One-year caloric restriction and 12-week exercise training intervention in obese adults with type 2 diabetes: emphasis on metabolic control and resting metabolic rate.

PURPOSE: The effect of combined lifestyle interventions (LSI) including dietary and physical activity on metabolic health, energy metabolism and VO2max in diabetic patients has provided mixed results. We evaluated the impact of 1-year caloric restriction (CR), and 12-week supervised structured exercise training (SSET) on metabolic health, RMR and VO2max in obese adults with type 2 diabetes. METHODS: After 1-month education for LSI, 33 participants had anthropometric, biochemical and metabolic assessments. They then started CR based on RMR, and 3-month SSET during the months 1-3 (Early-SSET) or 4-6 (Late-SSET). Reassessments were planned after 3, 6 and 12 months. Using a per-protocol analysis, we evaluated parameter changes from baseline and their associations for the 23 participants (11 Early-SSET, 12 Late-SSET) who completed the study. RMR was adjusted (adjRMR) for age, sex, fat-free mass (FFM) and fat mass (FM). RESULTS: Compared with baseline, after 6 months we found significant increases in VO2max (+ 14%) and HDL-cholesterol (+ 13%), and reduction in body mass index (- 3%), FM (- 8%) and glycated hemoglobin (HbA1c, - 7%). Training-related caloric expenditure negatively correlated with changes in body weight (p < 0.001), FM (p < 0.001) and HbA1c (p = 0.006). These results were confirmed at the 12-month follow-up. Pooling together all follow-up data, adjRMR changes correlated with changes in glycemia (r = 0.29, p = 0.02), total-cholesterol (r = 0.29, p = 0.02) and VO2max (r = - 0.26,p = 0.02). No significant differences emerged between the Early- and Late-SSET groups. CONCLUSIONS: Combined intervention with SSET and CR improved metabolic control. Changes in metabolic health and fitness correlated with changes of adjRMR, which was reduced improving fitness, glycemia and cholesterolemia. CLINICAL TRIAL REGISTRY: Trial registration number: NCT03785379. URL of registration: http://clinicaltrials.gov .

Priorities for future research into asthma diagnostic tools: A PAN-EU consensus exercise from the European asthma research innovation partnership (EARIP).

The diagnosis of asthma is currently based on clinical history, physical examination and lung function, and to date, there are no accurate objective tests either to confirm the diagnosis or to discriminate between different types of asthma. This consensus exercise reviews the state of the art in asthma diagnosis to identify opportunities for future investment based on the likelihood of their successful development, potential for widespread adoption and their perceived impact on asthma patients. Using a two-stage e-Delphi process and a summarizing workshop, a group of European asthma experts including health professionals, researchers, people with asthma and industry representatives ranked the potential impact of research investment in each technique or tool for asthma diagnosis and monitoring. After a systematic review of the literature, 21 statements were extracted and were subject of the two-stage Delphi process. Eleven statements were scored 3 or more and were further discussed and ranked in a face-to-face workshop. The three most important diagnostic/predictive tools ranked were as follows: "New biological markers of asthma (eg genomics, proteomics and metabolomics) as a tool for diagnosis and/or monitoring," "Prediction of future asthma in preschool children with reasonable accuracy" and "Tools to measure volatile organic compounds (VOCs) in exhaled breath."

The Association Between Bone Mineral Density and Airflow Limitation in a Cohort of Fit Elderly Women.

PURPOSE: As studies examining the association between bone mineral density (BMD) and airflow limitation (AL) have produced conflicting results, the current one set out to analyze if and to what degree there are any correlations between these variables in a population of fit elderly women. METHODS: One hundred and twenty-one non-smoking, fit and healthy women (age ≥ 65 years) underwent anthropometric assessment, laboratory testing (serum 25-hydroxy vitamin D, parathormone, and cytokine levels), pulmonary function testing (PFT), and dual-energy X-ray absorptiometry to evaluate BMD values of the lumbar and femoral regions. RESULTS: A significant positive association was found between FEV1/FVC ratio (Tiffeneau index), a sensitive index of AL, and lumbar and femoral BMD; a 10 % increase in the FEV1/FVC ratio resulted in a significant increase of 0.025 g/cm2 in the total hip (p = 0.05), 0.027 g/cm2 in the femoral neck (p = 0.02), 0.028 g/cm2 in the femoral trochanter (p = 0.01), and 0.047 g/cm2 in the lumbar (p = 0.03) BMDs. Binary logistic analyses demonstrated more than a threefold higher risk of low BMD values for the lowest FEV1/FVC quartile in the lumbar (OR 4.62, 95 % CI 1.48-14.40, p = 0.008), total hip (OR 4.09, 95 % CI 1.28-13.05, p = 0.02 for the second quartile), and femoral trochanter regions (OR 3.90, 95 % CI 1.25-12.20, p = 0.02 for the third quartile). CONCLUSIONS: AL was associated with a higher risk of reduced BMD in healthy, fit elderly women.

TL1A/DR3 axis involvement in the inflammatory cytokine network during pulmonary sarcoidosis.

BACKGROUND: TNF-like ligand 1A (TL1A), a recently recognized member of the TNF superfamily, and its death domain receptor 3 (DR3), firstly identified for their relevant role in T lymphocyte homeostasis, are now well-known mediators of several immune-inflammatory diseases, ranging from rheumatoid arthritis to inflammatory bowel diseases to psoriasis, whereas no data are available on their involvement in sarcoidosis, a multisystemic granulomatous disease where a deregulated T helper (Th)1/Th17 response takes place. METHODS: In this study, by flow cytometry, real-time PCR, confocal microscopy and immunohistochemistry analyses, TL1A and DR3 were investigated in the pulmonary cells and the peripheral blood of 43 patients affected by sarcoidosis in different phases of the disease (29 patients with active sarcoidosis, 14 with the inactive form) and in 8 control subjects. RESULTS: Our results demonstrated a significant higher expression, both at protein and mRNA levels, of TL1A and DR3 in pulmonary T cells and alveolar macrophages of patients with active sarcoidosis as compared to patients with the inactive form of the disease and to controls. In patients with sarcoidosis TL1A was strongly more expressed in the lung than the blood, i.e., at the site of the involved organ. Additionally, zymography assays showed that TL1A is able to increase the production of matrix metalloproteinase 9 by sarcoid alveolar macrophages characterized, in patients with the active form of the disease, by reduced mRNA levels of the tissue inhibitor of metalloproteinase (TIMP)-1. CONCLUSIONS: These data suggest that TL1A/DR3 interactions are part of the extended and complex immune-inflammatory network that characterizes sarcoidosis during its active phase and may contribute to the pathogenesis and to the progression of the disease.

Asthma severity in childhood and metabolomic profiling of breath condensate.

BACKGROUND: Asthma is a heterogeneous disease and its different phenotypes need to be better characterized from a biochemical-inflammatory standpoint. This study aimed to apply the metabolomic approach to exhaled breath condensate (breathomics) to discriminate different asthma phenotypes, with a particular focus on severe asthma in children. METHODS: In this cross-sectional study, we recruited 42 asthmatic children (age, 8-17 years): 31 with nonsevere asthma (treated with inhaled steroids or not) and 11 with severe asthma. Fifteen healthy children were enrolled as controls. Children performed exhaled nitric oxide measurement, spirometry, exhaled breath condensate (EBC) collection. Condensate samples were analyzed using a metabolomic approach based on mass spectrometry. RESULTS: A robust Bidirectional-Orthogonal Projections to Latent Structures-Discriminant Analysis (O2PLS-DA) model was found for discriminating both between severe asthma cases and healthy controls (R(2)  = 0.93; Q(2)  = 0.75) and between severe asthma and nonsevere asthma (R(2)  = 0.84; Q(2)  = 0.47). The metabolomic data analysis leads to a robust model also when the 3 groups of children were considered altogether (K = 0.80), indicating that each group is characterized by a specific metabolomic profile. Compounds related to retinoic acid, adenosine and vitamin D (Human Metabolome Database) were relevant for the discrimination between groups. CONCLUSION: The metabolomic profiling of EBC could clearly distinguish different biochemical-metabolic profiles in asthmatic children and enabled the severe asthma phenotype to be fully discriminated. The breathomics approach may therefore be suitable for discriminating between different asthma metabolic phenotypes.

Asthma, allergy and respiratory infections: the vitamin D hypothesis.

The recent discovery that every tissue in the human body has vitamin D receptors and that vitamin D has pleiotropic effects has prompted an increased interest in this hormone. Vitamin D deficiency is widespread and on the increase. There is no consensus on the serum vitamin D levels to consider appropriate for global health, the cutoffs for its deficiency, or the doses to use for its supplementation. Vitamin D seems to correlate closely with host reactions against various respiratory infections. Epidemiological studies have shown that low serum 25-hydroxyvitamin D levels are associated with a higher risk of upper and lower respiratory infections in children and a shortage of vitamin D may contribute to asthmatic patients' symptoms and morbidity rates. There are studies highlighting associations between childhood asthma, fetal lung and/or immune development, and maternal vitamin D intake. An insufficiency of this vitamin also seems to be implicated in the onset of childhood atopy and food allergies. The hypothesis is that vitamin D could have a central role in these pathological situations and that it may represent a novel preventive and/or therapeutic strategy. This article reviews and discusses published data on the relationship between vitamin D and asthma and allergy, emphasizing the need for controlled, prospective studies on vitamin D supplementation to clarify whether it has a role in the prevention of and treatment for asthma and allergic conditions.

Impact of oral immunotherapy on quality of life in children with cow milk allergy: a pilot study.

Quality of life is negatively affected in children with food allergy. Oral immunotherapy is an approach to food allergy that leads to patient desensitization by administering gradually increasing amounts of a given food allergen. The aim of this pilot study is to evaluate how oral immunotherapy affects quality of life in children allergic to cow milk proteins. Thirty children (aged 3-12 years) with cow milk allergy were recruited. Their parents were provided with a validated disease specific quality of life questionnaire (the food allergy quality of life questionnaire -- parent form, FAQLQ-PF) before and again 2 months after completing an oral immunotherapy protocol with cow milk. A significant improvement in all the investigated domains -- emotional impact, food anxiety and social and dietary limitations -- was found. The separate analysis of the different age groups demonstrated that the emotional impact and the food-related anxiety improved in children older than 4, while the social domains improved in each age group. In this pilot experience, oral immunotherapy significantly improves quality of life in children with cow milk allergy. The improvement seems particularly evident in children over 4 years old, who are most likely to benefit from the oral immunotherapy approach. Further placebo-controlled studies are needed to confirm these preliminary results.

EIA and GC/MS analysis of 8-isoprostane in EBC of children with problematic asthma.

Asthmatic airways are characterised by enhanced oxidative stress, which can be studied by measuring biomarkers, such as 8-isoprostane. The aims of the present study were: 1) to measure the concentrations of 8-isoprostane in exhaled breath condensate (EBC) and urine of children with problematic and well-controlled asthma; 2) to compare the concentrations of 8-isoprostane measured by gas chromatographic/negative ion chemical ionisation mass spectrometry (GC/NICI-MS) and by an enzymatic immunoassay (EIA). We recruited 20 asthmatic allergic children, 13 with well-controlled asthma and seven with problematic asthma. They underwent exhaled nitric oxide measurements and spirometry, and both EBC and urine samples were collected. 8-isoprostane was measured in EBC by GC/NICI-MS and EIA. 8-isoprostane concentrations in EBC were significantly higher in children with problematic asthma than in children with well-controlled asthma (p = 0.01). An acceptable reproducibility emerged between GC/NICI-MS and EIA (coefficient of reproducibility 11.5 pg x mL(-1)). 8-isoprostane levels measured in urine did not correlate with those measured in EBC. We showed that 8-isoprostane in EBC was significantly increased in children with problematic asthma, suggesting a role for oxidative stress in this asthma phenotype. In addition we found an acceptable reproducibility of EIA compared to GC/NICI-MS, even if the latter method had higher accuracy.

Clinical application of nasal nitric oxide measurement.

Nitric oxide is present in high concentration in the upper respiratory tract. The main source of this gaseous molecule is the paranasal sinus epithelium. The physiological role of this mediator is to contribute to local host defense, modulate ciliary motility and serve as an aerocrine mediator in helping to maintain adequate ventilationperfusion matching in the lung. Abnormal values of nasal NO (nNO) have been reported in different pathological conditions of the respiratory tract. Reduced nNO values have been recorded in subjects with acute and chronic sinusitis, cystic fibrosis and nasal polyps. Particularly low concentrations have been described in children with primary ciliary dyskinesia, so nNO measurement has been proposed as a reliable screening test for this chronic lung disease.

Apoptotic effect of cyclosporin a and dexamethasone in malignant cells of patients with B-chronic lymphocytic leukemia.

B-chronic lymphocytic leukemia (B-CLL) is a malignant disorder characterized by the accumulation of the leukemic cells in the G0-G1 phase of the cell cycle and expressing high levels of the anti-apoptotic protein Bcl-2. Since we observed that the treatment of autoimmune complications with Cyclosporine A (CsA) determined in some CLL patients an improvement not only of the autoimmune phenomena, but also of the leukemic process, we evaluated the in vitro cytotoxicity of CsA as compared to Dexamethasone (Dex) on leukemic cells. Leukemic cells obtained from 32 B-CLL patients showed a heterogeneous pattern of spontaneous apoptosis at 24 h interval and this pattern permitted to identify: Group 1 (14/32) with high (>20%) apoptotic rate and Group 2 (18/32) with low cell death. CsA and Dex increased cell death in both groups with a different timing by an apoptotic mechanism that does not involve Bcl-2. Furthermore, in Group 2, CsA-induced apoptosis was significant higher than that observed with Dex both at 4 and 24 h. We suggest that, in B-CLL, CsA has a significant pro-apoptotic activity manifested also in patients with low spontaneous apoptosis. Our observations might be taken into account to consider new therapeutic strategies in B-CLL.

Factors Influencing Serum-Hydroxivitamin D Levels and Other Bone Metabolism Parameters in Healthy Older Women.

OBJECTIVE: Older women have frequently low serum 25-hydroxivitamin D (25[OH]D) concentrations, high parathormone (PTH) levels and low bone mineral density (BMD) values. Endogenous synthesis, dietary habits, sunlight exposure and fat-mass-mediated storage may influence 25(OH)D levels and bone metabolism, but the relevance of these factors in the elderly has yet to be fully elucidated. We aimed to investigate the influence of dietary vitamin D intake and fat mass on serum 25(OH)D levels and bone metabolism in older women. DESIGN: Cross-sectional. SETTING: Community. PARTICIPANTS: 218 fit older women attending a biweekly mild fitness program. MEASUREMENTS: Dietary habits was investigated through a 3-day record questionnaire. Serum 25(OH)D and intact parathormone (PTH) concentrations were measured by radioimmunoassay and by a 2-step immunoradiometric assay, respectively. BMD and body composition were estimated using dual-energy X-ray absorptiometry with fan-beam technology. RESULTS: Only fat mass showed a significant negative association with 25(OH)D (ß=-3.76, p<0.001), and positive associations with whole body, lumbar, femoral neck and total hip BMD. Binary logistic analysis revealed a protective effect of adiposity on secondary hyperparathyroidism (OR=0.42, 95%CI:0.19-0.92, p=0.03). Dietary vitamin D intake was not associated to any of these outcomes. CONCLUSION: Fat mass has a greater influence on serum 25(OH)D than dietary vitamin D intake.

Hypovitaminosis D and fat mass in healthy older people.

Prospective studies have suggested that hypovitaminosis D can predict the onset of obesity, but they relied mainly on body mass index, which could be scarcely reliable in older people. We investigated whether baseline hypovitaminosis D could predict higher fat mass (FM) levels using dual-energy X-ray absorptiometry in a sample of 116 fit and healthy older subjects. Although no significant differences in FM estimates emerged between subjects with and without hypovitaminosis D at the baseline, abdominal FM was found significantly higher in the former group (with hypovitaminosis D at the baseline) than in the latter after 3 years of follow-up. Adjusted logistic regression analysis confirmed these findings: hypovitaminosis D coincided with an approximately sixfold higher risk of subjects having higher abdominal FM levels at the follow-up. In conclusion, hypovitaminosis D predicts higher abdominal FM levels in the elderly.

Effect of weight loss on mortality in overweight and obese nursing home residents during a 5-year follow-up.

BACKGROUND/OBJECTIVES: The objective of this study was to ascertain the effect of weight loss over the course of 1 year on 5-year mortality in old nursing home (NH) residents in different classes of body mass index (BMI). SUBJECTS/METHODS: A longitudinal study was conducted on 161 NH residents aged ⩾ 70 years at the Istituto di Riposo per Anziani, Padova, Italy. Data were collected using a comprehensive geriatric assessment at baseline and at a 1-year follow-up visit. Mortality was recorded over a 5-year follow-up. We divided our sample into four groups using as cutoffs a BMI of 25 and a weight gain or loss of 5% at 1 year (BMI ⩾ 25 and weight stable/gain, BMI ⩾ 25 and weight loss, BMI<25 and weight stable/gain and BMI <25 and weight loss). RESULTS: People with a BMI ⩾ 25 and weight loss suffered the worst decline in activities of daily living, whereas those with a BMI <25 and weight loss had the most significant decline in nutritional status, which coincided with the worst decline in the Multidimensional Prognostic Index among the groups whose weight changed. Compared with those with a BMI ⩾ 25 and weight stable/gain (reference group), those with a BMI <25 were at the highest risk of dying (in association with weight loss: hazard ratio HR=3.60, P=0.005; in association with weight stable/gain: HR=2.45, P=0.01), and the mortality risk was also increased in people with a BMI ⩾ 25 and weight loss (HR=1.74, P=0.03). CONCLUSIONS: In conclusion, weight loss increases the mortality risk in frail, disabled NH residents, even if they are overweight or obese.

Mitochondrial DNA in platelets from aged subjects.

This study aimed to assess platelets as a possible model for screening the accumulation of mitochondrial DNA mutations, particularly during normal ageing. For this purpose we isolated platelets from young and old donors selected by lack of systemic and haematological diseases. We studied the accumulation of a particular deletion (4977-bp deletion) that usually accumulates in an age-related manner in different post-mitotic tissues, such as brain, heart and skeletal muscle, and in some non-post-mitotic tissues (skin, liver). Using different primers, we failed to detect this particular species of deletion in platelets both from young and old individuals. However, we cannot exclude the presence of other species of deletions or point mutations affecting the mitochondrial DNA in platelets during the aging process.

Combined intensive chemoradiotherapy for organ preservation in patients with resectable and non-resectable oesophageal cancer.

From January 1990 to April 1993, 60 oesophageal cancer patients were enrolled in a protocol of non-surgical treatment that consisted of induction chemotherapy followed by concurrent chemoradiotherapy. Induction chemotherapy consisted of cisplatin 40 mg/m2 intravenous bolus days 1, 2, 14, 15; 24 h continuous infusion of 5-fluorouracil (5-FU) 1000 mg/m2 days 1 and 14; leucovorin 20 mg/m2 days 1 and 14 given before and with 5-FU; bleomycin 30 UI days 1 and 14; mitomycin C 10 mg/m2 day 14. Concurrent chemoradiotherapy consisted of 60 Gy (6 weeks) from day 21 and cisplatin 70 mg/m2 days 28, 42 and 56; leucovorin 20 mg/m2 followed by 5-FU 425 mg/m2 days 28, 35, 42, 49 and 56. Complete response occurred in 44 of 55 evaluable patients (80%). The median survival is 32 months; the actuarial survival at 40 months is 35% (CI 18-53). These results appear improved over those reported with surgery or radiation alone, and suggest that organ preservation as a secondary treatment goal should be vigorously investigated.

Quinolinic acid but not MK-801 protects the dopaminergic system from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced toxicity in goldfish retina.

The toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, intravitreally injected in goldfish eye, involves interplexiform retinal neurons and depletes tyrosine hydroxylase immunoreactivity and dopamine levels. This induced neurotoxicity was prevented by the concomitant administration in non-toxic doses (10 micrograms) of quinolinic acid, an endogenous structural analogue of N-methyl D-aspartate with excitotoxic properties. Quinolinic acid is ineffective on the retinal degeneration induced by 1-methyl-4-phenylpyridinium ion. This fact suggests that quinolinic acid inhibits the MAO-B oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. MK-801, a noncompetitive antagonist of glutamate NMDA-receptors, exerts partial protective effects on MPTP-induced delayed toxicity in mammals. In the goldfish eye, MK-801, injected in low concentration, and in conjunction with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or 1-methyl-4-phenylpyridinium ion, did not prevent retinal neurodegeneration. Ten micrograms of MK-801 alone did not affect retinal neurons, while a higher concentration (20 micrograms) causes the chromatolysis of some photoreceptor nuclei.

6,7-Dinitroquinoxaline-2,3-dione but not MK-801 exerts a protective effect against kainic acid neurotoxicity in the goldfish retina.

Recent findings indicated that the excitotoxicity of glutamate analogues was prevented in the mammalian nervous system by N-methyl-D-aspartate (NMDA) antagonists. The neurodegenerative effects of kainic acid, and the putative protection of MK-801 and 6,7-dinitroquinoxaline-2,3-dione (DNQX), were investigated by morphological studies showing the toxicity of kainic acid to the neurons of the inner nuclear layer, and measuring choline acetyltransferase and glutamate decarboxylase activities in the retina. In addition, the proliferation of Müller retinal cells was assumed as an index of neuronal degeneration and was quantified by counting glial fibrillary acidic protein immunopositive cells. Our observations suggest that the non-NMDA receptor antagonist DNQX exerted a protective effect on goldfish retinal neurons, while MK-801 did not prevent the neurotoxicity induced by kainic acid in the goldfish retina. This finding is in agreement with previous work on kainic acid toxicity in the goldfish optic tectum.