Frequent L1 retrotranspositions originating from TTC28 in colorectal cancer

L1 element retrotranspositions have been found to alter expression of genes neighboring the insertion sites, potentially involving them in tumorigenesis and tumor progression. In colorectal cancer (CRC), L1 insertions have been found to target genes with a role in tumorigenesis. Structural changes such as L1 insertions are identifiable by whole genome sequencing (WGS). In this study, we observed frequent somatic L1 retrotranspositions originating from TTC28 using deep coverage WGS data from 92 CRC tumor-normal sample pairs. In two cases the event had targeted NOVA1 gene (p=0.025). In addition, a germline retrotransposition event from TTC28 to GABRA4 was found to be a common polymorphism in the Finnish population. Thus while some events may be tumorigenic, others are likely to be neutral. Our data contradict a recent study where a similar signal in TTC28 was interpreted as a common inactivating translocation. While much work remains to be performed to understand the biological significance of retrotranspositions in cancer, accurate identification of these events is a prerequisite for success.     

Cancer patients' views and experiences of participation in care and decision making

The purpose of this study was to explore the views and experiences of adult cancer patients about patient participation in care and decision making and the preconditions for this participation. The data were collected by means of focused interviews; in addition the patients completed depression and problem-solving instruments. The sample comprised 34 cancer patients from the haematological and oncological wards of one university hospital in Finland. The results revealed considerable variation in the patients' views on their participation in care and decision making. Some of the patients understood participation either in terms of contributing to the decision making or in terms of expressing their views on treatment options. Some considered that their participation in care was impossible. Patient participation in care and decision making was promoted by good health, access to information, assertiveness, good interactive relationships with nurses and physicians, and encouragement by nurses and physicians to participate. Factors restricting such patient participation were poor health, ignorance, anxiety, age, time pressures of staff, lack of time, high staff turnover and poor interactive relationships. With regard to participation in medical decision making, the patients were divided into three groups: (1) active participants (n = 7), (2) patients giving active consent (n = 9), and (3) patients giving passive consent to medical decisions (n = 18).     

Prevalence of sleep apnea syndrome in lone atrial fibrillation: a case-control study

BACKGROUND: According to several studies, obstructive sleep apnea predisposes to cardiac arrhythmias, but the prevalence of sleep apnea in specific arrhythmias has not been determined. Our case-control study assesses prevalence of sleep apnea syndrome (SAS) in lone atrial fibrillation (AF). METHODS: Patients with AF (n = 59; 48 men and 11 women; mean age, 59 years; age range, 25 to 84 years) without evident cardiovascular diseases, and their 56 gender-matched, age-matched, and cardiovascular morbidity-matched community control subjects underwent an overnight sleep study. RESULTS: Prevalence of SAS in the AF group was 32%, which did not differ from that in control subjects (29%, p = 0.67). In men, mean neck circumference was higher in the AF group (40.9 cm vs 39.5 cm, p = 0.01) than in control subjects. In men, after adjusting for body mass index and waist circumference, neck circumference was independently related to AF, with an odds ratio (OR) of 1.8 (95% confidence interval, 1.3 to 2.5) per 1-cm increase, and an OR of 5.2 (95% confidence interval, 1.6 to 17.0) for values > 40 cm. Compared to control subjects, the AF group reported more daily/almost-daily tiredness (29% vs 4%, p < 0.001), daily/almost-daily sleepiness (27% vs 7%, p = 0.005), and nightly/almost-nightly breathing pauses during sleep (12% vs 2%, p = 0.03). CONCLUSIONS: SAS seems to be common in lone AF. Nevertheless, we could not show SAS to be more common in patients with AF than in gender-matched, age-matched, and cardiovascular morbidity-matched community control subjects. Compared to control subjects, men with AF seem to have thicker necks, and patients with lone AF report more daytime tiredness, daytime sleepiness, and breathing pauses during sleep.     

Value of serial P wave changes in indicating left heart failure in myocardial infarction

In order to evaluate ventricular failure in acute myocardial infarction, electrocardiographic left atrial overloading was correlated to several simultaneous clinical and radiological signs of left ventricular dysfunction in 200 consecutive patients. Analyses were made at three time periods after infarction. Left atrial overloading, measured by P terminal force, was significantly associated with the signs of left ventricular dysfunction, though in this unselected series of infarctions the prevalence of abnormal values was not high (46%). This finding is to be considered rather as a contributory sign than as a diagnostic one in the entire clinical picture. In an individual patient, however, conspicuous serial changes are helpful in indicating the direction of course of the haemodynamic disorder. The prognostic value of the P terminal force was found to be significant.     

Calcium channel antagonism reduces exercise-induced ventricular arrhythmias in catecholaminergic polymorphic ventricular tachycardia patients with RyR2 mutations

Calcium channel antagonism in RyR2 defects. INTRODUCTION: Recently, gain-of-function mutations of cardiac ryanodine receptor RyR2 gene have been identified as a cause of familial or catecholaminergic polymorphic ventricular tachycardia. We examined the influence of the calcium channel blockers, verapamil and magnesium, on exercise-induced ventricular arrhythmias in patients with RyR2 mutations. METHODS AND RESULTS: Six molecularly defined catecholaminergic polymorphic ventricular tachycardia patients, all carrying a RyR2 mutation and on beta-adrenergic blocker therapy, underwent exercise stress test four times: at baseline, after verapamil and magnesium sulphate infusions, and finally, without interventions. The number of isolated and successive premature ventricular complexes during exercise ranged from 40 to 374 beats (mean 165 beats) at baseline, and was reduced during verapamil by 76+/-17% (P<0.05). Premature ventricular complexes appeared later and at higher heart rate during verapamil than at baseline (119+/-21 vs. 127+/-27 min-1, P<0.05). Magnesium did not inhibit the arrhythmias. Results in the fourth exercise stress test without interventions were similar to those in the first baseline study. CONCLUSIONS: This study provides the first in vivo demonstration that a calcium channel antagonist, verapamil, can suppress premature ventricular complexes and nonsustained ventricular salvoes in catecholaminergic polymorphic ventricular tachycardia caused by RyR2 mutations. Modifying the abnormal calcium handling by calcium antagonists might have therapeutic value.     

Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease

Alzheimer's disease (AD) is an age-related disorder characterized by deposition of amyloid beta-peptide (Abeta) and degeneration of neurons in brain regions such as the hippocampus, resulting in progressive cognitive dysfunction. The pathogenesis of AD is tightly linked to Abeta deposition and oxidative stress, but it remains unclear as to how these factors result in neuronal dysfunction and death. We report alterations in sphingolipid and cholesterol metabolism during normal brain aging and in the brains of AD patients that result in accumulation of long-chain ceramides and cholesterol. Membrane-associated oxidative stress occurs in association with the lipid alterations, and exposure of hippocampal neurons to Abeta induces membrane oxidative stress and the accumulation of ceramide species and cholesterol. Treatment of neurons with alpha-tocopherol or an inhibitor of sphingomyelin synthesis prevents accumulation of ceramides and cholesterol and protects them against death induced by Abeta. Our findings suggest a sequence of events in the pathogenesis of AD in which Abeta induces membrane-associated oxidative stress, resulting in perturbed ceramide and cholesterol metabolism which, in turn, triggers a neurodegenerative cascade that leads to clinical disease.     

A fragment of the HMGN2 protein homes to the nuclei of tumor cells and tumor endothelial cells in vivo

We used a screening procedure to identify protein domains from phage-displayed cDNA libraries that bind both to bone marrow endothelial progenitor cells and tumor vasculature. Screening phage for binding of progenitor cell-enriched bone marrow cells in vitro, and for homing to HL-60 human leukemia cell xenograft tumors in vivo, yielded a cDNA fragment that encodes an N-terminal fragment of human high mobility group protein 2 (HMGN2, formerly HMG-17). Upon i.v. injection, phage displaying this HMGN2 fragment homed to HL-60 and MDA-MB-435 tumors. Testing of subfragments localized the full binding activity to a 31-aa peptide (F3) in the HMGN2 sequence. Fluorescein-labeled F3 peptide bound to and was internalized by HL-60 cells and human MDA-MB-435 breast cancer cells, appearing initially in the cytoplasm and then in the nuclei of these cells. Fluorescent F3 accumulated in HL-60 and MDA-MB-435 tumors after an i.v. injection, appearing in the nuclei of tumor endothelial cells and tumor cells. Thus, F3 can carry a payload (phage, fluorescein) to a tumor and into the cell nuclei in the tumor. This peptide may be suitable for targeting cytotoxic drugs and gene therapy vectors into tumors.     

Cutting seton for anal fistulas

PURPOSE: Long-term results of cutting seton in the treatment of anal fistulas were studied. METHODS: Of the 44 patients with anal fistulas, mainly of the high variety, managed with this method, 35 (25 men) attended a clinical and manometric follow-up examination on average 70 (range, 28–184) months after operation. Fistula distribution was high transsphincteric (25), low transsphincteric (5), extrasphincteric (3), and suprasphincteric (2). The seton was tightened at one-week to two-week intervals to achieve gradual sphincter division. RESULTS: Time required to achieve complete fistula healing ranged from 37 to 557 (mean, 151) days. Two (6 percent) of the 35 patients reexamined had recurrence of fistula and 22 (63 percent) reported symptoms of minor impairment in anal control, which in four patients had existed already before operation. Anal resting pressures were similar for defective and normal control, but other manometric variables were inferior in incontinence, although total squeeze pressure only showed statistically significant difference from normal continence ( P =0.0345). Incontinence was likely associated with hard and gutter-shaped operation scars in the anal canal, but the difference from normal continence was not statistically significant. CONCLUSION: Cutting seton yields fairly good results in regard to cure of fistula, but the risk of anal incontinence, despite its minor degree, seems to be too high to recommend its routine use for all high fistulas. The suprasphincteric fistulas and some extrasphincteric fistulas are difficult to treat otherwise, but especially for high transsphincteric fistulas, other methods of treatment (preferably those in which sphincter division can be avoided and the risk of anal canal deformity and incontinence are minimized) are advocated.No reprints are available.