Nanodissection and high-resolution imaging of the Rhodopseudomonas viridis photosynthetic core complex in native membranes by AFM. Atomic force microscopy

In photosynthesis, highly organized multiprotein assemblies convert sunlight into biochemical energy with high efficiency. A challenge in structural biology is to analyze such supramolecular complexes in native membranes. Atomic force microscopy (AFM) with high lateral resolution, high signal-to-noise ratio, and the possibility to nanodissect biological samples is a unique tool to investigate multiprotein complexes at molecular resolution in situ. Here we present high-resolution AFM of the photosynthetic core complex in native Rhodopseudomonas viridis membranes. Topographs at 10-A lateral and approximately 1-A vertical resolution reveal a single reaction center (RC) surrounded by a closed ellipsoid of 16 light-harvesting (LH1) subunits. Nanodissection of the tetraheme cytochrome (4Hcyt) subunit from the RC allows demonstration that the L and M subunits exhibit an asymmetric topography intimately associated to the LH1 subunits located at the short ellipsis axis. This architecture implies a distance distribution between the antenna and the RC compared with a centered location of the RC within a circular LH1, which may influence the energy transfer within the core complex. The LH1 subunits rearrange into a circle after removal of the RC from the core complex.     

Neuropsychological deficit in early subcortical vascular dementia: comparison to Alzheimer's disease

To further clarify the cognitive syndrome in subcortical vascular dementia (VaD), we investigated 20 patients with early-stage VaD as compared with 30 patients with Alzheimer's disease (AD) and 22 normal controls using episodic memory, attention/executive function and language tests. The patient groups were closely matched in terms of age, education and severity of dementia. The VaD patients had a significantly better free recall, cued recall and recognition memory than AD patients, the recognition being within normal limits in VaD. In addition, VaD patients had a greater number of perseverative errors during the Modified Card Sorting test, while AD patients exhibited more perseverations of semantic fluency. The results of retrieval deficit syndrome and increased number of perseverations during tasks sensitive to frontal lobe function are in agreement with the studies emphasizing the importance of frontal dysfunction in subcortical VaD. These findings are relevant for the early diagnosis of VaD and might be useful in the differential diagnosis with AD.     

Current approach to the management of gastrinoma and insulinoma in adults with multiple endocrine neoplasia type I

The difficult and controversial diagnostic and therapeutic management of patients having gastrinoma or insulinoma with multiple endocrine neoplasia type I (MEN-I) has been discussed by reference to the literature and a personal series of 45 gastrinoma/MEN-I patients followed consecutively at Bichat Hospital. In both gastrinoma/ and insulinoma/MEN-I patients, anatomic distribution and morphology of tumoral process(es) are usually multiple, diffuse, of small size, and associated with endocrine cell hyperplasia and even nesidioblastosis. These features enhance the difficulty of tumor localization and eradication. Despite the dramatic development of modern medical imagery and surgical experience, the real possibility, on a long-term basis, of curing the patients from their disease remains limited, especially in the gastrinoma/MEN-I patients. In the latter group, according to our experience, persistence or recurrence of the disease after surgery is usual, and metachronous hepatic metastasis development is frequently observed when the follow-up is long enough. Patients with liver metastases, however, seem to undergo a more indolent course than sporadic gastrinoma cases. In insulinoma/MEN-I patients, removal of the functionally dominant islet cell area(s) is essential. Various preoperative and intraoperative localization techniques allow efficacious selective pancreatic surgery in many cases. The latter refinements and the promises of long-acting somatostatin analogs, if confirmed, might restrict to exceptional circumstances the indication of near-total or total pancreatectomy.

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Resumen El controvertido y difícil manejo diagnóstico y terapeútico de pacientes con gastrinoma o insulinoma y síindrome de neoplasia endocrina múltiple tipo I (NEM I) es discutido con referencia a la literatura y una serie personal de 45 pacientes con gastrinoma MEN I seguidos en forma consecutiva en el Hospital Bichat.Tanto en los pacientes con NEM I y gastrinoma o insulinoma, la distribución anatómica y morfológica de los procesos tumorales es usualmente múltiple, difusa y de tamaño pequeño, y asociada con hiperplasia celular endocrina y aún nesidioblastosis. Tales características incrementan la dificultad en la localización y erradicación del tumor. A pesar del dramático avance en la imagenología médica moderna y de la experiencia quirúrgica, la posibilidad real, a largo plazo, de curar al paciente permanece limitada, especialmente en los pacientes con NEM I. En este grupo, según la experiencia del Hospital Bichat, la persistencia o la recurrencia de la enfermedad luego de la cirugía es común y se desarrollan metástasis hepáticas metácronas cuando el seguimiento es lo suficientemente prolongado. Sin embargo, los pacientes con metástasis hepáticas parecen tener una evolución más indolente que los casos de gastrinoma esporádico.En los pacientes con insulinoma-NEM I es esencial la resección del área celular funcionalmente dominante. Diversas técnicas de localización preoperatoria e intraoperatoria permiten una eficaz cirugía pancreática. Los últimos refinamientos y los promisorios análogos sintéticos de la somatostatina, si se confirma su eficacia, podrian restringir a circunstancias realmente excepcionales la indicación para pancreatectomía casi total o total.

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Résumé Les méthodes diagnostiques et thérapeutiques propres aux gastrinomes ou aux insulinomes faisant partie du syndrome des néoplasies endocrines de type I (MEN-I), difficiles et controversées, sont discutées en fonction des données de la littérature et ane série personnelle de 45 gastrinomes MEN-I suivis à l'Hôpital Bichat à Paris, France. Chez les patients ayant soit un gastrinome MEN-I, soit un insulinome MEN-I, les tumeurs se caractérisent anatomiquement et morphologiquement comme étant des formations généralement petites, multiples, diffuses, et associées à une hyperplasie cellulaire endocrine et parfois même une nésidoblastose. Ces caractéristiques augmentent les difficultés de la localisation et de l'exérèse. Malgré les progrès extraordinaires dans l'imagerie moderne et l'expérience chirurgicale, les possibilités réelles de cure durable restent maigres, surtout chez les patients ayant un gastrinome MEN-I. Selon notre expérience, la persistence ou la récidive de ces derniers après chirurgie sont la règle et on constate souvent des métastases hépatiques métachrones lorsque le suivi est suffisamment long. Lorsque ces métastases existent, cependant, il semble que l'évolution soit moins douleureuse qu'en cas de gastrinome sporadique. Chez le patient ayant un insulinome MEN-I, l'exérèse de la tumeur fonctionnelle est essentielle. Des techniques de localisation pré- et per-opératoires diverses permettent généralement une technique chirurgicale adaptée. L'espoir de disposer d'analogues de la somatostatine agissant à long terme pourrait restreindre à l'avenir les indications de la pancréatectomie totale ou presque totale.

     

Disclosure of diagnosis of Alzheimer's disease in French general practice

Most practitioners find disclosing the diagnosis of Alzheimer s disease (AD) to an individual with dementia very difficult. Literature results show a wide variability in attitudes and clinicalpractice, and diagnosis seems to be more often disclosed to caregivers than to patients. The objective of this study was to examine whether and how diagnosis of AD is disclosed in French general practice and which issues are addressed with the patient. A questionnaire was sent via mail to 1,629 general practitioners (GPs), 1,105 belonging to the Sentinel's network and 524 specially recruited doctors practicing in the Rh?ne-Alpes region. A total of 631 questionnaires were returned (response rate, 39 percent), of which 616 were eligible for analysis. Twenty-eight percent of GPs reported having disclosed diagnosis to the patient (25 percent mentioned "Alzheimer's disease"), whereas 88 percent considered it their role to announce the diagnosis to the patient. Regarding the type of information provided to the patient, only 25 percent discussed the nature of the illness, 23 percent behavioral problems, and 47 percent depression, mainly for psychological reasons (63 percent). Stress was discussed with 79 percent of the caregivers. We concluded that GPs do not discuss the consquences of AD and symptoms (e.g., behavioral disorders) with patients, mainly for psychological reasons, whereas they have a less-reluctant attitude toward caregivers. As the GP has the weighty task of providing ropriate community care and psychological support to the patient, it is of utmost importance to reflect on how disclosure of diagnosis can be facilitated.     

Effects of skull thickness, anisotropy, and inhomogeneity on forward EEG/ERP computations using a spherical three-dimensional resistor mesh model

Bone thickness, anisotropy, and inhomogeneity have been reported to induce important variations in electroencephalogram (EEG) scalp potentials. To study this effect, we used an original three-dimensional (3-D) resistor mesh model described in spherical coordinates, consisting of 67,464 elements and 22,105 nodes arranged in 36 different concentric layers. After validation of the model by comparison with the analytic solution, potential variations induced by geometric and electrical skull modifications were investigated at the surface in the dipole plane and along the dipole axis, for several eccentricities and bone thicknesses. The resistor mesh permits one to obtain various configurations, as local modifications are introduced very easily. This has allowed several head models to be designed to study the effects of skull properties (thickness, anisotropy, and heterogeneity) on scalp surface potentials. Results show a decrease of potentials in bone, depending on bone thickness, and a very small decrease through the scalp layer. Nevertheless, similar scalp potentials can be obtained using either a thick scalp layer and a thin skull layer, and vice versa. It is thus important to take into account skull and scalp thicknesses, because the drop of potential in bone depends on both. The use of three different layers for skull instead of one leads to small differences in potential values and patterns. In contrast, the introduction of a hole in the skull highly increases the maximum potential value (by a factor of 11.5 in our case), because of the absence of potential drop in the corresponding volume. The inverse solution without any a priori knowledge indicates that the model with the hole gives the largest errors in both position and dipolar moment. Our results indicate that the resistor mesh model can be used as a robust and user-friendly simulation tool in EEG or event-related potentials. It makes it possible to build up real head models directly from anatomic magnetic resonance imaging without tessellation, and is able to take into account head heterogeneities very simply by changing volume elements conductivity. Hum. Brain Mapping 21:84-95, 2004.     

Cerebral complications of hypertension

Ischaemic and degenerative brain diseases are a major health problem leading to a devastating loss of autonomy. Hypertension has been shown to carry an increased risk not only for cerebrovascular morbidity and mortality but also for cognitive impairment and dementia. Although diastolic blood pressure is considered an important risk factor, it is now clear that isolated systolic hypertension and elevated pulse pressure also play an important role in the development of brain complications. Therefore the treatment of these conditions must urgently become a widespread tool of prevention. All the randomised placebo-controlled trials completed for the last 30 years have shown a reduction in fatal and/or non-fatal strokes. In the most recent trials in isolated systolic hypertension in older patients, the benefit was even greater because of the higher risk in these populations. The new classes of drugs, in particular, calcium-channels blockers and angiotensin-converting enzyme inhibitors, have been shown to be as effective as the originally used diuretics and beta-blockers. Active treatment in the Syst-Eur trial based on nitrendipine as first step, possibly associated with enalapril and/or hydrochlorthiazide reduced not only stroke and cardiovascular complications but also the incidence of dementia including Alzheimer's disease. This important finding must be confirmed by further trials specifically focusing on the prevention of dementia. In addition, the importance of pulse pressure as a risk factor, underlines the need for new drugs which could increase aortic distensibility and decrease systolic blood pressure without greatly reducing diastolic pressure. Improving the management of hypertension offers new opportunities to reduce age-related disease in older people and to promote healthy aging.