Skin epidermis lacking the c-Myc gene is resistant to Ras-driven tumorigenesis but can reacquire sensitivity upon additional loss of the p21Cip1 gene

The target gene(s) required for Myc-mediated tumorigenesis are still elusive. Here we show that while endogenous c-Myc is surprisingly dispensable for skin homeostasis and TPA-induced hyperplasia, c-Myc-deficient epidermis is resistant to Ras-mediated DMBA/TPAinduced tumorigenesis. This is mechanistically linked to p21(Cip1), which is induced in tumors by the activated Ras-ERK pathway but repressed by c-Myc. Acute elimination of c-Myc in established tumors leads to the up-regulation of p21(Cip1), and epidermis lacking both p21(Cip1) and c-Myc reacquires normal sensitivity to DMBA/TPA-induced tumorigenesis. This identifies c-Myc-mediated repression of p21(Cip1) as a key step for Ras-driven epidermal tumorigenesis.     

Eye movement deficits in schizophrenia

BACKGROUND: Deficits in antisaccade (AS) and smooth pursuit eye movements (SPEM) are promising endophenotypes in genetic studies of schizophrenia. The Icelandic population lends itself ideally to genetic studies due to its ethnic homogeneity and well-documented genealogy. The primary aim of this study was to assess AS and SPEM performance in a large Icelandic sample. Additional aims were to investigate the relationship between AS and SPEM task performance and to assess internal consistency, within-session performance changes and effects of SPEM target velocity on performance. METHOD: Patients with schizophrenia (N = 118) and healthy controls (N = 109) matched for age and gender underwent infrared oculographic assessment of AS and SPEM (at target velocities of 12 degrees , 24 degrees and 36 degrees /s). RESULTS: On the AS task patients displayed significantly more reflexive errors, longer latency, increased intra-individual latency variability, and reduced amplitude gain compared to controls. On the SPEM task, patients had significantly lower velocity gain and more frequent saccades during pursuit at all velocities, but group differences in velocity gain increased with increasing target velocity. Internal consistency of performance was high for all variables in both groups (Cronbach's alpha >0.77 for AS and >0.85 for SPEM) except for AS spatial error in patients (alpha = 0.38). A moderate association was found between AS and SPEM performance. By and large, patients and controls showed similar patterns of systematic within-session performance changes. CONCLUSIONS: Our findings confirm the existence of robust eye movement deficits in schizophrenia in a large sample. These measures may be studied as endophenotypes in future studies of potential schizophrenia risk genotypes in the genetically homogenous Icelandic population.     

Predictors of ongoing implantation in IVF in a good prognosis group of patients

BACKGROUND: The aim of this study was to investigate whether, in a large randomized trial, it is possible to identify specific maternal and/or embryo variables that could independently correlate with ongoing implantation in IVF/ICSI. METHODS: In a Scandinavian study, 661 women were randomized to elective single embryo transfer or double embryo transfer. Women aged <36 years undergoing their first or second IVF cycle and with at least two good quality embryos were eligible. Only one cycle per subject was included. In the present study, cycles with 0 or 100% ongoing implantation (n = 520) were analysed regarding maternal and embryo variables. RESULTS: In this selected study group, the ongoing implantation rate was 195/734 (26.6%). In the univariate analysis, first IVF cycle, conventional IVF as fertilization method and 4-cell embryos showed a statistically higher ongoing implantation rate than did second IVF cycle, ICSI and non-4-cell embryos. In the multivariate analysis the same variables correlated independently to ongoing implantation. In addition, ovarian sensitivity correlated independently to ongoing implantation. CONCLUSION: This information should be used when selecting the number of embryos for transfer with the overall aim to reduce the rate of multiple births while maintaining a satisfactory birth rate.     

c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation

The activity of adult stem cells is essential to replenish mature cells constantly lost due to normal tissue turnover. By a poorly understood mechanism, stem cells are maintained through self-renewal while concomitantly producing differentiated progeny. Here, we provide genetic evidence for an unexpected function of the c-Myc protein in the homeostasis of hematopoietic stem cells (HSCs). Conditional elimination of c-Myc activity in the bone marrow (BM) results in severe cytopenia and accumulation of HSCs in situ. Mutant HSCs self-renew and accumulate due to their failure to initiate normal stem cell differentiation. Impaired differentiation of c-Myc-deficient HSCs is linked to their localization in the differentiation preventative BM niche environment, and correlates with up-regulation of N-cadherin and a number of adhesion receptors, suggesting that release of HSCs from the stem cell niche requires c-Myc activity. Accordingly, enforced c-Myc expression in HSCs represses N-cadherin and integrins leading to loss of self-renewal activity at the expense of differentiation. Endogenous c-Myc is differentially expressed and induced upon differentiation of long-term HSCs. Collectively, our data indicate that c-Myc controls the balance between stem cell self-renewal and differentiation, presumably by regulating the interaction between HSCs and their niche.     

Additive effects of moderate dietary salt reduction and captopril in hypertension

In a randomized, cross-over study 27 patients had diastolic blood pressure of greater than or equal to 96 mmHg during four visits without treatment. Following captopril 25 mg b.i.d. nine patients' blood pressure was less than or equal to 90 mmHg. The remaining 18 were randomized into two treatment modalities, captopril and moderate dietary salt reduction, and captopril and hydrochlorothiazide 25 mg daily. Following a wash-out period the groups crossed over to the alternative treatment. At the end of the control period the average blood pressure was 151/100 +/- 12/6 mmHg recumbent and 140/91 +/- 11/7 standing, following captopril 144/94 +/- 13/5 and 132/92 +/- 12/6, respectively, with low salt diet added to captopril 140/91 +/- 12/6 and 128/89 +/- 11/6 and with hydrochlorothiazide and captopril 133/86 +/- 12/7 and 120/84 +/- 11/7 mmHg supine and erect, respectively. It is concluded that moderate dietary salt reduction, which is easily advised, will significantly potentiate the blood pressure fall following captopril treatment in moderate arterial hypertension.     

Craniofacial skeletal and soft tissue morphology in Icelandic adults

The purpose of the study was to describe the craniofacial characteristics of Icelandic adults on lateral skull cephalograms. The material consisted of 155 (47.8%) males and 169 (52.5%) females. The mean ages were 35.5 and 34.2 years, respectively. Twenty-two skeletal reference points and 11 soft tissue points were digitized and processed by standard methods with the Dentofacial Planner computer software program. The 45 variables calculated were both angular and linear. Two-sample t-tests were used to study the differences between sexes. Mandibular prognathism was significantly greater in males (P < or = 0.05), but the inclination of both the upper and lower jaws was greater in females (P < or = 0.01). Linear measurements were usually larger for males. The lips were less protrusive in males (P < or = 0.01), but the thickness was greater compared with females (P < or = 0.001). The nose was significantly more protrusive in males (P < or = 0.001). When the Icelandic sample was compared with closely related ethnic groups, such as the Swedes and the Danes, it was interesting to note that the Icelanders seem to be more like the Swedes than the Danes.     

Human blastocysts for the development of embryonic stem cells

Establishment of human embryonic stem cells (hES) from surplus human IVF embryos has been successful when both fresh and frozen-thawed cleavage stage embryos have been cultured to the blastocyst stage. This study reports the characteristics of the starting material, the blastocysts, for hES cell lines that were first derived at the University of Gothenburg, Sahlgrenska University Hospital in 1999. Twenty-two hES cell lines were derived by Cellartis AB from 114 blastocysts, giving an overall success rate of 19.3%. The blastocysts from which the hES cell lines were established were of varying morphological quality, both fresh and frozen-thawed. Two techniques of hES establishment were applied, i.e. direct application of the blastocysts on feeder cells or the standard immunosurgery method. It was further found that the efficiency by which frozen-thawed embryos gave rise to new hES cell lines was 3.7 times better than with fresh surplus embryos. These findings suggest that frozen-thawed embryos are superior to fresh surplus human embryos in hES cell establishment, which also avoids specific ethical problems associated with embryo donation in a fresh IVF cycle.     

Hippocampal volume in familial and nonfamilial schizophrenic probands and their unaffected relatives.

BACKGROUND: There is evidence for hippocampal volume loss in schizophrenia, but the etiology of this remains unclear. The aim of our study was to assess the contribution of familial liability and obstetric complications to hippocampal volume reduction in schizophrenia. METHODS: Hippocampal volumes were obtained using stereological methods from magnetic resonance scans performed on 35 schizophrenic probands from multiply affected families and 63 of their unaffected relatives, as well as 31 schizophrenic probands from families with no other affected members, 33 of their unaffected relatives, and 68 control subjects. RESULTS: Probands with schizophrenia, regardless of family history, had significant volume reduction of the left hippocampus. Hippocampal volume was not significantly reduced in either group of relatives. Obstetric complications were associated with left hippocampal volume reduction. CONCLUSIONS: We failed to find evidence that hippocampal volume loss is associated with familial liability to schizophrenia but have confirmed the association between hippocampal volume reduction and exposure to obstetric complications.