Regulation and subcellular localization of the microtubule-destabilizing stathmin family phosphoproteins in cortical neurons

Stathmin is a ubiquitous cytosolic phosphoprotein, preferentially expressed in the nervous system, and the generic element of a protein family that includes the neural-specific proteins SCG10, SCLIP, and RB3 and its splice variants, RB3' and RB3". All phosphoproteins of the family share with stathmin its tubulin binding and microtubule (MT)-destabilizing activities. To understand better the specific roles of these proteins in neuronal cells, we performed a comparative study of their expression, regulation, and intracellular distribution in embryonic cortical neurons in culture. We found that stathmin is highly expressed ( approximately 0.25% of total proteins) and uniformly present in the various neuronal compartments (cell body, dendrites, axon, growth cones). It appeared mainly unphosphorylated or weakly phosphorylated on one site, and antisera to specific phosphorylated sites (serines 16, 25, or 38) did not reveal a differential regulation of its phosphorylation among neuronal cell compartments. However, they revealed a subpopulation of cells in which stathmin was highly phosphorylated on serine 16, possibly by CaM kinase II also active in a similar subpopulation. The other proteins of the stathmin family are expressed about 100-fold less than stathmin in partially distinct neuronal populations, RB3 being detected in only about 20% of neurons in culture. In contrast to stathmin, they are each mostly concentrated at the Golgi apparatus and are also present along dendrites and axons, including growth cones. Altogether, our results suggest that the different members of the stathmin family have complementary, at least partially distinct functions in neuronal cell regulation, in particular in relation to MT dynamics.     

X-linked myotubular myopathy with probable germline mosaicism

X-linked myotubular myopathy is a disorder characterized by severe neonatal hypotonia and respiratory insufficiency. The mutation of MTMI gene results in a defective production of myotubularin, which is responsible for the maturational arrest of muscle development. An identical mutation in the carrier mother and the diseased child establishes the inheritance. We report the disease in a neonate with a mutation on exon 6 of the MTMI gene. Surprisingly, the mother was healthy and did not carry this mutation, she is likely to have germline mosaicism.     

Surgical repair for degenerative and rheumatic mitral valve disease. Operative and mid-term results

BACKGROUND: Non randomized studies suggest that mitral valve repair for rheumatic disease is technically more difficult than repair for degenerative disease, and that operative and late results are worse. New surgical techniques have been developed in our and other institutes during the last 5 years, and this moved us to review the experience with these two pathologies and to compare the operative and mid-term RESULTS: METHODS: From March 1996 to September 1997, 66 patients underwent primary mitral valve repair for treatment of degenerative or rheumatic disease. Fifty-two patients (79%) were in the former group (group A) and 14 in the latter (group B). Surgery was performed by 2 experienced cardiac surgeons. A new technique to calculate the exact artificial chordae length was introduced. In 2 cases, tricuspid autografts were transposed to mitral position and reinforced with artificial chordae. Patients were followed both clinically and echocardiographically. The follow-up data were collected in a 1-month period (May 2000). The average clinical follow-up was 3.1+/-0.9 years (range 1.7 to 4.2 years) while the average echocardiographic follow-up was 2.7+/-0.7 years (range 9 months to 4 years). All values were expressed by means of the average and standard deviation. chi(2) and Student's "t"-test were used to analyze the significance between variables. The Kaplan-Meyer method was used for actuarial statistics. RESULTS: There were no operative deaths in either group. In group A, 1 patient underwent a second surgical repair 1 week later, successfully. In group B no patients underwent reoperation within 30 days or during the initial hospitalization. At follow-up of group A there were the following events: deaths from cancer (n=2), endocarditis (n=1), aortic dissection (n=1). At follow-up of group B there were mitral valve replacement (1 year after first operation, n=1), Ross procedure (n=1), ischemic heart failure (n=1). Among the remaining 62 patients followed, 32 were in NYHA class I, 15 in class II, 3 in class III, and none in class IV, in group A. In group B, 7 patients were in class I, 4 in class II, 1 in class III and none in class IV (p=ns). In group A mitral regurgitation was absent in 23 patients, mild in 21, moderate in 6, while in group B it was absent in 4, mild in 6, and moderate in 2 (p=ns). In both groups there were no cases of severe insufficiency. The mean gradient was 1.1+/-1.7 mmHg in group A (median=0), and 2.4+/-3.1 mmHg in group B (median=0), (p=ns). No case of systolic anterior movement was seen at mid-term. The event free-survival rate was 92.8% in group A and 92.3% in B. CONCLUSIONS: Perfecting and innovation of surgical techniques make possible nowadays to reach good and equivalent operative and mid-term results in both pathologies.     

Comparison of atlas- and magnetic resonance imaging-based stereotactic targeting of the globus pallidus internus in the performance of deep brain stimulation for treatment of dystonia

OBJECT: To assess the validity of relying on atlases during stereotactic neurosurgery, the authors compared target coordinates in the globus pallidus internus (GPi) obtained using magnetic resonance (MR) imaging with those determined using an atlas. The targets were used in deep brain stimulation (DBS) for the treatment of generalized dystonia. METHODS: Thirty-five patients, who were treated using bilateral DBS of the GPi, were included in this study. The target was selected on three-dimensional MR images by direct visual recognition of the GPi. The coordinates were automatically recorded using dedicated software. They were translated into the anterior commissure-posterior commissure (AC-PC) coordinate system by using a matrix transformation process. The same GPi target was defined, based on the locations of brain structures shown in the atlases of Schaltenbrand and Talairach. Magnetic resonance imaging-based GPi target coordinates were statistically compared with the corresponding atlas-based coordinates by applying the Student t-test. A significant difference (p < 0.001) was demonstrated in x, y, and z directions between MR imaging-based and Schaltenbrand atlas-derived target coordinates. The comparison with normalized Talairach atlas coordinates demonstrated a significant difference (p < 0.01) in the y and z directions, although not in the x direction (p = 0.12). No significant correlation existed between MR imaging-based target coordinates and patient age (p > 0.1). No significant correlation was observed between MR imaging-based target coordinates and patient sex in the y and z directions (p > 0.9), although it was significant in the x direction (p < 0.05). A significant variation in coordinates and the length of the AC-PC line was revealed only in the y direction (p < 0.005). CONCLUSIONS: A significant difference was found between target coordinates obtained by direct visual targeting on MR images (validated by postoperative clinical results) and those obtained by indirect targeting based on atlases.     

Anthropometric measurements of infants and under five children in Riyadh City

The data presented in this paper are part of the ongoing pediatric nutrition surveillance in ten primary health centers from Riyadh City. A total of 21,507 infants and children under five were included. The mean birth weight was 3027 g, and 8.6% of the children had low birth weights. The measurements showed that there had been no obvious change in the weights and heights of children during the past 13 years. In our results the children classified as moderate and severely underweight were 4.5% and 0.8% respectively. The data showed the average growth of all infants, regardless of feeding pattern, was same or faster than the NCHS reference population, up to approximately six months of age after which their growth became slower than that of the NCHS standards. The prevalence of malnutrition in Saudi Arabia is moderately high, in spite of the high per capita income, and the fact that the government subsidizes locally produced and imported food items. The malnutrition among this age group may be attributed to reproductive or social behavior and genetic factors. The reduction of malnutrition in the last ten years could be largely due to the nutrition and health education programs. There is a need for more comprehensive nutritional health education among the local population.     

Epidemiological features of uterine rupture in West Africa (MOMA Study)

The aim of the study was (1) to assess the incidence of uterine rupture in West Africa; (2) to identify its risk factors there; (3) to assess their predictiveness. The study (MOMA study) was prospective and population based. Data on a large cohort of pregnant women were collected. Univariable and multivariable analysis was used including stepwise logistic regression. We identified 25 cases of clinically symptomatic uterine rupture in a population of 20 326 pregnant women giving an incidence rate of 1.2 uterine ruptures per 1000 deliveries. Five variables were significantly associated with uterine rupture (in both the univariable and multivariable analyses): uterine scars, malpresentation, limping, cephalopelvic disproportion and high parity (>or=7). In conclusion, the incidence of uterine rupture is high in West Africa, even in large cities where essential obstetric care is available and despite the low prevalence of uterine scars. A uterine scar multiplies the risk of uterine rupture by 11. Uterine rupture cannot be predicted from currently known risk factors, including uterine scars. The high case fatality rate (33.3%) and the associated perinatal mortality (52%) bear witness to the absence or inadequacy of health facilities in providing essential obstetric care and to the poor quality of maternal health care, even in major cities.     

Cell permeable BH3-peptides overcome the cytoprotective effect of Bcl-2 and Bcl-X(L)

Peptides corresponding to the BH3 domains of Bax (BaxBH3) or Bcl-2 (Bcl2BH3) are potent inducers of apoptosis when fused to the Atennapedia plasma membrane translocation domain (Ant). BaxBH3Ant and Bcl2BH3Ant caused a mitochondrial membrane permeabilization (MMP) and apoptosis, via a mechanism that was not inhibited by overexpressed Bcl-2 or Bcl-X(L), yet partially inhibited by cyclosporin A (CsA), an inhibitor of the mitochondrial permeability transition pore. When added to isolated mitochondria, BaxBH3 and Bcl2BH3 induced MMP, which was inhibited by CsA. However, Bcl-2 or Bcl-X(L) failed to inhibit MMP induced by BaxBH3 and Bc2BH3 in vitro, while they efficiently suppressed the induction of MMP by the Vpr protein (from human immunodeficiency virus-1), a ligand of the adenine nucleotide translocator (ANT). BaxBH3 but not Bcl2BH3 was found to interact with ANT, and only BaxBH3 (not Bcl2BH3) permeabilized ANT proteoliposomes and induced ANT to form non-specific channels in electrophysiological experiments. In contrast, both BaxBH3 and Bcl2BH3 were able to stimulate channel formation by recombinant Bax protein. Thus, BaxBH3 might induce MMP via an action on at least two targets, ANT and Bax-like proteins. In contrast, Bcl2BH3 would elicit MMP in an ANT-independent fashion. In purified mitochondria, two ligands of ANT, bongkrekic acid and the protein vMIA from cytomegalovirus, failed to prevent MMP induced by BaxBH3 or Bcl2BH3. In conclusion, BaxBH3 and Bcl2BH3 induce MMP and apoptosis through a mechanism which overcomes cytoprotection by Bcl-2 and Bcl-X(L).     

Hypoglycaemic effect of the lyophilised aqueous extract of Ajuga iva in normal and streptozotocin diabetic rats

The purpose of this study was to examine the hypoglycaemic effect of the lyophilised aqueous extract of the whole plant of Ajuga iva (L.) Schreber (Labiatae) in normal and streptozotocin-induced diabetic rats. Single and repeated oral administration of the extract of Ajuga iva L (AI) at a dose of 10 mg/kg produced a slight and significant decrease in plasma glucose levels in normal rats 6 h after administration and after 3 weeks of treatment. AI reduced plasma glucose levels of streptozotocin diabetic rats from 337±9.3 to 102.2±17.7 mg/dl after 6 h of oral administration (P<0.001). Repeated oral administration of AI to streptozotocin diabetic rats significantly decreased the plasma glucose levels after 1 week of treatment (112±14.4 mg/dl at 1 week vs 337±9.3 mg/dl at the baseline values, (P<0.001). It continuously decreased thereafter and showed a rapid normalisation after 1 week of AI treatment. It is concluded that these results demonstrated that the water extract of the whole plant of AI possess a strong hypoglycaemic effect in diabetic rats, and support therefore, its traditional use in diabetes mellitus control.     

Autologous cell vaccine as a post operative adjuvant treatment for high-risk melanoma patients (AJCC stages III and IV). The new American Joint Committee on Cancer

This study evaluates the overall survival and disease free survival of melanoma patients that were treated with an autologous melanoma cell vaccine, administered as a post-operative adjuvant. Included are 43 patients with totally resected metastatic melanoma (28-AJCC stage III, 15-AJCC stage IV), with a median follow up of 34 months (6-62). The treatment consisted of eight doses of a vaccine made of 10-25x10(6) autologous melanoma cells either released from the surgical specimen or grown in cell cultures. Tumour cells were conjugated with hapten dinitrophenyl, mixed with Bacille Calmette Guérin and irradiated to 110 Gy. Both disease free survival and overall survival were found to be correlated with intensity of evolving delayed type hypersensitivity to subcutaneous injection of unmodified melanoma cells. Patients with a delayed type hypersensitivity reaction of > or =10 mm had a median disease free survival of 17 months (mean 35 months) and a mean overall survival of 63 months (median not reached). In contrast, patients with a negative or weak delayed type hypersensitivity had a median disease free survival of 9 months (relative risk of recurrence=4.5, P=0.001), and a median overall survival of 16 months (relative risk of death=15, P=0.001). Stage III patients with a positive delayed type hypersensitivity reaction had an improved disease free survival of 16 months and a mean overall survival of 38 months, whereas patients with a negative delayed type hypersensitivity had a median disease free survival of 7 months (relative risk=4.5, P=0.02) and a median overall survival of 16 months (relative risk=9.5, P=0.005). The adjuvant administration of autologous melanoma vaccine was associated with improved disease-free and overall survival to selected patients who successfully attained anti-melanoma reactivity as detected by positive delayed type hypersensitivity reactions to unmodified melanoma cells.     

Prevalence and clinical characteristics of migraine in France

OBJECTIVE: To determine the prevalence and clinical features of migraine and related headache types in France. METHODS: The authors recruited a population of subjects with headache representative of the national population using a stratified sampling method. They screened 10,585 subjects aged 15 and older who were representative of the general population. They identified 1,486 of these as having headaches, and these subjects were subsequently interviewed for information on clinical features, natural history, and functional impact of headache. The authors categorized subjects based on the International Headache Society (IHS) classification and assessed disability using the MIDAS questionnaire. RESULTS: The authors found a standardized prevalence for migraine (IHS categories 1.1 and 1.2) of 7.9% (11.2% for women and 4.0% for men) and 9.1% for migrainous disorder (IHS category 1.7). Migraine attacks were associated with a considerable degree of handicap in activities of daily living, with a MIDAS grade distribution of 74.7% (grade 1), 13.3% (grade 2), 7.7% (grade 3), and 4.3% (grade 4). The prevalence of migraine with MIDAS grade 3 or 4 was 1.6%. CONCLUSIONS: The prevalence of migraine (IHS categories 1.1 and 1.2) in France is 7.9%, and that of total migraine is 17.0%; this does not seem to have evolved over the past 10 years.