Allele-specific gene expression patterns in primary leukemic cells reveal regulation of gene expression by CpG site methylation

To identify genes that are regulated by cis-acting functional elements in acute lymphoblastic leukemia (ALL) we determined the allele-specific expression (ASE) levels of 2, 529 genes by genotyping a genome-wide panel of single nucleotide polymorphisms in RNA and DNA from bone marrow and blood samples of 197 children with ALL. Using a reproducible, quantitative genotyping method and stringent criteria for scoring ASE, we found that 16% of the analyzed genes display ASE in multiple ALL cell samples. For most of the genes, the level of ASE varied largely between the samples, from 1.4-fold overexpression of one allele to apparent monoallelic expression. For genes exhibiting ASE, 55% displayed bidirectional ASE in which overexpression of either of the two SNP alleles occurred. For bidirectional ASE we also observed overall higher levels of ASE and correlation with the methylation level of these sites. Our results demonstrate that CpG site methylation is one of the factors that regulates gene expression in ALL cells.     

Hereditary iron and copper deposition: diagnostics, pathogenesis and therapeutics

Hereditary deposition of iron (primary haemochromatosis) or copper (Wilson's disease) are autosomal recessive metabolic disease characterized by progressive liver pathology and subsequent involvement of various other organs. The prevalence of primary haemochromatosis is approximately 0.5%, about 200 times higher than the prevalence of Wilson's disease. The two diseases are characterized by homozygous occurrences of mutations in the HFE gene on chromosome 6 (primary haemochromatosis) and the ATP7B gene on chromosome 13 (Wilson's disease). Unlike most other inherited conditions, these diseases can be successfully treated, emphasizing the importance of early diagnosis. Serum ferritin values, transferrin saturation and genetic analysis are used when diagnosing haemochromatosis. The diagnostics of Wilson's disease depends on the use of urinary copper values, serum ceruloplasmin and liver biopsy. If untreated, both of these genetic diseases result in rapidly progressing multiorgan damage and early death. The key treatment for haemochromatosis is phlebotomy, for Wilson's disease chelation or Zn treatment. Although the present treatments considerably improve the prognosis of patients, they may be inadequate in patients diagnosed so late that extensive body deposits of metal have been developed. The main research needs in this field are to further clarify molecular mechanisms of disease progression and to develop new chelators that are more effective and less toxic than those presently available.     

High-risk hypertrophic cardiomyopathy associated with a novel mutation in cardiac Myosin-binding protein C

Hypertrophic cardiomyopathy is an autosomal dominant inherited disease characterized by ventricular hypertrophy and myofibril disarray. Mutations responsible for hypertrophic cardiomyopathy have been identified in 11 genes that encode for cardiac sarcomere proteins. Traditionally, hypertrophic cardiomyopathy due to mutation of the myosin-binding protein C gene (MYBPC3) has been thought to follow a benign course. We report a family with several members affected by hypertrophic cardiomyopathy in which there was a high incidence of sudden death. Disease was presumably caused by the substitution of cytosine by guanine at nucleotide 269 of MYBPC3 mRNA. This mutation, which has not previously been described, modifies codon 79, which encodes for the incorporation of a tyrosine, and gives rise to a stop codon. The mutation described here appears to confer a higher risk than that previously associated with hypertrophic cardiomyopathy due to MYBPC3 gene mutation.     

Patients' experiences and clinicians' ratings of the quality of outpatient teams in psychiatric care units in Norway

OBJECTIVE: Patients' experiences and satisfaction ratings are increasingly used to evaluate quality of care. This study assessed the extent to which outpatient teams, clinics, and health trusts contributed to patients' experiences and to what extent clinicians' evaluations of quality were related to patients' experiences. METHODS: A questionnaire was mailed to 15,422 outpatients who attended Norwegian clinics in September 2004; 43% responded. Patients' experiences were measured on an 11-item index and three subscales: outcomes, interaction with clinicians, and information. Aggregated responses from clinicians were linked to the data on patients' experiences. Multilevel analyses were used to divide the variance between the different organizational levels and to assess the relationship with clinicians' opinions and individual-level factors. RESULTS: Data were analyzed for 6,570 outpatients within 222 teams derived from 89 outpatient clinics within 33 health trusts. Differences in patients' scores were determined largely at the patient level, with teams accounting for 2% of the total variance and organizational levels of clinics and health trusts not contributing to patients' experiences. Team-level clinician quality scores were not significantly associated with patients' experiences. Better experiences were significantly associated with patients' female gender, older age, better self-perceived health, absence of an inpatient history, longer treatment episodes, frequent consultations, and waiting times perceived as acceptable. CONCLUSIONS: The organizational contributions to patients' experience scores were minimal. Although clinicians' ratings of quality are not a substitute for patients' perceptions of quality, surveys of outpatients' experiences and satisfaction may not be appropriate for cross-sectional comparisons of health care providers.     

Risk factors for mortality in diabetic nephropathy patients accepted for transplantation

BACKGROUND: There is a high incidence of silent coronary artery disease (CAD) in patients with diabetes. We wanted to investigate risk factors for mortality, and especially CAD, in a well-defined cohort of diabetic nephropathy transplant candidates accepted for transplantation. METHODS: From 1999 through 2004, 155 patients underwent work up for living or deceased kidney (KA) or simultaneous pancreas-kidney (SPK) transplantation. The work up included coronary angiography for all patients and 136 were accepted. Mean (SD) age was 50 (12) years, 62% had type 1 diabetes, 73% were males, and 34% were on dialysis. Mean follow-up from time of acceptance for transplantation was 3.6 (1.9) years. RESULTS: Survival of KA transplanted patients was 97% at 1 year, 89% at 3 years, and 76% at 5 years, whereas in SPK patients 100%, 94%, and 90%, respectively (P=0.065). One- and 3- year survival was only 57% and 20% in those remaining wait-listed (P<0.001). In univariate analysis mortality was associated with KA transplantation (hazard ratio [HR]=0.30, P=0.011) and SPK transplantation (HR=0.10, P=0.001), and age (HR=1.04, P=0.014). In multivariable analysis, KA transplantation (HR=0.28, P=0.006), SPK transplantation (HR=0.09, P=0.001), age (HR=1.06, P=0.002), type 2 diabetes (HR=0.14, P=0.003), and duration of diabetes (HR=0.94, P=0.019) were parameters associated with mortality. CONCLUSIONS: The only modifiable risk factor was transplantation with risk reduction up to 90%. CAD was not a risk factor for mortality when medically treated and revascularized according to standard guidelines.     

Trace elements in cerebrospinal fluid and blood from patients with a rare progressive central and peripheral demyelinating disease

A hereditary neurological disease in a family in Norway has been reported recently. The disease, which we refer to as Skogholt's disease, is a demyelinating disorder of both the central and the peripheral nervous system with adult onset. We investigated whether changes in trace element concentrations could play a role in Skogholt's disease. Using high resolution inductively coupled plasma mass spectrometry, we determined 31 elements in cerebrospinal fluid (CSF), blood plasma and whole blood from these patients, multiple sclerosis patients and a control group. More than threefold increased levels of Cu and Fe, and a twofold increase in Zn were found in the CSF of Skogholt patients compared to controls. Several other significant differences in trace element levels were also found. The increased levels of Cu and Fe in CSF may indicate an active role of these metals in the pathogenesis of Skogholt's disease. Apparently, these metal ions are transferred into the CSF through their protein chelation, as raised protein levels were also seen. We suggest that redistribution of metals from transport proteins into vulnerable sites in the central (and peripheral) nervous system may initiate critical lesions.     

Does esophageal atresia influence the mother-infant interaction?

Purpose

Chronic illness in infancy may influence parent-infant interaction. We assessed quality of mother-infant interaction in children with esophageal atresia (EA) and searched for predictors for impaired interaction.

Methods

The study group comprised 37 one-year-old infants with EA born in 1999 to 2002 and their mothers. A comparison group comprised 10 infants with urologic problems without feeding difficulties and their mothers. Parent Child Early Relational Assessment was used to assess mother-child interaction in feeding and play situation. General Health Questionnaire and State Trait Anxiety Inventory were used to assess maternal psychological distress and anxiety.

Results

Many aspects of mother-EA infant interaction showed strength. However, mothers of EA children were compared to control-mothers significantly influenced in their ability to interact and the EA-mothers' “positive affective involvement, sensitivity, and responsiveness” during feeding was in range of concern. Small but significant effect of the mother's feeling of incompetence on their interaction was found.

Conclusion

Mothers' attitude during feeding was negatively influenced in interaction between mother and infant with EA. The results suggest possibility for improvement in mother infant interaction by enhancing mothers' welfare when caring for infants with EA in medical services.     

Are positive surgical margins in radical prostatectomy specimens an independent prognostic marker?

OBJECTIVE: A positive surgical margin (PSM) is considered an adverse prognostic indicator in patients undergoing radical prostatectomy (RP). However, there are discrepancies among studies concerning the effect of PSM on prognosis. In addition, the significance of PSM location and extent is uncertain. The aim of this study was to examine the impact of surgical margin status on serum prostate-specific antigen (sPSA) relapse in men consecutively receiving RP in a non-screened population. MATERIAL AND METHODS: In total, 219 prostatectomy specimens were examined microscopically. The mean follow-up time was 62 months (range 6-121 months). Tumour grade (Gleason score), pathological tumour stage and tumour involvement of the surgical margins were recorded. The 71 specimens with one or more PSM were re-examined with regard to location, number of locations and total linear extent of PSM. Kaplan-Meier plots and Cox proportional hazards regression were used in the univariate analyses. Multivariate analyses controlling for the known preoperative sPSA, pathological stage and Gleason score were also performed, using Cox proportional hazards regression. RESULTS: In the univariate analyses, PSM without regard to location, PSM at the anterior prostate or at the apex, PSM at three or more locations and linear extent of PSM > or =6mm were associated with a statistically significant higher hazard ratio of PSA relapse. However, none of these variables remained statistically significant when controlling for the known risk factors. CONCLUSIONS: In this non-screened prostate cancer population PSM status (linear extent, location and number of locations) had an impact on postoperative sPSA recurrence. In multivariate analyses PSM showed a strong trend (p approximately 0.06) towards having an independent statistically significant negative influence on the risk of PSA relapse following RP.     

Incidence,causes, and management of failed awake fibreoptic intubation—A retrospective study of 833 procedures

Awake fibreoptic intubation has been considered a gold standard in the management of the difficult airway. However, failure may cause critical situations. The aim of this study was to investigate the incidence and causes of failed awake fibreoptic intubation at a tertiary care hospital. The study was conducted at St. Olav University Hospital in Trondheim, Norway. Problems occurring during anaesthesia are routinely recorded in the electronic anaesthesia information system (Picis Clinical Solutions Inc.), including difficult intubations. We applied text search on all anaesthesia records between 2011 and 2021 and identified 833 awake fibreoptic intubations. The anaesthesia records were examined to identify failed awake fibreoptic intubations, the cause of failure and how the airway ultimately was secured. Among 233,938 patients who received anaesthesia, 90,397 received tracheal intubation and 833 received awake fibreoptic intubation. Twenty-nine of the procedures failed. In nine patients the failure caused loss of airway control with desaturation and hypoventilation. The major causes of failure were dislodged tube after induction of general anaesthesia (n = 8), patient distress (n = 5), tube not able to pass (n = 5), and airway bleeding (n = 3). The situations were primarily solved using direct laryngoscopy, with or without bougie, or with video laryngoscopy. Tracheostomy was performed in four patients. Awake fibreoptic intubation failed in 3.5% of patients, most often due to dislocation, problems passing the tracheal tube, or patient discomfort. The failure rate was higher than in previous studies.