In silico experimental modeling of cancer treatment.

In silico experimental modeling of cancer involves combining findings from biological literature with computer-based models of biological systems in order to conduct investigations of hypotheses entirely in the computer laboratory. In this paper, we discuss the use of in silico modeling as a precursor to traditional clinical and laboratory research, allowing researchers to refine their experimental programs with an aim to reducing costs and increasing research efficiency. We explain the methodology of in silico experimental trials before providing an example of in silico modeling from the biomathematical literature with a view to promoting more widespread use and understanding of this research strategy.

Active regulation of the epidermal calcium profile.

A distinct calcium profile is strongly implicated in regulating the multi-layered structure of the epidermis. However, the mechanisms that govern the regulation of this calcium profile are currently unclear. It clearly depends on the relatively impermeable barrier of the stratum corneum (passive regulation) but may also depend on calcium exchanges between keratinocytes and extracellular fluid (active regulation). Using a mathematical model that treats the viable sublayers of unwounded human and murine epidermis as porous media and assumes that their calcium profiles are passively regulated, we demonstrate that these profiles are also actively regulated. To obtain this result, we found that diffusion governs extracellular calcium motion in the viable epidermis and hence intracellular calcium is the main source of the epidermal calcium profile. Then, by comparison with experimental calcium profiles and combination with a hypothesised cell velocity distribution in the viable epidermis, we found that the net influx of calcium ions into keratinocytes from extracellular fluid may be constant and positive throughout the stratum basale and stratum spinosum, and that there is a net outflux of these ions in the stratum granulosum. Hence, the calcium exchange between keratinocytes and extracellular fluid differs distinctly between the stratum granulosum and the underlying sublayers, and these differences actively regulate the epidermal calcium profile. Our results also indicate that plasma membrane dysfunction may be an early event during keratinocyte disintegration in the stratum granulosum.

REMOVAL: Pelvic MRI in a 17-year-old XY girl with 5-alpha reductase deficiency and a homozygous Gly115Asp mutation in SRD5A2.

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Development of a COPD severity score.

OBJECTIVE: Treatment of chronic obstructive pulmonary disease (COPD) is based on symptom control. This suggests that COPD severity can be determined by analyzing treatment intensity. The objective of this analysis was to develop and validate a severity score for adult COPD based on treatments. RESEARCH DESIGN: Using principal components analysis, a COPD severity score was developed using data based on treatments extracted from an employer claims database (development group). Variables included were identified from literature review and clinical expert opinion. External validity was tested in a separate group of adult chronic bronchitis patients in whom principal components analysis was re-conducted and factor loadings were compared to the development group. Construct validity was tested by comparing the incidence of acute exacerbations of chronic bronchitis (AECB) in patients with high and lower severity scores. To illustrate the use of the COPD severity score, effectiveness of alternative AECB antibiotic treatments was compared in a separate patient sample categorized by severe versus mild/moderate COPD. RESULTS: In the development group (n = 2068), principal components analysis produced a single main factor for severity scoring. Of the 12 variables contributing to this factor, the 6 with the highest factor loadings were treatment related. The factor performed similarly in the external validity group (n = 9127) as it did in the development group. In construct validity testing, severe COPD patients were 4 times more likely to have AECB episodes than mild/moderate patients. Patients with severe COPD and an AECB were more likely to fail treatment with antibiotics than those with mild/moderate COPD. Based on the COPD severity score developed, we found that treatment of patients with severe COPD and an AECB with fluoroquinolones was more likely to result in treatment failure than treatment with macrolides (OR = 2.01; p = 0.03). CONCLUSIONS: The analysis was successful in developing and validating a method to score COPD severity based on treatments. This method may prove useful in providing insights about the benefits of COPD treatments.

A mathematical model of integrin-mediated haptotactic cell migration.

Haptotactic cell migration, a directed response to gradients of cell-extracellular matrix adhesion, is an important process in a number of biological phenomena such as wound healing and tumour cell invasion. Previously, mathematical models of haptotaxis have been developed on the premise that cells migrate in response to gradients in the density of the extracellular matrix. In this paper, we develop a novel mathematical model of haptotaxis which includes the adhesion receptors known as integrins and a description of their functional activation, local recruitment and protrusion as part of lamellipodia. Through the inclusion of integrins, the modelled cell matter is able to respond to a true gradient of cell-matrix adhesion, represented by functionally active integrins. We also show that previous matrix-mediated models are in fact a subset of the novel integrin-mediated models, characterised by specific choices of diffusion and haptotaxis coefficients in their model equations. Numerical solutions suggest the existence of travelling waves of cell migration that are confirmed via a phase plane analysis of a simplified model.

A cellular automata model of tumor-immune system interactions.

We present a hybrid cellular automata-partial differential equation model of moderate complexity to describe the interactions between a growing tumor next to a nutrient source and the immune system of the host organism. The model allows both temporal and two-dimensional spatial evolution of the system under investigation and is comprised of biological cell metabolism rules derived from both the experimental and mathematical modeling literature. We present numerical simulations that display behaviors which are qualitatively similar to those exhibited in tumor-immune system interaction experiments. These include spherical tumor growth, stable and unstable oscillatory tumor growth, satellitosis and tumor infiltration by immune cells. Finally, the relationship between these different growth regimes and key system parameters is discussed.

Quantification of the sensitivity increase of a micro-high-performance liquid chromatography-electrospray ionization mass spectrometry system with decreasing column diameter.

This study details the sensitivity achieved with capillary columns when used with a micro-HPLC-electrospray ionization MS system. It is comprised of two sections, the first is the comparative study of three columns, one of narrow-bore diameter and two of capillary diameter. The second section compares three columns of decreasing diameter in the capillary scale. All the experiments achieved enhanced sensitivity using capillary columns. The increase in the experimental MS response ranged from -20% to +20% compared to the UV experimental response when decreasing the internal diameter of the columns used. When comparing the experimental MS response to the maximum theoretical UV response achievable, the increase in response ranged from 40 to 50%.

[Society, medicine and caregiver stress]. / Société, médecine et souffrance des soignants.

CARING STAFF DISTRESS: Is a theme regularly discussed among those who care for patients. The current approach is in favor of the psychological interpretation of this distress. This approach is obviously pertinent, but could be widened to a more sociological vision: is the demand that society places on medicine excessive? THE SEARCH FOR AUTONOMY: The demand of the society emerges in a social universe that privileges the autonomy of the individual. Medicine serves this research for autonomy. Techniques, instrumentalization of the body, and the search for mastery engender the collective utopia of the perfect body; medicine has become a new faith, keeper of potential redemption measures. THE MEDIATOR FUNCTION OF CARING STAFF: Part of the caring staff distress is generated by the encounter between the utopia of health and the reality of suffering patients. In the present context of our society, one of the caring staff's missions is to act as mediator between the patient and the experience of the disease, the patient and the representation that he/she has of his/her body and health, and society and the expectations society projects on medicine.

Modalities of palliative care in hospitalized patients with advanced AIDS.

This prospective multidisciplinary survey started in October 1994. The survey assessed the modalities of care of hospitalized patients with advanced AIDS in an Infectious and Tropical Diseases Unit with regards to the practices of palliative care in a Palliative Care Unit. Seventy-eight (78) AIDS patients with CD4 < or = 30/mm3 who had 102 consecutive hospitalizations were recruited. Types (symptomatic or curative) and number of drugs administered to the patients, as well as biological and radiological investigations performed were recorded. Symptoms were concomitantly assessed on a weekly basis by self-evaluation of the patients themselves and by physicians. The results showed that the practices of care were different in the two units according to the specific goals and norms of each unit. A higher density of care was delivered at the Infectious and Tropical Diseases Unit. Symptoms assessed by both patients and physicians were underestimated by physicians in frequency and in intensity. In conclusion, an integrated approach including objective and subjective criteria should enable a better adjustment of the palliative and curative therapeutic strategies in advanced AIDS. These would concomitantly take into account the wishes of the patient and the goals regarding care in the unit where the patient is hospitalized.

Adenosine and migraine.

BACKGROUND: Adenosine is a powerful natural vasodilator that participates in the control of cerebral and meningeal blood flow. In this context, it could be involved in the pathophysiology of migraine, since it was previously reported that intravenous adenosine can precipitate crises in migraine patients. METHODS: We have investigated circulating adenosine levels in 12 patients suffering from migraine without aura, during crises and in crisis-free periods, and have compared the levels noted to those of a population of 10 controls. To determine if there are interactions between adenosine and serotonin, we examined the effect of adenosine and antagonists on the uptake and the release of (14C) serotonin by platelets. RESULTS AND CONCLUSION: We have reached a dual conclusion: 1) during migraine headaches there is an increase (mean 68%) in circulating adenosine levels and this increase may participate in cephalalgia; 2) activation of A2 receptors by adenosine causes a dose-dependent serotonin uptake by platelets. This inhibition of uptake could participate in the rapid elimination of serotonin in migraine sufferers. As a result of this, the use of adenosine antagonists could be an effective complementary treatment for migraine.

Antibiotic susceptibilities of Afipia felis in axenic medium and in cells.

Afipia felis, one of the putative agents of cat scratch disease (CSD), is a facultative intracellular bacterium. Although CSD is considered not to be susceptible to antibiotic therapy, sporadic case reports indicated that aminoglycosides may be effective. We determined the in vitro antibiotic susceptibilities of three A. felis strains in axenic medium and in a cell model. In axenic medium, A. felis was susceptible to imipenem, aminoglycosides, and rifampin when using either the broth dilution technique or the agar technique. When grown in HeLa cells, A. felis was susceptible to amikacin and tobramycin but was resistant to the other compounds tested. Despite its intracellular location, A. felis can apparently be reached by aminoglycosides. Thus, the in vitro data presented here are in accord with the clinical data obtained in patients suffering CSD.