Abstract

The visible brain: What can we see with MRI?

Denis Le Bihan

For the last 25 years Magnetic Resonance Imaging (MRI) has established itself as the method of choice to obtain images of the brain non invasively and with the utmost accuracy. Using a strong magnetic field MRI scanners produce virtual slices of the living brain anatomy, providing exquisite details within gray and white matter. These anatomical images have been used worldwide by radiologists to detect and localize brain lesions in patients. More recently MRI has also become a «functional» imaging tool (fMRI), showing the activity of the many structured present in our brain. FMRI is based on two major findings: The first one, suspected back from antiquity, but only clearly demonstrated by the French surgeon Broca in 1863 is that the brain is not an homogeneous organ, but is rather organized around regions which are more or less specialized in given sensori-motor or cognitive processes. The second one, pointed out by Roy and Sherrington about 30 years later is that metabolism and blood flow increase locally in active brain regions. Since the early 1990s it has been shown that MRI can be made sensitive to this transient and local increase in blood flow. In practice one has to collect fMRI images of the brain "in real time" while the subject lying in the scanner executes a particular task (motor, cognitive,...). Using a computer software regions where blood flow has changed in synchrony with the task performance can be highlighted and displayed on the brain images using colors. Although brain activity is not seen directly (at the neuron level), but through blood flow the results are astonishing. It is now possible to visualize the network of brain regions involved in high order cognitive processes, such as language, mathematics, mental imagery or even unconscious events... Recent studies have shown that many brain circuits are commonly activated during the actual performance of a task and the simple imagery or simulation of the task. How far will we be able to "read the mind" using fMRI is clearly an interesting prospect. In medicine fMRI has also become a great tool, for instance to help neurosurgeons navigate more safely throughout the brain or to detect functional disorders. Lately MRI has also become capable to address the wiring of the brain: With diffusion MRI it is now possible to produce non invasively and on an individual basis three dimensional maps of the white matter tracks connecting brain cortical (gray matter) regions. This approach has already been successfully used to demonstrate that some functional disorders could be linked to defects in connectivity. The combined potential of diffusion MRI and fMRI to understand the normal or the diseased brain, the development of the brain and the interaction between genes and environment is tremendous and work is under way to build even more powerful MRI scanners.

What is your diagnosis?: ten interesting cases from St John's Institute of Dermatology

John McGrath

The skin is the largest and most visible of all the body's organs. Indeed, one of the fundamental properties of human skin is to build a protective barrier against the external environment. This construction work is orchestrated in utero by complex networks of transcription factors, signalling molecules and an assortment of structural proteins, sugars and lipids. In recent years, clues to the specific contributions made by individual molecules in skin ontogeny have emerged from the characterization of a number of naturally occurring inherited disorders that compromise the integrity of the skin. All told, there are over 400 single gene disorders that have a skin phenotype. This presentation will provide 10 clinico-pathological examples of "genodermatoses" in which mutations in key genes lead to defective skin formation, or compromise cell adhesion, migration or differentiation. Several of the disorders involve primary defects in components of adhesion junctions such as hemidesmosomes or desmosomes, a number of which have extra-cutaneous manifestations, depending on the tissue distribution of the mutated targets. Others involve ubiquitous transcription factors, such as p63, or components of metabolic pathways, such as enzymes within the Kreb's cycle: all of which display particular abnormalities in the skin. Understanding the precise genetic basis of these and similar inherited skin disorders has profound implications for unravelling the mysteries of skin development and homeostasis. Moreover, such insight is very relevant clinically in terms of genetic counselling, prenatal diagnosis and strategies to develop new forms of treatment for these very significant and often devastating inherited skin disorders.

Adult epithelial tissue stem cells: some comments on their numbers, characteristics and genome protective mechanisms

Christopher S. Potten

All cells in adult replacing tissues are ultimately dependent on a small number of self-maintaining stem cells. These crucial cells make up less than 1% of the proliferating cell compartment of the tissues. The progeny of stem cells enter a dividing transit population with a variable number of cell generations in this lineage depending on the tissue. One consequence of these stem cell derived lineages is a spatial patterning of stem cells and their progeny into clearly recognisable tissue units of proliferation (e.g. in tongue, epidermis, stomach, intestine). This precise spatial distribution of stem cells enables them to be studied in the absence of stem cell specific markers. The stem cells in the small intestinal crypts have been extensively studied. There are about 5 per crypt, each with its own transit lineage with about 6 generations. These stem cells occur at a precise position in the crypt and divide once a day while their progeny divide twice a day. Thus, in the lifetime of a mouse, the stem cells divide about 1000 times (probably up to 6000 times in man). In spite of the very large number of stem cells in the entire small intestine, their rapid rate of proliferation, and the very large number of total divisions in a lifetime, cancer of the small intestine is very rare. This implies that these cells have efficient genome protection mechanisms. Evidence will be presented showing that stem cells in the intestine protect themselves against the risk of replication induced errors by selectively sorting old (template) and new DNA strands at mitosis, retaining the old error - free strands in the daughter cell destined to remain in the stem cells. Random template or double strand errors are efficiently detected and removed by an altruistic apoptosis process. This latter protective mechanism is compromised in the large bowel by bcl-2 expression in the stem cells. Some of these studies have led to techniques that label stem cells, thus raising the potential of further more detailed studies as well as stem cell isolation.