Genetics and early disturbances of breathing control

Early disturbances in breathing control, including apneas of prematurity and apparently life-threatening events, account for some cases of sudden infant death syndrome and for a rare disorder called congenital central hypoventilation syndrome (CCHS). Data suggesting a genetic basis for CCHS have been obtained. Recently, we found heterozygous de novo mutations of the PHOX2B gene in 18 of 29 individuals with CCHS. Most mutations consisted of five to nine alanine expansions within a 20-residue polyalanine tract, probably resulting from nonhomologous recombination. Other mutations, generally inherited from one of the parents, in the coding regions of genes involved in the endothelin and RET signaling pathways and in the brain-derived-neurotrophic factor (BDNF) gene have been found in a few CCHS patients. Interestingly, all these genes are involved in the development of neural crest cells. Targeted disruption of these genes in mice has provided information on the pathophysiological mechanisms underlying CCHS. Despite the identification of these genes involved in breathing control, none of the genetically engineered mice developed to date replicate the full human CCHS respiratory phenotype. Recent insights into the genetic basis for CCHS may shed light on the genetics of other early disturbances in breathing control, such as apnea of prematurity and sudden infant death syndrome.     

Human granulocytic ehrlichiosis in Europe

Human granulocytic ehrlichiosis is an emerging infectious disease, which is transmitted by the tick Ixodes ricinus in Europe, like other diseases: Lyme disease, tick-borne encephalitis, babesiosis... This tick lives in the forest and its hematophagic activity ranges from April to October. Flu and febrile symptoms ten days after tick bite should suggest diagnosing the disease. Disease evolution is generally favorable, even if serious complications may occur. Leukopenia, thrombocytopenia, and elevated serum transaminases are common laboratory findings. Complementary assays useful for the diagnosis are: blood smear, indirect immunofluorescence, and polymerase chain reaction. Biological diagnostic criteria are more and more accurate, with the evolution of knowledge and technique. Tetracycline treatment generally leads to clinical and biological recovery. Informing physicians and occupationally exposed people should reinforce current prevention measures against tick bites.     

Deletion of 5q31 and 7q31 in patients with stable melphalan treated multiple myeloma

Multiple myeloma represents a malignant proliferation of plasma cells derived from a single clone. It is well known that alkylating agents are capable of inducing myelodysplastic syndromes (MDS) and acute myelocytic leukemias (AML). This risk of both diseases in patients with multiple myeloma has been estimated to be 10-20% after 10 years. We aimed to evaluate the time course and the type of genetic abnormalities in melphalan-treated patients in the chronic stage of the disease. We applied fluorescence in situ hybridization methods with probes to 5q31 and 7q31 to mononuclear peripheral blood leukocytes of 18 melphalan-treated patients and compared the results to those of 8 untreated myeloma patients. We found three patients (17%) with a 5q31 deletion in their peripheral white blood cells, but no 7q31 deletion. These findings suggest that 5q- occurs before the overt development of MDS/AML and raise important concerns regarding long-term treatment of myeloma patients with alkylating agents. Also, the performance of cytogenetic evaluation should be considered before autologous transplantation. The clinical and biological implications of these findings should be evaluated in larger clinical and laboratory studies.     

Relation between pain symptoms and the anatomic location of deep infiltrating endometriosis

OBJECTIVE: To investigate whether specific types of pelvic pain are correlated with the anatomic locations of deeply infiltrating endometriosis (DIE). DESIGN: Retrospective data analysis. SETTING: University tertiary referral center. PATIENT(S): Two hundred and twenty-five women with pelvic pain symptoms and DIE. INTERVENTION(S): During surgery, we recorded the anatomic locations of DIE implants and associated endometriosis. MAIN OUTCOME MEASURE(S): We studied the incidence of pelvic pain symptoms including severe dysmenorrhea, deep dyspareunia, noncyclic chronic pelvic pain, painful defecation during menstruation, urinary tract symptoms, and gastrointestinal symptoms as related to the location of DIE. RESULT(S): The frequency of severe dysmenorrhea increased with Douglas pouch adhesions and decreased with parity. The frequency of dyspareunia increased with a uterosacral ligament DIE location and decreased when it involved the bladder. The frequency of noncyclic chronic pelvic pain was higher when it involved the bowel and was lower for women who were treated for infertility. The frequency of painful defecation during menstruation was higher when DIE involved the vagina; lower urinary tract symptoms were more frequent when DIE involved the bladder and less frequent in women with a lower body mass index. Gastrointestinal symptoms were associated with bowel or vaginal DIE locations. CONCLUSION(S): The types of pelvic pain are related to the anatomic location of DIE. Knowledge of the characteristics of pelvic pain symptoms is important in the preoperative assessment of patients with suspected DIE.     

Facial appearance in persistent hyperinsulinemic hypoglycemia

Persistent hyperinsulinism is the most common cause of recurrent hypoglycemia in infancy because of inappropriate oversecretion of insulin by the pancreas. Pancreatic lesions can be either focal or diffuse, and they have distinct molecular bases. We have studied the facial features in 17 unrelated patients presenting with neonatal (n = 8) or infancy-onset (n = 9) hyperinsulinism. Hyperinsulinism was related to focal adenomatous hyperplasia (n = 7), diffuse hyperinsulinism (n = 5), non-operated hyperinsulinism (n = 2), and hyperinsulinism with hyperammonemia (n = 3). SUR1 or Kir6.2 mutations were found in six of seven focal adenomatous hyperplasia and three of five diffuse hyperinsulinism. A loss of the maternal allele from chromosome 11p15 in the lesion was found in all focal adenomatous hyperplasia. GLUD1 mutations were found in all patients with hyperammonemia. Large birth weight (mean > 3,800 g) was consistently observed (11/17) but protruding tongue, exomphalos, or visceromegaly were never noted and Wiedemann-Beckwith syndrome could always be ruled out. All patients presented with high forehead, small nasal tip, and short columella giving the impression that the nose is large and bulbous, smooth philtrum, and thin upper lip. A square appearance to the face was more obvious in younger patients. These specific facial features, observed in patients with hyperinsulinism of various molecular mechanisms, could be the consequence of fetal intoxication by insulin. However, to date, facial anomalies have not been noted in infants of diabetic mothers and inversely, malformations that are commonly reported in infants of diabetic mothers were not present in our hyperinsulinemic patients.     

Open-label trial of riluzole in generalized anxiety disorder

OBJECTIVE: There is a need to identify novel pharmacotherapies for anxiety disorders. The authors examined the safety and efficacy of riluzole, an antiglutamatergic agent, in adult outpatients with generalized anxiety disorder. METHOD: In an 8-week, open-label, fixed-dose study, 18 medically healthy patients with DSM-IV generalized anxiety disorder received treatment with riluzole (100 mg/day) following a 2-week drug-free period. The primary efficacy measure was the Hamilton Anxiety Rating Scale (HAM-A) score at endpoint. RESULTS: Twelve of the 15 patients who completed the trial responded positively to riluzole. At 8 weeks, eight of the 15 patients had HAM-A score indicating remission of their anxiety. The median time to response was 2.5 weeks. CONCLUSIONS: Riluzole appears to be an effective, well-tolerated, and rapidly acting anxiolytic medication for some patients with generalized anxiety disorder. Larger, placebo-controlled studies are indicated.     

Effect of several growth factors on canine flexor tendon fibroblast proliferation and collagen synthesis in vitro

PURPOSE: Growth factor delivery may be useful to accelerate the rate of tendon healing. Before in vivo use, however, the effects of growth factors on tendon cells need to be well characterized. The purpose of this study was to evaluate the effects of 4 growth factors on intrasynovial tendon fibroblast proliferation and collagen production in vitro. Our first hypothesis was that platelet-derived growth factor BB (PDGF-BB) and basic fibroblast growth factor (bFGF) would promote cell proliferation and collagen production. Our second hypothesis was that there would be a positive effect from the combination of PDGF-BB and bFGF. METHODS: The growth factors PDGF-BB, bFGF, vascular endothelial growth factor (VEGF), and bone morphogenetic protein 2 (BMP-2) were evaluated in vitro with canine flexor tendon fibroblasts. The effects of single factors (PDGF-BB, bFGF, VEGF, or BMP-2) or a combination of factors (PDGF-BB and bFGF) on cell proliferation (ie, thymidine incorporation) and collagen production (ie, proline incorporation) were evaluated. RESULTS: The results supported our hypotheses. Cell proliferation increased significantly with PDGF-BB and bFGF. Collagen production also increased significantly with PDGF-BB and bFGF. Cell proliferation and collagen production were unchanged with VEGF and BMP-2. A dose-response effect was seen for PDGF-BB combined with bFGF. The combination of PDGF-BB and bFGF led to an increase in cell proliferation but no change in collagen production compared with each factor alone. CONCLUSIONS: The growth factors PDGF-BB and bFGF significantly increased flexor tendon fibroblast proliferation and matrix synthesis when applied singly. Administration of PDGF-BB and bFGF combined led to increased proliferation to single factors.     

Interactions between traditional regional determinants and socio-economic status on dietary patterns in a sample of French men

The aim of the present study was to assess the respective contributions of regional and socio-economic factors to dietary pattern. We used the data from the final MONICA (MONItoring of trends and determinants in Cardiovascular disease) population survey conducted in the three French centres in 1995-7 among a representative sample of 976 men aged 45-64 years. Dietary intake was assessed using a 3-d record method. Dietary patterns were identified by a factor analysis, based on fifteen food items. An analysis of variance was then used to study their relationship with regional and socio-economic determinants. Two major dietary patterns were identified: a 'Western diet', characterized by high intakes of sugar and sweets, grains, butter, added fats, eggs, potatoes and cheese; a 'prudent diet', mainly distinguished by high intakes of fruit, vegetables, olive oil and fish and low intakes of alcohol, high-fat meat and potatoes. Strong associations were mostly observed with the 'prudent diet' pattern, with a significant relationship with region, educational and income-tax levels, leisure-time physical activity and smoking status. There was also a statistically significant interaction between region and educational level (P=0.05), and between region and income-tax level (P=0.03), indicating that the influence of socio-economic factors is different among regions. In conclusion, these results indicate large regional and socio-economic differences in the dietary patterns of this French male population. When considering the 'prudent diet' pattern, they also suggest that traditional regional influences may now be overcome by socio-economic determinants.     

Dendritic cell-derived exosomes in cancer immunotherapy: exploiting nature's antigen delivery pathway

Dendritic cells release large quantities of exosomes, known as dexosomes. These dexosomes are heat-stable, small vesicles (60-90 nm in diameter) made up of a lipid bilayer displaying an enrichment in sphingomyelin and a decrease in phosphatidylcholine content with no measurable asymmetry. They incorporate a characteristic set of proteins, including a large quantity of tetraspanins such as CD9 and CD81, all the known antigen presenting molecules (major histocompatibility complex class I and II, CD1 a, b, c and d) and the costimulatory molecule CD86. The function of dexosomes is to transfer antigen-loaded major histocompatibility complex class I and II molecules, and other associated molecules, to naive dendritic cells, potentially leading to the amplification of the cellular immune response. In preclinical mouse models, antigen-loaded dexosomes elicit strong antitumor activity. Human dexosomes can be prepared ex vivo relatively easily from dendritic cells derived from monocytes isolated by leukapheresis of healthy individuals or cancer patients. The feasibility of using dexosomes as a cancer therapeutic vaccine has been tested in two Phase I clinical studies in melanoma and lung cancer patients, respectively. These studies demonstrate that dexosomes can be prepared from cancer patient blood cells and be safely administered. Clinical observations suggested that dexosomes can stimulate both the adaptive (T-cells) and innate (natural killer cells) cellular immune responses. This review focuses on the perspective of using dexosomes in cancer immunotherapy. Concepts for using the exosome pathway in other possible pharmacologic applications are also discussed.