Everolimus in combination with vandetanib in children, adolescents, and young adults: a phase I study.

BACKGROUND: Combined use of inhibitors of mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF-2) receptors is a potential strategy to overcome resistance to either class of drugs when used alone. PATIENTS AND METHODS: We designed a phase 1 trial to test the drug combination of a multikinase VEGF receptor 2 inhibitor, vandetanib, and an mTOR inhibitor, everolimus, in a pediatric and young adult patient cohort with advanced cancers. Exceptional responders were probed for tumor mutational profile to explore possible molecular mechanisms of response. RESULTS: Among 21 enrolled patients, clinical benefit was observed in 38% (one patient with partial response and eight patients with stable disease) with a median progression-free survival of 3.3 months. The most common treatment-related adverse event was rash (n = 13). Other treatment-related toxicities included diarrhea, fatigue, hypertension, QT prolongation, hypertriglyceridemia/hypercholesterolemia, transaminitis, thrombocytopenia, and weight loss. None of the patients experienced dose-limiting toxicities. Three exceptional responders were analyzed and were found to harbor genetic alterations including kinase insert domain receptor (KDR) Q472H mutation, EWSR1-CREB3L1, CDKN2A/B loss, and ASPL/ASPSCR1-TFE3 fusion. CONCLUSIONS: The combination of vandetanib and everolimus showed early activity and tolerable toxicity profile in pediatric patients with advanced cancers.

The impact of a haemophilia education intervention on the knowledge and health related quality of life of parents of Indian children with haemophilia.

INTRODUCTION: The impact of haemophilia education on the quality of life of parents of children with haemophilia from low income settings has not been studied. AIM: The purpose of this study was to determine the impact of an education intervention on health related quality of life (HRQOL) of parents of children with haemophilia, parent's knowledge about haemophilia and its management, and to determine whether education about haemophilia can positively impact these outcomes. METHODS: One hundred thirty-three parents from across Maharashtra state, India were provided information about haemophilia, care of child and self-care. The impact of the intervention was measured as changes occurring from baseline to 6 months and 1 year after intervention. Knowledge and practice of management of bleeding was measured using pretested structured questionnaires. HRQOL was measured using a validated Peds Quality of Life™ Family Impact Module (PedsQL™ FIM) tool. RESULTS: There was improvement in knowledge scores immediately after intervention, which remained significantly higher than baseline 1 year after intervention. HRQOL showed significant improvement at 6 months but reduced to baseline levels 1 year after intervention. There were statistically significant changes in terms of practice of management of bleeding episodes at 6 months and 1 year after intervention. CONCLUSION: Education about haemophilia resulted in improvement of knowledge, and practice of management of bleeding which was retained till a year after the intervention. However, a long-term effect on the HRQOL of parents could not be observed after administration of a single education intervention.

Out-of-pocket and catastrophic expenditure on treatment of haemophilia by Indian families.

In low-income countries, haemophilia treatment is not supported by national health services. Data on the burden of out-of-pocket (OOP) expenditure on households are unavailable from these countries. This study measured the OOP expenditure on treatment of haemophilia by Indian households. We used 20 weeks of follow-up data of 24 haemophilia A patients to estimate the annual bleeding rate for each patient and the actual OOP expenditure on treatment. We used this observational data to calculate the annual OOP expenditure on treatment if all bleeding episodes were to be treated with clotting factor concentrate. Using previously published methodology, we estimated if the expenditure was catastrophic to households or not. The observed monthly expenditure on treatment ranged from 1.5% to 12% of monthly income as not all bleeding episodes were treated with clotting factor concentrate. The estimated monthly expenditure if all bleeding episodes occurring over 1 year were to be treated would range from 21 to 314 times the monthly income of families. Nearly 68% of households would have experienced catastrophic expenditure. Treatment for haemophilia results in significant OOP expenditure for households, which is avoided by not providing standard treatment to patients. There is a need to mobilize prevention and care services for haemophilia in India and other low-income countries to mitigate the suffering due to lack of affordable treatment.

Hydatoxi lualba: the worm that wasn't!

Pre-eclampsia is a disorder that occurs only during pregnancy and the postpartum period and affects both the mother and the unborn child. Affecting at least 5-8% of all pregnancies, it can be a rapidly progressive condition characterised by hypertension and proteinuria. Oedema, sudden weight gain, headaches and changes in vision are important symptoms. However, some women with rapidly advancing disease report few symptoms.

Impact of colour pigments on biochemical parameters of bivalve, Lamellidens marginalis.

The present study was carried out to investigate the effect of colour pigments used for painting the decorative articles like idols, on the freshwater bivalve, Lamellidens marginalis. The effects of subchronic exposure were studied by the changes in the biochemical constituents like total protein, glycogen and lactic acid, in different tissues like muscle, mantle, gills, foot, hepatopancreas and gonads for 10 and 20 days period. The glycogen contents in the muscle, mantle and gonads were significantly decreased with increase in concentration of colour pigments. It decreased from 26.77 mg gm(-1) in control to 19.17 mg gm(-1) at 900 ppm after 20 days of exposure; whereas protein contents in the tissues studied decreased significantly from 22.5 mg gm(-1) in control to 15.5 mg gm(-1) at 900 ppm after 10 days of exposure. The increase in lactic acid content in all the tissues except gills and gonads may be due to acute hypoxia.

Regeneration of cervix after excisional treatment for cervical intraepithelial neoplasia: a study of collagen distribution.

OBJECTIVE: To study the distribution of collagen in the regenerated cervical tissue after excisional treatment for cervical intraepithelial neoplasia (CIN). DESIGN: Cohort study. SETTING: A large tertiary teaching hospital in London. POPULATION: Women who underwent repeat excisional treatment for treatment failure or persistent CIN. METHODS: Eligible women who underwent a repeat excisional treatment for treatment failure, including hysterectomy, between January 2002 and December 2007 in our colposcopy unit were identified by the Infoflex(®) database and SNOMED encoded histopathology database. Collagen expression was assessed using picro-Sirius red stain and the intensity of staining was compared in paired specimens from the first and second treatments. MAIN OUTCOME MEASURE: Differences in collagen expression were examined in the paired excisional treatment specimens. RESULTS: A total of 17 women were included. Increased collagen expression in the regenerated cervical tissue of the second cone compared with the first cone was noted in six women, decreased expression was noted in five women, and the pattern of collagen distribution was equivocal in six women. CONCLUSION: There is no overall change in collagen distribution during regeneration following excisional treatment for CIN.

Secondary excision for cervical intraepithelial neoplasia: an evaluation of two treatment methods.

A small proportion of women require repeat treatments for cervical intraepithelial neoplasia (CIN). This study aimed to compare the effectiveness of two cervical excisional techniques offered within a London teaching hospital (large loop excision of the transformation zone (LLETZ) and laser cone biopsy) when carried out as secondary procedures. A significantly larger volume of tissue was excised following laser cone biopsy, however the depth of the specimen did not differ significantly. A trend for a larger percentage of secondary specimens, resulting in complete endo-cervical margins and a larger proportion of women achieving cytology negative for CIN post-treatment was shown within the laser cone biopsy group.

The volume perspective: a comparison of two excisional treatments for cervical intraepithelial neoplasia (laser versus LLETZ).

OBJECTIVE: To compare two excisional treatments, laser cone biopsy and large loop excision of the transformation zone (LLETZ), in terms of the volume of tissue removed, and to determine the relation between the height and the total volume of the cone specimen. DESIGN: Retrospective cross-sectional study. SETTING: Large teaching hospital in London. POPULATION: A total of 1136 eligible excisional treatments (laser cone or large loop excision of the transformation zone, LLETZ). METHODS: Eligible excisional treatments (laser cone or LLETZ) performed between 1 January 2002 and 31 December 2007 in our colposcopy unit were identified using the Infoflex(R) database. The total volume of the cone biopsy was calculated mathematically using the data provided in the histopathology reports. MAIN OUTCOME MEASURES: The volume of the cone biopsy was compared with the technique of excision and the histology grades. RESULTS: Three hundred and thirty-nine laser cone biopsies were performed, whereas 797 LLETZ biopsies were recorded, during the study period. There was no difference in the mean age in the two groups. However, there is a proportional increase in the volume of the cone as the height of the cone increases, and a significant number of the values are skewed, suggesting that the diameter of the base of the cone contributes significantly to the total volume. Laser cone biopsies (median volume 1.84 cm(3), 95% CI 1.98-2.54 cm(3)) account for a larger volume of tissue excised compared with LLETZ (median volume 0.78 cm(3), 95% CI 0.91-1.02 cm(3)) (P < 0.0001). This relationship is not altered when the two procedures are stratified for grade of lesion, i.e. excision for low-grade cervical intraepithelial neoplasia (CIN) (laser median volume 1.55 cm(3), 95% CI 1.46-2.06; LLETZ median volume 0.62 cm(3), 95% CI 0.73-0.88 cm(3)) (P < 0.0001) or high-grade CIN (laser median volume 1.84 cm(3), 95% CI 2.11-2.53 cm(3); LLETZ median volume 0.82 cm(3), 95% CI 0.94-1.07 cm(3)) (P < 0.0001). CONCLUSIONS: The volume of cervical tissue removed during laser conisation is significantly more than that removed with LLETZ. The indication of the cone biopsy does influence the volume of tissue removed.

In situ synthesis of water dispersible bovine serum albumin capped gold and silver nanoparticles and their cytocompatibility studies.

A simple and convenient one step room temperature method is described for the synthesis of bovine serum albumin (BSA) capped gold and silver nanoparticles. BSA reduces silver ions to silver nanoparticles but does not directly reduce gold ions to gold nanoparticles at room temperature and varying pH conditions. However, when silver and gold ions are simultaneously added to BSA, silver ions get reduced to metallic silver first and these in turn reduce gold ions to gold nanoparticles through a galvanic exchange reaction. The so synthesized silver and gold nanoparticles are easily water dispersible and can withstand addition of salt even at high concentrations. It is shown that the capped protein retains its secondary structure and the helicity to a large extent on the nanoparticles surface and that the protein capping makes the nanoparticles cytocompatible.

Surgical management of ectopic pregnancy in a district general hospital.

The mainstay of management of ectopic pregnancies is laparoscopic surgery. Other treatment options include open laparotomy, methotrexate or expectant approach. Recently the Royal College of Obstetricians and Gynaecologists (RCOG) revised its guidelines regarding management of suspected ectopic pregnancies. We undertook a retrospective study looking at management of ectopic pregnancies over a defined 12-month period (1 October 2003 - 30 September 2004) in a district general hospital to the north of London and compared this with the recommended RCOG guidelines 2004. Cases of ectopic pregnancy were identified from the theatre, ward log, and cross-referenced with histopathological reports. The case notes of these women were reviewed and data extracted according to a drawn-up questionnaire. A total of 64 cases met the diagnostic criteria and were included in the study. Nine of the 64 cases were haemodynamically unstable and seven underwent rapid laparotomy. All of the stable 55 cases underwent laparoscopy, which was converted to open laparotomy in 13 cases (23.6%). Three patients were treated with methotrexate all of whom had been previously managed surgically. The majority of cases of ectopic pregnancy were managed according to the RCOG recommendations. Further changes in practice will be required to incorporate expectant and primary medical management as proposed by the recent guidelines (RCOG 2004). This study reveals progress achieved in management of ectopic pregnancies in UK with the introduction of RCOG guidelines 1999.

Treatment of spentwash using chemically modified bagasse and colour removal studies.

Studies were carried out on derivatisation of bagasse into an ion exchange material and application of this chemically modified bagasse in the treatment of distillery wastewater. It was found that CHPTAC bagasse with HCl treatment and DEAE-bagasse in its free base form were most effective in colour removal and the mechanism of colour removal indicated significant contribution of both, the conventional ion exchange and the chemical sorption.

Prospective blinded trial of a fecal antigen test for the detection of Helicobacter pylori infection.

OBJECTIVE: We prospectively studied an FDA-approved stool test for the diagnosis of Helicobacter pylori infection based on the detection of antigens shed in stool. METHODS: We studied 108 patients undergoing endoscopy. Stool samples were collected on the day of the endoscopy and read in a blinded manner by a technician who was unaware of the findings of the endoscopy. The results of stool testing were compared to those of the rapid urease test (Pyloritek). RESULTS: There were 51 patients infected with H. pylori by rapid urease testing and 57 who were not. The sensitivity of the stool test was 86% (95% confidence interval: 77-96%), the specificity was 91% (81-97%), with a positive predictive value of 89% (77-96%) and a negative predictive value of 88% (81-97%). The likelihood ratio for a positive test was 10.18 and the likelihood ratio for a negative test was 0.11. CONCLUSIONS: The stool test was sensitive and specific for the detection of H. pylori in a U.S. population.

Identification of a novel penicillin-binding protein from Helicobacter pylori.

The Helicobacter pylori genome encodes four penicillin-binding proteins (PBPs). PBPs 1, 2, and 3 exhibit similarities to known PBPs. The sequence of PBP 4 is unique in that it displays a novel combination of two highly conserved PBP motifs and an absence of a third motif. Expression of PBP 4, but not PBP 1, 2, or 3, is significantly increased during mid- to late-log-phase growth.

Identification of virulence genes of Helicobacter pylori by random insertion mutagenesis.

The complete genome of the gram-negative bacterial pathogen Helicobacter pylori, an important etiological agent of gastroduodenal disease in humans, has recently been published. This sequence revealed that the putative products of roughly one-third of the open reading frames (ORFs) have no significant homology to any known proteins. To be able to analyze the functions of all ORFs, we constructed an integration plasmid for H. pylori and used it to generate a random mutant library in this organism. This integration plasmid, designated pBCalpha3, integrated randomly into the chromosome of H. pylori. To test the capacity of this library to identify virulence genes, subsets of this library were screened for urease-negative mutants and for nonmotile mutants. Three urease-negative mutants in a subset of 1,251 mutants (0.25%) and 5 nonmotile mutants in a subset of 180 mutants (2.7%) were identified. Analysis of the disrupted ORFs in the urease-negative mutants revealed that two had disruptions of genes of the urease locus, ureB and ureI, and the third had a disruption of a unrelated gene; a homologue of deaD, which encodes an RNA helicase. Analysis of the disrupted ORFs in the nonmotile mutants revealed one ORF encoding a homologue of the paralyzed flagellar protein, previously shown to be involved in motility in Campylobacter jejuni. The other four ORFs have not been implicated in motility before. Based on these data, we concluded that we have generated a random insertion library in H. pylori that allows for the functional identification of genes in H. pylori.

Unsedated transnasal EGD: an alternative approach to conventional esophagogastroduodenoscopy for documenting Helicobacter pylori eradication.

BACKGROUND: The aim of this study was to assess the yield of antral biopsies performed via unsedated transnasal esophagogastroduodenoscopy, a technique that does not require conscious sedation with its concomitant costs and complications, for documentation of Helicobacter pylori eradication. METHODS: Nineteen patients who were previously CLO test positive on conventional esophagogastroduodenoscopy and subsequently treated for H pylori infection were enrolled. The subjects had not received antibiotic therapy in the prior month and had no prior gastric surgery. By using a GIF-N30 fiberoptic endoscope and a tiny cup biopsy forceps (1.8 mm diameter), unsedated transnasal endoscopy was performed and antral biopsy specimens were taken for a CLO test, histologic analysis (Dieterle stain), and tissue culture. On the same day, the subjects underwent a carbon 13-labeled area urea breath test. All subjects completed a visual analog scale, rating the acceptability of the unsedated transnasal examination and the previous sedated conventional esophagogastroduodenoscopy. RESULTS: There was no statistically significant difference between the results of the CLO tests (5/19 positive) versus the 13C-urea breath test (4/19 positive) (p = 0.96), the CLO tests versus histologic findings (5/19 positive) (p = 0.71), or the 13C-urea breath test versus histologic findings (p = 0.96). All tissue culture results were negative. The overall acceptability of unsedated transnasal esophagogastroduodenoscopy was similar to that of sedated conventional esophagogastroduodenoscopy. CONCLUSION: Unsedated transnasal esophagogastroduodenoscopy, a technique that eliminates the costs and complications associated with conscious sedation, is a feasible and accurate alternative to conventional esophagogastroduodenoscopy when documentation of H pylori eradication and confirmation of gastric ulcer healing are both indicated.