AIM:To assesses the safety and efficacy of Aspergillus niger prolyl endoprotease(AN-PEP)to mitigate the im-munogenic effects of gluten in celiac patients.METHODS:Patients with initial diagnosis of celiac disease as co...AIM:To assesses the safety and efficacy of Aspergillus niger prolyl endoprotease(AN-PEP)to mitigate the im-munogenic effects of gluten in celiac patients.METHODS:Patients with initial diagnosis of celiac disease as confirmed by positive serology with subtotal or total villous atrophy on duodenal biopsies who adhere to a strict gluten-free diet(GFD)resulting in normalised antibodies and mucosal healing classified as Marsh 0 orⅠwere included.In a randomised double-blind placebo-controlled pilot study,patients consumed toast(approximately 7 g/d gluten)with AN-PEP for 2 wk(safety phase).After a 2-wk washout period with adherence of the usual GFD,14 patients were randomised to gluten intake with either AN-PEP or placebo for 2 wk(efficacy phase).Measurements at baseline included complaints,quality-of-life,serum antibodies,immunophenotyping of T-cells and duodenal mucosa immunohistology.Furthermore,serum and quality of life questionnaires were collected during and after the safety,washout and efficacy phase.Duodenal biopsies were collected after the safety phase and after the efficacy phase.A change in histological evaluation according to the modified Marsh classification was the primary endpoint.RESULTS:In total,16 adults were enrolled in the study.No serious adverse events occurred during the trial and no patients withdrew during the trial.The mean score for the gastrointestinal subcategory of the celiac disease quality(CDQ)was relatively high throughout the study,indicating that AN-PEP was well tolerated.In the efficacy phase,the CDQ scores of patients consuming gluten with placebo or gluten with AN-PEP did not significantly deteriorate and moreover no differences between the groups were observed.During the efficacy phase,neither the placebo nor the AN-PEP group developed significant antibody titers.The IgA-EM concentrations remained negative in both groups.Two patients were excluded from entering the efficacy phase as their mucosa showed an increase oftwo Marsh steps after the safety phase,yet with undetectable serum antibodies,while 14 patients were considered histologically stable on gluten with AN-PEP.Also after the efficacy phase,no significant deterioration was observed regarding immunohistological and flow cytometric evaluation in the group consuming placebo compared to the group receiving AN-PEP.Furthermore,IgA-tTG deposit staining increased after 2 wk of gluten compared to baseline in four out of seven patients on placebo.In the seven patients receiving AN-PEP,one patient showed increased and one showed decreased IgA-tTG deposits.CONCLUSION:AN-PEP appears to be well tolerated.However,the primary endpoint was not met due to lack of clinical deterioration upon placebo,impeding an effect of AN-PEP.展开更多
Fundamental organelles that occur in every cell type with the exception of mammal erythrocytes,the mitochondria are required for multiple pivotal processes that include the production of biological energy,the biosynth...Fundamental organelles that occur in every cell type with the exception of mammal erythrocytes,the mitochondria are required for multiple pivotal processes that include the production of biological energy,the biosynthesis of reactive oxygen species,the control of calcium homeostasis,and the triggering of cell death.The disruption of anyone of these processes has been shown to impact strongly the function of all cells,but especially of neurons.In this review,we discuss the role of the mitochondria impairment in the development of the neurodegenerative diseases Amyotrophic Lateral Sclerosis,Parkinson's disease and Alzheimer's disease.We highlight how mitochondria disruption revolves around the processes that underlie the mitochondria's life cycle:fusion,fission,production of reactive oxygen species and energy failure.Both genetic and sporadic forms of neurodegenerative diseases are unavoidably accompanied with and often caused by the dysfunction in one or more of the key mitochondrial processes.Therefore,in order to get in depth insights into their health status in neurodegenerative diseases,we need to focus into innovative strategies aimed at characterizing the various mitochondrial processes.Current techniques include Mitostress,Mitotracker,transmission electron microscopy,oxidative stress assays along with expression measurement of the proteins that maintain the mitochondrial health.We will also discuss a panel of approaches aimed at mitigating the mitochondrial dysfunction.These include canonical drugs,natural compounds,supplements,lifestyle interventions and innovative approaches as mitochondria transplantation and gene therapy.In conclusion,because mitochondria are fundamental organelles necessary for virtually all the cell functions and are severely impaired in neurodegenerative diseases,it is critical to develop novel methods to measure the mitochondrial state,and novel therapeutic strategies aimed at improving their health.展开更多
Background: With the introduction of new therapies in peri-and neonatology, the clinical picture of bronchopulmonary dysplasia (BPD) seems to alter. The consequences of this “new BPD”are of interest. Aim: To evaluat...Background: With the introduction of new therapies in peri-and neonatology, the clinical picture of bronchopulmonary dysplasia (BPD) seems to alter. The consequences of this “new BPD”are of interest. Aim: To evaluate cardiovascular findings during the surfactant era in very low birthweight (VLBW, birth weight <1500 g) schoolchildren with and without BPD. Methods: At 7-8 years of age, 34 VLBW children with BPD born in one hospital underwent blood pressure (BP) measurement, electrocardiography (ECG), two-dimensional Doppler and M-mode echocardiography, flow-volume spirometry and whole-body plethysmography. The age-and sex-matched control groups comprised 34 VLBW children without BPD (no-BPD group) and 34 term children (term group). Results: The mean(SD) diastolic BP was significantly higher in the no-BPD than in the BPD group (65(9) vs. 59(8) mm Hg, p<0.05). No clinically significant tricuspid regurgitations were found. The groups did not differ with respect to right ventricular systolic time intervals corrected for heart rate. The results of all M-mode measurements were within normal range. Compared to term controls, the BPD cases had lower mean(SD) forced expiratory flow in 1 s (90(14)%vs. 99(11)%of ref., p<0.05)-and more often high ratio of residual volume to total lung capacity (15(52%) vs. 4(13%), p<0.01). No clinically significant correlations were found between current lung function and echocardiographic findings. Conclusion: In the surfactant era, school-aged VLBW survivors with and without BPD do not seem to evince indirect signs of elevated pulmonary pressure. The increased pulmonary vascular resistance associated with BPD appears to resolve with time more rapidly than abnormalities in respiratory function.展开更多
Aim: To assess whether children with Noonan syndrome on long-term growth hormone (GH) therapy improve their final height to near mid-parental height. Methods: Twenty-five prepubertal children (13 girls) with Noonan sy...Aim: To assess whether children with Noonan syndrome on long-term growth hormone (GH) therapy improve their final height to near mid-parental height. Methods: Twenty-five prepubertal children (13 girls) with Noonan syndrome (NS) were studied. A single clinician made the diagnosis based on clinical criteria. GH treatment started at an age ranging from 3.1 to 13.8 y and was continued for at least 2 y. Improvement or “ gain” in final height (FH) was defined as either the difference between adult height SD scores (SDS) and pre-treatment height SDS (the childhood component of the Swedish reference) or height SDS compared to the Noonan reference. Results: Ten children received a GH dose of 33 μ g/kg/d (mean age at start 7.7 ± 2.1 y, mean age at stop 17.6 ± 1.7 y) and 15 received a dose of 66 μ g/kg/d(mean age at start 8.6 ± 3.3 y, mean age at stop 18.4 ± 2.1 y). Eighteen out of 25 patients reached FH. A substantial improvement in FH of 1.7 SDS, equivalent to 10.4 cm compared to pre-treatment height, was observed. No significant difference was seen between the two GH doses. Females gained a mean height of 9.8 cm and males 1-13 cm (FH 174.5 ± 7.8 cm vs mean adult height of 162.5 ± 5.4 cm for males with NS) at final height. Moreover, 60% reached a midparental height of ± 1 SD. Conclusion: GH treatment improves final height in patients with Noonan syndrome, with a mean gain of 1.7 SDS. The prepubertal height gain is maintained to final height and the children achieve a height close to their mid-parental height.展开更多
文摘AIM:To assesses the safety and efficacy of Aspergillus niger prolyl endoprotease(AN-PEP)to mitigate the im-munogenic effects of gluten in celiac patients.METHODS:Patients with initial diagnosis of celiac disease as confirmed by positive serology with subtotal or total villous atrophy on duodenal biopsies who adhere to a strict gluten-free diet(GFD)resulting in normalised antibodies and mucosal healing classified as Marsh 0 orⅠwere included.In a randomised double-blind placebo-controlled pilot study,patients consumed toast(approximately 7 g/d gluten)with AN-PEP for 2 wk(safety phase).After a 2-wk washout period with adherence of the usual GFD,14 patients were randomised to gluten intake with either AN-PEP or placebo for 2 wk(efficacy phase).Measurements at baseline included complaints,quality-of-life,serum antibodies,immunophenotyping of T-cells and duodenal mucosa immunohistology.Furthermore,serum and quality of life questionnaires were collected during and after the safety,washout and efficacy phase.Duodenal biopsies were collected after the safety phase and after the efficacy phase.A change in histological evaluation according to the modified Marsh classification was the primary endpoint.RESULTS:In total,16 adults were enrolled in the study.No serious adverse events occurred during the trial and no patients withdrew during the trial.The mean score for the gastrointestinal subcategory of the celiac disease quality(CDQ)was relatively high throughout the study,indicating that AN-PEP was well tolerated.In the efficacy phase,the CDQ scores of patients consuming gluten with placebo or gluten with AN-PEP did not significantly deteriorate and moreover no differences between the groups were observed.During the efficacy phase,neither the placebo nor the AN-PEP group developed significant antibody titers.The IgA-EM concentrations remained negative in both groups.Two patients were excluded from entering the efficacy phase as their mucosa showed an increase oftwo Marsh steps after the safety phase,yet with undetectable serum antibodies,while 14 patients were considered histologically stable on gluten with AN-PEP.Also after the efficacy phase,no significant deterioration was observed regarding immunohistological and flow cytometric evaluation in the group consuming placebo compared to the group receiving AN-PEP.Furthermore,IgA-tTG deposit staining increased after 2 wk of gluten compared to baseline in four out of seven patients on placebo.In the seven patients receiving AN-PEP,one patient showed increased and one showed decreased IgA-tTG deposits.CONCLUSION:AN-PEP appears to be well tolerated.However,the primary endpoint was not met due to lack of clinical deterioration upon placebo,impeding an effect of AN-PEP.
文摘Fundamental organelles that occur in every cell type with the exception of mammal erythrocytes,the mitochondria are required for multiple pivotal processes that include the production of biological energy,the biosynthesis of reactive oxygen species,the control of calcium homeostasis,and the triggering of cell death.The disruption of anyone of these processes has been shown to impact strongly the function of all cells,but especially of neurons.In this review,we discuss the role of the mitochondria impairment in the development of the neurodegenerative diseases Amyotrophic Lateral Sclerosis,Parkinson's disease and Alzheimer's disease.We highlight how mitochondria disruption revolves around the processes that underlie the mitochondria's life cycle:fusion,fission,production of reactive oxygen species and energy failure.Both genetic and sporadic forms of neurodegenerative diseases are unavoidably accompanied with and often caused by the dysfunction in one or more of the key mitochondrial processes.Therefore,in order to get in depth insights into their health status in neurodegenerative diseases,we need to focus into innovative strategies aimed at characterizing the various mitochondrial processes.Current techniques include Mitostress,Mitotracker,transmission electron microscopy,oxidative stress assays along with expression measurement of the proteins that maintain the mitochondrial health.We will also discuss a panel of approaches aimed at mitigating the mitochondrial dysfunction.These include canonical drugs,natural compounds,supplements,lifestyle interventions and innovative approaches as mitochondria transplantation and gene therapy.In conclusion,because mitochondria are fundamental organelles necessary for virtually all the cell functions and are severely impaired in neurodegenerative diseases,it is critical to develop novel methods to measure the mitochondrial state,and novel therapeutic strategies aimed at improving their health.
文摘Background: With the introduction of new therapies in peri-and neonatology, the clinical picture of bronchopulmonary dysplasia (BPD) seems to alter. The consequences of this “new BPD”are of interest. Aim: To evaluate cardiovascular findings during the surfactant era in very low birthweight (VLBW, birth weight <1500 g) schoolchildren with and without BPD. Methods: At 7-8 years of age, 34 VLBW children with BPD born in one hospital underwent blood pressure (BP) measurement, electrocardiography (ECG), two-dimensional Doppler and M-mode echocardiography, flow-volume spirometry and whole-body plethysmography. The age-and sex-matched control groups comprised 34 VLBW children without BPD (no-BPD group) and 34 term children (term group). Results: The mean(SD) diastolic BP was significantly higher in the no-BPD than in the BPD group (65(9) vs. 59(8) mm Hg, p<0.05). No clinically significant tricuspid regurgitations were found. The groups did not differ with respect to right ventricular systolic time intervals corrected for heart rate. The results of all M-mode measurements were within normal range. Compared to term controls, the BPD cases had lower mean(SD) forced expiratory flow in 1 s (90(14)%vs. 99(11)%of ref., p<0.05)-and more often high ratio of residual volume to total lung capacity (15(52%) vs. 4(13%), p<0.01). No clinically significant correlations were found between current lung function and echocardiographic findings. Conclusion: In the surfactant era, school-aged VLBW survivors with and without BPD do not seem to evince indirect signs of elevated pulmonary pressure. The increased pulmonary vascular resistance associated with BPD appears to resolve with time more rapidly than abnormalities in respiratory function.
文摘Aim: To assess whether children with Noonan syndrome on long-term growth hormone (GH) therapy improve their final height to near mid-parental height. Methods: Twenty-five prepubertal children (13 girls) with Noonan syndrome (NS) were studied. A single clinician made the diagnosis based on clinical criteria. GH treatment started at an age ranging from 3.1 to 13.8 y and was continued for at least 2 y. Improvement or “ gain” in final height (FH) was defined as either the difference between adult height SD scores (SDS) and pre-treatment height SDS (the childhood component of the Swedish reference) or height SDS compared to the Noonan reference. Results: Ten children received a GH dose of 33 μ g/kg/d (mean age at start 7.7 ± 2.1 y, mean age at stop 17.6 ± 1.7 y) and 15 received a dose of 66 μ g/kg/d(mean age at start 8.6 ± 3.3 y, mean age at stop 18.4 ± 2.1 y). Eighteen out of 25 patients reached FH. A substantial improvement in FH of 1.7 SDS, equivalent to 10.4 cm compared to pre-treatment height, was observed. No significant difference was seen between the two GH doses. Females gained a mean height of 9.8 cm and males 1-13 cm (FH 174.5 ± 7.8 cm vs mean adult height of 162.5 ± 5.4 cm for males with NS) at final height. Moreover, 60% reached a midparental height of ± 1 SD. Conclusion: GH treatment improves final height in patients with Noonan syndrome, with a mean gain of 1.7 SDS. The prepubertal height gain is maintained to final height and the children achieve a height close to their mid-parental height.
