Tailoring heated intraperitoneal mitomycin C for peritoneal metastases originating from colorectal carcinoma: a translational approach to improve survival.

BACKGROUND: Patients with peritoneal metastases (PMs) originating from colorectal carcinoma (CRC) are curatively treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC). We aim to improve patient selection for HIPEC by predicting MMC sensitivity. METHODS: The MMC sensitivity was determined for 12 CRC cell lines and correlated to mRNA expression of 37 genes related to the Fanconi anaemia (FA)-BRCA pathway, ATM-ATR pathway and enzymatic activation of MMC. Functionality of the FA-BRCA pathway in cell lines was assessed using a chromosomal breakage assay and western blot for key protein FANCD2. Bloom syndrome protein (BLM) was further analysed by staining for the corresponding protein with immunohistochemistry (IHC) on both CRC cell lines (n=12) and patient material (n=20). RESULTS: High sensitivity correlated with a low BLM (P=0.01) and BRCA2 (P=0.02) at mRNA expression level. However, FA-BRCA pathway functionality demonstrated no correlation to MMC sensitivity. In cell lines, weak intensity staining of BLM by IHC correlated to high sensitivity (P=0.04) to MMC. Low BLM protein expression was significantly associated with an improved survival in patients after CRS and HIPEC (P=0.04). CONCLUSIONS: Low BLM levels are associated with high MMC sensitivity and an improved survival after HIPEC.

Accuracy of tympanic and infrared skin thermometers in children.

BACKGROUND: Rectal measurement is considered a gold standard in many healthcare systems for body temperature measurement in children. Although this method has several disadvantages, an ideal alternative thermometer has not yet been introduced. However tympanic and infrared skin thermometers are potential alternatives. METHODS: A prospective cohort study was performed including 100 children between 0 and 18 years of age admitted to the general paediatric ward of Spaarne Hospital in The Netherlands between January and March 2009. The objectives of this study are to evaluate the accuracy of tympanic and two types of infrared skin thermometers (Beurer and Thermofocus) compared to rectal measurement and furthermore to evaluate the influence of different variables on temperature measurements. RESULTS: Compared to rectal measurement (37.56°C), the mean temperatures of the tympanic (37.29°C), Beurer (36.79°C) and Thermofocus (37.30°C) thermometers differed significantly (p<0.001). Mean and SD of differences between rectal temperature and temperature measured with these alternative devices varied significantly (p<0.001). Sensitivity, specificity, positive and negative predictive values for detecting rectal fever measured with the tympanic, Beurer and Thermofocus thermometers are unacceptable, especially for the Beurer thermometer. This difference in temperature between rectal and the alternative thermometers remained after stratification on gender, age, skin colour and otoscopic abnormalities. CONCLUSIONS: In this study the authors demonstrated that the tympanic, Beurer and Thermofocus thermometers cannot reliably predict rectal temperature. Therefore the authors do not advise replacement of rectal measurement as the gold standard for detecting fever in children by one of these devices. When rectal measurement is not used, the infrared skin thermometers appear to perform less well than tympanic measurements.

Nephrotoxic effects of iodixanol and iopromide in patients with abnormal renal function receiving N-acetylcysteine and hydration before coronary angiography and intervention: a randomized trial.

BACKGROUND: The use of contrast agents during coronary intervention can result in nephropathy, particularly in patients with renal dysfunction. We aimed to determine whether the use of iso-osmolar iodixanol is less nephrotoxic than that of low-osmolar iopromide when patients are adequately prehydrated and have received N-acetylcysteine. METHODS: We conducted a randomized, double-blind, multicentre study of patients with impaired renal function undergoing a coronary interventional procedure. Primary end-point was the incidence of contrast-induced nephropathy (CIN) on day 2, defined as an increase in serum creatinine concentration of > or =44 micromol/L (0.5 mg/dL) or by a relative increase of > or =25% from baseline. Secondary end-points included peak increase in serum creatinine between baseline and day 7. RESULTS: Of 191 patients recruited, 15% (95% CI: 8-22) of the patients receiving iopromide and 12% (95% CI: 5-19) of the patients receiving iodixanol developed CIN (95% CI of the difference: 13 to -7, P = 0.56). When including peak serum creatinine on day 7, CIN developed in 23% of patients receiving iopromide and in 27% of patients receiving iodixanol (95% CI of the difference: 8 to -16, P = 0.48). The peak increase in serum creatinine concentration at day 7 was similar in both groups (patients receiving iopromide, 18.4 +/- 24.4 micromol/L, vs patients receiving iodixanol, 21.9 +/- 24.2 micromol/L; P = 0.33). CONCLUSION: There remains a high incidence of CIN despite prehydration and routine use of N-acetylcysteine in patients with pre-existing renal dysfunction undergoing coronary interventional procedures. Although our study is underpowered, iodixanol was not associated with a statistically significant lower incidence of CIN when compared with iopromide.

[Outbreak of coxsackievirus infection in children]. / Uitbraak van coxsackievirusinfectie bij kinderen.

During the summer of 2006 in the paediatric ward of the Spaarne Hospital in Hoofddorp, the Netherlands, a large number of children were admitted with a coxsackievirus type-B infection, one of the enteroviruses. A total of 27 children were diagnosed with this virus. Patient A, a one-month-old boy, was admitted with fever. The spinal fluid showed a high leukocyte count. He was treated with amoxicillin, ceftriaxon and acyclovir, and recovered rapidly. The spinal fluid culture was positive for coxsackievirus type B5. Patient B, a 3-year-old girl, presented with attacks of abdominal pain and groaning respiration. Infection parameters were mildly elevated. The chest X-ray was normal. She was admitted for observation and recovered spontaneously. Viral faeces culture revealed coxsackievirus type B4. Rapid recognition of an enterovirus infection is important to prevent unnecessary diagnostic and therapeutic interventions. PCR is a diagnostic technique of great importance.

[Varicella: previously healthy children sometimes develop complications]. / Waterpokken: soms complicaties bij voorheen gezonde kinderen.

Three healthy boys, 3.5, 5 and 1.5 years of age, were admitted to hospital with a severe bacterial skin infection, cerebellar ataxia, and pneumonia, respectively, one week after the onset of varicella. They recovered completely after treatment. Studies in Europe report complications from varicella in 2.5% of healthy children. Most of these are neurological complications and secondary bacterial infections of skin and soft tissue. Last year, a European consensus was published that recommended that all healthy children be vaccinated against chickenpox. In The Netherlands, routine varicella zoster virus (VZV) vaccination has not (yet) been implemented. We propose a new discussion on the possible inclusion of VZV vaccination in the national vaccination programme.

Reducing overclaiming in needs assessment studies. An experimental comparison.

A randomized experiment investigated the effect of various instructional sets on reducing agency awareness overclaiming, that is, claiming knowledge of fictitious agencies. As predicted, respondents who were warned that the list contained fake agencies exhibited less agency awareness overclaiming than respondents who were not warned. However, providing respondents a memory retrieval strategy had no effect on agency awareness overclaiming. A multivariate model, which included demographic variables, response style variables, and knowledge variables, explained 40% of the variance of agency awareness overclaiming.

Should disability items in the census be used for planning services for elders?

PURPOSE: The main goal of this study was to determine how well the disability questions of both the 1990 and 2000 Census correlated with a standard measure of disability. If the census questions were to correlate moderately well with a standard measure of disability, then Area Agencies on Aging (AAA) and other organizations would be able to use census information in estimating service needs for their catchment (service) area. DESIGN AND METHODS: Questionnaires containing both the census disability questions and a standard measure of disability were mailed to 4,508 older adults; 1,514 completed surveys were returned. In order to assess reliability, 472 of the respondents who completed the mail survey were reinterviewed by phone. All three disability measures were collapsed into the following three categories: no needs, instrumental activities of daily living (IADL) needs only, and activities of daily living (ADL) needs. RESULTS: All three disability measures exhibited moderate to good test-retest reliability. Using a standard measure of disability as the criterion, validity for the 1990 Census measure was quite low (Kappas of approximately 0.35). Validity for the 2000 Census measure was moderate to good (Kappas of approximately 0.60). IMPLICATIONS: These results suggest that the 2000 Census disability questions may be sufficiently valid for planning purposes. However, additional research with more representative samples of older adults is needed.

Spectrum of mutations in the Fanconi anaemia group G gene, FANCG/XRCC9.

FANCG was the third Faconi anaemia gene identified and proved to be identical to the previously cloned XRCC9 gene. We present the pathogenic mutations and sequence variants we have so far identified in a panel of FA-G patients. Mutation screening was performed by PCR, single strand conformational polymorphism analysis and protein truncation tests. Altogether 18 mutations have been determined in 20 families - 97% of all expected mutant alleles. All mutation types have been found, with the exception of large deletions, the large majority is predicted to lead to shortened proteins. One stop codon mutation, E105X, has been found in several German patients and this founder mutation accounts for 44% of the mutant FANCG alleles in German FA-G patients. Comparison of clinical phenotypes shows that patients homozygous for this mutation have an earlier onset of the haematological disorder than most other FA-G patients. The mouse Fancg sequence was established in order to evaluate missense mutations. A putative missense mutation, L71P, in a possible leucine zipper motif may affect FANCG binding of FANCA and seems to be associated with a milder clinical phenotype.

The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG.

Fanconi anemia (FA) is a chromosomal instability syndrome associated with a strong predisposition to cancer, particularly acute myeloid leukemia and squamous cell carcinoma. At the cellular level, FA is characterized by spontaneous chromosomal breakage and a unique hypersensitivity to DNA cross-linking agents. Complementation analysis has indicated that at least seven distinct genes are involved in the pathogenesis of FA. Despite the identification of four of these genes (FANCA, FANCC, FANCF and FANCG), the nature of the 'FA pathway' has remained enigmatic, as the FA proteins lack sequence homologies or motifs that could point to a molecular function. To further define this pathway, we studied the subcellular localizations and mutual interactions of the FA proteins, including the recently identified FANCF protein, in human lymphoblasts. FANCF was found predominantly in the nucleus, where it complexes with FANCA, FANCC and FANCG. These interactions were detected in wild-type and FA-D lymphoblasts, but not in lymphoblasts of other FA complementation groups. This implies that each of the FA proteins, except FANCD, is required for these complexes to form. Similarly, we show that the interaction between FANCA and FANCC is restricted to wild-type and FA-D cells. Furthermore, we document the subcellular localization of FANCA and the FANCA/FANCG complex in all FA complementation groups. Our results, along with published data, culminate in a model in which a multi-protein FA complex serves a nuclear function to maintain genomic integrity.

Isolation of a cDNA representing the Fanconi anemia complementation group E gene.

Fanconi anemia (FA) is an autosomal recessive chromosomal instability syndrome with at least seven different complementation groups. Four FA genes (FANCA, FANCC, FANCF, and FANCG) have been identified, and two other FA genes (FANCD and FANCE) have been mapped. Here we report the identification, by complementation cloning, of the gene mutated in FA complementation group E (FANCE). FANCE has 10 exons and encodes a novel 536-amino acid protein with two potential nuclear localization signals.

Estimation of individual genetic effects from binary observations on relatives applied to a family history of respiratory illnesses and chronic lung disease of newborns.

This paper considers methods for estimating the relationship between a binary response Y and the genetic effects responsible for a second binary trait Z. The responses Y are observed only for target individuals, and the responses Z are observed only for the relatives of these targets. The analysis consists of two parts. The first part concerns the analysis of the family data Z and the second part estimates the relation between the genetic effects and Y. For the family data, a generalized linear mixed model with a logit link and Gaussian genetic (random) effects is used. Estimates of the variances of the genetic effects are obtained by using a pseudo-profile log-likelihood method. Estimation of the log likelihood involves averaging over n-dimensional normal distributions, which is done by importance sampling. The methods used in the second part are straightforward. The methods are applied to a data set containing chronic lung disease (CLDN) responses of newborns and asthma (AS), allergy (AL), chronic bronchitis (CB) and eczema (EC) responses observed for the relatives of these newborns. The clinical question is whether genetic effects of AS, AL, CB, and EC have an effect on the risk for CLDN. It can be concluded that for AS, AL, CB, and EC, the influence of genetic effects is significant. However, these genetic predispositions have no significant effect on CLDN.

The Dartmouth Assertive Community Treatment Scale (DACTS). A generalizability study.

Generalizability theory was used to assess the reliability of the Dartmouth Assertive Community Treatment Scale (DACTS), which was developed to assess treatment reliability to assertive community treatment (ACT). Program staff and local evaluators who were participating in a national demonstration program to serve homeless mentally ill clients provided data. The total scale score for the DACTS demonstrated acceptable internal consistency and interrater reliability. Although the stability of the total DACTS score was quite low, many items on the DACTS were quite stable. The generalizability analyses provide additional detail on the effects of site, occasion, and site by occasion interactions on the reliability of the DACTS.

Fanconi anemia A due to a novel frameshift mutation in hotspot motifs: lack of FANCA protein.

Homozygosity for a frameshift mutation at codon 1213 of FANCA gene was identified in a Turkish patient. Immunoprecipitation-western blot analysis showed the complete absence of the FANCA protein band. This novel mutation, a deletion of T at position 3639 in exon 37 (3639delT), is responsible for the disease and causes premature termination of translation 32 aa downstream. The deletion is (i) the T residue of 2 overlapping TGAGGC and CCTG hot spot motifs, (ii) flanked by several direct repeats, (iii) surrounded by the highly GC rich region that have frequently been identified at the site of human DNA deletions. The patient is the third living child of a first degree cousin marriage. The major abnormalities of the patient at the age of 6 months were growth retardation, microcephaly, hypoplastic right thumb, distal displacements of both thumbs and pelvic displacement of left kidney. Hematological presentation of the disease started before the age of 4 years.

Do consumers who have a choice of treatment have better outcomes?

This study used a non-equivalent control group design to investigate the effect of consumer choice of treatment on both process and outcome variables. All study participants suffered from severe mental illness, were homeless at baseline, and were enrolled in a modified Assertive Community Treatment (ACT) program. Consumers in the choice condition had selected the ACT program from a menu of five treatment programs; clients in the no-choice condition were simply assigned to the ACT program by an intake worker. Results found that consumers in the choice condition visited the ACT staff at their offices more than consumers in the no-choice condition, but there were no significant differences between groups on the other treatment process variables. Although consumers in the choice condition increased their income more than consumers in the no-choice condition, there were no significant differences between groups on the other outcome variables (stable housing, psychotic symptoms, depression, and substance abuse).

Functional residual capacity and static compliance during the first year in preterm infants treated with surfactant.

Individual lung development during the first year of life was studied in surfactant treated preterm infants with respiratory distress syndrome (RDS) and healthy controls, as well as in a group who subsequently developed chronic lung disease of the newborn (CLDN). Lung development was assessed from functional residual capacity (FRC) and compliance of the respiratory system (Crs). Twenty-one infants with RDS after preterm birth received surfactant treatment. Six of them developed CLDN. Eighteen preterm infants without RDS served as a control group. Lung function measurements were performed at term age and 4, 8, and 12 months afterwards. FRC was obtained by means of the closed-system helium dilution technique whereas static Crs was obtained by means of the weighted spirometer technique. At term age, FRC was lower in the CLDN group compared with uncomplicated RDS and controls (p < 0.05). No significant differences between groups were found in the development of FRC during the first year of life (p = 0.4). No differences were found in Crs during the first year of life in surfactant treated infants who recovered from uncomplicated RDS and the control group. However, lower values were found in the CLDN group (p < 0.05). We conclude that surfactant treated infants without CLDN have similar lung development during the first year of life as control preterm infants.

Aberrant Fanconi anaemia protein profiles in acute myeloid leukaemia cells.

Fanconi anaemia (FA) is an autosomal recessive disease strongly predisposing to bone marrow failure and acute myeloid leukaemia (AML). Four FA genes, corresponding to complementation groups A, C, F and G, have been cloned, but the molecular functions of the corresponding proteins are unknown. The high risk of AML in FA patients suggests that the 'FA pathway' helps to prevent AML in non-FA individuals. We examined 10 AML cell lines, as well as primary cells from 15 AML patients representing the French-American-British subclasses M1-M5a, for possible deficiencies in the 'FA pathway'. Cellular lysates were analysed for the presence of the FA proteins FANCA, FANCC, FANCF and FANCG, as well as the complexes reported to be formed between these proteins, using immunoprecipitation and Western blot analysis. Aberrant protein profiles were observed in five of the 10 cell lines and in 11 of the 15 primary AML samples. Aberrations, that included absence or reduced presence of FA proteins and/or their complexes, were noted in the subclasses M1-M4, but not in M5a (n = 3). Our results suggest that a significant proportion of general AML is characterized by a disturbance of the 'FA pathway' that may represent an early event in the development of this type of leukaemia.

Understanding and controlling response bias in needs assessment studies.

This study demonstrated that estimates of agency awareness in the typical needs assessment study are probably inflated by a response bias labeled "agency awareness overclaming." Overclaimers (respondents who reported being aware of fictitious agencies) reported being aware of more real agencies than other respondents. Estimates of agency awareness may also be biased, because certain segments of the population were more likely to exhibit agency awareness overclaiming. Age was positively correlated with overclaiming, and African Americans were more likely to exhibit agency awareness overclaiming than Caucasians. General overclaiming was correlated with agency awareness overclaiming, but social desirability and acquiescence were not.