Cerebral microangiopathies

Cerebral small vessels disease are characterized by lesions of the wall of the small cerebral arteries. They are responsible for 25 to 30% of strokes due to cerebral infarction or hemorrhage and/or cognitive impairment, dementia. Lipohyalinosis and cerebral amyloid angiopathy are the most common etiologies. They are associated with age, arterial hypertension, and diabetes. The localization of the lesions by MRI could help to differentiate both etiologies: deep localisation for lipohyalinosis and lobar (cortical) for cerebral amyloid angiopathy. Physiopathology of these diseases is not presently understood, and no specific treatment is available. Therefore, treatment of vascular risk factors (diabetes, arterial hypertension) is the only therapeutic measure available.     

Douleur chronique : la place du psychiatre

Objectives

Chronic pain affects nineteen percent of the European adult population and its impact on morbidity is major. Considering psychosocial factors allows improving functional re-establishment. Psychiatric comorbidities are under-diagnosed and worsen the prognosis. The psychiatrist has an important role to play in the assessment and treatment of these subjects.

Methods

We will detail the relationship between chronic pain and some psychiatric diseases as well as their psychological and biological correlation. Then, we will discuss the therapeutic implements available to the psychiatrist.

Results

We have to distinguish the psychosomatic disorders, which is a somatic disorder closely intertwined with a psychic disorder, from the somatoform disorder which is a body complaint to indicate a psychosocial distress. These disorders induce huge medico-economic costs: high prevalence and wrong care pathways, rarely using the psychiatrist expertise. The subjects with post-traumatic disorder combined with chronic pain have more severe post-traumatic symptoms with greater functional impairment. Twenty to fifty percent of subjects suffering of chronic pain have a depressive syndrome and fifty percent of the depressed subjects complain about chronic pain. Their symptoms are more numerous, more intense and longer lasting. Regardless of the used assessment tools, there are more pathological personality traits in chronic pain subjects with heterogeneous profiles than in general population which is useful for offering more targeted therapeutic strategies. Neurobiological integration of painful experience is based on two components : A somatosensory component (S1 and S2 areas) and an affective component with a central role of the anterior cingulate cortex. Functional dysfunctions involved in chronic pain affects the affective component of the pain experience and this component can be modulated. The psychiatrist should definitely avoid psychological explanation for the pain. He should focus on a multidisciplinary approach with partnership and complementarity. Its assessment identifies involved psychosocial factors, not for disqualifying the complaint but for considering all its aspects. Among drug treatments, antidepressants have a specific analgesic action particularly for IRS and MAOIs. Among non-drug treatments, reconditioning through physical activity combined or not with behavioral experiments can be associated with psycho education. Mindfulness, therapy of acceptance and commitment are used to promote voluntary consciousness of the body, of the pain and of thoughts. In some situations, transcranial magnetic stimulation can provide a useful aid. Analytical inspired therapies allow the subjects who are questioning about the meaning of the pain, better understanding a broader suffering.

Conclusion

Chronic pain is closely linked to some psychiatric disorders. We should propose specific therapeutic strategies to each patient and the psychiatrist should be involved in assessment and treatment of chronic pain. In particular, the fear related to pain should be always assessed and supported. There are drug and non-drug strategies available for the psychiatrist to help taking care of these patients.     

Fragment-guided design of subnanomolar β-lactamase inhibitors active in vivo

Fragment-based design was used to guide derivatization of a lead series of β-lactamase inhibitors that had heretofore resisted optimization for in vivo activity. X-ray structures of fragments overlaid with the lead suggested new, unanticipated functionality and points of attachment. Synthesis of three derivatives improved affinity over 20-fold and improved efficacy in cell culture. Crystal structures were consistent with the fragment-based design, enabling further optimization to a K_i of 50 pM, a 500-fold improvement that required the synthesis of only six derivatives. One of these, compound 5, was tested in mice. Whereas cefotaxime alone failed to cure mice infected with β-lactamase-expressing Escherichia coli, 65% were cleared of infection when treated with a cefotaxime:5 combination. Fragment complexes offer a path around design hurdles, even for advanced molecules; the series described here may provide leads to overcome β-lactamase-based resistance, a key clinical challenge.