Improved diet quality and nutrient adequacy in children and adolescents with abdominal obesity after a lifestyle intervention

High rates of childhood obesity require integral treatment with lifestyle modifications that achieve weight loss. We evaluated a lifestyle intervention on nutrient adequacy and diet quality in children and adolescents with abdominal obesity. A randomized controlled trial was performed on 107 participants, assigned either to a usual care group or to an intensive care group that followed a moderate hypocaloric Mediterranean diet and received nutritional education. Intake adequacy was evaluated using Dietary Reference Intakes and diet quality through the Diet Quality Index for Adolescents (DQI-A), the Healthy Lifestyle Diet-Index (HLD-I) and the Mediterranean Diet Quality Index (KIDMED). Both groups achieved a significant reduction in BMI standard deviation score (BMI-SDS), glucose and total cholesterol levels. Intake of Calcium, Iodine and vitamin D were higher in the intensive care group, with enhanced compliance with recommendations. Higher dietary scores were associated with lower micronutrient inadequacy. DQI-A and HLD-I were significantly higher in the intensive care group vs. usual care group after the treatment. In conclusion, we observed that an intensive lifestyle intervention was able to reduce BMI-SDS in children with abdominal obesity. Furthermore, participants significantly improved dietary indices getting closer to the nutritional recommendations. Therefore, these diet quality indices could be a valid indicator to evaluate micronutrient adequacy.High rates of childhood obesity require integral treatment with lifestyle modifications that achieve weight loss. We evaluated a lifestyle intervention on nutrient adequacy and diet quality in children and adolescents with abdominal obesity. A randomized controlled trial was performed on 107 participants, assigned either to a usual care group or to an intensive care group that followed a moderate hypocaloric Mediterranean diet and received nutritional education. Intake adequacy was evaluated using Dietary Reference Intakes and diet quality through the Diet Quality Index for Adolescents (DQI-A), the Healthy Lifestyle Diet-Index (HLD-I) and the Mediterranean Diet Quality Index (KIDMED). Both groups achieved a significant reduction in BMI standard deviation score (BMI-SDS), glucose and total cholesterol levels. Intake of Calcium, Iodine and vitamin D were higher in the intensive care group, with enhanced compliance with recommendations. Higher dietary scores were associated with lower micronutrient inadequacy. DQI-A and HLD-I were significantly higher in the intensive care group vs. usual care group after the treatment. In conclusion, we observed that an intensive lifestyle intervention was able to reduce BMI-SDS in children with abdominal obesity. Furthermore, participants significantly improved dietary indices getting closer to the nutritional recommendations. Therefore, these diet quality indices could be a valid indicator to evaluate micronutrient adequacy

Levofloxacino. Experiencia clínica en tratamientos de larga duración de infecciones osteoarticulares

Se ha realizado un estudio con el fin de evaluar la eficacia y la tolerancia de la administración de larga duración de levofloxacino en el tratamiento de infecciones osteoarticulares. Se incluyeron 50 pacientes con una previsión inicial de realizar tratamiento antibiótico de duración superior a cuatro semanas, durante los años 1999-2001. El 46% de los pacientes eran varones y recibieron tratamiento con levofloxacino durante una media de 122,8 días. En el 83,7% de los pacientes evaluables (41/49 pacientes) la evolución fue satisfac- toria, por la desaparición o mejoría de la infección. Se realizaron controles médicos y analíticos seriados, sin objetivarse en ellos alte- raciones significativas. Cinco de los pacientes estudiados presenta- ron un total de 7 efectos adversos: molestias digestivas (3), micosis oral (1), petequias (1), parestesias (1) y erupción pruriginosa(1). En tres de ellos se suspendió el tratamiento por este motivo. Se concluye que levofloxacino es un fármaco eficaz y bien tolerado, por ello puede ser utilizado en el tratamiento de infecciones que requieran terapia prolongada.We evaluated the efficacy and safety profile of the long-term administration of levofloxacin in osteoarticular infections. For this purpose, 50 patients were included during the years 1999 to 2001 on an initial estimation to be under treatment with this antibiotic for at least 4 weeks. Forty six percent (46%) of patients were male and received treatment during a mean-time of 122.8 days. In forty one of a total of forty nine evaluable patients (83.7%) outcome was considered satisfactory with a total recovery or improvement of disease. Clinical and analytical series of examinations were performed, with no significant abnormalities being observed. Five (5) patients presented a total of 7 adverse events: gastrointestinal intolerance (3), oral mycosis (1), petechia (1), parestesia (1) and pruriginous rash(1). Only in three cases interruption of therapy was considered necessary. In conclusion, levofloxacin presents an adequate efficacy and is a well-tolerated therapy; both characteristics make it an appropriate treatment for those infections that require long-term therapy

Randomized crossover pharmacokinetic evaluation of subcutaneous versus intravenous granisetron in cancer patients treated with platinum-based chemotherapy

BACKGROUND: 5-HT3-receptor antagonists are one of the mainstays of antiemetic treatment, and they are administered either i.v. or orally. Nevertheless, sometimes neither administration route is feasible, such as in patients unable to admit oral intake managed in an outpatient setting. Our objective was to evaluate the bioavailability of s.c. granisetron. PATIENTS AND METHODS: Patients receiving platinum-based chemotherapy were randomized to receive 3 mg of granisetron either s.c. or i.v. in a crossover manner during two cycles. Blood and urine samples were collected after each cycle. Pharmacokinetic parameters observed with each administration route were compared by analysis of variance. RESULTS: From May to November 2005, 31 patients were included and 25 were evaluable. Subcutaneous granisetron resulted in a 27% higher area under the concentration-time curve for 0-12 hours (AUC(0-12h)) and higher levels at 12 hours, with similar values for AUC(0-24h). The maximum concentration was lower with the s.c. than with the i.v. route and was observed 30 minutes following s.c. administration. CONCLUSION: Granisetron administered s.c. achieves complete bioavailability. This is the first study that shows that s.c. granisetron might be a valid alternative to i.v. delivery. Further trials to confirm clinical equivalence are warranted. This new route of administration might be especially relevant for outpatient management of emesis in cancer patients

Fluorescence polarisation activity-based protein profiling for the identification of deoxynojirimycin-type inhibitors selective for lysosomal retaining alpha- and beta-glucosidases

Lysosomal exoglycosidases are responsible for processing endocytosed glycans from the non-reducing end to produce the corresponding monosaccharides. Genetic mutations in a particular lysosomal glycosidase may result in accumulation of its particular substrate, which may cause diverse lysosomal storage disorders. The identification of effective therapeutic modalities to treat these diseases is a major yet poorly realised objective in biomedicine. One common strategy comprises the identification of effective and selective competitive inhibitors that may serve to stabilize the proper folding of the mutated enzyme, either during maturation and trafficking to, or residence in, endo-lysosomal compartments. The discovery of such inhibitors is greatly aided by effective screening assays, the development of which is the focus of the here-presented work. We developed and applied fluorescent activity-based probes reporting on either human GH30 lysosomal glucosylceramidase (GBA1, a retaining & beta;-glucosidase) or GH31 lysosomal retaining & alpha;-glucosidase (GAA). FluoPol-ABPP screening of our in-house 358-member iminosugar library yielded compound classes selective for either of these enzymes. In particular, we identified a class of N-alkyldeoxynojirimycins that inhibit GAA, but not GBA1, and that may form the starting point for the development of pharmacological chaperone therapeutics for the lysosomal glycogen storage disease that results from genetic deficiency in GAA: Pompe disease.NWOChemThemMedical BiochemistryBio-organic Synthesi

Consequences of excessive glucosylsphingosine in glucocerebrosidase-deficient zebrafish

In Gaucher disease (GD), the deficiency of glucocerebrosidase causes lysosomal accumulation of glucosylceramide (GlcCer), which is partly converted by acid ceramidase to glucosylsphingosine (GlcSph) in the lysosome. Chronically elevated blood and tissue GlcSph is thought to contribute to symptoms in GD patients as well as to increased risk for Parkinson's disease. On the other hand, formation of GlcSph may be beneficial since the water soluble sphingoid base is excreted via urine and bile. To study the role of excessive GlcSph formation during glucocerebrosidase deficiency, we studied zebrafish that have two orthologs of acid ceramidase, Asah1a and Asah1b. Only the latter is involved in the formation of GlcSph in glucocerebrosidase-deficient zebrafish as revealed by knockouts of Asah1a or Asah1b with glucocerebrosidase deficiency (either pharmacologically induced or genetic). Comparison of zebrafish with excessive GlcSph (gba1-/- fish) and without GlcSph (gba1-/-:asah1b-/- fish) allowed us to study the consequences of chronic high levels of GlcSph. Prevention of excessive GlcSph in gba1-/-:asah1b-/- fish did not restrict storage cells, GlcCer accumulation, or neuroinflammation. However, GD fish lacking excessive GlcSph show an ameliorated course of disease reflected by significantly increased lifespan, delayed locomotor abnormality, and delayed development of an abnormal curved back posture. The loss of tyrosine hydroxylase 1 (th1) mRNA, a marker of dopaminergic neurons, is slowed down in brain of GD fish lacking excessive GlcSph. In conclusion, in the zebrafish GD model, excess GlcSph has little impact on (neuro)inflammation or the presence of GlcCer-laden macrophages but rather seems harmful to th1-positive dopaminergic neurons.Animal science

Role of β-glucosidase 2 in aberrant glycosphingolipid metabolism: model of glucocerebrosidase deficiency in zebrafish

β-glucosidases (GBA1 [glucocerebrosidase], GBA2, and GBA3) are ubiquitous, essential enzymes. Lysosomal GBA1 and cytosol-facing GBA2 degrade glucosylceramide (GlcCer); GBA1 deficiency causes Gaucher disease (GD), a lysosomal storage disorder characterized by lysosomal accumulation of GlcCer, which is partly converted to glucosylsphingosine (GlcSph). GBA1 and GBA2 also may transfer glucose from GlcCer to cholesterol, yielding glucosylated cholesterol (GlcChol). Here, we aimed to clarify the role of zebrafish Gba2 in glycosphingolipid metabolism during Gba1 deficiency in zebrafish (Danio rerio), which are able to survive total Gba1 deficiency. We developed Gba1 and Gba2 zebrafish knockouts (gba1-/- and gba2-/-, respectively) using CRISPR/Cas9, modulated glucosidases genetically and pharmacologically, studied GlcCer metabolism in individual larvae, and explored the feasibility of pharmacologic or genetic interventions. Activity-based probes and quantification of relevant glycolipid metabolites confirmed enzyme deficiency. GlcSph increased in gba1-/- larvae (0.09 pmol/fish) but did not increase more in gba1-/-:gba2-/- larvae. GlcCer was comparable in gba1-/- and wild-type (WT) larvae but increased in gba2-/- and gba1-/-:gba2-/- larvae. Independent of Gba1 status, GlcChol was low in all gba2-/- larvae (0.05 vs. 0.18. pmol/fish in WT). Pharmacologic inactivation of zebrafish Gba1 comparably increased GlcSph. Inhibition of glucosylceramide synthase in Gba1-deficient larvae reduced GlcCer and GlcSph, and concomitant inhibition of glucosylceramide synthase and Gba2 with iminosugars also reduced excessive GlcChol. Finally, overexpression of human GBA1 and injection of recombinant GBA1 both decreased GlcSph. We determined that zebrafish  larvae offer an attractive model to study glucosidase actions in glycosphingolipid metabolism in vivo, and we identified distinguishing characteristics of zebrafish Gba2 deficiency. Animal science

Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors

Medical BiochemistryBio-organic Synthesi

Randomized pharmacokinetic study comparing subcutaneous and intravenous palonosetron in cancer patients treated with platinum based chemotherapy

BACKGROUND: Palonosetron is a potent second generation 5- hydroxytryptamine-3 selective antagonist which can be administered by either intravenous (IV) or oral routes, but subcutaneous (SC) administration of palonosetron has never been studied, even though it could have useful clinical applications. In this study, we evaluate the bioavailability of SC palonosetron. PATIENTS AND METHODS: Patients treated with platinum-based chemotherapy were randomized to receive SC or IV palonosetron, followed by the alternative route in a crossover manner, during the first two cycles of chemotherapy. Blood samples were collected at baseline and 10, 15, 30, 45, 60, 90 minutes and 2, 3, 4, 6, 8, 12 and 24 h after palonosetron administration. Urine was collected during 12 hours following palonosetron. We compared pharmacokinetic parameters including AUC0-24h, t1/2, and Cmax observed with each route of administration by analysis of variance (ANOVA). RESULTS: From October 2009 to July 2010, 25 evaluable patients were included. AUC0-24h for IV and SC palonosetron were respectively 14.1 and 12.7 ng × h/ml (p = 0.160). Bioavalability of SC palonosetron was 118% (95% IC: 69-168). Cmax was lower with SC than with IV route and was reached 15 minutes following SC administration. CONCLUSIONS: Palonosetron bioavailability was similar when administered by either SC or IV route. This new route of administration might be specially useful for outpatient management of emesis and for administration of oral chemotherapy