Anorectal malformations

Anorectal malformations comprise a wide spectrum of diseases, which can affect boys and girls, and involve the distal anus and rectum as well as the urinary and genital tracts. They occur in approximately 1 in 5000 live births. Defects range from the very minor and easily treated with an excellent functional prognosis, to those that are complex, difficult to manage, are often associated with other anomalies, and have a poor functional prognosis. The surgical approach to repairing these defects changed dramatically in 1980 with the introduction of the posterior sagittal approach, which allowed surgeons to view the anatomy of these defects clearly, to repair them under direct vision, and to learn about the complex anatomic arrangement of the junction of rectum and genitourinary tract. Better imaging techniques, and a better knowledge of the anatomy and physiology of the pelvic structures at birth have refined diagnosis and initial management, and the analysis of large series of patients allows better prediction of associated anomalies and functional prognosis. The main concerns for the surgeon in correcting these anomalies are bowel control, urinary control, and sexual function. With early diagnosis, management of associated anomalies and efficient meticulous surgical repair, patients have the best chance for a good functional outcome. Fecal and urinary incontinence can occur even with an excellent anatomic repair, due mainly to associated problems such as a poorly developed sacrum, deficient nerve supply, and spinal cord anomalies. For these patients, an effective bowel management program, including enema and dietary restrictions has been devised to improve their quality of life

Study of the reaction e^{+}e^{-} -->J/psi\pi^{+}\pi^{-} via initial-state radiation at BaBar

We study the process $e^+e^-\to J/\psi\pi^{+}\pi^{-}$ with initial-state-radiation events produced at the PEP-II asymmetric-energy collider. The data were recorded with the BaBar detector at center-of-mass energies 10.58 and 10.54 GeV, and correspond to an integrated luminosity of 454 $\mathrm{fb^{-1}}$. We investigate the $J/\psi \pi^{+}\pi^{-}$ mass distribution in the region from 3.5 to 5.5 $\mathrm{GeV/c^{2}}$. Below 3.7 $\mathrm{GeV/c^{2}}$ the $\psi(2S)$ signal dominates, and above 4 $\mathrm{GeV/c^{2}}$ there is a significant peak due to the Y(4260). A fit to the data in the range 3.74 -- 5.50 $\mathrm{GeV/c^{2}}$ yields a mass value $4244 \pm 5$ (stat) $\pm 4$ (syst)$\mathrm{MeV/c^{2}}$ and a width value $114 ^{+16}_{-15}$ (stat)$\pm 7$(syst)$\mathrm{MeV}$ for this state. We do not confirm the report from the Belle collaboration of a broad structure at 4.01 $\mathrm{GeV/c^{2}}$. In addition, we investigate the $\pi^{+}\pi^{-}$ system which results from Y(4260) decay

Valacyclovir in the treatment of acute retinal necrosis

Background: To report the outcome of oral valacyclovir as the sole antiviral therapy for patients with acute retinal necrosis (ARN). Methods: This study reports a retrospective, interventional case series of nine consecutive patients with ten eyes with newly diagnosed ARN treated with oral valacyclovir as the sole antiviral agent. Eight patients received oral valacyclovir 2 g tid (Valtrex, GlaxoSmithKline) and one patient with impaired renal function received oral 1 g tid. The main outcome measures were response to treatment, time to initial response to treatment, time to complete resolution of retinitis, best corrected visual acuity (BCVA) at final follow-up, retinal detachment and development of recurrent or second eye disease. Results: Retinitis resolved in ten of ten (100%) affected eyes. The median time to initial detectable response was seven days and the median time to complete resolution was 21 days. A final BCVA of 20/40 or better was achieved in 6/10 (60%) of eyes. 3/10 eyes (30%) developed a retinal detachment. No patients developed either disease reactivation or second eye involvement over the course of the study (mean follow up 31 weeks, range 7 to 104 weeks). Conclusions: Treatment with oral valacyclovir as the sole antiviral therapy resulted in complete resolution of retinitis. Final BCVA and retinal detachment rate were comparable with previously reported outcomes for intravenous acyclovi

Nicotinic Acetylcholine Receptor Variants Are Related to Smoking Habits, but Not Directly to COPD

Genome-wide association studies identified single nucleotide polymorphisms (SNPs) in the nicotinic acetylcholine receptors (nAChRs) cluster as a risk factor for nicotine dependency and COPD. We investigated whether SNPs in the nAChR cluster are associated with smoking habits and lung function decline, and if these potential associations are independent of each other. The SNPs rs569207, rs1051730 and rs8034191 in the nAChR cluster were analyzed in the Vlagtwedde-Vlaardingen cohort (n = 1,390) that was followed for 25 years. We used GEE and LME models to analyze the associations of the SNPs with quitting or restarting smoking and with the annual FEV1 decline respectively. Individuals homozygote (CC) for rs569207 were more likely to quit smoking (OR (95%CI) = 1.58 (1.05–2.38)) compared to wild-type (TT) individuals. Individuals homozygote (TT) for rs1051730 were less likely to quit smoking (0.64 (0.42; 0.97)) compared to wild-type (CC) individuals. None of the SNPs was significantly associated with the annual FEV1 decline in smokers and ex-smokers. We show that SNPs in the nAChR region are associated with smoking habits such as quitting smoking, but have no significant effect on the annual FEV1 decline in smokers and ex-smokers, suggesting a potential role of these SNPs in COPD development via smoking habits rather than via direct effects on lung function

First line chemotherapy with planned sequential administration of gemcitabine followed by docetaxel in elderly advanced non-small-cell lung cancer patients: a multicenter phase II study

This multicenter phase II study evaluated, in chemonaive patients with stage IIIB–IV NSCLC, age ⩾70 and with a performance status 0–2, the activity, efficacy and tolerability of planned sequential administration of gemcitabine 1200 mg m−2 on days 1 and 8 every 3 weeks for three courses followed by three cycles of docetaxel 37.5 mg m−2 on days 1 and 8 every 3 weeks, provided there was no evidence of disease progression. A total of 56 patients entered the study. According to intention-to-treat analysis, the objective response rate was 16.0% (95% CI 7.6–28.3%); 23 patients (41.0%) had stable disease and 24 patients (43%) had progressive disease. Five patients who had a stable disease after three courses of gemcitabine obtained a conversion to partial response by docetaxel. Median time to progression was 4.8 months (95% CI 3.6–6.0 months) and median duration of survival was 8.0 months (95% CI 5.6–10.5 months). The 1-year survival rate was 34%. No grade 4 haematological toxicity was observed and grade 3 neutropenia and thrombocytopenia were reported in 5.4 and 3.6% of the patients, respectively. Grade 3/4 mucositis and grade 3 diarrhoea, both occurred in 3.6% of the patients and grade 3 asthenia was observed in 9% of patients. One patient reported a grade 4 skin toxicity. No treatment-related deaths occurred. Sequential gemcitabine and docetaxel is a well-tolerated and effective regimen in elderly advanced NSCLC patients

Bacterial RuBisCO Is Required for Efficient Bradyrhizobium/Aeschynomene Symbiosis

Rhizobia and legume plants establish symbiotic associations resulting in the formation of organs specialized in nitrogen fixation. In such organs, termed nodules, bacteria differentiate into bacteroids which convert atmospheric nitrogen and supply the plant with organic nitrogen. As a counterpart, bacteroids receive carbon substrates from the plant. This rather simple model of metabolite exchange underlies symbiosis but does not describe the complexity of bacteroids' central metabolism. A previous study using the tropical symbiotic model Aeschynomene indica/photosynthetic Bradyrhizobium sp. ORS278 suggested a role of the bacterial Calvin cycle during the symbiotic process. Herein we investigated the role of two RuBisCO gene clusters of Bradyrhizobium sp. ORS278 during symbiosis. Using gene reporter fusion strains, we showed that cbbL1 but not the paralogous cbbL2 is expressed during symbiosis. Congruently, CbbL1 was detected in bacteroids by proteome analysis. The importance of CbbL1 for symbiotic nitrogen fixation was proven by a reverse genetic approach. Interestingly, despite its symbiotic nitrogen fixation defect, the cbbL1 mutant was not affected in nitrogen fixation activity under free living state. This study demonstrates a critical role for bacterial RuBisCO during a rhizobia/legume symbiotic interaction

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients

The pharmacokinetics (PK) and pharmacodynamics (PD) of metronomic irinotecan have not been studied in cancer patients. The aim of the study is to investigate the PK/PD profile of irinotecan/SN-38 administered by metronomic schedule. Twenty chemotherapy-refractory or chemotherapy-resistant patients with metastatic colorectal carcinoma were enrolled. Irinotecan was infused continuously as follows: irinotecan 1.4 mg m−2 day−1 (n=7), 2.8 mg m−2 day−1 (n=5) and 4.2 mg m−2 day−1 (n=8). Drug levels were examined by HPLC, whereas ELISAs and real-time RT-PCR were used, respectively, for the measurement of plasma levels and gene expression in peripheral blood mononuclear cells of vascular endothelial growth factor/thrombospondin-1. Pharmacokinetic analysis demonstrated that the steady-state levels (Css) of SN-38 were between 1 and 3.3 ng ml−1. From a PD point of view, higher thrombospondin-1 (TSP-1) plasma levels (153.4±30.1 and 130.4±9.2% at day 49 vs pretreatment values at 1.4 and 2.8 mg m−2 day−1 dose levels, respectively) and increased gene expression in PBMC were found during the metronomic irinotecan infusion, especially at the lower doses. Four patients (20%) obtained a stable disease (median 3.9 months) despite progressing during previous standard irinotecan schedule. Toxicities >grade 1 were not observed. Metronomic irinotecan administration is very well tolerated and induces an increase of gene expression and plasma concentration of TSP-1 at low plasma SN-38 concentrations

Evaluation of Continuous Tumor-Size-Based End Points as Surrogates for Overall Survival in Randomized Clinical Trials in Metastatic Colorectal Cancer

IMPORTANCE: Tumor measurements can be used to estimate time to nadir and depth of nadir as potential surrogates for overall survival (OS). OBJECTIVE: To assess time to nadir and depth of nadir as surrogates for OS in metastatic colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: Pooled analysis of 20 randomized clinical trials within the Aide et Recherche en Cancerologie Digestive database, which contains academic and industry-sponsored trials, was conducted. Three sets of comparisons were performed: chemotherapy alone, antiangiogenic agents, and anti–epidermal growth factor receptor agents in first-line treatment for patients with metastatic colorectal cancer. MAIN OUTCOMES AND MEASURES: Surrogacy of time to nadir and depth of nadir was assessed at the trial level based on joint modeling of relative tumor-size change vs baseline and OS. Treatment effects on time to nadir and on depth of nadir were defined in terms of between-arm differences in time to nadir and in depth of nadir, and both were assessed in linear regressions for their correlation with treatment effects (hazard ratios) on OS within each set. The strengths of association were quantified using sample-size–weighted coefficients of determination (R2), with values closer to 1.00 indicating stronger association. At the patient level, the correlation was assessed between modeled relative tumor-size change and OS. RESULTS: For 14 chemotherapy comparisons in 4289 patients, the R2 value was 0.63 (95% CI, 0.30-0.96) for the association between treatment effects on time to nadir and OS and 0.08 (95% CI, 0-0.37) for depth of nadir and OS. For 11 antiangiogenic agent comparisons (4854 patients), corresponding values of R2 were 0.25 (95% CI, 0-0.72) and 0.06 (95% CI, 0-0.35). For 8 anti–epidermal growth factor receptor comparisons (2684 patients), corresponding values of R2 were 0.24 (95% CI, 0-0.83) and 0.21 (95% CI, 0-0.78). CONCLUSIONS AND RELEVANCE: In contrast with early reports favoring depth of response as a surrogate, these results suggest that neither time to nadir nor depth of nadir is an acceptable surrogate for OS in the first-line treatment of metastatic colorectal cancer

PolyQ Repeat Expansions in ATXN2 Associated with ALS Are CAA Interrupted Repeats

Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressive disease leading to paralysis and death. Recently, intermediate length polyglutamine (polyQ) repeats of 27–33 in ATAXIN-2 (ATXN2), encoding the ATXN2 protein, were found to increase risk for ALS. In ATXN2, polyQ expansions of ≥34, which are pure CAG repeat expansions, cause spinocerebellar ataxia type 2. However, similar length expansions that are interrupted with other codons, can present atypically with parkinsonism, suggesting that configuration of the repeat sequence plays an important role in disease manifestation in ATXN2 polyQ expansion diseases. Here we determined whether the expansions in ATXN2 associated with ALS were pure or interrupted CAG repeats, and defined single nucleotide polymorphisms (SNPs) rs695871 and rs695872 in exon 1 of the gene, to assess haplotype association. We found that the expanded repeat alleles of 40 ALS patients and 9 long-repeat length controls were all interrupted, bearing 1–3 CAA codons within the CAG repeat. 21/21 expanded ALS chromosomes with 3CAA interruptions arose from one haplotype (GT), while 18/19 expanded ALS chromosomes with <3CAA interruptions arose from a different haplotype (CC). Moreover, age of disease onset was significantly earlier in patients bearing 3 interruptions vs fewer, and was distinct between haplotypes. These results indicate that CAG repeat expansions in ATXN2 associated with ALS are uniformly interrupted repeats and that the nature of the repeat sequence and haplotype, as well as length of polyQ repeat, may play a role in the neurological effect conferred by expansions in ATXN2