In vivo MRI of cancer cell fate at the single-cell level in a mouse model of breast cancer metastasis to the brain.

Metastasis (the spread of cancer from a primary tumor to secondary organs) is responsible for most cancer deaths. The ability to follow the fate of a population of tumor cells over time in an experimental animal would provide a powerful new way to monitor the metastatic process. Here we describe a magnetic resonance imaging (MRI) technique that permits the tracking of breast cancer cells in a mouse model of brain metastasis at the single-cell level. Cancer cells that were injected into the left ventricle of the mouse heart and then delivered to the brain were detectable on MR images. This allowed the visualization of the initial delivery and distribution of cells, as well as the growth of tumors from a subset of these cells within the whole intact brain volume. The ability to follow the metastatic process from the single-cell stage through metastatic growth, and to quantify and monitor the presence of solitary undivided cells will facilitate progress in understanding the mechanisms of brain metastasis and tumor dormancy, and the development of therapeutics to treat this disease.     

Expression of Human Recombination Activating Genes (RAG-1 and RAG-2) in Lymphoma

Two recently discovered genes, the recombination activating genes 1 and 2 (RAG-1 and RAG-2), are necessary to perform variable (V), diversity (D), and joining (J) recombination. They synergistically activate VDJ recombination to generate immunocompetent lymphocytes. Disruption of either gene results in a maturation arrest at a very early B and T cell progenitor stage. Expression and downregulation of RAG's are closely associated with interleukin 7, sIgM and TCR-CD3 complex, respectively. Assessment of RAG mRNA expression is a valuable marker in identifying the genotypic maturation status of leukemias and lymphomas. Persistent RAG expression in otherwise mature lymphoid proliferations may explain puzzling biological and clinical observations such as multiple rearrangements in lymphomas with a mature phenotype. Lack of RAG expression in Hodgkin's disease with abundant Reed-Stern-berg cells is consistent with a mature phenotype of the latter. Availability of a anti-RAG-1 monoclonal antibody in the near future will facilitate RAG analysis of lymphomas.     

Aberrant phenotypes in peripheral T cell lymphomas.

Seventy six peripheral T cell lymphomas were examined immunohistologically to test their reactivity with a panel of monoclonal antibodies against 11 T cell associated antigens (CD1-8, CD27, UCHL1, and the T cell antigen receptor). Sixty two (82%) lymphomas showed aberrant phenotypes, and four main categories were distinguished as follows: (i) lack of one or several pan-T cell antigens (49, 64% of the cases); (ii) loss of both the CD4 and CD8 antigens (11, 15% of the cases); (iii) coexpression of the CD4 and CD8 antigens (13, 17% of the cases); and (iv) expression of the CD1 antigen (eight, 11% of the cases). No correlation was seen between the occurrence of aberrant phenotypes and the histological subtype. It is concluded that the demonstration of an aberrant phenotype is a valuable supplement to histological assessment in the diagnosis of peripheral T cell lymphomas. It is recommended that the panel of monoclonal antibodies against T cell differentiation antigens should be fairly large, as apparently any antigen may be lost in the process of malignant transformation.     

Body Composition Changes after a Weight Loss Intervention: A 3-Year Follow-Up Study

Studies comparing different types of exercise-based interventions have not shown a consistent effect of training on long-term weight maintenance. The aim of this study was to compare the effects of exercise modalities combined with diet intervention on body composition immediately after intervention and at 3 years’ follow-up in overweight and obese adults. Two-hundred thirty-nine people (107 men) participated in a 6-month diet and exercise-based intervention, split into four randomly assigned groups: strength group (S), endurance group (E), combined strength and endurance group (SE), and control group (C). The body composition measurements took place on the first week before the start of training and after 22 weeks of training. In addition, a third measurement took place 3 years after the intervention period. A significant interaction effect (group × time) (p = 0.017) was observed for the fat mass percentage. It significantly decreased by 5.48 ± 0.65%, 5.30 ± 0.65%, 7.04 ± 0.72%, and 4.86 ± 0.65% at post-intervention for S, E, SE, and C, respectively. Three years after the intervention, the fat mass percentage returned to values similar to the baseline, except for the combined strength and endurance group, where it remained lower than the value at pre-intervention (p < 0.05). However, no significant interaction was discovered for the rest of the studied outcomes, neither at post-intervention nor 3 years later. The combined strength and endurance group was the only group that achieved lower levels of fat mass (%) at both post-intervention and 3 years after intervention, in comparison with the other groups.     

The effects of bright light treatment on subjective and objective sleepiness during three consecutive night shifts among hospital nurses – a counter-balanced placebo-controlled crossover study

Objectives:The objective was to investigate effects of timed bright light treatment on subjective and objective measures of sleepiness during three consecutive night shifts among hospital nurses.Methods:Thirty-five nurses were exposed to bright light (10,000 lux) and red dim light (100 lux) during three consecutive night shifts in a counter-balanced crossover trial lasting nine days, which included three days before and three days after the three night shifts. Light exposure for 30 minutes was scheduled between 02:00–03:00 hours on night 1, and thereafter delayed by one hour per night in order to delay the circadian rhythm. Subjective sleepiness was measured daily (heavy eyelids, reduced performance) and every second hour while awake (Karolinska Sleepiness Scale, KSS). Objective sleepiness (Psychomotor Vigilance Task, PVT) was measured at 05:00 hours during each night shift. Beyond nocturnal light exposure on the night shifts, no behavioral restrictions or recommendations were given at or off work.Results:Bright light treatment significantly reduced heavy eyelids during night shifts. However, results on KSS and PVT were unaffected by bright light. There were no differences in subjective sleepiness during the three days following the night shifts.Conclusions:This bright light treatment protocol did not convincingly reduce sleepiness among nurses during three consecutive night shifts. Nor did bright light impede the readaptation back to a day-oriented rhythm following the night shift period. Too few consecutive night shifts, inappropriate timing of light, and possible use of other countermeasures are among the explanations for the limited effects of bright light in the present study.     

The expression of placental alkaline phosphatase (PLAP) and PLAP-like enzymes in normal and neoplastic human tissues. An immunohistological survey using monoclonal antibodies

The immunohistological expression of placental alkaline phosphatase (PLAP) and PLAP-like enzyme was studied in frozen sections from a wide variety (n = 254) of normal and malignant tissues using monoclonal antibodies reactive with PLAP (H317) and PLAP/PLAP-like enzyme (H17E2; H315). PLAP/PLAP-like reactivity was seen in normal thymus, and foetal and neonatal testis, and in 21 out of 22 malignant germ cell tumours (GCTs), but was also found in normal endocervix, normal Fallopian tube and in 28 out of 167 non-GCTs (particularly in ovarian and proximal gastrointestinal tract tumours). Positivity for true PLAP (as demonstrated with H317) was seen in term placenta, in endocervix, and in Fallopian tube (but not in other normal tissues) and was commonly found in ovarian and proximal gastrointestinal tract tumours. Reactivity with H317 was unusual in malignant GCTs (2 out of 22 cases). These findings confirm that PLAP/PLAP-like positivity is a highly sensitive immunohistological marker for malignant GCTs, but one which by itself is of only moderate specificity. Furthermore, expression of true PLAP is rare in GCTs and favours instead an origin from the ovary or proximal gastrointestinal tract. The results also indicate that the predominant heat-stable alkaline phosphatase species in normal foetal and neonatal testis, and in thymus has a similar immunohistological profile to that found in malignant GCTs, and is a PLAP-like enzyme ("germ cell alkaline phosphatase") distinct from true PLAP. The occurrence of this marker in GCTs would appear to reflect increased eutopic production of an enzyme present in trace amount in corresponding normal tissues rather than a genuine example of ectopic expression.     

Decentralization of management responsibility: the case of Danish hospitals

This article examines a specific management reform at three hospitals in a Danish county. Management reform at the hospital level implies a decentralization of responsibility and power to the departmental level. Along with increased responsibility and power, departments get the message: keep your budgets and keep your output level. This preliminary analysis indicates that departmental budgets can be a way of containing costs in clinical departments. Non-staff expenditures especially are subjected to reductions. The system still seems to 'favour' doctors and nurses, but less than in a system with traditional budgetary institutions. The behaviour of the top-management teams shows that the output constraint is not seriously meant. Departments are allowed to reduce capacity, with declining output, with the knowledge of the top-management team. The declining output makes it easier to departments ceteris paribus to keep within their budgets. And that makes it easier for the top-management team to keep the overall hospital budget. The obligation to keep the overall hospital budget is thus an important criterion of success in the eyes of the political masters of hospitals.     

A growth model of human papillomavirus type 16 designed from cellular automata and agent-based models

ObjectiveThis paper presents a conceptual model that is developed upon a characterization of human papillomavirus type 16 (HPV16) which is used to build a simulation prototype of the HPV16 growth process.MethodologyThe human papillomavirus type 16 is the principal virus detected in invasive lesions of cervical cancer, and associated with the greater persistence and prevalence in pre-malignant and malignant lesions. The probability of acquiring an infection with HPV16 is extremely high in sexually active individuals. However, an HPV16 infection can disappear after becoming a histological confirmed case. According to the characterization of HPV16 proposed in this paper, cells as compared to a society behaves as a complex system, i.e., cells behave in a cooperative manner, following a set of rules defined by local interactions among them. Such complex system is defined by combining a cellular automaton and agent-based models. In this way, the behavior of the HPV16 is simulated by allowing the cellular automaton to follow such parameterized behavior rules.ResultsBoth cross-sectional and prospective studies indicate that HPV16 infection persistence increase the risk of high-grade CIN, as observed in the results provided by the growth simulation model of HPV16. The average growth rate extrapolated over 52 weeks (12 months) and calculated by the model showed a 37.87% growth for CIN1, 35.53% for CIN2 and 16.92% for CIN3. Remarkably, these results are similar to the results obtained and reported by clinical studies. For example, the results obtained using the proposed model for CIN2 and the results obtained by Östör [36], have a differential of 0.53 percentage points while have a differential of 2.23 percentage points with the results obtained by Insinga et al. [51]. Also, for the CIN3, the results obtained using the proposed model, have a differential of 2.92 percentage points with the Insinga et al. [52], results.ConclusionThrough the specification of parameterized behavior rules for HPV16 that are simulated under the combined technique of cellular automata and agent-based models, the HPV life cycle can be simulated allowing for observations at different stages. The proposed model then can be used as a support tool in the investigation of HPV16, in particular (as part of our future work) to develop drugs as agents in the control of the HPV16 disease.