Emergence and scattering of multiple neurofibromatosis (NF1)-related sequences during hominoid evolution suggest a process of pericentromeric interchromosomal transposition

Type 1 neurofibromatosis (NF1) gene encodes for a member of the GTPase activating protein family and is considered to be a tumor suppressor gene. Its very high rate of de novo mutation in humans led us to study a specific feature of this gene: the presence of numerous NF1-related sequences. According to our results, the human genome contains at least 11 NF1-related sequences, nine of which are scattered near centromeric sequences of seven different chromosomes. These NF1-related sequences, whose extent is quite varied according to loci, are unprocessed copies of the NF1 gene, and bear numerous mutations. A phylogenetic analysis of the six largest sequences indicates that they are all derived from a common ancestor, which would have appeared 22-33 million years ago, and was subsequently duplicated several times during hominoid evolution. The most recent duplication and interchromosomal transposition occurred in the last million years suggesting that the process could still be ongoing. Intriguing similarities between the evolution of alpha- satellite DNA and NF1-related sequences suggest the involvement of a common genetic mechanism for the generation and pericentric spreading of these NF1 partial copies.      

Intracellular Ca2+ buffers disrupt muscarinic suppression of Ca2+ current and M current in rat sympathetic neurons.

The role of intracellular Ca2+ concentration ([Ca2+]i) in the muscarinic suppression of Ca2+ current and M-type K+ current has been investigated in isolated rat sympathetic neurons using the whole-cell patch-clamp technique and fura-2 fluorescence measurements. Muscarinic stimulation suppressed currents without raising [Ca2+]i. Nonetheless, intracellular bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetate (BAPTA) (11-12 mM), a Ca2+ chelator, reduced Ca2(+)-current suppression from 82 to 15%. For the latter, we explain the BAPTA action by a requirement for a certain minimum [Ca2+]i for continued operation of the pathway coupling muscarinic receptors to M-type K+ channels. The pathway coupling muscarinic receptors to Ca channels also showed some dependence on [Ca2+]i, but there may also be a blocking action of BAPTA that is independent of Ca2+ chelation.     

Endotoxin shock in newborn dogs: serial hemodynamic studies

Using a newly modified dye dilution method for cardiac output determination, we successfully performed frequent serial hemodynamic measurements in newborn dogs to characterize hemodynamic changes in endotoxin shock in neonates. Sixty-seven mongrel newborn dogs (2 to 20 days old, 300 to 1500 gm) were divided into four groups: group 1 (2 to 20 days old, 300 to 1500 gm) received normal saline solution, group 2 (2 to 10 days old, 300 to 800 gm) received 1.5 mg/kg of Escherichia coli lipopolysaccharide (LPS), group 3 (2 to 10 days old, 300 to 800 gm) received 10 mg/kg of LPS, and group 4 (11 to 20 days old, 801 to 1500 gm) received 10 mg/kg of LPS. Cardiac output, heart rate, mean arterial pressure, systemic vascular resistance, and minute work were measured serially after endotoxin administration for 4 hours. Despite extensive manipulation, these measurements were stable in controls throughout the length of the study. Endotoxin, administered at two different doses of 1.5 mg/kg and 10 mg/kg, had profound effects on hemodynamic responses. These effects included a significant dose-related fall in cardiac output, minimal changes in heart rate, and a marked rise in systemic vascular resistance. The hemodynamic changes reported in this study lend additional support to the hypothesis that maturational factors are involved in the hemodynamic response to LPS.     

Cytogenomics of cancers: From chromosome to sequence

The role of acquired chromosomal rearrangements in oncogenesis (cytogenomics) and tumor progression is now well established. These alterations are multiple and diverse and the products of these rearranged genes play an essential role in the transformation and growth of cancer cells. The validity of this assumption is demonstrated by the development of specific inhibitors or antibodies that eliminate tumoral cells by targeting some of these changes. Imatinib, an inhibitor of the tyrosine kinase ABL, the prototype of these targeting drugs, is yielding complete remissions in most CML patients. Knowledge of chromosomal abnormalities is becoming an essential contribution to the diagnosis and prognosis of cancers but also for monitoring minimal residual disease or relapse. The concept of the “cytogenetic uniqueness” of each cancer has resulted in personalized treatment. This investigation will expound upon, besides the recurrent genomic alterations, the numerous products of perverted Darwinian selection at the cellular level.     

Total Parathyroidectomy With Autotransplantation in Haemodialysed Patients With Secondary Hyperparathyroidism--Should It Be Abandoned?

The development of secondary hyperparathyroidism is almost universalin patients with end-stage renal disease. Medical managementfrequently fails and in such circumstances parathyroidectomybecomes a necessity. Total parathyroidectomy with autotransplantationof parathyroid tissue into the patient's forearm has been advocatedas the surgical procedure of choice. In a previous publicationwe reported our experience with this technique in six haemodialysedpatients. We now extend our follow-up to 19 patients over anobservation period ranging from 6 to 66 months. Five of thesepatients required graft removal because of recurrent secondaryhyperparathyroidism. Despite total graft removal, two patientshad clinical and laboratory evidence of persistent hyperparathyroidism.Histology of the removed graft tissue demonstrated severe hyperplasiaas well as invasion of adjacent muscle, adipose tissue, andvascular channels by parathyroid cells. This raises the possibilityof local and distant metastatic spread of parathyroid tissueresulting in hyperparathyroidism. We suggest that parathyroidautotransplantation is potentially hazardous and should in factbe abandoned.     

Communication on end-of-life decisions with patients wishing to die at home: the making of a guideline for GPs in Flanders, Belgium

BACKGROUND: Communication with patients on end-of-life decisions is a delicate topic for which there is little guidance.AIM: To describe the development of a guideline for GPs on end-of-life communication with patients who wish to die at home, in a context where patient autonomy and euthanasia are legally regulated. DESIGN OF STUDY: A three-phase process (generation, elaboration and validation). In the generation phase, literature findings were structured and then prioritised in a focus group with GPs of a palliative care consultation network. In the elaboration phase, qualitative data on patients' and caregivers' perspectives were gathered through a focus group with next-of-kin, in-depth interviews with terminal patients, and four quality circle sessions with representatives of all constituencies. In the validation phase, the acceptability of the draft guideline was reviewed in bipolar focus groups (GPs-nurses and GPs-specialists). Finally, comments were solicited from experts by mail. SETTING: Primary home care in Belgium. SUBJECTS: Participants in this study were terminal patients (n = 17), next-of-kin of terminal patients (n = 17), GPs (n = 25), specialists (n = 3), nurses (n = 8), other caregivers (n = 2) and experts (n = 41). RESULTS: Caregivers and patients expressed a need for a comprehensive guideline on communication in end-of-life decisions. Four major communication themes were prioritised: truth telling; exploration of the patient's wishes regarding the end of life; dealing with disproportionate interventions; and dealing with requests for euthanasia in the terminal phase of life. Additional themes required special attention in the guideline: continuity of care by the GP; communication on foregoing food and fluid; and technical aspects of euthanasia. CONCLUSION: It was feasible to develop a guideline by combining the three cornerstones of evidence-based medicine: literature search, patient values and professional experience.     

Role of glomerular prostanoid in control of glomerular filtration rate in rats

Summary It is generally accepted that the main action of glomerular prostanoids (GPs) on glomerular filtration rate (GFR) is to modulate the activity of different vasoconstrictors, specially in states of renal hypoperfusion. However it was also suggested that GPs may directly affect GFR. The present study was focused on this last hypothesis, in different experimental models, in rats.In adriamycin induced acute renal failure, the transient decrease of GFR is associated with higher levels of thromboxane B₂. Later on, when GFR returns to normal, vasodilator prostaglandins synthesis was also increased.In captopril induced renal failure in Na depleted rats (where GPs synthesis remained normal), stimulation of PGE₂ and PGI₂ production by K and NaCl was associated with a significant improvement of GFR. Furthermore, the increase in GFR induce by NaCl was prevented by inhibition of prostaglandin synthesis.Infusion of atrial natriuretic peptide in euvolemic rats induce a marked elevation both of GFR and PGE₂ synthesis. It was abolished by previous administration of prostaglandin synthesis inhibitor.In conclusion, glomerular prostanoids may influence GFR, either directly, or as mediator or modulator of other vasoactive hormones.Abbreviations GPs glomerular prostanoids - PG prostaglandin - TX thromboxane - ANP atrial natriuretic peptide - GFR glomerular filtration rate - PE polyethylene Nachtrag zu den Hauptreferaten des 19. Kongresses der Gesellschaft für Nephrologie in Göttingen (Klin Wochenschr 66/18)     

Supplementary motor area encodes reward expectancy in eye-movement tasks

Neural activity signifying the expectation of reward has been found recently in many parts of the brain, including midbrain and cortical structures. These signals can facilitate goal-directed behavior or the learning of new skills based on reinforcements. Here we show that neurons in the supplementary motor area (SMA), an area concerned with movements of the body and limbs, also carry a reward expectancy signal in the postsaccadic period of oculomotor tasks. While the monkeys performed blocks of memory-guided and object-based saccades, the neurons discharged a burst after a approximately 200-ms delay following the target-acquiring saccade in the memory task but often fired concurrently with the target-acquiring saccade in the object task. The hypothesis that this postsaccadic bursting activity reflects the expectation of a reward was tested with a series of manipulations to the memory-guided saccade task. It was found that although the timing of the bursting activity corresponds to a visual feedback stimulus, the visual feedback is not required for the neurons to discharge a burst. Second, blocks of no-reward trials reveal an extinction of the bursting activity as the monkeys come to understand that they would not be rewarded for properly generated saccades. Finally, the delivery of unexpected rewards confirmed that in many of the neurons, the activity is not related to a motor plan to acquire the reward (e.g., licking). Thus we conclude that reward expectancy is represented by the activity of SMA neurons, even in the context of an oculomotor task. These results suggest that the reward expectancy signal is broadcast over a large extent of motor cortex, and may facilitate the learning of new, coordinated behavior between different body parts.