Existence and theoretical aspects of homomeric and heteromeric dopamine receptor complexes and their relevance for neurological diseases

Dopamine (DA) and other receptors physically interact in the plasma membrane of basal ganglia neurons forming receptor mosaics (RMs). Two types of RMs are discussed, homomers formed only by DA-receptor (DA-R) subtypes and heteromers formed by DA-R associated with other receptors, such as A2A, A1, mGluR5, N-methyl-d-aspartate (NMDA), γ-aminobutryic acid (GABA)-A, and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid. By being part of horizontal molecular networks, RMs tune multiple effector systems already at membrane level, such as G protein regulated inward rectifying potassium channels and dopamine transporter activity. Also, ligand-gated ion channels such as GABA-A and NMDA receptors are modulated by DA-R, e.g., in the striatal GABA output neurons through the formation of heteromeric complexes with these receptors. Thus, intramembrane DA-R-receptor interactions play an important role in the information handling in the basal ganglia. On this basis, functional implications of DA RM in physiological and pathological conditions are discussed. The effects of temperature on RM are discussed not only because receptor-decoding mechanisms are temperature sensitive, but also in view of the suggestion that possible ordering effects (i.e., changes in the entropy of a receptor complex) induced by a ligand are as a result of alterations in the receptor oligomerization (i.e., are related to rearrangements of the RM). Hence, brain temperature may have profound effects on brain integrative functions not only because its effects on the kinetics of biochemical reactions, but also for its effects on receptor geometry, building up of RM, and alterations in protein expression, as is the case of H-channels following febrile seizures. Note: This article is dedicated to Tullio Giacomini for his 70th birthday.     

Maternity wards or emergency obstetric rooms? Incidence of near-miss events in African hospitals

BACKGROUND: This study examines near-miss obstetric events in African hospitals as to the frequency, nature, and ratio of near miss to death and considers whether these could become useful indicators for monitoring the performance of obstetric services in Africa. METHODS: Prospective or retrospective reviews of medical records were conducted in nine referral hospitals in three countries (Benin, C?te d'Ivoire, and Morocco). We calculated the incidence of near-miss obstetric events, near-miss cases, and maternal deaths related to hemorrhage, hypertensive diseases of pregnancy, dystocia, infections, and anemia and analyzed these according to hospital and timing relative to admission. RESULTS: The incidence of near-miss cases was varied, and in some hospitals extremely large: from 1% to almost a quarter of all deliveries were near misses. Near-miss cases were 15 times more common than deaths (ranging from a ratio of 9:1-108:1). Most of the women with near-miss events (NMEs) (83%) were already in a critical condition on arrival at the hospital (range 54-90%), and two in three were referred from another facility. The most frequent types of NMEs were hemorrhage and hypertensive diseases of pregnancy, but anemia was the leading cause in three first referral level hospitals in Benin and C?te d'Ivoire. Near-miss events due to infections were rare. CONCLUSIONS: Near-miss events are extremely common in some African hospitals, with a high proportion arriving in critical conditions. Near-miss events must be estimated separately for those already in a critical condition on arrival and those developing after admission; the first as a good indicator of the effectiveness of emergency referrals and the second as a potential tool for monitoring the performance of obstetric services.     

Adenosine A2A and dopamine D2 heteromeric receptor complexes and their function

The existence of A2A-D2 heteromeric complexes is based on coimmunoprecipitation studies and on fluorescence resonance energy transfer and bioluminescence resonance energy transfer analyses. It has now become possible to show that A2A and D2 receptors also coimmunoprecipitate in striatal tissue, giving evidence for the existence of A2A-D2 heteromeric receptor complexes also in rat striatal tissue. The analysis gives evidence that these heteromers are constitutive, as they are observed in the absence of A2A and D2 agonists. The A2A-D2 heteromers could either be A2A-D2 heterodimers and/or higher-order A2A -D2 hetero-oligomers. In striatal neurons there are probably A2A-D2 heteromeric complexes, together with A2A-D2 homomeric complexes in the neuronal surface membrane. Their stoichiometry in various microdomains will have a major role in determining A2A and D2 signaling in the striatopallidal GABA neurons. Through the use of D2/D1 chimeras, evidence has been obtained that the fifth transmembrane (TM) domain and/or the I3 of the D2 receptor are part of the A2A-D2 receptor interface, where electrostatic epitope-epitope interactions involving the N-terminal part of I3 of the D2 receptor (arginine-rich epitope) play a major role, interacting with the carboxyl terminus of the A2A receptor. Computerized modeling of A2A-D2 heteromers are in line with these findings. It seems likely that A2A receptor-induced reduction of D2 receptor recognition, G protein coupling, and signaling, as well as the existence of A2A-D2 co-trafficking, are the consequence of the existence of an A2A-D2 receptor heteromer. The relevance of A2A-D2 heteromeric receptor complexes for Parkinson's disease and schizophrenia is emphasized as well as for the treatment of these diseases. Finally, recent evidence for the existence of antagonistic A2A-D3 heteromeric receptor complexes in cotransfected cell lines has been summarized.     

Single motherhood and neonatal survival of twins among blacks and whites

OBJECTIVE: We investigated whether an association existed between single motherhood and neonatal mortality among twins and whether such a linkage varied by race. STUDY DESIGN: Retrospective cohort analysis on 446,570 twin live births (between 24-44 gestational weeks inclusive) in the United States from 1995 through 1998. Neonatal survival was compared between twins of single and those of married mothers for blacks and whites separately using Cox proportional hazards regression that adjusted for the confounding effects of education, parity, adequacy of prenatal care and maternal smoking during pregnancy. The Robust Sandwich Estimator was employed to adjust for intracluster correlation. RESULTS: The rates for neonatal mortality among blacks were 34.9 per 1,000 among married and 43.4 per 1,000 among single mothers. Among whites, the rates were 20.6 per 1,000 for married and 28.9 per 1,000 for unmarried mothers. Neonatal mortality was significantly elevated among white twins of single mothers (Hazard Ratio (HR) = 1.23; 95% Confidence Interval (CI) = 1.14-1.31) and among black twins of single mothers (HR = 1.12; 95% CI = 1.01-1.25). However, when gestational age was adjusted for, the association between single motherhood and neonatal mortality disappeared. CONCLUSION: Single motherhood was a risk factor for neonatal mortality among twins, and the disparity in survival was more accentuated among whites. The association between single motherhood and neonatal mortality was explained by the preponderance of preterm births among twins of unmarried gravidas. Our findings reinforce the importance of future research to develop and test interventions that will decrease the incidence of preterm birth.     

Is the use of laparoscopy to determine presence of contralateral patent processus vaginalis justified in children greater than 2 years of age?

Purpose

Contralateral inguinal hernia exploration in cases of unilateral inguinal hernia remains a controversial topic. The authors have been using the in-line laparoscopic technique of contralateral evaluation for unilateral inguinal hernia in children less than 2 years of age. Because of the case of the procedure and lack of morbidity, we decided to expand the use of this procedure up to age 8 years in January 2000. The purpose of this study is to evaluate if the incidence of contralateral hernia in children greater than 2 years justifies the procedure.

Methods

This is a retrospective study of all children who underwent contralateral exploration for unilateral inguinal exploration over a 20-month period. The procedure was offered routinely to all patients up to age 8 years. During the repair, the contralateral inguinal ring was examined laparoscopically using the in-line technique for the presence of a contralateral hernia. The incidence of contralateral hernia was determined, and the results were stratified by age. Patients who underwent unilateral inguinal hernia repair without laparoscopic contralateral exploration or bilateral inguinal hernia repair without laparoscopic contralateral explorations were excluded from the study.

Results

A total of 284 laparoscopic explorations were performed. Positive explorations were seen in 65 of 171 (38%) of children less than 2 years of age, 19 of 101 (20%) of children 2 to 8 years of age, and 1 of 12 children greater than 8 years of age (8%). There were no operative complications.

Conclusions

Laparoscopic contralateral exploration is safe and effective. Because of the low morbidity, the risk to benefit ratio warrants its use in children up to 8 years of age. This sample size is too small to make any meaningful statement in children older than 8 years.     

Iron deficiency anemia and proteino-energetic status in woman from 15 to 49 years old in Tunisia

A foodstuffs survey has been carried out on young women aged from 15 to 49 in order to determine the total and available iron supplies, in proteins and in energy so as to establish the link between an iron deficiency and the protein-energy supplies in comparison to the needs required by the FAO and the WHO. The regions studied are the Great Tunis (GT) and the South West (SW) both in urban and rural backgrounds. These two regions have been selected because of the high prevailing rate of deficiency discovered after the 1996/1997 nutritional survey. Women have been divided into two groups: those who have a deficiency and those who don't have. The study concerned 1151 homes therefore about 1468 women and from them 712 are from GT and 756 from SW. The results of foodstuffs survey demonstrated that supply of meat is more elevated in non anemic women than anemic women concerning proteins supplies. A moderate energetic deficit is noticed in non deficient women and those anemic who have an iron deficiency. Women presented anemia have total and available iron deficient and a deficiency in energy supplies.     

Endometrial stromal nodule: a case report

The endometrial stromal nodule is the rarest of the endometrial stromal tumours. It is a benign tumour composed of well-differentiated endometrial stromal cells arranged as a well-circumscribed nodule with smooth, non invasive margins. We describe a case of uterine stromal nodule occurring in a 45-year-old woman with history of menometrorrhagia in which case ultrasonography conclude to a leiomyoma. Epidemiology, pathologic aspects, differential diagnosis, treatment and prognosis are reviewed.     

PACAP promotes neural stem cell proliferation in adult mouse brain

In recent years, it has become evident that neural stem cells in the adult mammalian brain continuously generate new neurons, mainly in the hippocampus and olfactory bulb. Although different growth factors have been shown to stimulate neurogenesis in the adult brain, very little is known about the role of neuropeptides in this process. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with pleiotropic effects acting through three receptors to which it has high affinity, namely, PACAP receptor 1 (PAC1), vasoactive intestinal peptide (VIP) receptor 1, and VIP receptor 2. We show that PAC1 is expressed in the neurogenic regions of the adult mouse brain, namely the ventricular zone of the lateral ventricle and the hippocampal dentate gyrus. Cultured neural stem cells isolated from the lateral ventricle wall of adult mice express PAC1 and proliferate in vitro in response to two PAC1 agonists, PACAP and Maxadilan, but not VIP at physiologic concentrations, indicating PAC1 as a mediator of neural stem cell proliferation. Pharmacologic and biochemical characterization of PACAP-induced neural stem cell proliferation revealed the protein kinase C pathway as the principal signaling pathway, whereas addition of epidermal growth factor synergistically enhanced the proliferating effect of PACAP. Further in vitro characterization of the effect of PACAP on neural stem cells showed PACAP capable of stimulating ex novo in vitro formation of multipotent neurospheres with the capacity to generate both neuronal and glial cells. Finally, intracerebroventricular infusion of PACAP increases cell proliferation in the ventricular zone of the lateral ventricle and the dentate gyrus of the hippocampus. We conclude that PACAP, through PAC1, is a potent mediator of adult neural stem cell proliferation.     

Expression of the vesicular glutamate transporters during development indicates the widespread corelease of multiple neurotransmitters

Three closely related proteins transport glutamate into synaptic vesicles for release by exocytosis. Complementary patterns of expression in glutamatergic terminals have been reported for VGLUT1 and VGLUT2. VGLUT3 shows expression by many cells not considered to be glutamatergic. Here we describe the changes in VGLUT expression that occur during development. VGLUT1 expression increases gradually after birth and eventually predominates over the other isoforms in telencephalic regions. Expressed at high levels shortly after birth, VGLUT2 declines with age in multiple regions, in the cerebellum by 14-fold. In contrast, Coexpression of the two isoforms occurs transiently during development as well as permanently in a restricted subset of glutamatergic terminals in the adult. VGLUT3 is transiently expressed at high levels by select neuronal populations, including terminals in the cerebellar nuclei, scattered neurons in the cortex, and progenitor-like cells, implicating exocytotic glutamate release in morphogenesis and development. VGLUT3 also colocalizes extensively during development with the neuronal vesicular monoamine transporter VMAT2, with the vesicular acetylcholine transporter VAChT, and with the vesicular gamma-aminobutyric acid transporter VGAT. Such coexpression occurs particularly at some specific developmental stages and is restricted to certain sets of cells. In skeletal muscle, VGLUT3 localizes to granular organelles in the axon terminal as well as in the muscle sarcoplasm. The results suggest novel mechanisms and roles for regulated transmitter release.