Familial aggregation and heterogeneity of non-Hodgkin lymphoma in population-based samples.

The importance of genetic factors in the etiology of non-Hodgkin lymphoma (NHL) is suggested by case-control and cohort studies. Most previous studies have been too small to estimate accurately risks of specific categories of lymphoproliferative malignancies in relatives of NHL cases or to quantify the contribution of NHL case characteristics to familial risk. We have overcome sample size limitations and potential recall bias by using large databases from Sweden and Denmark. Diagnoses of lymphoproliferative malignancies were compared in 70,006 first-degree relatives of 26,089 NHL cases (including 7,432 with subtype information) versus 161,352 first-degree relatives of 58,960 matched controls. Relatives of NHL cases were at significantly increased risk for NHL [relative risk (RR), 1.73; 95% confidence interval (95% CI), 1.39-2.15], Hodgkin lymphoma (RR, 1.41; 95% CI, 1.0-1.97), and nonsignificantly for chronic lymphocytic leukemia (CLL; RR, 1.31; 95% CI, 0.93-1.85). No increased risk was found for multiple myeloma among case relatives. Findings with respect to siblings compared with parents and offspring or with respect to age at diagnosis of proband were inconsistent. In both populations, relatives of cases with an aggressive NHL subtype were at substantially increased risk of NHL (combined RR, 3.56; 95% CI, 1.80-7.02). We conclude that NHL has an important familial component, which is shared with Hodgkin lymphoma and CLL. We estimate that the absolute lifetime risk for a first-degree relative of an NHL case to develop NHL is 3.6% (compared with a population risk of 2.1%) and higher if the index case had an aggressive subtype of NHL.     

Neither one‐time negative screening tests nor negative colposcopy provides absolute reassurance against cervical cancer

A population sample of 10,049 women living in Guanacaste, Costa Rica, was recruited into a natural history of human papillomavirus (HPV) and cervical neoplasia study in 1993–1994. At the enrollment visit, we applied multiple state‐of‐the‐art cervical cancer screening methods to detect prevalent cervical cancer and to prevent subsequent cervical cancers by the timely detection and treatment of precancerous lesions. Women were screened at enrollment with 3 kinds of cytology (often reviewed by more than one pathologist), visual inspection and cervicography. Any positive screening test led to colposcopic referral and biopsy and/or excisional treatment of CIN2 or worse. We retrospectively tested stored specimens with an early HPV test (hybrid capture tube test) and for >40 HPV genotypes using a research PCR assay. We followed women typically 5–7 years and some up to 11 years. Nonetheless, 16 cases of invasive cervical cancer were diagnosed during follow‐up. Six cancer cases were failures at enrollment to detect abnormalities by cytology screening; 3 of the 6 were also negative at enrollment by sensitive HPV DNA testing. Seven cancers represent failures of colposcopy to diagnose cancer or a precancerous lesion in screen‐positive women. Finally, 3 cases arose despite attempted excisional treatment of precancerous lesions. Based on this evidence, we suggest that no current secondary cervical cancer prevention technologies applied once in a previously under‐screened population is likely to be 100% efficacious in preventing incident diagnoses of invasive cervical cancer. © 2009 UICC     

Cellular pharmacology of P-ethoxy antisense oligonucleotides targeted to Bcl-2 in a follicular lymphoma cell line

A P-ethoxy oligonucleotide (oligo), 20 bases long and specific for the translation initiation site of human Bcl-2 mRNA, was incorporated into liposomes to increase its intracellular delivery. This oligo selectively inhibited Bcl-2 protein expression and induced growth inhibition in t(14;18)-positive transformed follicular lymphoma (FL) cell lines. We studied the inhibitory effects of shorter liposomal P-ethoxy oligos (7, 9, 11 or 15 mer) in order to determine the activity of different oligo chain lengths targeted to the same Bcl-2 mRNA. At 12 μM, all the oligos inhibited the growth of a FL cell line. We compared the 7-mer oligo with the 20-mer oligo. The two oligos inhibited Bcl-2 protein expression similarly: 66% and 60% for the 7- and 20-mer, respectively. The uptake and retention of both oligos were also very similar. Our results indicate that the Bcl-2 inhibitory activity is maintained with P-ethoxy antisense oligos ranging from 7 to 20 bases.     

Ability and willingness to pay for family planning services in low resource settings: evidence from an operational research

ObjectiveThis paper establishes levels and patterns of ability and willingness to pay (AWTP) for contraceptives, and associated factors.Study designA three-stage cluster and stratified sampling was applied in selection of enumeration areas, households and individuals in a baseline survey for a 5-year Family planning programme. Multivariable linear and modified Poisson regressions are used to establish factors associated with AWTP.ResultsAbility to pay was higher among men (84%) than women (52%). A high proportion of women (96%) and men (82%) were able to pay at least Ug Shs 1000 ($0.27) for FP services while 93% of women and 83% of men who had never used FP services will in future be able to pay for FP services costed at least Shs 2000 ($0.55). The factors independently associated with AWTP were lower age group (<25 years), residence in urban areas, attainment of higher education level, and higher wealth quintiles.ConclusionAWTP for FP services varied by different measures. Setting the cost of FP services at Shs 1000 ($0.27) will attract almost all women (96%) and most of men (82%). Key determinants of low AWTP include residence in poor regions, being from rural areas and lack of/low education.Implications statement: Private providers should institute price discrimination for FP services by region, gender and socioeconomic levels. More economic empowerment for disadvantaged populations is needed if the country is to realise higher contraceptive uptake. More support for total market approach for FP services needed.     

Functional and Immunological Studies Revealed a Second Superantigen Toxin in Staphylococcal Enterotoxin C Producing Staphylococcus aureus Strains

Staphylococcus aureus is a human and animal pathogen as well as a commensal bacterium. It can be a causative agent of severe, life-threatening infections with high mortality, e.g., toxic shock syndrome, septic shock, and multi-organ failure. S. aureus strains secrete a number of toxins. Exotoxins/enterotoxins are considered important in the pathogenesis of the above-mentioned conditions. Exotoxins, e.g., superantigen toxins, cause uncontrolled and polyclonal T cell activation and unregulated activation of inflammatory cytokines. Here we show the importance of genomic analysis of infectious strains in order to identify disease-causing exotoxins. Further, we show through functional analysis of superantigenic properties of staphylococcal exotoxins that even very small amounts of a putative superantigenic contaminant can have a significant mitogenic effect. The results show expression and production of two distinct staphylococcal exotoxins, SEC and SEL, in several strains from clinical isolates. Antibodies against both toxins are required to neutralise the superantigenic activity of staphylococcal supernatants and purified staphylococcal toxins.     

Including the voice of paediatric patients: Cocreation of an engagement game

BackgroundEngaging patients in health care, research and policy is essential to improving patient‐important health outcomes and the quality of care. Although the importance of patient engagement is increasingly acknowledged, clinicians and researchers still find it difficult to engage patients, especially paediatric patients. To facilitate the engagement of children and adolescents in health care, the aim of this project is to develop an engagement game.MethodsA user‐centred design was used to develop a patient engagement game in three steps: (1) identification of important themes for adolescents regarding their illness, treatment and hospital care, (2) evaluation of the draft version of the game and (3) testing usability in clinical practice. Adolescents (12–18 years) were engaged in all steps of the development process through focus groups, interviews or a workshop. These were audio‐recorded, transcribed verbatim and analysed in MAXQDA.Results(1) The important themes for adolescents (N = 15) were included: visiting the hospital, participating, disease and treatment, social environment, feelings, dealing with staff, acceptation, autonomy, disclosure and chronically ill peers. (2) Then, based on these themes, the engagement game was developed and the draft version was evaluated by 13 adolescents. Based on their feedback, changes were made to the game (e.g., adjusting the images and changing the game rules). (3) Regarding usability, the pilot version was evaluated positively. The game helped adolescents to give their opinion. Based on the feedback of adolescents, some last adjustments (e.g., changing colours and adding a game board) were made, which led to the final version of the game, All Voices Count.ConclusionsWorking together with adolescents, All Voices Count, a patient engagement game was developed. This game provides clinicians with a tool that supports shared decision‐making to address adolescents'' wishes and needs.Patient or Public ContributionPaediatric patients, clinicians, researchers, youth panel of Fonds NutsOhra and patient associations (Patient Alliance for Rare and Genetic Diseases, Dutch Childhood Cancer Organization) were involved in all phases of the development of the patient engagement game—from writing the project plan to the final version of the game.     

Percutaneous Absorption of Nicardipine and Ketorolac in Rhesus Monkeys

Vehicle effects on the percutaneous absorption of nicardipine base, nicardipine hydrochloride, ketorolac acid, and ketorolac tromethamine were determined using the rhesus monkey as an in vivo model for human skin penetration. Vehicles investigated included blends of propylene glycol, trimethylene glycol, ethanol, Azone, Tween 20, water, and long-chain fatty acids. Formulations were prepared such that the compound dose, application area, and percentage saturation of the compound in the vehicle were held constant. Variations in absorption of the compounds were therefore attributable to vehicle effects. Each formulation was applied to three monkeys for a period of 24 hr using 10 Hill Top Chambers. Plasma samples were taken at appropriate intervals for 36 to 48 hr. The results indicated that trimethylene glycol and Tween 20 did not enhance absorption of the test compounds despite claims by other investigators. Azone and ethanol provided moderate enhancement of both the rate and the extent of absorption, while long-chain fatty acids in combination with propylene glycol significantly enhanced penetration. In general, higher fluxes were observed with the more lipophilic compounds nicardipine base and ketorolac acid as compared to the hydrochloride and tromethamine salts.     

Phase I and pharmacologic study of the human DNA methyltransferase antisense oligodeoxynucleotide MG98 given as a 21-day continuous infusion every 4 weeks

Purpose: MG98 is a second generation phosphorothioate antisense oligodeoxynucleotide which is a highly specific inhibitor of translation of the mRNA for human DNA MeTase I (DNMT 1). This phase I study examined the toxicity and pharmacologic profile of MG98 administered as a continuous 21-day intravenous infusion every 4 weeks. Patients and methods: Fourteen patients with solid cancers received a total of 25 cycles of MG98 at doses ranging from 40 to 240 mg/m²/day. Steady-state concentrations of MG98 were measured as were several pharmacodynamic assessments including mRNA of the target gene, DNMT1, in PBMC. In addition, other potential surrogate markers of drug effects were explored, including hemoglobin F, Vimentin and GADD45. Results: Dose limiting effects were drug-related reversible transaminase elevation and fatigue seen at doses of 240, 200 and 160 mg/m²/day. The dose level of 80 mg/m²/day was felt to be safe and tolerable when delivered on this schedule. No evidence of antitumor activity was observed. Although pharmacokinetic analysis revealed that at the higher dose levels, mean Css values of MG98 were approximately 10-fold times the IC₅₀ values associated with target inhibition in vitro, the extent of MG98 penetration into target tumors in this trial was not determined. No consistent, dose-related changes in correlative markers including DNMT1 mRNA, hemoglobin F, Vimentin and GADD45, were observed. Conclusions: This schedule of MG98 given as a 21-day continuous intravenous infusion every 4 weeks was poorly tolerated in the highest doses; therefore, further disease-site specific evaluation of the efficacy of this agent will utilize a more favorable, intermittent dosing schedule. Pharmacodynamic evaluations undertaken in an attempt to explore and validate the biological mechanisms of MG98 did not show dose-related effects.