Subureteral polydimethylsiloxane injection versus extravesical reimplantation for primary low grade vesicoureteral reflux in children: a comparative study

PURPOSE: We compare the outcome of extravesical ureteral reimplantation to endoscopic polydimethylsiloxane (Macroplastique, Uroplasty, Inc., Minneapolis, Minnesota) subureteral injection for primary low grade vesicoureteral reflux in children. MATERIALS AND METHODS: Between 1997 and 2000, 180 patients underwent polydimethylsiloxane injection (74, 108 ureters) or extravesical ureteral reimplantation (106, 166 ureters) for low grade vesicoureteral reflux. Low grade reflux was defined as grades I to III. Outcome analysis included success rates, de novo hydronephrosis, voiding efficiency, urinary tract infections and complications. RESULTS: Mean patient age at surgery for the injection and surgery groups was 60 and 77 months, and mean followup was 12 and 15 months, respectively. Of the patients who underwent single injection 80.6% were cured of reflux at 3 months and 91.6% were cured at last followup. Success rate after reimplantation was 95.8% at 3 months which improved to 98.8% 1 year later. The success rate was significantly different between the injection and reimplantation groups at 3 and 12 months (p <0.01). Postoperative complications in the reimplantation group included transient urinary retention after bilateral surgery in 2 patients (3.3%), suprapubic fluid collections in 2 and wound seroma in 1. No complications occurred in the polydimethylsiloxane group. CONCLUSIONS: Extravesical ureteral reimplantation has near perfect success with a low but definite complication rate. Polydimethylsiloxane offers high success rates for reflux in an ambulatory setting with no short-term complications. Currently, endoscopic polydimethylsiloxane injection is our preferred mode of therapy for low grade vesicoureteral reflux in children when surgical correction is indicated.     

Zinc-naproxen complex: synthesis,physicochemical and biological evaluation

Naproxen has a propensity to cause ulcers whereas zinc ions are known to possess an anti-ulcer and anti-inflammatory activity. Therefore, zinc complex of naproxen was prepared by adding zinc sulfate to an aqueous solution of sodium naproxen and its structure was characterized by IR, ¹H NMR and ¹³C NMR, UV, DSC, atomic absorption spectroscopy, and elemental analysis. Anti-inflammatory studies, using the carrageenan-induced hind paw oedema showed that there was a significant difference (P<0.05, ANOVA plotted by Dunnet’s test) in the anti-inflammatory activity of naproxen, its zinc complex, and the physical mixture of naproxen and zinc sulfate. In addition, zinc complex of naproxen showed a significant reduction in ulcers (lesion index (LI)) as compared to that of naproxen and physical mixture of naproxen and zinc sulfate. Thus, the use of the complex may be preferable to naproxen alone.     

Food insecurity affects school children's academic performance, weight gain, and social skills

Food insecurity has been associated with diverse developmental consequences for U.S. children primarily from cross-sectional studies. We used longitudinal data to investigate how food insecurity over time related to changes in reading and mathematics test performance, weight and BMI, and social skills in children. Data were from the Early Childhood Longitudinal Study-Kindergarten Cohort, a prospective sample of approximately 21,000 nationally representative children entering kindergarten in 1998 and followed through 3rd grade. Food insecurity was measured by parent interview using a modification of the USDA module in which households were classified as food insecure if they reported > or =1 affirmative response in the past year. Households were grouped into 4 categories based on the temporal occurrence of food insecurity in kindergarten and 3rd grade. Children's academic performance, height, and weight were assessed directly. Children's social skills were reported by teachers. Analyses examined the effects of modified food insecurity on changes in child outcomes using lagged, dynamic, and difference (i.e., fixed-effects) models and controlling for child and household contextual variables. In lagged models, food insecurity was predictive of poor developmental trajectories in children before controlling for other variables. Food insecurity thus serves as an important marker for identifying children who fare worse in terms of subsequent development. In all models with controls, food insecurity was associated with outcomes, and associations differed by gender. This study provides the strongest empirical evidence to date that food insecurity is linked to specific developmental consequences for children, and that these consequences may be both nutritional and nonnutritional.     

NO-sulindac inhibits the hypoxia response of PC-3 prostate cancer cells via the Akt signalling pathway

Nitric oxide-donating non-steroidal anti-inflammatory drugs are safer than traditional NSAIDs and inhibit the growth of prostate cancer cells with greater potency than NSAIDs. In vivo, prostate cancer deposits are found in a hypoxic environment which induces resistance to chemotherapy. The aim of this study was to assess the effects and mechanism of action of a NO-NSAID called NO-sulindac on the PC-3 prostate cancer cell line under hypoxic conditions. NO-sulindac was found to have pro-apoptotic, cytotoxic, and anti-invasive effect on PC-3 cells under normoxia and hypoxia. NO-sulindac was significantly more cytotoxic than sulindac at all oxygen levels. The sulindac/linker and NO-releasing subunits both contributed to the cytotoxic effects of NO-sulindac. Resistance of PC-3 cells to NO-sulindac was induced as the oxygen concentration declined. Hypoxia-induced chemoresistance was reversed by knocking-down hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA using RNAi. Nuclear HIF-1alpha levels were upregulated at 0.2% oxygen but reduced by treatment with NO-sulindac, as was Akt phosphorylation. NO-sulindac treatment of hypoxic PC-3 cells transfected with a reporter construct, downregulated activation of the hypoxia response element (HRE) promoter. Co-transfection of PC-3 cells with the HRE promoter reporter construct and myr-Akt (constitutively active Akt) plasmids reversed the NO-sulindac induced reduction in HRE activation. Real-time polymerase chain reaction analysis of hypoxic, NO-sulindac treated PC-3 cells showed downregulation of lysyl oxidase and carbonic anhydrase IX mRNA expression. Collectively, these novel findings demonstrate that NO-sulindac directly inhibits the hypoxia response of PC-3 prostate cancer cells by inhibiting HIF-1alpha translation via the Akt signalling pathway. The ability of NO-sulindac to inhibit tumour adaption to hypoxia has considerable relevance to the future management of prostate cancer with the same cellular properties as PC-3.     

Clinical outcomes and immune phenotypes associated with STK11 co-occurring mutations in non-small cell lung cancer

BackgroundSTK11 mutation in non-small cell lung cancer (NSCLC) is associated with worse survival as well as primary resistance to PD-1/PD-L1 targeting immunotherapy. We hypothesize that co-occurring mutations and tumor mutation burden (TMB) may impact response to therapy and prognosis.MethodsForty-one patients with STK11-mutated NSCLC seen in our Thoracic oncology clinic with available next-generation sequencing tumor data were included in the analysis. Data from the Cancer Genome Atlas (TCGA) was used for survival and immune gene expression analysis. Overall and progression-free survival (PFS) was estimated by the Kaplan-Meier method and compared using a log-rank test.ResultsIn the 41 patients included, common co-occurring alterations with STK11 were KRAS (54%), TP53 (44%), CDKN2A (37%) and KEAP1 (27%). Overall 17 patients received locoregional therapy with surgery or radiation with median OS of 8.6 years and there was no significant difference in clinical outcomes with KRAS and TP53 co-occurring mutations. Response to both chemotherapy and immunotherapy was poor across all co-occurring mutations. However, TP53 co-mutation was associated with improved clinical benefit with immunotherapy. Patients with higher TMB had longer PFS with immunotherapy. In TCGA survival analysis, tumors with STK11 mutation with or without KRAS co-mutation were associated with worse survival (P<0.05) but tumors with STK11/TP53 co-mutation did not have worst survival compared to STK11 wild type tumors. Moreover, co-occurring mutations had significant effect on intratumoral immune status with both STK11 alone and STK11/KRAS co-mutated tumors showing more enrichment for wound healing immune subtype while STK11/TP53 co-mutated tumors showed more enrichment for IFN-g immune subtype.ConclusionsOur retrospective analysis in patients with STK11-mutated NSCLC found that both TMB and co-occurring mutations may be predictors for response to immunotherapy with worse outcomes in patients with low TMB or KRAS co-mutation and improved outcomes with TP53 co-mutation. Patients with STK11-mutated NSCLC also demonstrate chemotherapy resistance but have similar outcomes with localized treatment compared to STK11 wild type tumors. Moreover, co-mutations with KRAS or TP53 significantly alter tumor immune landscape of STK11-mutated tumors and therefore response to immunotherapy.     

The importance of rating scales in measuring patient-reported outcomes

ABSTRACT: BACKGROUND: A critical component that influences the measurement properties of a patient-reportedoutcome (PRO) instrument is the rating scale. Yet, there is a lack of general consensusregarding optimal rating scale format, including aspects of question structure, the number andthe labels of response categories. This study aims to explore the characteristics of ratingscales that function well and those that do not, and thereby develop guidelines forformulating rating scales. METHODS: Seventeen existing PROs designed to measure vision-related quality of life dimensions weremailed for self-administration, in sets of 10, to patients who were on a waiting list for cataractextraction. These PROs included questions with ratings of difficulty, frequency, severity, and global ratings. Using Rasch analysis, performance of rating scales were assessed byexamining hierarchical ordering (indicating categories are distinct from each other and followa logical transition from lower to higher value), evenness (indicating relative utilization ofcategories), and range (indicating coverage of the attribute by the rating scale). RESULTS: The rating scales with complicated question format, a large number of response categories, orunlabelled categories, tended to be dysfunctional. Rating scales with five or fewer responsecategories tended to be functional. Most of the rating scales measuring difficulty performedwell. The rating scales measuring frequency and severity demonstrated hierarchical orderingbut the categories lacked even utilization. CONCLUSION: Developers of PRO instruments should use a simple question format, fewer (four to five) andlabelled response categories.     

Synergistic therapeutic potential of dexamethasone and L-arginine in lipopolysaccharide-induced septic shock

BACKGROUND: Dexamethasone (DEX) is demonstrated to have anti-inflammatory properties and known to induce hemodynamic improvement in sepsis and septic shock. L-arginine (L-arg), a semi-essential amino acid, depending on its metabolic pathway, becomes very essential in stress situations such as heatstroke, burns, sepsis, trauma, and wound healing. The aim of this study was to evaluate the synergistic therapeutic effect of DEX and L-arg in rescuing the mice from experimental septic shock induced by bacterial lipopolysaccharide (LPS). The experiments were designed to delineate the molecular mechanisms responsible for the increased therapeutic benefit of the combination therapy (CT) in LPS-induced septic shock. METHODS: Acute endotoxemia was induced in Swiss male mice by i.p. injection of LPS (18 mg kg(-1)) at 0 h. LPS-treated mice were divided into four groups. The first group (DEX group) received DEX (2 mg kg(-1)) i.p. at +2 h of LPS. The second group (L-arg group) received L-arg i.p. at a dose of 120 mg/kg at +6 h of LPS injection. The third group (CT group) received DEX (2 mg kg(-1)) at +2 h LPS followed by L-arg at +6 h of LPS injection. The fourth group received saline in place of L-arg or DEX (LPS group). A sham group was also included, where normal mice received saline in place of LPS or L-arg or DEX. At +6 h, mice from sham group, LPS group, and DEX group were sacrificed at +24 h. Mice from sham group, DEX group, L-arg group, and CT group were sacrificed to examine various parameters associated with LPS endotoxemia. RESULTS: The CT with DEX followed by L-arg significantly increased the survival of mice injected with a lethal dose of LPS. Monotherapy with either DEX or L-arg given at the same dose and time did not increase the survival of the mice injected with LPS. DEX administration could significantly reduce the levels of serum TNF-alpha, IL-1beta, IFN-gamma, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), and nitrite. DEX also down-regulated the expression of liver-inducible nitric oxide synthase (iNOS), and up-regulated the levels of serum anti-inflammatory cytokines like TGF-beta1 and IL-4, hepatic and splenic arginase, in LPS-injected mice. The enhanced therapeutic effect of CT correlated with reduced pathological symptoms, decreased Th1 cytokines, increased TGF-beta1 and arginase levels compared to the mice administered with either of the monotherapies. The CT group had significantly increased expression of hepatic Hsp 70 and reduced septic shock associated histopathology, in lung and liver, compared to the mice treated with either DEX or L-arg. CONCLUSIONS: The therapeutic combination therapy with DEX and L-arg, at the appropriate dose, time, and sequence of administration, changed the cytokine profile, in favor of reducing the inflammatory response. The significantly enhanced survival observed in the CT group was accompanied by an increased hepatic Hsp 70, hepatic arginase, splenic arginase, and decreased organ injury. This novel concept of combined therapy could form the basis of an effective therapeutic approach in the treatment of sepsis and septic shock.     

Visual defects in Nepalese children with Down syndrome

Background: Down syndrome (DS) is a common chromosomal anomaly. People with this syndrome have recognisable physical characteristics and limited intellectual abilities. The aim of this study was to determine visual defects, especially refractive error and binocular anomalies, in a sample of Nepalese children with DS. Methods: Thirty‐six children with DS (19 boys and 17 girls) from the Kathmandu valley, aged from four months to 18 years, underwent detailed optometric examination. Cycloplegic refraction was performed on all subjects. Vision on presentation of all the children was assessed with preferential looking cards, the Kay picture cards, the Bailey‐Lovie logMAR chart or the Snellen chart. Binocular function was assessed with cover test, Hirschberg or Bruckner test. Results: Cycloplegic refraction of the children revealed that 80 per cent of the children had significant refractive error. Most of them had hyperopia (55 per cent), followed by astigmatism (44 per cent), myopia (25 per cent) and anisometropia (19 per cent). Only two (5.6 per cent) children were strabismic and both of them were alternating esotropes. Nystagmus was present in 10 (28 per cent). Other ocular findings were upward slanting palpebral fissures, blepharitis, congenital nasolacrimal duct obstruction, blepharoconjunctivitis, chalazion and lenticular opacities. Conclusion: Nepalese children with DS have a high prevalence of refractive error and nystagmus. Regular eye examinations are indicated for these children to enable early diagnosis and appropriate management of ocular disorders to improve their vision and quality of life.