Prevalence of sarcopenia in a population of nursing home residents according to their frailty status: results of the SENIOR cohort.

OBJECTIVE: To investigate the relationship between frailty and sarcopenia, by evaluating the prevalence of sarcopenia among frail, pre-frail and robust elderly nursing home residents in Belgium. METHODS: This is an analysis of baseline data collected from the SENIOR (Sample of Elderly Nursing home Individuals: an Observational Research) cohort. All subjects received a sarcopenia evaluation, based on the definition proposed by the European Working Group on Sarcopenia in Older People (EWGSOP). The frailty evaluation was primarily based on FRIED's definition but also on 9 other operational definitions. RESULTS: A total of 662 subjects (73.1% of women) were included in this analysis (mean age: 83.2±8.99 years). The prevalence of sarcopenia was 38.1% whereas the prevalence of frail and pre-frail persons was respectively 24.7% and 61.4%. Among frail, pre-frail and robust subjects, respectively 47%, 38.9% and 16.3% were diagnosed sarcopenic. The prevalence of sarcopenia according to ten different operational definitions of frailty ranged between 32.8 % (i.e. Frail scale Status and Frailty Index) and 47% (i.e. Fried definition). CONCLUSION: This research highlights that over a third of nursing home residents are sarcopenic and the percentage is almost 50% among frail subjects; those latter constitute about 1 in 4 of the population of nursing home residents studied here.

Signalling properties and pharmacology of a 5-HT7 -type serotonin receptor from Tribolium castaneum.

In the last decade, genome sequence data and gene structure information on invertebrate receptors has been greatly expanded by large sequencing projects and cloning studies. This information is of great value for the identification of receptors; however, functional and pharmacological data are necessary for an accurate receptor classification and for practical applications. In insects, an important group of neurotransmitter and neurohormone receptors, for which ample sequence information is available but pharmacological information is missing, are the biogenic amine G protein-coupled receptors (GPCRs). In the present study, we investigated the sequence information, pharmacology and signalling properties of a 5-HT7 -type serotonin receptor from the red flour beetle, Tribolium castaneum (Trica5-HT7 ). The receptor encoding cDNA shows considerable sequence similarity with cognate 5-HT7 receptors and phylogenetic analysis also clusters the receptor within this 5-HT receptor group. Real-time reverse transcription PCR demonstrated high expression levels in the brain, indicating the possible importance of this receptor in neural processes. Trica5-HT7 was dose-dependently activated by 5-HT, which induced elevated intracellular cyclic AMP levels but had no effect on calcium signalling. The synthetic agonists, α-methyl 5-HT, 5-methoxytryptamine, 5-carboxamidotryptamine and 8-hydroxy-2-(dipropylamino)tetralin hydrobromide, showed a response, although with a much lower potency and efficacy than 5-HT. Ketanserin and methiothepin were the most potent antagonists. Both showed characteristics of competitive inhibition on Trica5-HT7 . The signalling pathway and pharmacological profile offer important information that will facilitate functional and comparative studies of 5-HT receptors in insects and other invertebrates. The pharmacology of invertebrate 5-HT receptors differs considerably from that of vertebrates. The present study may therefore contribute to establishing a more reliable classification of invertebrate 5-HT receptors.

Analytical aspects of marinobufagenin.

Marinobufagenin (MBG), a steroid compound belonging to the bufadienolide cardiac inotropes, is a molecule enjoying a growing interest in the early diagnostic of volume expansion-mediated hypertensive states. This endogenous mammalian cardiotonic and natriuretic bufadienolide (characterized by vasoconstrictive activities) inhibits the α1 isoform of Na(+), K(+)-ATPase, implicating it in series of pathophysiological circumstances such as volume-expansion, essential hypertension and preeclampsia. Indeed, the enhanced production of MBG in preeclamptic patients has been confirmed in several studies, leading us to consider MBG as a biomarker for preeclampsia. The main source for MBG is located in the parotid and skin gland secretions of the toad Bufo marinus in which MBG is the major steroid cardiotonic component. This review emphasizes the key role of analytical development for dosage methods of MBG in biofluids, in the emergence of future perspectives in the diagnostic and therapeutic fields of preeclampsia (e.g. to investigate the biosynthetic origin of MBG and to better understand its implications).

Subset characterization of myeloid-derived suppressor cells arising during induction of BM chimerism in mice.

To date, myeloid-derived suppressor cells (MDSC) have been best studied in cancer, where they represent an escape mechanism for immune surveillance. MDSC are now also gaining interest in the context of transplantation. Suppressive CD11b(+) myeloid progenitor cells have been reported to expand endogenously during BM chimerism induction in mice; in particular, in irradiated MHC-matched BM chimeras and in parent-in-F1 BM chimeras. Myeloid cell expansion coincided with a time frame where donor lymphocyte infusion (DLI) therapy-mediated GVL effects without GVHD. Hypothesizing that regulatory myeloid cells may have a role in regulating post-transplant T-cell alloreactivity, we performed a detailed phenotypic and functional characterization of these cells in the parent-in-F1 C57BL/6 → [C57BL/6xDBA2] model. We found that transiently expanding CD11b(+) myeloid progenitor cells comprise the two phenotypically and functionally distinct mononuclear and polymorphonuclear MDSC subsets that were recently described in tumor-bearing mice. Both MDSC subsets suppressed in vitro and in vivo alloreactive T-cell proliferation. Also, both the subsets mediated enhanced in vitro suppression when harvested from chimeras, given a prior in vivo challenge with non-tolerant donor T cells, indicating that allo-activated T cells can activate MDSC in vivo. This study provides the basis to investigate the-potentially beneficial-role of expanding MDSC in influencing the risk of GVHD during chimerism induction.

Subclinical GvHD in non-irradiated F1 hybrids: severe lymphoid-tissue GvHD causing prolonged immune dysfunction.

GvHD is an important complication of allogeneic hematopoietic SCT. Parent-in-F1 models are frequently used to study GvHD immunobiology; the characteristics of parent-in-F1 GvHD vary between strain combinations and induction protocols. Here, we observed that a high-dose challenge of non-irradiated B6DBA2F1 and B6SJLF1 recipients with C57BL/6 splenocytes left the majority of recipients clinically healthy, while inducing progressive high-grade donor T-cell chimerism. We investigated this previously undescribed pattern of parent-in-F1 T-cell alloreactivity and studied the effect of serial parental splenocyte infusions on epithelial and lymphohematopoietic tissues. The majority of recipients of 4 weekly splenocyte infusions showed long-term survival with gradual establishment of high-grade donor chimerism and without any signs of epithelial-tissue GvHD. A minority of recipients showed BM failure type of GvHD and, respectively, graft rejection. Moreover, long-term F1 chimeras showed protracted pancytopenia, and in peripheral lymphoid tissues severe lymphopenia and near-complete eradication of APCs and dysfunction in antigen-presenting capacity in remaining APC. Hematopoiesis and lymphoid tissue composition recovered only after multilineage donor chimerism had established. In conclusion, we report on a novel type of parent-in-F1 hybrid GvHD, where a cumulative high dose of C57BL/6 parental splenocytes in non-irradiated F1 mice induces subclinical but severe hematolymphoid-tissue GvHD, causing prolonged immuno-incompetence.

Prevention of relapse by mesalazine (Pentasa) in pediatric Crohn's disease: a multicenter, double-blind, randomized, placebo-controlled trial.

AIM: This study aimed to test the efficacy of mesalazine in maintaining remission in pediatric Crohn's disease (CD) following successful flare-up treatment. METHODS: In this double-blind, randomized, placebo-controlled trial, 122 patients received either mesalazine 50mg/kg per day (n=60) or placebo (n=62) for one year. Treatment allocation was stratified according to flare-up treatment (nutrition or medication alone). Recruitment was carried out over two periods, as the first period's results showed a trend favoring mesalazine. Relapse was defined as a Harvey-Bradshaw score more than or equal to 5. Time to relapse was analyzed using the Cox model. RESULTS: The one-year relapse rate was 57% (n=29) and 63% (n=35) in the mesalazine and placebo groups, respectively. We demonstrated a twofold lower relapse risk (P<0.02) in patients taking mesalazine in the medication stratum (first recruitment period), and a twofold higher risk in patients taking mesalazine in the nutrition stratum (second recruitment period), compared with the other groups. None of the children's characteristics, which differed across the two recruitment periods, accounted for the between-period variation in mesalazine efficacy. One serious adverse event was reported in each treatment group. CONCLUSION: Overall, mesalazine does not appear to be an effective maintenance treatment in pediatric CD.

Allogeneic bone marrow transplantation and donor lymphocyte infusion in a mouse model of irradiation-induced myelodysplastic/myeloproliferation syndrome (MD/MPS): evidence for a graft-versus-MD/MPS effect.

The role of graft-versus-malignancy reactivity in the effects of allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusion (DLI) for myelodysplastic syndromes is as yet not well established. Clinical data are limited and animal models are scarce. Here, we report on the effects of allogeneic bone marrow transplantation (alloBMT) and DLI in a novel model of irradiation-induced murine myelodysplastic/myeloproliferation syndrome (MD/MPS). Total body irradiation with 8.5 Gy in SJL/J mice gave rise to a lethal wasting syndrome in 60% of mice, characterized by 1 degrees normocellular bone marrow with dysplastic features in erythroid, myeloid and megakaryocytic cell lineages, 2 degrees lymphosplenomegaly with spleens harboring a prominent extramedullary hematopoiesis with erythroid, myeloid and megakaryocytic lineages exhibiting dysplastic features, and foci of dysplastic hematomyelopoiesis in the liver, 3 degrees peripheral thrombocytopenia and 4 degrees evidence of disseminated infection or leukemic transformation in selected animals. This clinicopathological picture was consistent with a murine form of MD/MPS. Syngeneic or allogeneic (BALB/c) T cell-depleted BMT could not prevent the occurrence of lethal MD/MPS. In contrast, DLI at weeks 2-4 after BMT led to restoration of the dysbalanced hematomyelopoiesis. However, severe DLI-induced acute graft-versus-host disease occurred, precluding a survival advantage. We present evidence of the existence of a post-alloBMT DLI-induced graft-versus-MD/MPS effect in murine irradiation-induced MD/MPS.

CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease.

We studied the effect of CTLA-4 blockade on graft-versus-leukemia and graft-versus-host responses in a mouse model of minor histocompatibility-mismatched bone marrow transplantation. Early CTLA-4 blockade induced acute graft-versus-host disease. Delayed CTLA-4 blockade resulted in a lethal condition with lymphosplenomegaly, but with stable mixed T-cell chimerism, unchanged alloreactive T-cell frequencies and absent anti-host reactivity in vitro. In contrast, multiorgan lymphoproliferative disease with autoimmune hepatitis and circulating anti-DNA auto-antibodies were documented. Splenic lymphocytes exhibited ex vivo spontaneous proliferation and a marked proliferative response against host-type dendritic cells pulsed with syngeneic (host-type) tissue-peptides. Both phenomena were exclusively mediated by host and not donor T cells, supporting an autoimmune pathogenesis. Selectively host-derived T-cell immune reactivity was equally documented against leukemia-peptide-pulsed dendritic cells, and this was paralleled by a strong in vivo antileukemic effect in anti-CTLA-4-treated and subsequently leukemia-challenged chimeras. In conclusion, delayed CTLA-4 blockade induced a host-derived antileukemic effect, occurring in the context of an autoimmune syndrome and strictly separated from graft-versus-host disease. Both antileukemic and autoimmune responses depended on the allogeneic component, as neither effect was seen after syngeneic bone marrow transplantation. Our findings reveal the potential of using CTLA-4 blockade to establish antileukemic effects after allogeneic hematopoietic stem cell transplantation, provided autoimmunity can be controlled.

Omeprazole combined with amoxicillin and clarithromycin in the eradication of Helicobacter pylori in children with gastritis: A prospective randomized double-blind trial.

OBJECTIVES: The aim of this multicenter prospective, randomized, double-blind study was to assess the efficacy of the combination of omeprazole, amoxicillin, and clarithromycin (OAC) for the treatment of Helicobacter pylori gastritis in children. STUDY DESIGN: Seventy-three children with dyspeptic symptoms were included in the trial (mean age 10.8 years; range, 3.3 to 15.4). Patients were randomized to receive OAC or amoxicillin and clarithromycin (AC) for 7 days. H pylori status was assessed before and 4 weeks after eradication treatment, by use of the carbon 13-labeled urea breath test. RESULTS: In intent-to-treat analysis (n = 63), eradication rates were 74.2% (95% CI, 58.7 to 89.6) in the OAC group and 9.4% (95% CI, 0 to 19.5) in the AC group. In per-protocol analysis (n = 53), the eradication rate increased to 80% (95% CI, 64.3 to 95.7), remaining significantly higher than in AC group (10.7%; 95% CI, 0 to 22.2). Resistance of strains to clarithromycin was rare (3/39 = 7.7%) and was not associated with failure of treatment. Adverse events were reported in 24.6% of patients and remained mild. CONCLUSION: This study shows that 1-week OAC triple therapy results in successful eradication of H pylori in 75% of children with gastritis.

The mannose binding lectin gene influences the severity of chronic liver disease in cystic fibrosis.

Chronic liver disease is a major complication of cystic fibrosis. Its incidence and severity show marked heterogeneity, even among the homogeneous group of homozygous DeltaF508 patients, suggesting that environmental or genetic factors other than the deletion DeltaF508 may influence the development of cystic fibrosis related liver disease. We investigated whether the allelic variants of mannose binding lectin, an important protein of the immune system, could be associated with the presence of cirrhosis in a population of 216 homogeneous homozygous DeltaF508 patients. Analysis of the data shows that the presence of cirrhosis in cystic fibrosis patients is significantly associated with a mutated mannose binding lectin genotype (homozygous or compound heterozygous for mannose binding lectin variants). The modulating role of mannose binding lectin in the occurrence of cirrhosis in cystic fibrosis could be explained by the fact that hepatotoxic damage from viruses or bacteria might be increased by the immunodeficiency associated with mannose binding lectin variants and might facilitate the degradation of liver status. These data highlight the crucial role of mannose binding lectin in the clinical outcome of cystic fibrosis, as it has recently been shown that the mannose binding lectin gene is a modulating gene of the respiratory involvement in cystic fibrosis patients.

[Incidence of symptomatic celiac disease in French children]. / Incidence de la maladie coeliaque symptomatique de l'enfant en France.

OBJECTIVE: The study was carried out by the GFHGNP to determine the annual incidence of symptomatic celiac disease in children. PATIENTS AND METHODS: The diagnostic criteria were: symptomatic patients diagnosed under 15 years of age during 1996, villous atrophy and positivity of antigliadin and/or other antibodies. Cases were collected from referral centers, general hospital pediatric departments and private pediatricians with endoscopic practice. RESULTS: The study involved roughly half of the French pediatric population in 41 out of the 95 French districts. In all, 124 patients were collected: 76 girls and 48 boys. By geographical areas, in 30 districts where collection of data was complete which counted 186,285 births, the yearly incidence varied from 1/1731 births to 1/3110. (0.57@1000 to 0.32@1000). On the whole there were 77 cases i.e. an annual incidence of 1/2419 or 0.41@1000 (confidence interval 95%: 0.32 to 0.50@1000). Lower incidences were observed in the district of Paris: 1/4865 (0.21@1000) and Lyon: 1/3310 (0.27@1000). Those lower incidences could be explained by the difficulties of collecting the data in the biggest urban areas. The first signs occurred before one year of age in 73% of the cases, during the second year of life in 20.5% and after 3 in only 6.5%. The diagnosis was made before 2 years of age in 77% of the cases and after 3 in only 13%. In order of frequency symptoms were: failure to thrive (80%), diarrhea (59%), anorexia (59%), abdominal distension (57%), weight under 2 standard deviations (43%), short stature (43%). CONCLUSION: Compared with previous studies in two French districts between 1975 and 1990, the annual incidence of symptomatic celiac disease in children appears to be on the rise. The usual clinical signs continue to be observed.

Evaluation of a Helicobacter pylori stool antigen test for the diagnosis and follow-up of infections in children.

The aim of this study was to evaluate the performance of a newly developed enzyme immunoassay kit (HpSA) for detecting Helicobacter pylori antigens in the stool of children. This study was comprised of 58 children referred to various endoscopy units for evaluation of gastrointestinal symptoms and upper gastroduodenal endoscopy and 11 children for post-therapy follow-up. In the first group, 23 children were diagnosed as positive for Helicobacter pylori using bacteriological and/or histological methods. Stool antigens were detected in 20 of these positive patients, for a sensitivity of 86.9% and a negative predictive value of 91.9%. Since only one false-positive reaction was observed with the HpSA kit, the specificity was 97.1% and the positive predictive value 95.2%. Results obtained for post-therapy follow-up were also promising. The HpSA assays were negative for the eight children whose infections were eradicated after therapy, and a positive result was obtained for two of three patients who had a persistent infection.

Liver disease in children with cystic fibrosis: US-biochemical comparison in 195 patients.

PURPOSE: To determine if abnormal liver architecture at ultrasonography (US) is related to abnormal function in children with cystic fibrosis (CF). MATERIALS AND METHODS: For 1 year, all 195 children (112 boys, 83 girls; mean age, 8.5 years) attending a CF clinic underwent abdominal US and a standard set of liver function tests. Aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltransferase levels were analyzed. US signs were interpreted as follows: hypoechogenicity with prominent portal tracks as edema, hyperechogenicity as steatosis, and increased attenuation and nodules within or at the edge of the liver as cirrhosis. Signs of portal hypertension also were sought. US signs were compared with liver function test results. RESULTS: Liver sonograms were abnormal in 38 children (19%); of these, 24 (63%) had abnormal test results. The 157 children with normal liver architecture had a much lower prevalence of biochemical abnormality (33 patients [21%]; P < or = .001). All eight children with signs of portal hypertension had abnormal test results. Fourteen (82%) of 17 children with signs of cirrhosis had abnormal liver function. Eight (57%) of 14 patients with signs of steatosis had abnormal function. Diffuse hypoechogenicity of the liver with prominent portal tracks in 16 patients was associated with abnormal function in only five patients. CONCLUSION: The relation between abnormal liver architecture at US and results of three liver function tests in children with CF was significant. The most specific US abnormalities related to abnormal function are signs suggestive of portal hypertension and cirrhosis.

Ursodeoxycholic acid improves the hepatic metabolism of essential fatty acids and retinol in children with cystic fibrosis.

OBJECTIVE: Several clinical trials of ursodeoxycholic acid (UDCA) have shown improvement of liver-function test results in cystic fibrosis (CF) with liver disease; however, there is no evidence that the long-term course will be affected. In view of the observations that UDCA can change the lipid profile and that patients with CF and liver disease are more likely to have essential fatty acid (EFA) deficiency, we elected to examine changes in the lipid profile and in the status of fat-soluble vitamins in response to UDCA. METHODS: Nineteen children with CF and liver dysfunction were recruited for a double-blind, crossover study of 1 year's duration, followed by treatment of the entire group. UDCA was administered at a dosage of 15 mg/kg per day, which, in the absence of a 50% decrease of alanine transaminase or aspartate transaminase or both within 2 months, was increased to 30 mg/kg per day. RESULTS: At entry, all patients had biochemical evidence of EFA deficiency. The lipid profiles during an average period of 25 months of follow-up showed a significant decrease in triglycerides (p <0.002), cholesterol (p <0.02), and total fatty acids (p <0.006). In addition, UDCA therapy led to an improvement in EFA status, as indicated by an increase (p <0.05) in the n-6 fatty acid concentration and a reduction (p <0.04) in the 20:3n-9/20:4n-6 fatty acid ratio. Although no change in vitamin E levels was observed, retinol metabolism was altered. There was an increase (p <0.02) in the unesterified retinol/retinol binding protein molar ratio in the absence of a difference in retinol binding protein concentration. Furthermore, retinyl esters, which normally account for less than 3% of circulating retinol, decreased (p <0.05) from 13.7% +/- 3.6% to 8.1% +/- 1.7%. CONCLUSIONS: This study confirms that UDCA alters lipoprotein metabolism and shows that it improves the EFA and retinol status of patients with CF and liver disease.

[Presymptomatic detection of familial colonic polyposis]. / Dépistage présymptomatique de la polypose colique familiale.

In familial adenomatous polyposis coli (APC) it is possible to detect APC carriers either by research of bilateral congenital hypertrophy of the retinal pigment epithelium (CHRPE) or by genetic diagnosis (APC gene is localized in 5q21). These detections were performed in 33 patients of four families with the same positivity for genetic typing (11 patients) or for CHRPE (11 patients) which thus avoided annual coloscopy.