 a T10-based multidrug regimen consisting of six cycles of doxorubicin 30 mg/mOverall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method . OS was Long-term toxicities after chemotherapeutic treatment were evaluated regarding development of secondary malignancies, cardiotoxicity, and ototoxicity. The length of time at risk for the secondary malignancy neoplasm (SMN) was calculated from the date of diagnosis of primary osteosarcoma until the date of diagnosis of the second malignancy. The cumulative incidence rate of second malignancies was calculated based on the method of Gray . For theThe median age at diagnosis was 14.4 years (range from 4.5 to 19.9 years). There were 72 male patients  and 58 female patients . At diagnosis, 29 patients (22.3%) had metastases and in 9 patients (6.6%) the tumor was located in the axial skeleton. P = 0.13; At a followup ranging between 4 and 33 years (median 8.9 years), 51 patients (39%) died. Of all deaths, 45 were directly related to osteosarcoma with 16 deaths due to progressive disease, eight due to local recurrence, and 21 after the development of distant metastases. The development of recurrent disease was predictive of death. Incidence of recurrences was relatively stable after 5 years with only three patients developing disease recurrence more than 5 years after diagnosis. Of the remaining six patients that died, four patients developed a second malignancy which was fatal, and two patients passed away due to anthracycline-induced cardiomyopathy. The 5-year OS of the whole population was 66.9% ± 0.15 the 10-year OS was 64.6% ± 0.23; the 20-year OS was 62.3% ± 0.82. These findings are in concordance with earlier reports in the literature , 13. In The 5-year DFS of the whole group was 59.2% ± 0.18. Patients with nonmetastatic osteosarcoma disease showed a DFS of 65.3% versus 37.9% in patients with metastases at diagnosis. During the past 3 decades the DFS of patients with metastases increased from 28.6% in 1979–1983, 40.0% in 1984–2002 to 42.9% in 2003–2008. The same trend is seen in patients with bad histologic response to neoadjuvant chemotherapy: 5-year DFS increased from 30.0% in 1979–1983, 57.6% in 1984–2002 to 65.4% in 2003–2008. Comparison of DFS in patients with axial involvement was not possible due to a small group. P = 0.083). Although an increased rate of good histologic responders was seen in the group additionally treated with methotrexate, comparing the regimen arms with and without methotrexate, no evident difference was seen in 5-year OS  or 5-year DFS . The effect of high-dose methotrexate in the treatment of osteosarcoma is not unambiguously proven in the literature. Several studies have shown a relationship between peak serum concentrations of methotrexate and improved histologic response [In the first era, surgical resection was performed after 4 weeks of neoadjuvant chemotherapy, after 1984 resection was performed in the 10th week of induction therapy. Good histologic response to neoadjuvant chemotherapy was observed in 13.3% of patients treated with cisplatin and doxorubicin and in 29.4% of patients additionally treated with methotrexate (response –16. Howeresponse .N = 6), renal toxicity (N = 3), ototoxicity (N = 3), cardiotoxicity (N = 3), and adverse effects to methotrexate, like methotrexate encephalopathy (N = 1) or allergic reactions to methotrexate (N = 3). Interestingly, treatment reduction due to acute toxicity is less frequent in patients treated between 2003 and 2008 than in patients treated between 1984 and 1998 and in patients treated between 1979 and 1983 . The advancement of patients with limb salvage treatment could be expected considering that amputation patients might have had more advanced disease. A slightly but not significant improvement of DFS was seen in both surgical methods over the past three decades (data not shown). Analysis of surgical treatment method showed a rise from 26.9% of patients with limb salvage treatment in 1979–1983 to 69% in 2003–2008. The 5-year DFS rates were 57.8% for limb salvage treatment and 66.1% for amputation  developed a second malignancy, with a median latency from original diagnosis to second malignancy of 12 years (range 2.4–23 years). Second malignancies were two patients with acute lymphatic leukemia, four patients with breast cancer, and one patient with gastric adenocarcinoma. Of the seven patients who developed secondary malignancy neoplasm (SMN), two patients had a history of Li-Fraumeni syndrome. Both patients developed SMN within 5 years after treatment of osteosarcoma. The 5- and 10-year estimated cumulative SMN incidence rates were 1.5% ± 1.1% and 3.1% ± 1.3%, respectively, which is similar to earlier studies in survivors of osteosarcoma , 19. Ove2. In 46 patients sufficient data concerning baseline and followup echocardiogram was available. No patient had clinically evident cardiac disease before chemotherapy. Before starting therapy with doxorubicin the median FS value was 36%. In 8 patients the FS decreased <28% during therapy, with a median change in the percent FS value of 4% which is in concordance with earlier studies on this subject . The lon2 [2) versus patients with grade 0,1 or 2 hearing loss . Furthermore, no difference in prevalence of severe ototoxicity was seen between the drug regimens using either 600 mg/m2 or 480 mg/m2 cisplatin (P = 0.25) or continuous infusion versus repeated 6-hour infusions (P = 0.76).Cisplatin-associated hearing loss develops in the period when cisplatin is administered, and it has already been observed in patients treated with a single dose of 50 mg/m2 . However2 , it is c2, cisplatin 480 or 600 mg/m2, and high-dose methotrexate 96–144 g/m2 appropriate to age. Furthermore, there was no difference in method of administration regarding doxorubicin and high-dose methotrexate. Cisplatin was administered as a 6-hour infusion during 1979–1983 in our study and then as continuous infusion. While continuous cisplatin infusions are observed to be considerably ototoxic (Lanvers-Kaminsky PBC 2006 [Like other studies in childhood cancer  we showePBC 2006 ), we fou In conclusion, these data elucidate the prevalence of toxicity to therapy in children with osteosarcoma. Further studies concerning the management of long-term toxicities are needed to finally improve survival rates in patients with osteosarcoma.


Background: Air pollutants have been associated with childhood asthma and wheeze. Epigenetic regulation of nitric oxide synthase—the gene responsible for nitric oxide production—may be affected by air pollutants and contribute to the pathogenesis of asthma and wheeze.Objective: Our goal was to investigate the association between air pollutants, DNA methylation, and respiratory outcomes in children.2.5 and PM10  exposures for 940 participants in the Children’s Health Study. Methylation of 12 CpG sites in three NOS (nitric oxide synthase) genes was measured using a bisulfite-polymerase chain reaction Pyrosequencing assay. Beta regression models were used to estimate associations between air pollutants, percent DNA methylation, and respiratory outcomes.Methods: Given residential address and buccal sample collection date, we estimated 7-day, 1-month, 6-month, and 1-year cumulative average PM3 increase in PM2.5 was associated with a 0.20%  to 1.0%  lower DNA methylation at NOS2A position 1, 0.06%  to 0.58%  lower methylation at position 2, and 0.34%  to 0.89%  lower methylation at position 3, depending on the length of exposure and CpG locus. One-year PM2.5 exposure was associated with 0.33%  higher in average DNA methylation of 4 loci in the NOS2A CpG island. A 5-µg/m3 increase in 7-day and 1-year PM2.5 was associated with 0.6%  and 2.8%  higher NOS3 DNA methylation. No associations were observed for NOS1. PM10 showed similar but weaker associations with DNA methylation in these genes.Results: A 5-µg/m2.5 exposure was associated with percent DNA methylation of several CpG loci in NOS genes, suggesting an epigenetic mechanism through which these pollutants may alter production of nitric oxide.Conclusions: PM The availability of intracellular l-arginine is a rate-limiting factor in NO production (Production of nitric oxide (NO) is regulated via the nitric oxide synthase pathway. NO is synthesized from oduction . All throduction .In vitro and animal studies have demonstrated that epigenetic changes, including DNA methylation and histone modifications in both iNOS and eNOS, are associated with gene expression  repeat-elements in a cohort of elderly men (NOS2A was observed in a group of steel workers after a 3-day work shift (FOXP3 (ACSL3 (Studies in humans are beginning to suggest that air pollution exposure is associated with DNA methylation. Traffic particles were associated with a decrease in DNA methylation levels in LINE-1 (long interspersed nuclear element-1) and erly men , and decrk shift . Childret  were associated with DNA methylation levels at CpG loci in the NOS genes. CpG loci were selected in the promoter regions of each gene based on previous evidence from http://genome.ucsc.edu/), ENCODE data on DNase hypersensitivity (http://genome.ucsc.edu/ENCODE/downloads.html), and transcription factor binding sites. We also evaluated whether DNA methylation in these genes was associated with asthma and wheeze. We tested these hypotheses in a population-based study of children who had participated in the southern California Children’s Health Study (CHS).In the present study, we investigated whether short- and long-term exposure to PMStudy population. This study was nested in the ongoing CHS  containing 100 μg/mL proteinase K overnight at 55°C. DNA extraction was performed according to manufacturer’s recommendations. The DNA samples were resuspended in the hydration solution (GENTRA) and stored at –80°C.Buccal-cell suspensions were centrifuged at 2,000 × Selection of CpG methylation loci. We examined CpG loci located in NOS1, NOS2A, and NOS3  of the promoter because the promoter was previously shown to be inversely related to iNOS  mRNA expression (http://genome.ucsc.edu/) but whose methylation status had not previously been investigated. For NOS3, we examined two CpG loci located in the positive regulatory domain in the proximal promoter, which has a binding affinity with Sp1/Sp3, an important transcription factor involved in NOS3 transcription ].Polymerase chain reaction (PCR) primers targeting these loci were developed using MethPrimer software . PrimersDNA methylation. Laboratory personnel performing DNA methylation analysis were blinded to study subject information. Bisulfite conversion of 1 μg of genomic DNA extracted from buccal mucosal cells was performed with the EZ-96 DNA Methylation-Gold Kit™ , according to the manufacturer’s recommended protocol. Final elution was performed with 40 μL M-elution buffer. Bisulfite-converted DNA was stored at –70°C until further use. Methylation analyses were performed by bisulfite-PCR. Pyrosequencing assays were performed using the HotMaster Mix  and the Pyrosequencing (PSQ) HS 96 Pyrosequencing System    as descr Sweden) . Hct116 Air pollutants. Air pollution data were obtained from central monitoring sites in each study community operated by local air pollution control agencies in conformance with U.S. Environmental Protection Agency (EPA) monitoring requirements (U.S. EPA 2012). Each community contained a single central-site monitor. At each monitoring site, 24-hr average measurements PM2.5 were obtained daily or every third day. In addition, hourly PM2.5 measurements were collected at selected community air monitoring sites. Continuous hourly average measurements were made for PM10. When pollution data were not available for certain days, the gaps were filled by using data from nearby monitors provided that the monitors were not more than 7 km apart and the measurements from the monitors were reasonably well correlated  with each other. Daily 24-hr averages of PM2.5 and PM10 were extracted for the buccal cell collection date to calculate cumulative average exposure levels 7 days, 1 month, 6 months, and 1 year before the date of DNA collection.Assessment of covariates. Race/ethnicity, physician diagnosis of asthma, current wheeze, allergy, annual family income, parental education, and exposure to in utero and secondhand tobacco smoke (SHS) were obtained through annual written questionnaires completed by the parents. Children were considered to have asthma if their parents reported on the questionnaire that their child had ever been physician-diagnosed; questionnaires were collected at the school visit during which the child’s buccal cell sample was collected. Children were considered to have current wheeze if their parents reported on the same questionnaire that their child had wheezed in the previous 12 months. History of respiratory allergy was assessed by whether the child had a problem with sneezing or runny nose when he or she did not have a cold or the flu. Height and weight were measured on the day of collection. Age- and sex-specific percentiles based on the Statistical analysis. Descriptive analyses were first conducted to examine the distribution of DNA methylation in NOS genes and air pollutants by subject characteristics. Spearman correlations were used to study the pairwise correlations of percent methylation between different CpGs in the same gene. For genes with multiple CpG loci measured, percent DNA methylation at individual loci as well as average percent DNA methylation were analyzed. For the NOS2A CpG island, only the average of the percent methylation of four loci was evaluated.a priori in the model; however, further adjustment for allergy and wheeze status did not change the regression results and were dropped from final models. Beta regression was used to address the non-normal distribution of DNA methylation values, which are bounded by 0 and 1 and in many cases heavily skewed toward one end or the other (3 increase in PM2.5 exposure because this was very close to the interquartile range in the population (4.8 µg/m3). One subject with an extremely high methylation value for NOS2A CpG island average was considered an outlier and removed from analyses.To investigate the association between air pollutants and percent DNA methylation, we fitted beta regression models adjusted for age, sex, race/ethnicity, experimental plate (for Pyrosequencing reactions), town of residence, month of DNA collection, and parental education. Additional adjustment for asthma, allergy, and wheeze were evaluated, because presence of disease may affect methylation status. Asthma status was retained he other . Beta reA priori variables included for adjustment were age, sex, race/ethnicity, experimental plate, allergy, and town. Within asthmatics, stratified analyses by medication use, which can be used as an indicator of severity of asthma, were also conducted. For analyses restricted to asthmatics (n = 133), plate and town were dropped from models given the small sample size and large degrees of freedom required by these variables.We also used beta regression models to model differences in methylation levels by asthma and wheeze status in this population. n = 704).Sensitivity analyses were also conducted to evaluate whether the inclusion of children with asthma or wheeze influenced our results. Thus, the analyses of air pollutants and DNA methylation were rerun in a population in which children with asthma and wheeze were removed  and in the R programming language, version R2.12.2 .2.5 and PM10 were right-skewed, median PM2.5 ranged from 11.5 to 15.8 µg/m3, and median PM10 ranged from 27.0 to 33.8 µg/m3 (http://dx.doi.org/10.1289/ehp.1104439), and the correlations for PM2.5 and PM10 are shown in Supplemental Material, On average, children were 9 years old, two-thirds were of Hispanic white ethnicity, 14% had been diagnosed with asthma by the time of buccal cell collection, 11% had current wheezing reported by their parents, and 56% had a parentally-reported history of respiratory allergies . Cumulat.8 µg/m3 . DistribNOS1, NOS2A, and NOS3 were methylated > 75%. The proportion of methylation at the CpG locus in NOS2A position 3 (located in a non-CpG island between exon 1 and 2) was 51%, whereas CpG island loci in NOS2A were largely unmethylated (< 2.5%). Within each gene, the multiple CpG loci measured were not strongly correlated, with correlation coefficients < 0.5 for all but NOS1 positions 1 and 3 .Distribution of percent methylation of NOS loci is shown in 2.5 was negatively associated with percent DNA methylation in the non-CpG island regions of NOS2A  and long-term  cumulative averages of PM2.5 was associated with a 0.2%  to 1%  lower DNA methylation at position 1. In addition, cumulative averages of PM2.5 were associated with lower methylation of NOS2A at position 2 for 1-month and 1-year averages and at position 3 for 7-day and 6-month averages. In contrast, PM2.5 exposure was associated with small but significantly higher in percent DNA methylation of the average of positions 4–7 in the NOS2A CpG island region (PMof NOS2A . In betad region .2.5 and NOS2A methylation in a population restricted to children without diagnosis of asthma or wheeze (n = 720). Associations were consistent with those for all children combined .Because these analyses were conducted in all children, including those with a diagnosis of asthma or wheeze, we conducted a sensitivity analysis in which we estimated the associations between PM2.5 was also positively associated with percent DNA methylation in both positions measured in NOS3. A 5-µg/m3 increase in acute (7 day) and long-term (1 year) cumulative average PM2.5 levels was associated with 0.6%  to 2.8%  higher absolute level of percent DNA methylation in the two loci ].PMtwo loci . PM10 shNOS2A was investigated with respect to current childhood wheeze. Children with current wheeze had 0.21%  higher methylation in NOS2A position 1, 0.39%  lower methylation in the NOS2A position 2 and 0.25%  lower methylation in the NOS2A position 3 compared with children without wheeze. No direct association between DNA methylation and asthma overall was observed. However, among 133 children with asthma, children with current wheeze only (n = 54) and children taking asthma medications (n = 66) had lower DNA methylation in the NOS2A promoter region than did asthmatic children without a recent history of wheeze or medication use, respectively. Children using asthma medication had 0.49% , 1.72% , and 1.37%  lower DNA methylation in NOS2A positions 1, 2, and 3, respectively, compared with asthmatic children not taking medication. Asthmatic children with current wheeze had 0.28% , 0.90% , and 0.93%  lower DNA methylation in NOS2A positions 1, 2, and 3, respectively, compared with asthmatic children without wheeze.DNA methylation in 2.5 was consistently and significantly associated with DNA methylation levels in NOS genes, primarily NOS2A and NOS3. PM10 showed similar associations with DNA methylation in these genes as compared with PM2.5 but the magnitude of association was weaker. No statistically significant associations were observed for NOS1 (results not shown).Of the pollutants evaluated, PM2.5 was associated with differences in level of percent DNA methylation in NOS genes, suggesting that NO homeostasis may be influenced by air pollution. NOS DNA methylation was also associated with wheeze and medication use, a proxy for active disease, in children with asthma.In this study, PMNOS2A—the gene encoding iNOS—that increases transcription of the gene is one hypothesis to explain such an observed association. A recent study by Tarantini et al. provided preliminary evidence in support of such a theory , although stronger associations were observed for short and long-term cumulative averages at the two NOS2A promoter CpG loci more proximal to the transcription start site.Particulate matter is associated with increased expression of iNOS . A decrea theory . In that workers . In the 2.5 was associated with lower methylation in the NOS2A promoter, it was also associated with higher methylation in the CpG island in the body of the gene. Regulation of iNOS activity is complex, and the inducibility of iNOS by cytokines is known to involve DNA methylation, histone H3 lysine 9 methylation, and MeCP2 binding at the promoter  had increased methylation of the FOXP3 locus, a locus important in Treg-cell function and asthma morbidity, compared with children residing in a low-pollution community   . In a cochildren . Emergin2.5 exposure was significantly associated with higher FeNO levels, whereas no association was seen at lower methylation levels , PMn levels . NOS2A gWe have observed particulate matter-associated differences in DNA methylation in buccal cells. Our associations are similar in direction of effect and magnitude to those of In evaluating childhood wheeze and asthma, buccal mucosal cells—an aerodigestive tract epithelium—were used for DNA methylation analysis. Previous studies have demonstrated that buccal epithelium can serve as a surrogate tissue for the lung when measuring DNA methylation . In addiBuccal-cell DNA was collected after diagnosis of asthma and wheeze, so we cannot address whether DNA methylation in NOS genes precedes or is the result of childhood respiratory disease. Similarly, we cannot rule out the possibility that asthma medications may have altered DNA methylation in the asthmatic children. However, the observed trends showing that children with wheeze had intermediate levels of DNA methylation, compared with healthy children and children with active asthma, support the conclusion that DNA methylation levels in NOS genes may play a role in asthma pathogenesis. Further investigation in a longitudinal study design that collects DNA samples at or near birth would clarify these lingering concerns and is currently underway.2.5 and PM10 before the date of DNA collection. Our choice to evaluate short-term cumulative averages was based on previous evidence of an association between cumulative pollutant exposure and FeNO, the product of the genetic pathway of interest  PDFClick here for additional data file.


Introduction. Pyelonephritis is a common complication of pregnancy. It is also exacerbated by immunocompromised states and also the sickle cell gene. We reviewed this condition in Jamaican women. Method. We did a six year hospital database docket review. We found 102 confirmed cases. Results. Pyelonephritis was found in 0.7% of deliveries. The mean maternal age was 24 ± 5.83 years with 51% primiparity. Most (58.8%) occurred in the second trimester. The main symptoms were loin pain (96.2%) and abdominal pain (84.6%). It was more common on the right side in 67% of cases. On urinalysis, 81.4% had pyuria. The commonest organism was Escherichia coli, in 61% of cases. Patients given Antibiotics prior to admission had quicker resolution, P < 0.02. Haemoglobin S was found in 16% cases . However diabetes was only found in 1.3% cases (1.5% expected). 61.3% had positive urine culture after treatment showed that 61.3% and 25% had recurrent pyelonephritis. Complications included 32% threatened preterm labour and 17% preterm delivery. About 6% of neonates had intrauterine growth restriction. There were no ICU admissions and no deaths. Conclusion. Early recognition and treatment of pyelonephritis result in good outcome. The condition is more prevalent in patients with the sickle cell gene and recurrence is high. Acute pyelonephritis complicates approximately 1-2% of pregnancies, and is one of the leading causes of nonobstetric antepartum hospitalization , but witThe incidence of asymptomatic urinary tract infection does not increase in pregnancy compared to the non-pregnant state , but phyIn pyelonephritis, infection usually ascends from the bladder, due to vesicoureteral reflux in pregnancy . Other rSeveral studies have demonstrated maternal and fetal morbidity , 11 assoManagement of suspected urinary tract infections at UHWI is very aggressive. The presence of leukocytes or persistent proteinuria on dip stick testing mandates that a midstream urine sample (MSU) be sent for culture and sensitivity, with treatment based on the results. Women with abdominal discomfort suspicious of UTI and all women with preterm labor have MSU testing and are started on empirical antibiotics. All suspected cases of pyelonephritis are hospitalized and treated with intravenous antibiotics until afebrile for 24 hours and symptomatically improved . This agIn Jamaica, the prevalence of Type 2 diabetes, in adult women is 15.7% and the pThe maternal and foetal outcomes as well as the determinants of pyelonephritis in pregnancy at the UHWI are unknown. This study was therefore done to evaluate these.The study was retrospective, using the UHWI Hospital database from January 2003 through December 2008 using a diagnosis of acute pyelonephritis in pregnancy. The dockets were retrieved and reviewed and those who met the clinical or laboratory criteria for the diagnosis of acute pyelonephritis were included. 5 CFU per mL of organisms. For patients who had multiple admissions, the information obtained was for the first admission. The diagnostic criteria of acute pyelonephritis employed were flank pain, nausea/vomiting, fever (>38°C) before or on admission, and/or costovertebral angle tenderness, in the presence or absence of cystitis symptoms. A positive urine culture was defined as >10Demographic data collected were age, weight, body mass index, gravidity, and parity. The gestational age of diagnosis was recorded. Medical history deemed to place patients at risk for pyelonephritis was also collected. Outcome analyzed were length of hospital stay, time to defervesce, organisms involved and the sensitivity to antibiotics, presence of preterm labour and premature rupture of membranes, interval between infection and delivery, Apgar scores, and birth weight.The study was approved by the ethics committee of the University of the West Indies.t test as appropriate. For continuous outcome variables that were skewed, differences in distribution by categories were tested with Kruskal-Wallis test or the Mann-Whitney test.Values are presented as means with standard deviation (SD), medians with interquartile ranges or counts as appropriate. For continuous outcome variables with normal distribution differences in means by categories were tested with analysis of variance (ANOVA) or For categorical outcome variables, differences were tested with chi square. The binomial test was used to compare the observed proportion in this study with expected proportion in the general population.A total of 282 patients were coded as pyelonephritis. We recovered 184 dockets (65.2%). Of these, acute pyelonephritis was confirmed in 102 (55.4%). During the time period there were a total of 14651 deliveries, giving an incidence of 0.71% of deliveries. The mean maternal age at diagnosis was 24 ± 5.83 years (mean ± SD), with the majority of cases (62 of 102 patients or 61%) within the age range of 20–29 years. There were 8 patients (8%) who were older than age 35 years . About aThe majority of cases of acute pyelonephritis (58.8%) occurred in the second trimester, followed by third trimester (28.5%) and first trimester (14.7%). The mean gestational age at diagnosis was 22 ± 7.8 weeks . χ2 = 5.58, df(1), P < 0.02).All patients were admitted for treatment and received intravenous fluid and antibiotics on admission. The commonest complaints on admission were loin pain (96.2%), abdominal pain (84.6%), dysuria (70.2%), fever (64.4%), and chills and rigors (51.9%). Twenty three percent of patients gave a history of antibiotic use in the week prior to admission. Fever defined as temperature >38°C on admission was less common in patients who gave a history of antibiotic use in the week prior to admission  with electrolyte derangements, but no patients required intensive care admission.The mean body temperature at admission was 37.8 ± 1.0 degrees Celsius and renal angle tenderness was more common on the right side in 68 of 102 cases (67%) than left side , and was bilateral in 14 cases (14%) The mean haemoglobin at admission was 10.4 g/dL. 32 patients (30.7%) had haemoglobin of less than 10 g/dL at admission and of these, 5 had sickle cell disease. 20 patients (19.2%) had absolute white blood cell count (WBC) greater than 15.0. The median WBC was 12.1 × 10Escherichia coli, accounting for approximately 61% (36 of 59) of cases. The other major organisms were Klebsiella spp.  and Proteus spp. (5.1% three of 59). E. coli was most sensitive to intravenous Amoxicillin-Clavulanate in 88.8% and Gentamycin in 83.3%. Oral Amoxicillin-Clavulanate was used most commonly in 76.3%, followed by oral Cefuroxime in 17.9% of cases. Other antibiotics used were Cotrimoxazole and the urinary antiseptic Nitrofurantoin. Six patients were placed on Nitrofurantoin (as long term prophylaxis) for the remainder of the pregnancy.Fifty-nine cases (56.7%) had positive urine culture, whereas 11 (10.6%) had no growth. There were 15 cases each (14.4%) of insignificant mixed growth and gross contamination. Four subjects had no data regarding urine culture. The predominating organism was The median duration of intravenous antibiotics was three days (range 1–10 days), and seven days (range 1–14) for oral antibiotics. P < 0.02) (The majority of patients (42/62 67.7%) became afebrile within 48 hours of admission. There was no statistical difference in the number of days (median with interquartile range) admitted by trimester. These were 5 (IQR2) days, 5 (IQR 2.5) days, and 4 (IQR2) days for the first, second, and third trimesters, respectively. The number of days to become afebrile was significantly shorter in the women who were treated with antibiotics prior to admission  .Sickle cell status was available for 73 patients. Of these, 57 (78.1%) were negative, 11 (15.1%) had the trait, and 5 (6.8%) had sickle cell disease.P = 0.002) Patients who were sickle negative spent an average of 4.8 ± 1.7 days compared with patients with sickle cell disease who were admitted for 6.4 ± 1.14 days P = 0.14. This was however not statistically significant  had gestational diabetes. Seventy patients (68.6%) had obstetric ultrasound at admission, and all these were normal. Twenty patients had urinary tract ultrasonography done during admission, 6 of these were normal, 10 (50%) revealed hydronephrosis, and 4 (20%) revealed ureteric stones. Seventy patients (68.6%) had repeat urine culture done after completion of the antibiotic course. Of these, 43 specimens (61.3%) were positive and 25 patients (24.0%) were readmitted for recurrent pyelonephritis. Of 102 patients diagnosed and admitted with pyelonephritis, 68 (65.4%) were patients of the antenatal clinic with complete antenatal records including delivery outcome. In 36 (34.6%) patients delivery outcome was unavailable for outcome analysis.Of the 68 cases that were delivered at UHWI, 22 (32%) had threatened preterm labour, 4 (3.9%) had preterm labour, 6 (8.8%) had premature rupture of membranes. Four infants (5.9%) were found to have intrauterine growth restriction on ultrasound. P = 0.03). The median birth weight was 3.14 kg, with a range of 1.67–4.36 kg. The Apgar scores were within normal range with no statistical difference demonstrated by trimester (Twelve (17.6%) subjects delivered prematurely despite the use of tocolytics and 10 infants (14.7%) were found to have low birth weight. The mean infection to delivery interval was 103 days (SD 50.6) median 110 days range 3–217 IQR 72 days. The median gestational age at delivery was 39.0 weeks, with a range of 31.7–41.0 weeks. The gestational age at delivery was statistically less in patients who had acquired the infection in the first trimester (rimester .The incidence of obstetric pyelonephritis at UHWI was 0.7%, slightly lower than reported by others, 1.3–2% , 25. It The majority of patients demonstrated pyuria on urine dipstick, but less than a third demonstrated positive for leucocyte esterase nitrite, which is said to be a useful cost effective screening test when the prevalence of pyelonephritis is 2% or less as is the case here . PreviouAnaemia was found in 30% of cases exactly the same as reported by Cox et al. . The datThe majority of patients became symptomatic in the second trimester. This is consistent with the peak period of urinary stasis and maximal immunological changes on the urinary tract under hormonal influence , 28. AddEscherichia coli, consistent with previous international studies [The predominant organism isolated was  studies , 30 with studies , 31. The studies .Previous studies have demonstrated an incidence of acute pyelonephritis in pregnant sickle cell trait patients that was significantly higher than that in matched control patients . Our popDiabetes mellitus has been shown to be a risk factor for acute pyelonephritis , 19. TheIdeally, repeat urine culture after treatment is important to identify patients at risk of recurrence . In otheThe presence of urinary tract abnormalities is also possible in some of these women and should be sought in those not responding to treatment . NephrolThere was no significant adverse maternal outcome in this study, probably due to aggressive management . The litAcute pyelonephritis is associated with sickle cell gene and results in preterm delivery. Persistent bacteriuria is very high but severe maternal complications are low in this cohort.


Long-term outcome of patients after band ligation have been poorly defined. Therefore, we conducted a long-term follow-up study to delineate the outcome of ligation in patients with portal hypertension in the Hassan II university hospital, Fes, Morocco.Over 118 months patients treated by endoscopic variceal ligation were received regular follow- up and detailed clinical assessment of at least 24 months.One hundred twenty five patients were followed up for a mean of 31 months (range 12-107 months). Obliteration of the varices was achieved in 89.6 % (N = 112) of patients, with 3 +/-1.99 (range 1-8) endoscopy sessions over a period of 14 + /-6.8 weeks (range 3-28). The percentage of variceal recurrence during follow-up after ligation was 20.5 % (N = 23). Recurrence were observed in a mean of 22 months +/- 7.3 (range 3-48). Bleeding rate from recurrent varices was 30.4 % (7/23). Rebleeding from esophageal ulcers occurred in 5.6 % (7/125) of patients. Portal hypertensive gastropathy before and after eradication of varices was 17.6% (N = 22) and 44.6% (N = 50) respectively; p< 0.05. Fundal gastric varices was 30.4% (N = 38) and 35.7% (N = 40) before and after eradication of varices respectively; p> 0.05. The overall mortality was 4 % (N = 5).Band ligation was an effective technical approach for variceal obliteration with low rates of variceal recurrence, rebleeding and development of gastric varices. Furthermore, it was associated with frequent development of portal hypertensive gastropathy. Approximately fifty-nine percent of patients with cirrhosis develop esophageal varices, and one-third of these patients experience esophageal variceal bleeding (EVB) . There iThis retrospective study was conducted in Endoscopy Unit of Department of Gastroenterology and Hepatology of Hassan II University Hospital Fez, Morocco, from December 2001 to October 2011. All adult patients with an episode of upper gastrointestinal bleeding (hematemesis or melena or both) were admitted to the emergency service, and underwent endoscopy as soon as they had been resuscitated. Patients with endoscopically proven esophageal variceal hemorrhage were treated by endoscopic variceal ligation if they had active variceal bleeding at endoscopy ; or if they had non bleeding varices but evidence of blood with no other potential source of gastrointestinal bleeding. Patients who were followed-up for at least 24 months were enrolled in the study. A full clinical history, physical examination, laboratory tests and ultrasonography were performed. Propranolol was initiated. The dose was increased stepwise, every two-three days, up to the maximum tolerated dose or up to 160 mg/day. The severity of liver disease was classified according to Child′s classification. The esophageal varices gradings were made as follows: 1= disappeared with air insufflation; 2= did not disappear with air insufflation; 3= occluded more than one-third of esophageal lumen .Endoscopies were performed in a single endoscopy unit using an Olympus video endoscope GIF 160. Esophageal varices were classified according to uniform criteria. Fundal varices and portal hypertensive gastropathy were also noted. After local application of lidocaine, an endoscope was introduced, and the ligation was carried out by placing a multiple rubber band (Saeed's multiband ligator Wilson's Cook) over a varice. Application of the bands was started at the gastro-esophageal junction and progressed upward in a helical way for approximately 5-8 cm. Patients underwent regular EVL until varices eradication .Patients were followed up from December 2001 to October 2011. Endoscopic ligation was performed every three weeks until the varices were obliterated or were reduced to a size of grade 1. In the latter instance, it was impossible to apply more bands because of the small size of the varices. The presence of ulcers, esophagitis or strictures was noted on endoscopic examination. After the varices had been obliterated or reduced in size to grade 1, patients underwent endoscopy every three months until the end of follow-up. If varices recurred and became larger or grade 2 in size, repeated ligation to obliterate was done. Patients were advised to refrain from consuming alcohol and from taking non steroidal anti-inflammatory drugs.Variceal rebleeding: Any patient who had overt upper gastrointestinal bleeding during the study was admitted to the hospital and underwent endoscopy of the upper gastrointestinal tract within 24 hours to determine the source of bleeding. Bleeding from esophageal varices was diagnosed if active bleeding or a clot was seen on endoscopy and if there was evidence of recent bleeding in a patient with an esophageal varice and no other visible mucosal lesion. Bleeding was considered to be caused by esophageal ulcers as a result of band ligation if there was active bleeding or if there was an adherent clot on the esophageal ulcer .The main endpoint of the study was bleeding from any source. Secondary endpoints were the number of banding sessions, the time to eradication , the incidence of variceal recurrence, variceal rebleeding, complications and mortality.Data were analyzed by the Epi Info 2000. Quantitative data were expressed as means (± SD) or as medians.This study was approved by the local Scientific Ethics Committee.One hundred twenty five eligible patients were included in the study. They were followed up for a mean of 31 months (range 12-107 months). Fifty-eight (46.4%) were females, and sixty seven (53.6%) were males. Mean age of patients was 49.2 years (+/-7). Medical co morbidity associated with portal hypertension was noted in 11 patients (8.8%). Diabetes (8 cases), arterial hypertension (3 cases). Portal hypertension was due to cirrhosis in 67.2 % of cases (N = 84). The cause of cirrhosis was hepatitis C (HCV) alone 39,2 % (N = 33), hepatitis B (HBV) alone 9.5% (N = 8), combined HCV and HBV 4.7% (N = 4), alcohol 1.2 % (N = 1). Sixty nine (82.2 %) belonged to Child class A, twelve (14.3%) to child class B, and three patients (3.5%) were in Child class C. Propranolol was prescribed in association with esophageal variceal ligation as a secondary prophylaxis in 40.8 % of patients (N = 51). The dosage was variable according to the patient . The characteristics of the patients are shown in Table1. High grade varices were seen in 67 patients (53.6%) while low grade varices were noted in 58 patients (46.4%). Obliteration of the varices was achieved in 89.6% (N = 112) of patients; with 3 +/-1.99 (range 1-8) endoscopy sessions; over a period of 14 + /-6.8 weeks (range 3-28). The percentage of variceal recurrence during follow-up was 20.5% (N = 23). Recurrence was observed in a mean of 22 months (range 3-48). Bleeding rate from recurrent varices was 30.4% (7/23). Rebleeding from EVL induced ulcers occurred in 5.6% (7/125) of ligation sessions. Portal hypertensive gastropathy before and after eradication of varices was 17.6% (N = 22) and 44.6% (N = 50) respectively; p < 0.05. The overall mortality was 4% (N = 5). One death (0.8%) were bleeding-related; the other causes of death were spontaneous ascites infection (2 cases), liver failure (2 cases). The results of endoscopic band ligation are shown in Table 2.Endoscopic variceal ligation (EVL) is a purely mechanical method of obliterating varices that was introduced to preclude the undesirable effects of sclerotherapy . SeveralVariceal recurrence during this period of study occurred in 20.5% (N = 23) of patients. While those found by others studies ranged between 8% and 48% after banding and 2% and 50% after sclerotherapy. InterprDuring the study period, bleeding rate from recurrent varices was 30.4% (7/23). Others studies found rates ranged between 10% and 50% –33. A reDuring the study period, the incidence of bleeding from treatment-induced ulcers was 5.6%. In others published studies, variceal ulcers have been reported between 3.3% and 36% , 42. HowIn this study, band ligation influences the development of portal hypertensive gastropathy . Some studies have shown that EVL results in an increase in the incidence and worsening of portal hypertensive gastropathy . Others In this study we were confronted with some limitations. First, our study is retrospective which make it difficult to compare to other studies generally prospective. Second, portal hypertensive gastropathy wasn't classified using the Baveno scoring system to classify its severity. And finally, the follow up time for these patients had varied from one year to ten years.In our population, endoscopic variceal ligation was an effective technical approach for variceal obliteration with low rates of variceal recurrence, rebeeding and development of fundal gastric varices. Furthermore, it was associated with frequent development of portal hypertensive gastropathy.


To investigate clinical features of infantile hypertrophic pyloric stenosis (IHPS) in Chinese Han population.Three hundred and sixteen hospitalized patients with IHPS from January 1998 to February 2010 were retrospectively reviewed, and data including patient's sex, onset age, other coexisting congenital defects, pyloric circular muscle thickness evaluated by ultrasonograph, serum electrolytes concentration, and results of arterial blood gas analysis on admission were collected. The patients were divided into two groups: the duration between first onset and admission less than or equal to 10 days (early onset group), and more than 10 days (late onset group). The results of arterial blood gas and serum electrolyte concentration were compared between the two groups.P<0.0001; 46.03% VS 71.01%, P = 0.003; 56.58% VS 83.44%, P = 2.17×10−5; respectively).There were 271 males and 45 females in 316 patients; the onset age ranged between 1 and 351 (26.5±26.6) days. The birth weight ranged between 1.6 and 4.5 (3.23±0.44) kilograms; coexisting congenital defects were found in 65 cases (20.6%). Pyloric circular muscle thickness was 4–8 (5.4±1.0) millimetres (mm). For the early onset group, the rates of hypokalemia, hypochloraemia and hypercapnia were significantly lower than those in the late onset group (18.67% VS 50%, The symptom duration in Chinese Han population was longer than that in other populations. And as the prolongation of symptom duration, the incidence of acid-base imbalance increased significantly. Infants with persistent vomiting at the age of 3∼5 weeks after birth should be considered IHPS, and go to hospital as soon as possible in order to reduce the incidence of hypokalemia, hypochloraemia and hypercapnia, and avoid deterioration. Infantile hypertrophic pyloric stenosis (IHPS) is a condition affecting young infants, in which gastric outlet obstruction results from hypertrophy and thickening of the circular muscle of the pylorus. It has been shown that IHPS occurs much more frequently in males than in females To the best of our knowledge, there were no clinical feature analysis reports with IHPS in mainland China, although a lower incidence of IHPS in Chinese has been reported from American, Singapore and Taiwan The study was approved by the Ethics Committee of Guangzhou First People's Hospital and Guangzhou Women and Children's Medical Center. Surgical informed consent was obtained from each infant's legal guardian before operation and was stored in the hospitals' Medical record room, undoubtedly before samples collection. From January, 1998 to February, 2010, all patients diagnosed with IHPS treated with open pyloromyotomy or laparoscopic pyloromyotomy, or endoscopic pyloromyotomy in both Guangzhou First People's Hospital and Guangzhou Women and Children's Medical Center were included in this study. From this retrospective series, all data was collected from medical records by two or three of the authors . The diagnosis of IHPS was based on a history of projectile vomiting, palpation of an olive mass, and ultrasonography, upper gastrointestinal brium series and was confirmed with surgery.The following data was retrospectively collected: demographics, clinical manifestations, birth order, birth weight, gestational age, other congenital malformations, ultrasonographic findings, serum electrolytes concentration and acid–base status. All these data gained before any therapeutic interventions. According to Huang P value<0.05 was defined as statistically significant. Statistical analysis was performed using SPSS 13.0 software package for windows .The data was expressed using frequencies, percentages or mean and standard deviation (SD). Chi-square tests were performed to analyze differences between the two groups. A There were 316 patients with IHPS during the past 12-year period. There were 271 boys and 45 girls. All patients had classic projectile,and persistent non-bilious vomiting. All the parents denied the familial genetic diseases and there were no use of macrolide antibiotics during pregnancy. The age of symptom onset ranged between 1 and 351 days, and the mean was 26.5±26.6 days . The durThe birth weight was 3.23±0.44 kilograms (ranging between 1.60 kilograms and 4.50 kilograms). The weight at presentation was 3.85±0.89 kilograms (range from 1.75 to 9.0 kilograms). The firstborn child was noted in 76.3% (241/316) of the cases, the second was 19.6% (62/316), 10 for third, two for forth and one for fifth, and a pair of twins affected. There were two triplet pedigrees, with one being affected in each pedigree. Premature birth was seen in 13 cases .Other coexisting other congenital malformations were found in 65 cases (20.6%). Fifty cases had one other congenital defect. Two other congenital defects were seen in 12 cases and three in 3 cases. The most common congenital defect concomitant with IHPS was congenital cardiovascular defects , followed by the gastrointestinal tract defects  were positive and 5 cases were negative which the diagnosis being confirmed by contrast barium (UGI) study. For 268 infants, the mean length of pyloric muscle was 20.8±3.8 mm (ranged 11.0∼38.0 mm), and the mean thickness of pyloric circular muscle ranged from 3 mm to 8 mm  was observed in 179 of 232 patients (77.16%) and pH was above 7.45 in 85.35% (198/232) of patients. Hypoxemia (PO2<10.7 kpa) was seen in 60.34% (140/232) of the patients. Serum sodium and potassium were available for 76.27% (241/316) and 75.63% (239/316) patients when admission, while serum chloride was available for 63.61% (201/316) patients. The hypochloraemia (Cl<95 mmol/L) was found in 127 of 201 measurements (63.18%). Hyponatraemia (<135 mmol/L) was seen in only 54.36% (131/242) of patients, with 40.17% (96/239) patients displaying hypokalemia (<3.5 mmol/L).The results of arterial blood gas analysis were available for 232 (73.42%) patients at admission. An elevated bicarbonate level , and more than 10 days (late onset group). There were 103 patients in early onset group, and 213 patients in late onset group.P = 0.001), arterial partial pressure of oxygen , serum potassium concentration , bicarbonate level  and serum chlorine concentration  between late and early onset groups  brium series and ultrasound are noninvasive and accurate methods to diagnose infantile hypertrophic pyloric stenosis. The UGI barium series requires oral contrast to indirectly outline the pylorus and the disadvantages are obvious, including exposure to ionizing radiation and the risk of aspiration. Therefore, ultrasound examination has been largely applied to diagnose IHPS. Ultrasonographic examination can be performed with an accuracy approaching 100% in diagnosing IHPS For the length of the pyloric channel, Ostlie et al In most cases, the typical projectile, non-bilious vomiting usually occurred between the age of 2 weeks and 8 weeks For birth weight, Pedersen Though IHPS is characterized by familial occurrence, we found only one pair of monozygotic twins both diagnosed with IHPS, only one affected in another monozygotic twins, and only one affected in both triplets. In addition, there was no report about familiar history in our study.Other coexisting other congenital defects were found in 65 cases(20.6%). Among them, one other congenital defect was seen in 50 cases, two other congenital defects were seen in 12 cases, three in 3 cases. The cardiovascular system congenital defects were the most common ; followed by the gastrointestinal tract congenital defects  and central nervous system congenital defects . The rate of other associated congenital anomalies was higher than that reported by Huang We further analyzed the relationship between the coexisting congenital defects in gastrointestinal tract and non- coexisting congenital defects in gastrointestinal tract,and found that coexisting congenital defects had no significant impact on biochemistry laboratory data.−6), serun potassium concentration , serun chlorine concentration  and bicarbonate level  . The rat13×10−9) .In conclusion, this study shows the onset age of IHPS is 3∼5 weeks in Chinese Han population. The mean pyloric circular muscle thickness is 5.4±1.0 mm, and more than 20% of the patients are accompanied with other congenital defects. Most of the patients suffered hypokalemia, hypochloraemia and hypercapnia. For infants with persistent vomiting at the age of 3∼5 weeks after birth, IHPS should be considered, and go to hospital as soon as possible in order to avoid deterioration.


Patients requiring ICU management risk deterioration following discharge. Readmission to the ICU is used as a marker of performance  with somProspective data were collected on all patients admitted to a multidisciplinary adult ICU between 2001 and 2009 and entered into a computerised database. This included length of ICU stay, ICU and hospital outcomes, readmission to ICU and days prior to readmission. Data for all ICU admissions were analysed annually.There were 5,004 patients admitted during 2001 to 2009; 1,315 (26%) were elective postoperative admissions and 3,689 (74%) emergency admissions. The ICU mortality during this period was 15.8% and mean APACHE II score was 17.7 (1 to 55). There were 299 readmissions (6%). The average time between discharge and readmission was 8.5 days (0 to 89) with a mean length of ICU stay of 5.89 days (0.2 to 48.8). The average hospital mortality rate of readmitted patients was 33% and fell from 69% in 2003 to 24% in 2007. The proportion of readmitted patients increased from 3% (11) in 2001 to 10% (68) in 2007. As the proportion of patients readmitted increased, the hospital mortality rates for all ICU admissions fell 10% from 31% in 2001 to 21% in 2009.As the number of patients readmitted has increased, hospital mortality of both readmitted patients and total ICU patients have fallen. Those readmitted have had a short length of stay (mean 5.89 days).


Background: Epidemiologic evidence for a causative association between black carbon (BC) and health outcomes is limited.2.5) in ambient air before and during the air pollution intervention for the 2008 Beijing Olympics.Objectives: We estimated associations and exposure–response relationships between acute respiratory inflammation in schoolchildren and concentrations of BC and particulate matter with an aerodynamic diameter of ≤ 2.5 μm  as an acute respiratory inflammation biomarker and hourly mean air pollutant concentrations to estimate BC and PM2.5 concentrations averaged over 0–24 hr were strongly associated with eNO, which increased by 16.6%  and 18.7%  per interquartile range (IQR) increase in BC (4.0 μg/m3) and PM2.5 (149 μg/m3), respectively. In the two-pollutant model, estimated effects of BC were robust, but associations between PM2.5 and eNO decreased with adjustment for BC. We found that eNO was associated with IQR increases in hourly BC concentrations up to 10 hr after exposure, consistent with effects primarily in the first hours after exposure.Results: Air pollution concentrations and eNO were clearly lower during the 2008 Olympics. BC and PMConclusions: Recent exposure to BC was associated with acute respiratory inflammation in schoolchildren in Beijing. Lower air pollution levels during the 2008 Olympics also were associated with reduced eNO. In vitro and in vivo studies have shown that BC stimulates reactive oxygen species production and cytokine-mediated inflammation (A number of epidemiologic studies have shown that urban particulate matter (PM) is associated with pulmonary inflammation and increased respiratory symptoms, deterioration of lung function, increased hospital admissions, and mortality from inflammatory lung injury . PM is aammation , which mammation . Epidemiammation , decreasammation , and decammation . Howeverammation  and BS (ammation  but has 10 (PM with an aerodynamic diameter of ≤ 10 μm) in Beijing are consistently higher than recommended by World Health Organization air quality guidelines (WHO 2006), and daily BC concentrations up to 20 μg/m3 have been occasionally observed , carbon monoxide (CO), sulfur dioxide (SO2), and nitrogen dioxide (NO2) as exposure metrics for the air pollutants. We estimated associations between eNO and air pollutant exposures, examined exposure–response relationships between eNO and BC and PM2.5 over large ranges of BC and PM2.5 concentrations, assessed the relative importance of BC and other pollutants with two-pollutant models, and estimated effects of lagged exposure to BC on eNO. Some of the results of these studies have been previously reported as abstracts in conference proceedings ], which is 178 m and 300 m away from two busy roads. A continuous air pollution monitoring station is located about 650 m southwest of the school. A comparison of the air pollutant concentrations between the monitoring station and the elementary school showed good agreement  with doctor-diagnosed asthma. In addition, we randomly recruited 30 healthy children  in grade 4 with no personal or family history of chronic respiratory disease or chronic inflammation. In total, we had 38  participants in the present study .The study included five observation periods, three in 2007  and two in 2008 . The last three observation periods each lasted 2 weeks and consisted of 10 weekday observations per subject. Only 8 days of observations were collected in June 2007 because of instrument malfunctions, and only 9 days of observations were collected in September 2007 because of a school holiday. During each period, we measured eNO for each subject every weekday (Monday through Friday), during the school lunch break. Data from one subject who withdrew after V2 in 2007, and one who withdrew before V5 in 2008 were not included in the analysis. Thus, we collected 1,581 valid observations from 36 subjects who each completed five visits.The study protocol was approved by the Ethics Committee of the Centre of Health Sciences, Peking University. The guardians of all children gave their written consent for the children to participate in the research.eNO monitoring. We collected the exhaled air samples from the subjects following the recommendations of the ATS/ERS (2005) for offline measurement. The exhaled air collection device was made of Teflon. A tube filled with activated carbon was used to filter out NO from the ambient air and was shown to remove up to 99.6% of NO in a laboratory simulation of the protocol used in the field. The device was equipped with a flow meter as a flow restrictor and a pressure indicator  (ATS/ERS 2005).Before sampling, each subject was asked to put the mouthpiece of the device tightly in his or her mouth, inhale deeply, and then exhale to wash the “dead space” from the device. This procedure was repeated twice. To sample the exhaled air, the subjects were instructed to inhale to tidal capacity and then exhale into a 4-L air-sampling bag made of aluminium foil, with a constant flow of 150 L/hr and a positive pressure of 13 cm H2–NOx (nitrogen oxides) analyzer , which had a detection limit of 0.4 ppb and a detection range of 0–100 ppb. The analyzer was calibrated every day with five concentrations (0–80 ppb) of NO  mixed in ultrahigh purity nitrogen . We used a calibration curve to calculate the eNO concentrations in exhaled air of the subjects.We measured eNO concentrations in the 4-L air-sampling bag within 4 hr with a chemiluminescence NO–NOAmbient air pollutant measurement. Hourly averaged concentrations of PM2.5 , BC , NOx, SO2, and CO , and meteorologic parameters  were concurrently measured at the continuous monitoring site during V1–V5. The instruments for gaseous pollutants were automatically calibrated at 2300 hours every day. Additional details on methods and a comparison of PM2.5 and BC concentrations measured at the school and the fixed monitoring site are provided in the Supplemental Material (http://dx.doi.org/10.1289/ehp.1103461). In this study, we only report the results associated with outdoor concentrations of PM2.5, BC, CO, SO2, and NO2.Statistical analysis. t-Tests were used to derive p-values for differences in mean air pollutants and eNO before and during the Olympic Games air quality intervention. Generalized estimating equations (GEE) (ns (GEE) , which cns (GEE) , which iTo graphically analyze the exposure–response relationship between BC and predicted eNO, a nonparametric smoothed function (LOESS) was created with R statistical software  . The deg2.5 alone and then considered the effects of SO2, NO2, and CO. These two-pollutant models provided the estimates of the individual effects of CO, SO2, and NO2 on eNO after adjustment for BC and PM2.5. All estimates were calculated with adjustment for temperature, RH, BMI, and asthma (yes or no).Two-pollutant models were used to investigate the stability of single-pollutant estimates and to check whether estimates for single pollutants might be biased because of confounding by other pollutants. We initially conducted the analysis including BC alone and PMTo estimate effects of lagged BC exposures, we used a polynomial distributed-lag (PDL) model . The PDLi) = β0X0 + β1X1 + β2X2 + β3X3  + β4temperature + β5RH  + β6asthmai + β7BMIi,ln during the intervention relative to the other time periods (p < 0.05). We found no statistically significant differences between boys and girls.Of the 1,581 observations, eNO concentrations varied from 1.3 to 71.5 ppb, with an overall mean ± SD concentration of 13.7 ± 7.9 ppb. Among all the subjects, the concentration of eNO decreased by about 27% , BC (16.6% per 148.8 μg/m3), SO2 (8.1% per 11.38 ppb), CO (10.4% per 1.04 ppm), and NO2 (11.0% per 10.51 ppb)  increases in 0–24 hr PM.51 ppb) . PM2.5 a2.5 and BC averaged over 25–48 hr , but percent increases were much less than those associated with 0–24 hr averages  only for an IQR increase in PM2.5 over the prior 25–48 hr.Increases in eNO per IQR increases in PMchildren , but dif2.5 and BC concentrations and the predicted eNO value from GEE, we fit an exposure–response curve using the LOESS model. eNO increased almost linearly over the large range of BC (0.6–10.7 μg/m3) and PM2.5 (21.5–311.2 μg/m3) concentrations observed during the study  when adjusted for BC. Overall, BC had the most robust association with eNO when adjusted for confounding by other pollutants.Adjusting for PM with BC . AdjustiPDL model estimates for BC lagged up to 47 hr indicated that IQR increases in BC during the 10 hr before eNO measurements had the strongest associations with eNO .3 increase in outdoor BC was associated with a 2.3-ppb increase in eNO in 16 older subjects with chronic respiratory diseases. 3 increase in BS was associated with a 10-ppb increase in eNO at lag 1 day and a 9 ppb increase at lag 3 days in a study of 82 children 8–13 years of age. 3 increase in BS on the previous day in 68 children 10–11 years of age. Direct quantitative comparisons are not possible given differences in exposure metrics and study designs, but our findings are consistent with previous studies with regard to the association between BC and eNO and extend them by providing information on hourly lagged effects.Our findings suggest that reducing the concentrations of urban ambient pollutants during the 2008 Beijing Olympic Games air quality intervention was rapidly followed by a decrease in respiratory inflammation in children. Furthermore, we found a robust association between ambient BC and acute respiratory inflammation in children that persisted with adjustment for other pollutants. Previous studies also support effects of BC on airway inflammatory response. 2.5 and its constituent BC during the 2008 Beijing Olympics, we were able to estimate the eNO exposure–response relationship based on a wide range of measured BC concentrations and show that it was more or less linear over the entire range. In our study, the BC IQR was 4.02 μg/m3, whereas in other studies IQRs were between 0.11 and 1.68 μg/m3   . DelfinoOur findings also suggest that exposure to BC may have a lagged effect on eNO for up to 10 hr, in addition to an immediate effect. Previous studies have also supported rapid and delayed effects of PM on eNO in children, showing that exposures in the preceding 5–11 hr were associated with respiratory inflammation .Inflammation is a key factor in the pathogenesis of respiratory diseases , includi2.5 exposure appeared to have less of an impact on eNO in asthmatic children than in nonasthmatic children, but differences were not statistically significant, possibly because of limited power because of the small number of asthmatic children. The absence of effect modification by asthma has also been reported by 2.5, and other traffic-related air pollutants in their study, with exposures somewhat similar to those our study. Our findings call for further investigation of asthmatic responses to BC using larger numbers of subjects.In the present study, BC and PM2.5, which was not as strongly associated with eNO. The substantially lower air pollution levels during the 2008 Olympics were associated with reduced eNO.Short-term exposure to BC showed a positive monotonic dose–response relationship with acute respiratory inflammation in schoolchildren living in Beijing. This relationship was not confounded by PM(180 KB) PDFClick here for additional data file.


To the Editor: Since 2005, new parvoviruses forming a novel genus of the proposed name Partetravirus, within the subfamily Parvovirinae, have been described  according to the manufacturer’s instructions. DNA samples were pooled, with each pool containing 3 different samples. A total of 94 pooled samples from 282 animals originating from 3 districts in Cameroon  were investigated by using quantitative real-time PCR . A pool size of 3 with a total of 94 pooled samples and 65 positive samples resulted in an estimated general prevalence of 32.4% (95% CI 27%–39%). For Bamenda, the estimated prevalence was 5.4% (95% CI 1%–16%); for Douala, 32.8% (95% CI 25%–41%); and for Yaoundé, 65.8% (95% CI 44%–87%).We detected HoV in 65 (69%) of the 94 pooled samples: 2 (15%) of 13 from Bamenda, 39 (70%) of 56 from Douala, and 24 (96%) of 25 from Yaoundé. We used an online tool to estimate the individual prevalence from pooled samples for fixed pool size and perfect test with exact 5% upper and lower CIs . The regional prevalence was 10% (4/39) for Bamenda, 41% (65/160) for Douala, and 83% (59/71) for Yaoundé.These prevalences are higher than the estimates, but lie within the regional estimates within the range of the CI determined with the online tool. The discrepancy in the total prevalence might be due to the missing samples for the individual testing. Our results show that pooled sample testing can yield a good approximation of the actual prevalence, at least for settings in Africa. The varying prevalence and inhomogeneous regional distribution of porcine HoV correspond to previous findings from Europe, China, and the United States in wild boar and domestic pigs (Near full-length genome data were generated from 3 positive samples, and partial sequence information was retrieved for 8 additional samples  as descr


Several indices exist to monitor adequate oxygenation, but no such index exists for ventilatory efficiency. The ventilatory ratio (VR) is a simple tool to monitor changes in ventilatory efficiency using variables commonly measured at the bedside :2 5 kPa).See Figure ex vivo. Three virtual patients were configured, representing healthy lung, ARDS and COPD. VR was calculated while minute ventilation, ventilation rate and VCO2 were each varied in isolation. The clinical uses of VR were then examined in a database comprising 122 patients with ALI and ARDS [The Nottingham Physiology Simulator (NPS), a validated computational model of cardiopulmonary physiology , was useand ARDS . Standar2 . Similarly, VCO2 had a linear relationship with VR at constant Vd/Vtphys. Across the various ventilatory configurations the median values and ranges of calculated VR for the three patients were as follows: normal patient VR 0.89 (0.61 to 1.36), COPD 1.36 (0.95 to 1.89) and ARDS 1.73 (1.2 to 2.62). In the ALI/ARDS database the range of values for VR was 0.56 to 3.93 (median 1.36). Patients with ARDS had a significantly higher VR in comparison with patients with ALI . VR was significantly higher in nonsurvivors as compared with survivors . There was poor correlation between PaO2/FiO2 ratio and VR in the population .The NPS model showed significant correlation between VR and physiological deadspace fraction (Vd/Vtphys) at constant VCOEx vivo modling shows that VR can be simply and reliably used to monitor ventilatory efficiency at the bedside. VR is influenced by changing CO2 production and deadspace ventilation. As a clinical tool it is a predictor of outcome and is independent to PaO2/FiO2 ratio.


The aim was to analyse trends in clinically relevant resistance to first-line antiretroviral drugs in Spain, applying the Stanford algorithm, and to compare these results with reported Transmitted Drug Resistance (TDR) defined by the 2009 update of the WHO SDRM list.We analysed 2781 sequences from ARV naive patients of the CoRIS cohort (Spain) between 2007–2011. Using the Stanford algorithm “Low-level resistance”, “Intermediate resistance” and “High-level resistance” categories were considered as “Resistant”.70% of the TDR found using the WHO list were relevant for first-line treatment according to the Stanford algorithm. A total of 188 patients showed clinically relevant resistance to first-line ARVs [6.8% ], and 221 harbored TDR using the WHO list [7.9% (6.9–9.0)]. Differences were due to a lower prevalence in clinically relevant resistance for NRTIs [2.3% (1.8–2.9) vs. 3.6% (2.9–4.3) by the WHO list] and PIs [0.8% (0.4–1.1) vs. 1.7% (1.2–2.2)], while it was higher for NNRTIs [4.6% (3.8–5.3) vs. 3.7% (3.0–4.7)]. While TDR remained stable throughout the study period, clinically relevant resistance to first line drugs showed a significant trend to a decline (p = 0.02).Prevalence of clinically relevant resistance to first line ARVs in Spain is decreasing, and lower than the one expected looking at TDR using the WHO list. Resistance to first-line PIs falls below 1%, so the recommendation of screening for TDR in the protease gene should be questioned in our setting. Cost-effectiveness studies need to be carried out to inform evidence-based recommendations. HIV drug resistance due to transmitted mutations in the reverse transcriptase (RT) and protease (Pro) regions has been associated with a higher risk of virological failure to first line antiretroviral therapy (ART) The Spanish cohort of naïve HIV infected individuals (CoRIS) offers relevant information about the current epidemiological profile of HIV infection WHO mutations list has overcome the major limitation of TDR studies across the world, thus providing high levels of standardization into these studies. However, it defines TDR to the different classes of antiretroviral drugs based on the presence of at least one mutation related to drug resistance, while first line treatment drugs that are currently approved by many of the latest updates of clinical guidelines, often include compounds, for which more than one mutation is necessary in order to reduce in vivo drug activity . Further approaches, such as the Stanford HIV Drug Resistance Database algorithm, calculate the effective resistance given the combination of mutations present in a particular strain, allowing analyzing clinically relevant resistance to specific antiretroviral drugs (ARVs) and regimens, providing a complementary and invaluable input for informing clinical recommendations.The objective of this study was to analyse clinically relevant resistance to drugs included in recommended first-line regimens in Spain (CoRIS) from 2007 to 2011, using the Stanford algorithm, and compare it to TDR, defined by the WHO list of mutations.CoRIS is an open, multicentre, prospective cohort of HIV-positive, antiretroviral-naïve subjects over 13 years of age, including both seroprevalent and seroconverter patients. Subjects are recruited and followed up in 31 HIV units from 13 of the 17 Autonomous Communities of Spain. Ethics approval was obtained from participating sites and a written informed consent was obtained from every patient included in the study. Detailed descriptions of the cohort have been previously published Clinically relevant drug resistance to the first line antiretrovirals (ARVs) included in recommended first-line regimens in Spain as of current guidelines Alternatively, transmitted drug resistance (TDR) associated mutations were evaluated following the WHO surveillance drug resistance mutation list updated in 2009 by Bennett and colleagues The sample was described using proportion or median (interquartile range) for categorical and continuous variables, respectively; and bivariate analysis was performed using Chi Square or Kruskall-Wallis test as appropriate. Resistance mutations were described using prevalence, and the corresponding confidence intervals were calculated with an analytically derived variance estimator. Their linear trend over the study period was analysed using chi-square test for trend. Significance level was 5%. All the analyses were conducted using Stata software .3). All differences were statistically significant at p<0.01.A total of 23 out of the 28 centres in CoRIS contributed FASTA sequences from 2007 to 2011. These centres provided 7,351 patients, 92.2% of the CoRIS cohort, and a complete naïve sequence was submitted for 2,781 (37.8%). Compared to the total cohort, those with an available FASTA sequence were younger (median age 33.9 vs. 34.9), more frequently males (88.3% vs. 83.9%), infected through sex between men (69.2% vs. 58.9%), with a higher educational level (63.5% vs. 56.2%), originating from Spain compared to other regions (70.1% vs. 68.0%), and recruited in earlier stages of HIV disease progression . Regarding mutations affecting specific ARV classes, similar prevalence of TDR was found for nucleoside reverse transcriptase inhibitors (NRTIs) and non-NRTIs (NNRTIs), being 3.6% (2.9–4.3) for NRTIs and 3.7% (3.0–4.7) for NNRTIs. TDR to protease inhibitors (PIs) was less prevalent, of 1.7% (1.2–2.2). When investigating clinically relevant resistance to ARV drugs that make part of recommended initial regimens, the number of patients that showed any resistance was 188, for a total prevalence of 6.8% (5.8–7.7). Prevalence of clinically relevant resistance to any first line ARV was lower than TDR for NRTIs [2.3% (1.8–2.9)] and PIs [0.8% (0.4–1.1)], while it increased in the case of NNRTIs to reach 4.6% (3.8–5.3). In fact, only 70.1% of patients harboring TDR actually showed any clinically relevant resistance to first-line drugs. Percentages for NRTIs and PIs were 65.3% and 35.4%, respectively. For NRTIs, the mutations responsible for having TDR, but without clinically relevant resistance to first line drugs, were present mainly as singletons: a Thymidine Associated Mutation (TAM) alone , a T215 revertant alone (D/N/S n = 7), a F77L alone (n = 2), or a combination of D67N+K219Q (n = 4), or D67N+T69D (n = 1). For PIs, mutations responsible for these discordances were always detected as singletons . On the other hand, the increase in clinically relevant resistance for NNRTIs was driven mainly by the combination of two or more mutations that are not present in the WHO list , and in 7 cases by the presence of a A98G singleton.For individual first line NRTIs, clinically relevant resistance was 2.2% (1.7–2.8) for abacavir, 0.7% (0.4–1.0) for emtricitabine and lamivudine, and 1.6% (1.1–2.1) for tenofovir; for first line NNRTIs, resistance was observed in 4.0% (3.3–4.8) for efavirenz and 4.6% (3.8–5.3) for nevirapine; finally, for PIs, resistance was observed in 0.7% (0.4–1.0) for atazanavir, 0.1% (0.0–0.3) for darunavir, and 0.3% (0.1–0.5) for lopinavir.Our study shows that, in Spain for the period 2007–2011, the prevalence of clinically relevant resistance to approved first line ARV drugs analyzed using the Stanford HIV interpretation system is lower than the one we would expect when looking at the Transmitted Drug Resistance (TDR) defined in the WHO mutations list. Moreover, a significant trend to a reduction in resistance was found, driven by a decrease in resistance to the first line NNRTIs efavirenz and nevirapine, as well as to the NRTIs abacavir, emtricitabine, lamivudine, and tenofovir, while resistance to the PIs atazanavir, darunavir and lopinavir, remained stable and very low throughout the whole period. In contrast, no significant trend in the TDR defined by WHO list has been observed. Resistance to more than one antiretroviral class was very uncommon by year 2011.Many studies have evaluated trends in TDR transmission across Europe and the US In our study, TDR was of 7.9%, higher than clinically relevant resistance to first line drugs . This shows that effective resistance to first line regimens in Spain would lie below the one we would expect when looking at the list of resistance mutations surveillance. In fact, up to 30% of patients harboring TDR did not actually show clinically relevant resistance, being this percentage higher in the case of PIs (65%) and NRTIs (34%). Specifically looking at clinical resistance to first line drugs is therefore relevant and can have important implications.Clinically relevant resistance to first line PIs remained below 1% for all years except 2007, and was mostly of intermediate level, showing that transmitted resistance to PIs is not threatening effectiveness of PI-based first line ART in Spain. In agreement with what was previously suggested by an Irish report In a similar way, we have also shown this effect for NRTIs, with a prevalence of TDR of 3.6%, and a prevalence of clinically relevant resistance to first line drugs of 2.3%. Again, singletons were responsible for these differences (55.5% of the patients with TDR to NRTIs harboured a single mutation). Abacavir and tenofovir are the two drugs in the NRTI class with the best resistance profile, being the least affected drugs by single mutations. In fact most of the discordant cases showing TDR showed resistance to zidovudine or stavudine, two NRTIs that are no longer included in Spanish and most international recommendations for first line treatment. In contrast, the NNRTI class, represented for first line with two low genetic barrier drugs, showed higher clinically relevant resistance than TDR. This difference was mainly driven by intermediate resistance calls for efavirenz and/or nevirapine by a combination of two or more mutations that are not included in the WHO list, or by the presence of A98G alone.Evaluating resistance to specific drugs also allows evaluating the global therapeutic barrier of a regimen, measuring the global robustness to resistance of a certain combination rather than resistance to a certain drug. This may be of extreme importance for evaluating clinical resistance to first line regimens, establishing recommendations on how resistance testing should be performed on newly diagnosed patients, and updating treatment guidelines. In our study, first line NNRTI containing regimens showed the lowest therapeutic barrier, as 5.6% to 6.2% of the newly diagnosed patients from CoRIS, showed any degree of resistance to at least one of the drugs in the regimen. In contrast, the therapeutic barrier to first line PI-based regimens was much higher, with between 2.2% and 2.7% showing any degree of resistance, and only 0.7% to 0.9% of the patients with two or less active drugs in the regimen, most of them being fully resistant to emtricitabine or lamivudine. To our knowledge, this is the first study to estimate the therapeutic barrier of first line regimens, and our results reinforce the previously mentioned notion that, in our setting, a reverse transcriptase-only approach for resistance screening in naïve patients is a strategy that should be considered. Cost-effectiveness studies evaluating the different strategies are urgently needed to better inform drug resistance testing recommendations in our setting. Some other issues, related to the epidemiological value of having the protease sequence information, should be considered and modelled in this analysis.Our study has several limitations. First, we have studied a subset of patients included in CoRIS, as a FASTA sequence was only available for 37.8% of the patients. Restricting to years after 2007, when the recommendation to screen for resistance in all patients was made, minimises the possibility of selective testing of patients with higher probability of resistance. Higher testing in younger males, MSM of Spanish origin and higher education could reflect clinicians' preferences and practices and higher agency of these patients. However, we cannot rule out that selection bias persists at a certain scale, resulting in an infra-estimation of resistance rates. Second, our sequencing data have been obtained through population sequencing and we have not investigated the presence of minor populations. As minor variants are known to have a greater impact on resistance to NNRTIs in naïve patients In summary, clinically relevant resistance to ART first line regimens in Spain estimated using the Stanford HIV resistance database algorithm has been found to be lower than the one we expected when looking at the WHO surveillance mutations list, and with a significant trend to a decline through the period 2007–2011. As PI-based first line regimens have shown the highest therapeutic barrier and primary resistance to first-line PIs has been found to be below 1%, we believe that there is a need to question the recommendation of screening for TDR in the protease gene in our setting, and that cost-effectiveness studies need to be carried out to inform evidence-based recommendations.


Juvenile idiophatic arthritis (JIA) is a heterogeneous disease and it’s associated with an increased use of various biological agents in recent years.Describe changes in treatment with biological agents in JIA patients.This is a retrospective study of 109 JIA patients from a tertiary centre. Variables included were: age, disease duration, sex, antinuclear antibodies (ANA), HLA B27, Rheumatoid Factor (RF), uveitis and data of systemic AIJ. Current and previous biological agents, reasons for change and adverse events were also recorded.The sample included 83 girls and 26 boys aged 10 ± 4.4 (2.4-19.6) with a disease duration of 5 ± 3.4 (0.1- 17) years. The initial biological agent was etanercept (ETA) in 87 cases, adalimumab (ADA) in 9, anakinra (AK) in 12 and infliximab (IFX) in 1. Twenty-eight patients switched to a second biological agent, 7 to a third and 2 to a fourth. Switching was due to inefficacy since adverse events were mild or moderate.Current treatment with ETA was associated with ANA positives , however ADA did so with uveitis  and AK y TCZ with s-JIA . Table 11. Switching to a second biological agent was necessary in 26% of patients. Only 6% of patients switched to a third, and 2% to a fourth.2. The results indicate that etanercept was chosen in patients with ANA positives, adalimumab in cases with uveitis and anakinra and tocilizumab in those with systemic symptoms.