Chylomicron Retention Disease: The Role of Ultrastructural Examination in Differential Diagnosis

Three children with malabsorption presumably caused by celiac disease had undergone jejunal biopsy. While a histological examination revealed microvacuolization of enterocytes in the absence of celiac lesions, an ultrastructural investigation disclosed numerous chylomicrons and larger lipid vacuoles inside the cytoplasm of enterocytes, mostly in the supranuclear region. No chylomicrons were evident in the interstitium between adjacent enterocytes, as observed in normal subjects. These ultrastructural findings allowed for the diagnosis of "Chylomicron retention disease" (CRD). CRD was described for the first time by Anderson in 1961, and it is included in the group of disorders of biosynthesis and secretion of B apolipoproteins (apoB). This disease, in particular, appears to result from a specific defect involving the secretion of lipoproteins containing apoB-48 from the gut, with the complete absence of post prandial chylomicrons in the sera. CRD needs to be recognized early because of its adverse effects on growth and its potential for neurological and ocular complications, and the ultrastructural identification of chylomicron-size lipid droplets clustered in the enterocytes, with the absence of fat outside the cells, represents the gold standard to identify CRD. together with clinical aspects and laboratory measurements. In this study, we describe the histological and ultrastructural aspects observed in three pediatric cases of CRD.     

Malignancy-associated allelic losses on the X-chromosome in foregut but not in midgut endocrine tumours

Information on genetic changes involved in the progression of gastroenteropancreatic (GEP) endocrine tumours is scanty. On the other hand, the identification of molecular markers of malignancy could be crucial for the prognostic evaluation of these neoplasms, which is hardly predictable on the basis of conventional histological criteria. An association of X-chromosome deletions with malignancy has already been found in gastric endocrine tumours. To investigate this further, a comparative loss of heterozygosity (LOH) analysis was performed on 17 pancreatic endocrine tumours (PETs) and 17 intestinal (ten ileal, six appendiceal, and one rectal) carcinoids from female patients. The relationship of X-chromosome LOH with the ploidy status of the neoplasms was also investigated. LOH was found in six of eight malignant PETs (60% of the informative markers), but was infrequent in the nine benign ones (4.5%). In contrast, although retention of heterozygosity was consistently observed in benign midgut tumours, LOH was infrequent in malignant carcinoids (15%). No correlation was found between LOH and the ploidy status. These results indicate an association between X-chromosome LOH and malignancy in foregut endocrine tumours. The lack of such an association in midgut carcinoids suggests that different molecular mechanisms are involved in the progression of these two categories of endocrine neoplasms, which are otherwise considered to be closely related. These findings emphasize the need for further molecular studies on GEP endocrine tumours, carefully subdivided according to their anatomical site of origin.     

Chromosomal localization of a highly repeatedEcoRI DNA fragment inMegoura viciae (Homoptera,Aphididae) by nick translation and fluorescencein situ hybridization

To investigate the genome of the aphidMegoura viciae at molecular level, we have studied total DNA by agarose gel electrophoresis after cleavage with different restriction endonucleases.EcoRI digestion produced a highly repeated DNA fragment, about 600 bp long. The contribution of thisEcoRI element to the total genome ofM. viciae was estimated at about 6% by means of densitometric scanning of agarose gel photographs. The chromosomal localization of this fragment, investigated by fluorescentin situ hybridization (FISH), constantly showed one large and two narrower fluorescent bands located on the X chromosome, all corresponding to C-positive heterochromatic areas. These results are in full accordance with the data obtained byin situ nick translation experiments carried out afterEcoRI digestion, and clearly demonstrate that a substantial amount ofM. viciae heterochromatin consists ofEcoRI fragments which are mainly located on the X chromosome. Using theEcoRI restriction fragment as a molecular probe may prove to be a practical tool for the investigation of taxonomic and evolutionary relationships in this group of insects.accepted for publication by J. S. (Pat) Heslop-Harrison     

A one-year follow-up on the effects of raloxifene on thyroid function in postmenopausal women

OBJECTIVE: Estrogens increase serum thyroxine-binding globulin (TBG) and total thyroxine (TT4) concentrations. Serum free thyroxine (FT4) concentrations, however, remain normal. Raloxifene (RAL) is a selective estrogen receptor modulator used to treat postmenopausal osteoporosis. Data on the long-term effects of RAL on thyroid physiology are scanty. We evaluated the effects of RAL administration for 1 year on thyroid function in osteopenic, postmenopausal women. DESIGN: Fifty osteopenic, postmenopausal women were randomly assigned to receive either RAL (60 mg/day, n = 25) or placebo (PL, n = 25) for 1 year, in a double-blind study. Measurements of serum TBG, TT4, FT4, thyroid-stimulating hormone (TSH), thyroid hormone-binding ratio (THBR), FT4 index (FT4-I) and TT4/TBG ratio were carried out at baseline and after 4 and 12 months of therapy. RESULTS: Baseline values were similar in both treatment groups. Serum TBG concentrations were increased during RAL treatment from baseline values of 29.60 +/- 0.9 microg/mL to 31.45 +/- 1.33 and 32.34 +/- 1.37 microg/mL at 4 months and 1 year, respectively (P < 0.05, baseline v 1-year values) but were unchanged during PL treatment. A small, insignificant increase in TT4 and TSH concentrations occurred in the RAL group and no changes in the PL group. All other values were unchanged during either treatment. CONCLUSIONS: These results demonstrate that RAL significantly increased serum TBG levels, but the changes were small and not accompanied by changes in FT4-I, FT4, or TSH concentrations, suggesting that long-term RAL treatment is unlikely to clinically affect the thyroid status in euthyroid, postmenopausal women.     

A novel mutation of varicella-zoster virus associated to fatal hepatitis.

BACKGROUND: Lethal varicella in immunocompetent hosts is rare and its pathogenesis is largely unknown. The discovery of glycoprotein E (gE) mutants showing attributes consistent with increased virulence in vitro and in animal models, provided a possible molecular mechanism underlying a more aggressive virus infection. However, these mutants have never been associated with unusually severe clinical cases. OBJECTIVES: To varicella-zoster virus (VZV) mutations that correlate with increased virulence. RESULTS: We report a case of fatal hepatitis caused by a VZV bearing a novel mutation on the 3B3 monoclonal antibody epitope of gE in an immunocompetent host. CONCLUSIONS: This report describes a mutant VZV responsible for an aggressive clinical course in an immunocompetent host. Linking these severe clinical presentations of VZV infection to virus mutations might provide insights into the underlying pathogenic mechanisms.     

Immunomagnetic cell selection performed for HLA haploidentical transplants with the CliniMACS device: effect of additional platelet removal on CD34+ cell recovery

Immunomagnetic CD34+ cell selection (ICS) is a widely employed technology in autotransplant and allotransplant settings. When an haploidentical transplant is performed, a high dose of purified CD34+ cells together with efficient T and B cell depletion are required to minimize the risks of graft versus host disease (GVHD) and Epstein-Barr virus (EBV)-related lymphoma. To ameliorate the performances of the CliniMACS (Miltenyi Biotec) ICS device, we compared 73 ICS performed following the manufacturer's recommended platelet depletion versus 48 performed after adjunctive centrifugations to increase platelet depletion of the leukapheresis (LKF) product. A total of 121 ICS (from single or fractioned LKF products) were carried out on 93 LKF collected from 47 related healthy donors. A statistical significance in terms of CD34+ cell recovery (81.8% vs. 71.2%) was found in favor of the modified ICS procedure (p=0.0049) with a comparable stem cell purity and viability. The modification of the standard manufacturer's technique for increasing platelet depletion can further improve the recovery of stem cells with no influence on T and B cell depletion. These results demonstrate the negative influence exerted on CD34+ cell recovery by LKF platelet contamination.     

Magnesium in Obesity,Metabolic Syndrome,and Type 2 Diabetes

Magnesium (Mg²⁺) deficiency is probably the most underestimated electrolyte imbalance in Western countries. It is frequent in obese patients, subjects with type-2 diabetes and metabolic syndrome, both in adulthood and in childhood. This narrative review aims to offer insights into the pathophysiological mechanisms linking Mg²⁺ deficiency with obesity and the risk of developing metabolic syndrome and type 2 diabetes. Literature highlights critical issues about the treatment of Mg²⁺ deficiency, such as the lack of a clear definition of Mg²⁺ nutritional status, the use of different Mg²⁺ salts and dosage and the different duration of the Mg²⁺ supplementation. Despite the lack of agreement, an appropriate dietary pattern, including the right intake of Mg²⁺, improves metabolic syndrome by reducing blood pressure, hyperglycemia, and hypertriglyceridemia. This occurs through the modulation of gene expression and proteomic profile as well as through a positive influence on the composition of the intestinal microbiota and the metabolism of vitamins B1 and D.     

Sarcopenia Risk Evaluation in a Sample of Hospitalized Elderly Men and Women: Combined Use of the Mini Sarcopenia Risk Assessment (MSRA) and the SARC-F

Background: SARC-F and Mini Sarcopenia Risk Assessment (MSRA) questionnaires have been proposed as screening tools to identify patients at risk of sarcopenia. The aim of this study is to test the use of SARC-F and MSRA, alone and combined, as a pre-screening tool for sarcopenia in geriatric inpatients. Methods: 152 subjects, 94 men and 58 women, aged 70 to 94, underwent muscle mass evaluation by dual energy X-ray absorptiometry (DXA), muscle strength evaluation by handgrip, and completed the MSRA, SARC-F and Activity of daily living (ADL) questionnaires. Results: 66 subjects (43.4%) were classified as sarcopenic according to the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criteria. The 7-item SARC-F and MRSA and 5-item MSRA showed an area under the curve (AUC) of 0.666 (95% confidence interval (CI): 0.542–0.789), 0.730 (95% CI: 0.617–0.842) and 0.710 (95% CI: 0.593–0.827), respectively. The optimal cut-off points for sarcopenia detection were determined for each questionnaire using the Youden index method. The newly calculated cut-off points were ≤25 and ≤40 for MSRA 7- and 5-items, respectively. The ideal cut-off for the SARC-F was a score ≥3. Applying this new cut-off in our study population, sensitivity and specificity of the 7-item MSRA were 0.757 and 0.651, and 0.688 and 0.679 for the 5-item MSRA, respectively. Sensitivity and specificity of SARC-F were 0.524 and 0.765, respectively. The combined use of the 7-item SARC-F and MSRA improved the accuracy in sarcopenia diagnosis, with a specificity and sensitivity of 1.00 and 0.636. Conclusion: 7-item SARC-F and MSRA may be co-administered in hospital wards as an easy, feasible, first-line tool to identify sarcopenic subjects.     

Vascular Effects of the Polyphenolic Nutraceutical Supplement Taurisolo®: Focus on the Protection of the Endothelial Function

Preservation of vascular endothelium integrity and functionality represents an unmet medical need. Indeed, endothelial dysfunction leads to decreased nitric oxide biosynthesis, which is prodromic of hypertension and hypercoagulability. In this panorama, the nutraceutical supplement Taurisolo^®, a polyphenolic extract from Aglianico cultivar grape, rich in catechin and procyanidins, was evaluated as a vasoprotective, vasorelaxing, anti-hypertensive and anti-coagulant agent in: cell lines, isolated vessels, in vivo models of chronic hypertension and hypercoagulability, and in clinical tests of endothelial reactivity. Taurisolo^® demonstrated to fully protect vascular cell viability from oxidative stimulus at 100 µg/mL and evoke vasorelaxing effects (Emax = 80.6% ± 1.9 and pEC50 = 1.19 ± 0.03) by activation of the Sirtuins-AMPK-pathway. Moreover, Taurisolo^®, chronically administered at 20 mg/Kg/die in in vivo experiments, inhibited the onset of cardiac hypertrophy (heart weight/rat weight = 3.96 ± 0.09 vs. 4.30 ± 0.03), hypercoagulability (decrease of fibrinogen vs. control: p < 0.01) and hypertension (mean of Psys: 200 ± 2 vs. control 234 ± 2 mmHg) and improved endothelial function (Emax = 88.9% ± 1.5 vs. control 59.6% ± 3.6; flow-mediated dilation in healthy volunteers after 400 mg twice daily for 8 weeks vs. baseline: p = 0.019). In conclusion, Taurisolo^® preserves the vascular function against ox-inflamm-ageing process and the consequent cardiovascular accidents.     

Association of the Chronotype Score with Circulating Trimethylamine N-Oxide (TMAO) Concentrations

Individual differences in the chronotype, an attitude that best expresses the individual circadian preference in behavioral and biological rhythms, have been associated with cardiometabolic risk and gut dysbiosis. Up to now, there are no studies evaluating the association between chronotypes and circulating TMAO concentrations, a predictor of cardiometabolic risk and a useful marker of gut dysbiosis. In this study population (147 females and 100 males), subjects with the morning chronotype had the lowest BMI and waist circumference (p < 0.001), and a better metabolic profile compared to the other chronotypes. In addition, the morning chronotype had the highest adherence to the Mediterranean diet (p < 0.001) and the lowest circulating TMAO concentrations (p < 0.001). After adjusting for BMI and adherence to the Mediterranean diet, the correlation between circulating TMAO concentrations and chronotype score was still kept (r = −0.627, p < 0.001). Using a linear regression analysis, higher chronotype scores were mostly associated with lower circulating TMAO concentrations (β = −0.479, t = −12.08, and p < 0.001). Using a restricted cubic spline analysis, we found that a chronotype score ≥59 (p < 0.001, R² = −0.824) demonstrated a more significant inverse linear relationship with circulating TMAO concentrations compared with knots <59 (neither chronotype) and <41 (evening chronotype). The current study reported the first evidence that higher circulating TMAO concentrations were associated with the evening chronotype that, in turn, is usually linked to an unhealthy lifestyle mostly characterized by low adherence to the MD.