Treatment of Vitamin K Deficiency in Hemodialysis Patients - A Pilot Study Comparing Menaquinone-7 Tablets and a Vitamin K Rich Diet.

Purpose: Vitamin K deficiency and hence a high level of plasma dephosphorylated undercarboxylated matrix Gla protein (dp-ucMGP) is frequent in patients on hemodialysis. This group is recommended to restrict their potassium intake which often leads to restriction of vitamin K rich foods. A menaquinone-7 (MK-7) supplement has been shown to decrease dp-ucMGP, but it has yet to be examined if a vitamin K rich diet could be equally effective. Patients and Methods: A prospective randomized crossover intervention trial with two arms; 6 weeks of 360 µg MK-7 tablet/day and 6 weeks of a vitamin K rich diet with a 3-week washout period in between. Participants were 10 patients in hemodialysis and the primary outcome measures were changes in dp-ucMGP, total MGP (tMGP), and undercarboxylated osteocalcin (ucOC). Furthermore, the level of potassium and phylloquinone in broccoli was determined after different durations of boiling. Results: During the MK-7 intervention the dp-ucMGP and ucOC decreased significantly compared to baseline (-0.42 [-0.93; -0.22] nmol/L (p=<0.01) and -1.85 [-2.91; -1.30] nmol/L (p<0.01)), while these were unchanged during the dietary intervention (0.03 [-0.64; 0.37] nmol/L (p=1.00) and 0.30 [-1.71; 1.41] nmol/L (p=0.77)). Between the two interventions there was a greater decrease in ucOC (p=0.02) during the MK-7 compared to the dietary period. No significant changes in the total MGP levels were found in any of the periods. The retention of potassium following boiling for 2 minutes and 8 minutes was 76% and 49%, respectively, while for phylloquinone the retention was 92%, and independent of duration of boiling. Conclusion: A daily MK-7 supplement for 6 weeks lowered dp-ucMGP and ucOC significantly, while a vitamin K rich diet was not able to induce any significant effect. Boiled broccoli maintains a reasonable content of phylloquinone while potassium is extracted and is a reasonable source of phylloquinone for patients on hemodialysis.

Rapid changes of miRNAs-20, -30, -410, -515, -134, and -183 and telomerase with psychological activity: A one year study on the relaxation response and epistemological considerations.

BACKGROUND AND AIM: Mental stress represents a pivotal factor in cardiovascular diseases. The mechanism by which stress produces its deleterious effects is still under study, but one of the most explored pathways is inflammation-aging and cell senescence. In this scenario, circulating microRNAs appear to be regulatory elements of the telomerase activity and alternative splicing within the nuclear factor kappa-light-chain-enhancer (NF-κB) network. Anti-stress techniques appeared to be able to slow down the inflammatory and aging processes. As we recently verified, the practice of the relaxation response (RR) counteracted psychological stress and determined favorable changes of the NF-κB, p53, and toll-like receptor-4 (TLR-4) gene expression and in neurotransmitters, hormones, cytokines, and inflammatory circulating microRNAs. We aimed to verify a possible change in the serum levels of six other micro-RNAs of cardiovascular interest, involved in cell senescence and in the NF-κB network (miRNAs -20, -30, -410, -515, -134, and -183), and tested the activity of telomerase in peripheral blood mononuclear cells (PBMCs). EXPERIMENTAL PROCEDURE: We measured the aforementioned molecules in the serum of patients with ischemic heart disease (and healthy controls) immediately before and after a relaxation response session, three times (after the baseline), in one year of follow-up. RESULTS: According to our data, the miRNA-20 and -30 levels and PBMCs-telomerase activity increased during the RR while the -410 and -515 levels decreased. During the RR sessions, both miRNA-134 and -183 decreased. CONCLUSION: The mediators considered in this exploratory work appeared to vary rapidly with the psychological activity (in particular when focused on relaxation techniques) showing that psychological activity should be part of the future research on epigenetics. Epistemological perspectives are also discussed.

Effectiveness of In-Hospital Cholecalciferol Use on Clinical Outcomes in Comorbid COVID-19 Patients: A Hypothesis-Generating Study.

Little information is available on the beneficial effects of cholecalciferol treatment in comorbid patients hospitalized for COVID-19. The aim of this study was to retrospectively examine the clinical outcome of patients receiving in-hospital high-dose bolus cholecalciferol. Patients with a positive diagnosis of SARS-CoV-2 and overt COVID-19, hospitalized from 15 March to 20 April 2020, were considered. Based on clinical characteristics, they were supplemented (or not) with 400,000 IU bolus oral cholecalciferol (200,000 IU administered in two consecutive days) and the composite outcome (transfer to intensive care unit; ICU and/or death) was recorded. Ninety-one patients (aged 74 ± 13 years) with COVID-19 were included in this retrospective study. Fifty (54.9%) patients presented with two or more comorbid diseases. Based on the decision of the referring physician, 36 (39.6%) patients were treated with vitamin D. Receiver operating characteristic curve analysis revealed a significant predictive power of the four variables: (a) low (<50 nmol/L) 25(OH) vitamin D levels, (b) current cigarette smoking, (c) elevated D-dimer levels (d) and the presence of comorbid diseases, to explain the decision to administer vitamin D (area under the curve = 0.77, 95% CI: 0.67-0.87, p < 0.0001). Over the follow-up period (14 ± 10 days), 27 (29.7%) patients were transferred to the ICU and 22 (24.2%) died (16 prior to ICU and six in ICU). Overall, 43 (47.3%) patients experienced the combined endpoint of transfer to ICU and/or death. Logistic regression analyses revealed that the comorbidity burden significantly modified the effect of vitamin D treatment on the study outcome, both in crude (p = 0.033) and propensity score-adjusted analyses (p = 0.039), so the positive effect of high-dose cholecalciferol on the combined endpoint was significantly amplified with increasing comorbidity burden. This hypothesis-generating study warrants the formal evaluation (i.e., clinical trial) of the potential benefit that cholecalciferol can offer in these comorbid COVID-19 patients.

Toward a Unified View of Cognitive and Biochemical Activity: Meditation and Linguistic Self-Reconstructing May Lead to Inflammation and Oxidative Stress Improvement.

Stress appears to be the basis of many diseases, especially myocardial infarction. Events are not objectively "stressful" but what is central is how the individual structures the experience he is facing: the thoughts he produces about an event put him under stress. This cognitive process could be revealed by language (words and structure). We followed 90 patients with ischemic heart disease and 30 healthy volunteers, after having taught them the Relaxation Response (RR) as part of a 4-day Rational-Emotional-Education intervention. We analyzed with the Linguistic Inquiry and Word Count software the words that the subjects used across the study following the progression of blood galectin-3 (inflammation marker) and malondialdehyde (oxidative stress marker). During the follow-up, we confirmed an acute and chronic decrease in the markers of inflammation and oxidative stress already highlighted in our previous studies together with a significant change in the use of language by the subjects of the RR groups. Our results and the precise design of our study would seem to suggest the existence of an intimate relationship and regulatory action by cognitive processes (recognizable by the type of language used) on some molecular processes in the human body.

Selenium Supplementation, Body Mass Composition, and Leptin Levels in Patients with Obesity on a Balanced Mildly Hypocaloric Diet: A Pilot Study.

BACKGROUND: Adequate levels of selenium (Se) have protective effects against several chronic diseases, such as obesity. The aim of this study was to assess the effect of Se supplementation in a selected group of patients with obesity. METHODS: This randomized prospective study included 37 overweight/obese individuals aged 18-65 years, who adopted a slightly hypocaloric diet for 3 months. An intervention group received 240 µg/day of L-selenomethionine for 3 months; a control group received a placebo. Clinical and biochemical parameters, body composition measurements, and the Psychological General Well-Being Index (PGWBI) questionnaire were tested at the beginning and end of the treatment. RESULTS: A comparison of the two groups showed a significant change in body composition, involving a decrease in body fat mass, between the baseline and the end of the follow-up, in the intervention group. Unlike the placebo group, the group given Se had a significant increase in lean body and muscle mass and a significant decrease in leptin levels after 3 months on diet. At the end of the follow-up, the group given Se scored higher on the PGWBI than those who did not. CONCLUSION: Se could reinforce the effects of diet for overweight and obesity. This work was registered in the ISRCTN registry with study ID ISRCTN6106073.

The Effects of Iodine Supplementation in Pregnancy on Iodine Status, Thyroglobulin Levels and Thyroid Function Parameters: Results from a Randomized Controlled Clinical Trial in a Mild-to-Moderate Iodine Deficiency Area.

BACKGROUND: Iodine supplementation during pregnancy in areas with mild-to-moderate iodine deficiency is still debated. METHODS: A single-center, randomized, single-blind and placebo-controlled (3:2) trial was conducted. We enrolled 90 women before 12 weeks of gestation. From enrollment up until 8 weeks after delivery, 52 women were given an iodine supplement (225 ug/day, potassium iodide tablets) and 38 were given placebo. At recruitment (T0), in the second (T1) and third trimesters (T2), and 8 weeks after delivery (T3), we measured participants' urinary iodine-to-creatinine ratio (UI/Creat), thyroid function parameters (thyroglobulin (Tg), TSH, FT3, and FT4), and thyroid volume (TV). The newborns' urinary iodine concentrations were evaluated in 16 cases. RESULTS: Median UI/Creat at recruitment was 53.3 ug/g. UI/Creat was significantly higher in supplemented women at T1 and T2. Tg levels were lower at T1 and T2 in women with UI/Creat ≥ 150 ug/g, and in the Iodine group at T2 (p = 0.02). There was a negative correlation between Tg and UI/Creat throughout the study (p = 0.03, r = -0.1268). A lower TSH level was found in the Iodine group at T3 (p = 0.001). TV increased by +Δ7.43% in the Iodine group, and by +Δ11.17% in the Placebo group. No differences were found between the newborns' TSH levels on screening the two groups. CONCLUSION: Tg proved a good parameter for measuring iodine intake in our placebo-controlled series. Iodine supplementation did not prove harmful to pregnancy in areas of mild-to-moderate iodine deficiency, with no appreciable harmful effect on thyroid function.

Diabetes alert dogs: a narrative critical overview.

Owing to their virtually incomparable olfactory apparatus and the mutual loving relationship with man, the use of dogs for assisting humans in many activities has become commonplace. Dogs have been used for long for livestock herding, hunting and pulling. More recently, they have been employed for servicing or assisting people with disabilities, for rescuing, for pet therapy and, last but not least, for detecting a vast array of volatile organic compounds related to drugs, narcotics, explosives and foods. Although cancer detection seems the most distinguished use of "man's best friends" in science and medicine, increasing emphasis is being placed on their capacity to perceive chemical changes or human expressions associated with harmful, even life-threating, blood glucose variations. The evidence available in the current scientific literature attests that diabetes alerting dogs (DADs) have a heterogeneous efficiency for warning owners of episodes of hypoglycemia or hyperglycemia, with sensitivities and specificities ranging between 0.29-0.80 and 0.49-0.96, respectively. Although the adoption of DADs seems effective for improving the quality of life of many diabetics patients, some important drawbacks can be highlighted. These typically include adoption and keeping expenditures, lack of certification or accreditation of dog providers, poor harmonization of training procedures, significant inter-breed, intra-breed and intra-dog variabilities, wide-ranging alert behaviors, ability of owners to identify dog's alerts, as well as lack of quality assessment of a dog's "diagnostic" performance. Overcoming many of these limitations shall probably make DADs more efficient tools for improving diabetes management.

Warfarin, but not rivaroxaban, promotes the calcification of the aortic valve in ApoE-/- mice.

INTRODUCTION: Vitamin K antagonists, such as warfarin, are known to promote arterial calcification through blockade of gamma-carboxylation of Matrix-Gla-Protein. It is currently unknown whether other oral anticoagulants such as direct inhibitors of Factor Xa can have protective effects on the progression of aortic valve calcification. AIMS: To compare the effect of warfarin and rivaroxaban on the progression of aortic valve calcification in atherosclerotic mice. RESULTS: 42 ApoE-/- mice fed with Western-type Diet (WTD) were randomized to treatment with warfarin (n = 14), rivaroxaban (n = 14) or control (n = 14) for 8 weeks. Histological analyses were performed to quantify the calcification of aortic valve leaflets and the development of atherosclerosis. The analyses showed a significant increase in valve calcification in mice treated with warfarin as compared to WTD alone (P = .025) or rivaroxaban (P = .005), whereas no significant differences were found between rivaroxaban and WTD (P = .35). Quantification of atherosclerosis and intimal calcification was performed on the innominate artery of the mice and no differences were found between the 3 treatments as far as atherogenesis and calcium deposition is concerned. In vitro experiments performed using bovine interstitial valve cells (VIC) showed that treatment with rivaroxaban did not prevent the osteogenic conversion of the cells but reduce the over-expression of COX-2 induced by inflammatory mediators. CONCLUSION: We showed that warfarin, but not rivaroxaban, could induce calcific valve degeneration in a mouse model of atherosclerosis. Both the treatments did not significantly affect the progression of atherosclerosis. Overall, these data suggest a safer profile of rivaroxaban on the risk of cardiovascular disease progression.

Thoughts modulate the expression of inflammatory genes and may improve the coronary blood flow in patients after a myocardial infarction.

BACKGROUND: Mental stress is one of the main risk factors for cardiovascular disease. Meditation and music listening are two techniques that are able to counteract it through the activation of specific brain areas, eliciting the so-called Relaxing Response (RR). Epidemiological evidence reveals that the RR practice has a beneficial prognostic impact on patients after myocardial infarction. We aimed to study the possible molecular mechanisms of RR underlying these findings. METHODS: We enrolled 30 consecutive patients after myocardial infarction and 10 healthy controls. 10 patients were taught to meditate, 10 to appreciate music and 10 did not carry out any intervention and served as controls. After training, and after 60 days of RR practice, we studied the individual variations, before and after the relaxation sessions, of the vital signs, the electrocardiographic and echocardiographic parameters along with coronary flow reserve (CFR) and the carotid's intima media thickness (IMT). Neuro-endocrine-immune (NEI) messengers and the expression of inflammatory genes (p53, Nuclear factor Kappa B (NfKB), and toll like receptor 4 (TLR4)) in circulating peripheral blood mononuclear cells were also all observed. RESULTS: The RR results in a reduction of NEI molecules (p < 0.05) and oxidative stress (p < 0.001). The expression of the genes p53, NFkB and TLR4 is reduced after the RR and also at 60 days (p < 0.001). The CFR increases with the relaxation (p < 0.001) and the IMT regressed significantly (p < 0.001) after 6 months of RR practice. CONCLUSIONS: The RR helps to advantageously modulate the expression of inflammatory genes through a cascade of NEI messengers improving, over time, microvascular function and the arteriosclerotic process.

Impaired Release of Vitamin D in Dysfunctional Adipose Tissue: New Cues on Vitamin D Supplementation in Obesity.

Context: Vitamin D accumulates in adipose tissue (AT), and vitamin D deficiency is frequent in obesity. Objective: We hypothesize that trafficking of vitamin D is altered in dysfunctional AT. Design, Patients, Settings: Fifty-four normal-weight and 67 obese males were recruited in a prospective study and randomly assigned to supplementation with 50 µg/wk 25-hydroxyvitamin-D3 or 150 µg/wk vitamin D3 for 1 year, raising dosage by 50% if vitamin D sufficiency [serum 25-hydroxyvitamin-D3 >50 nmol/L], was not achieved at 6 months; 97 subjects completed the study. Methods: Vitamin D3 and 25-hydroxyvitamin-D3 were quantified by HPLC-MS in control and insulin-resistant (IR) 3T3-L1 cells and subcutaneous AT (SAT) from lean and obese subjects, incubated with or without adrenaline; expression of 25-hydroxylase (Cyp27a1), 1α-hydroxylase (Cyp27b1), and vitamin D receptor (Vdr) was analyzed by real-time polymerase chain reaction. Results: In IR adipocytes, uptake of D3 and 25-hydroxyvitamin-D3 was higher, but, after adrenaline stimulation, the decrement in D3 and 25-hydroxyvitamin-D3 was stronger in control cells, which also showed increased expression of Cyp27a1 and Cyp27b1 and higher levels of 25-hydroxyvitamin-D3. In SAT from obese subjects, adrenaline-induced release of D3 and 25-hydroxyvitamin-D3 was blunted; in both IR cells and obese SAT, protein expression of ß2-adrenergic receptor was reduced. Supplementation with 25-hydroxyvitamin-D3 was more effective in achieving vitamin D sufficiency in obese, but not in normal weight subjects. Conclusion: Dysfunctional AT shows a reduced catecholamine-induced release of D3 and 25-hydroxyvitamin-D3 and altered activity of vitamin D-metabolizing enzymes; for these reasons supplementation with 25-hydroxyvitamin-D3 is more effective in obese individuals.

Low vitamin K1 intake in haemodialysis patients.

BACKGROUND & AIMS: Vitamin K acts as a coenzyme in the γ-carboxylation of vitamin K-dependent proteins, including coagulation factors, osteocalcin, matrix Gla protein (MGP), and the growth arrest-specific 6 (GAS6) protein. Osteocalcin is a key factor for bone matrix formation. MGP is a local inhibitor of soft tissue calcification. GAS6 activity prevents the apoptosis of vascular smooth muscle cells. Few data on vitamin K intake in chronic kidney disease patients and no data in patients on a Mediterranean diet are available. In the present study, we evaluate the dietary intake of vitamin K1 in a cohort of patients undergoing haemodialysis. METHODS: In this multi-centre controlled observational study, data were collected from 91 patients aged >18 years on dialysis treatment for at least 12 months and from 85 age-matched control subjects with normal renal function. Participants completed a food journal of seven consecutive days for the estimation of dietary intakes of macro- and micro-nutrients (minerals and vitamins). RESULTS: Compared to controls, dialysis patients had a significant lower total energy intake, along with a lower dietary intake of proteins, fats, carbohydrates, fibres, and of all the examined minerals (Ca, P, Fe, Na, K, Zn, Cu, and Mg). With the exception of vitamin B12, vitamins intake followed a similar pattern, with a lower intake in vitamin A, B1, B2, C, D, E, folates, K1 and PP. These finding were confirmed also when normalized for total energy intake or for body weight. In respect to the adequate intakes recommended in the literature, the prevalence of a deficient vitamin K intake was very high (70-90%) and roughly double than in controls. Multivariate logistic model identified vitamin A and iron intake as predictors of vitamin K deficiency. CONCLUSIONS: Haemodialysis patients had a significantly low intake in vitamin K1, which could contribute to increase the risk of bone fractures and vascular calcifications. Since the deficiency of vitamin K intake seems to be remarkable, dietary counselling to HD patients should also address the adequacy of vitamin K dietary intake and bioavailability. Whether diets with higher amounts of vitamin K1 or vitamin K supplementation can improve clinical outcomes in dialysis patients remains to be demonstrated.

Calcimimetic and vitamin D analog use in hemodialyzed patients is associated with increased levels of vitamin K dependent proteins.

Matrix Gla protein (MGP) and bone Gla protein (BGP) are two vitamin K-dependent proteins (VKDPs) involved in the regulation of vascular calcification (VC). We carried out a secondary analysis of the VIKI study to evaluate associations between drug consumption and VKDP levels in 387 hemodialyzed patients. The VIKI study assessed the prevalence of vitamin K deficiency in hemodialysis patients. We evaluated drug consumption, determined BGP and MGP levels, and verified the presence of any vertebral fractures (VF) and VC by spine radiographs. Total BGP levels were twice as high with calcimimetics versus no calcimimetics (290 vs. 158.5 mcg/L, p < 0.0001) and 69 % higher with vitamin D analogs (268 vs. 159 mcg/L, p < 0.0001). Total MGP was 19 % higher with calcimimetics (21.5 vs. 18.1 mcg/L, p = 0.04) and 54 % higher with calcium acetate (27.9 vs. 18.1 mcg/L, p = 0.003); no difference was found with vitamin D analogs (21.1 vs. 18.3 mcg/L, p = 0.43). Median Total BGP level was 29 % lower in patients with ≥1 VF (151 vs. 213 mcg/L, p = 0.0091) and 36 % lower in patients with VC (164 vs. 262.1 mcg/L, p = 0.0003). In non-survivors, median BGP and MGP were lower, but only for MGP this difference reached the statistical significance (152 vs. 191 mcg/L, p = 0.20 and 15.0 vs. 19.7 mcg/L, p = 0.02, respectively). Pending studies on vitamin K supplementation, calcimimetics, and vitamin D analogs may play a role in preserving vitamin K-dependent protein activity, thus contributing to bone and vascular health in CKD patients.

Prevalence and Clinical Relevance of IgE Sensitization to Profilin in Childhood: A Multicenter Study.

BACKGROUND: Little is known about the prevalence and clinical relevance of hypersensitivity to the plant panallergen profilin in children. OBJECTIVES: The present study aimed to investigate prevalence, risk factors and clinical relevance of profilin sensitization in a large cohort of Italian children of different ages living in different geographic areas. METHODS: Children with pollen allergy enrolled by 16 pediatric outpatient clinics sited in three main geographic areas of Italy were studied. SPT were carried out with commercial pollen extracts and a commercial purified date palm pollen profilin. IgE specific for allergenic pollen molecules, Phl p 12 (grass profilin) and Pru p 3 (peach lipid transfer protein) were tested by ImmunoCAP FEIA. RESULTS: IgE to Phl p 12 (≥0.35 kU/l) was observed in 296 of the 1,271 participants (23%), including 17 of the 108 (16%) preschool children. Profilin SPT was positive (≥3 mm) in 320/1,271 (25%) participants. The two diagnostic methods were concordant in 1,151 (91%, p < 0.0001) cases. Phl p 12 IgE prevalence declined from northern to southern Italy and was directly associated with IgE to Phl p 1 and/or Phl p 5 and Ole e 1. Among children with IgE to Phl p 12, OAS was provoked by kiwi, melon, watermelon, banana, apricot and cucumber. CONCLUSIONS: Profilin sensitization is very frequent among pollen-allergic children, occurs at a very young age and contributes to the development of childhood OAS with a typical pattern of offending foods. Pediatricians should always consider IgE sensitization to profilin while examining pollen-allergic children, even if they are at preschool age.

Protein supplementation increases postexercise plasma myostatin concentration after 8 weeks of resistance training in young physically active subjects.

Myostatin (MSTN) is a negative regulator of muscle growth even if some studies have shown a counterintuitive positive correlation between MSTN and muscle mass (MM). Our aim was to investigate the influence of 2 months of resistance training (RT) and diets with different protein contents on plasma MSTN, interleukin 1 beta (IL-1ß), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), and insulin-like growth factor 1 (IGF-1). Eighteen healthy volunteers were randomly divided in two groups: high protein (HP) and normal protein (NP) groups. Different protein diet contents were 1.8 and 0.85 g of protein·kg bw(-1)·day(-1) for HP and NP, respectively. Subjects underwent 8 weeks of standardized progressive RT. MSTN, IGF-1, IL-1ß, IL-6, and TNF-α were analyzed before and after the first and the last training sessions. Lean body mass, MM, upper-limb muscle area, and strength were measured. Plasma MSTN showed a significant increase (P<.001) after the last training in the HP group compared with NP group and with starting value. IGF-1 plasma concentration showed a positive correlation with MSTN in HP after the last training (r(2)=0.6456; P=.0295). No significant differences were found between NP and HP for IL-1ß, IL-6, TNF-α, and strength and MM or area. These findings suggest a "paradoxical" postexercise increase of plasma MSTN after 8 weeks of RT and HP diets. This MSTN elevation correlates positively with IGF-1 plasma level. This double increase of opposite (catabolic/anabolic) mediators could explain the substantial overlapping of MM increases in the two groups.

Could molecular assessment of calcium metabolism be a useful tool to early screen patients at risk for pre-eclampsia complicated pregnancy? Proposal and rationale.

One of the most frequent causes of maternal and perinatal morbidity is represented by hypertensive disorders during pregnancy. Women at high risk must be subjected to a more intensive antenatal surveillance and prophylactic treatments. Many genetic risk factors, clinical features and biomarkers have been proposed but none of these seems able to prevent pre-eclampsia onset. English literature review of manuscripts focused on calcium intake and hypertensive disorders during pregnancy was performed. We performed a critical analysis of evidences about maternal calcium metabolism pattern in pregnancy analyzing all possible bias affecting studies. Calcium supplementation seems to give beneficial effects on women with low calcium intake. Some evidence reported that calcium supplementation may drastically reduce the percentage of pre-eclampsia onset consequently improving the neonatal outcome. Starting from this evidence, it is intuitive that investigations on maternal calcium metabolism pattern in first trimester of pregnancy could represent a low cost, large scale tool to screen pregnant women and to identify those at increased risk of pre-eclampsia onset. We propose a biochemical screening of maternal calcium metabolism pattern in first trimester of pregnancy to discriminate patients who potentially may benefit from calcium supplementation. In a second step we propose to randomly allocate the sub-cohort of patients with calcium metabolism disorders in a treatment group (calcium supplementation) or in a control group (placebo) to define if calcium supplementation may represent a dietary mean to reduce pre-eclampsia onset and to improve pregnancy outcome.

The effect of component-resolved diagnosis on specific immunotherapy prescription in children with hay fever.

BACKGROUND: Sensitization to profilins and other cross-reacting molecules might hinder proper specific immunotherapy (SIT) prescription in polysensitized patients with pollen-related allergic rhinitis (AR). In these patients, component-resolved diagnosis (CRD) might modify SIT prescription by improving the identification of the disease-eliciting pollen sources. OBJECTIVES: We sought to measure the effect of CRD on SIT prescription in children with pollen-related AR. METHODS: Children (n = 651) with moderate-to-severe pollen-related AR were recruited between May 2009 and June 2011 in 16 Italian outpatient clinics. Skin prick test (SPT) reactivity to grass, cypress, olive, mugwort, pellitory, and/or Betulaceae pollen was considered clinically relevant if symptoms occurred during the corresponding peak pollen season. IgE sensitization to Phl p 1, Phl p 5, Bet v 1, Cup a 1, Art v 1, Ole e 1, Par j 2, and Phl p 12 (profilin) was measured by using ImmunoCAP. SIT prescription was modeled on SPT responses first and then remodeled considering also CRD according to GA(2)LEN-European Academy of Allergology and Clinical Immunology guidelines and the opinions of 14 pediatric allergists. RESULTS: No IgE to the respective major allergens was detected in significant proportions of patients with supposed clinically relevant sensitization to mugwort (45/65 [69%]), Betulaceae (146/252 [60%]), pellitory (78/257 [30%]), olive (111/390 [28%]), cypress (28/184 [15%]), and grass (56/568 [10%]). IgE to profilins, polcalcins, or both could justify 173 (37%) of 464 of these SPT reactions. After CRD, the SPT-based decision on SIT prescription or composition was changed in 277 (42%) of 651 or 315 (48%) of 651 children according to the European or American approach, respectively, and in 305 (47%) of 651 children according to the opinion of the 14 local pediatric allergists. CONCLUSIONS: In children with pollen-related AR, applying CRD leads to changes in a large proportion of SIT prescriptions as opposed to relying on clinical history and SPT alone. The hypothesis that CRD-guided prescription improves SIT efficacy deserves to be tested.

Pollen-induced allergic rhinitis in 1360 Italian children: comorbidities and determinants of severity.

BACKGROUND: Pollen-induced allergic rhinoconjunctivitis (AR) is highly prevalent and rapidly evolving during childhood. General practitioners may not be fully aware of the nature and severity of symptoms experienced by patients and might underestimate the prevalence of moderate or severe disease. Thus, the relevance of early diagnosis and intervention may be overlooked. OBJECTIVES: To investigate the severity of pollen-induced AR and its determinants in Italian children referred to allergy specialists and who had never received specific immunotherapy (SIT). METHODS: Children (age 4-18 yr) affected by pollen-induced AR who had never undergone SIT were recruited between May 2009 and June 2011 in 16 pediatric outpatient clinics in 14 Italian cities. Recruited children's parents answered standardized questionnaires on atopic diseases (International Study of Allergy and Asthma in Childhood, Allergic Rhinitis and its Impact on Asthma, Global Initiative for Asthma). The children underwent skin-prick test (SPT) with several airborne allergens and six food allergens. Information on socio-demographic factors, parental history of allergic diseases, education, perinatal events, breastfeeding, nutrition and environmental exposure in early life was collected through an informatics platform shared by the whole network of clinical centers (AllergyCARD™). RESULTS: Among the 1360 recruited patients (68% males, age 10.5 ± 3.4 yr), 695 (51%) had moderate-to-severe AR, 533 (39%) asthma, and 325 (23.9%) oral allergy syndrome (OAS). Reported onset of pollen-induced AR was on average at 5.3 ± 2.8 yr, and its mean duration from onset was 5.2 ± 3.3 yr. Only 6.2% of the patients were pollen-monosensitized, and 84.9% were sensitized to ≥3 pollens. A longer AR duration was significantly associated with moderate-to-severe AR symptoms (p 0.004), asthma (p 0.030), and OAS comorbidities (p < 0.001). CONCLUSIONS: This nationwide study may raise awareness of the severity of pollen-induced AR among Italian children who have never received pollen SIT. The strong association between pollen-induced AR duration and several markers of disease severity needs replication in longitudinal studies, while suggesting that countrywide initiatives for earlier diagnosis and intervention should be planned.

Hyperhomocysteinemia in health and disease: where we are now, and where do we go from here ?

Homocysteine is a sulfur-containing amino acid, which is synthesized from the precursor methionine through a multi-step process, and then reconverted to methionine or catabolyzed into cysteine. The presence of vitamin B9 (folic acid), vitamin B6 (pyridoxine) and vitamin B12 (cobalamin) is essential in homocysteine metabolism, wherein deficiency of one or more of these nutrients is associated with various degree of hyperhomocysteinemia. There is little doubt that hyperhomocysteinemia is associated with several human disorders, such as cardiovascular disease, neurodegenerative disorders, pregnancy complications and fractures, so that its measurement might be useful for risk assessment. Nevertheless, several randomized homocysteine-lowering therapy trials have failed to show that supplementation with vitamins B substantially modifies (and ­ more importantly ­ improves) the end points and the related outcomes. According to the current state of scientific knowledge, it seems thus reasonable to conclude that lowering homocysteine alone is probably insufficient to mitigate the risk of thromboembolic, cardiovascular and neurodegenerative disorders inasmuch as this bizarre amino acid acts in strict synergy with other probably more powerful risk factors. Several lines of evidence suggest, however, that its measurement may be helpful for identifying subjects at greater risk of disease, who may thus benefit from a more aggressive treatment of other modifiable risk factors, as recently shown by result of the 5-year Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial.

VKORC1, CYP2C9 and CYP4F2 genetic-based algorithm for warfarin dosing: an Italian retrospective study.

AIM: A total of 371 patients under stable warfarin therapy were retrospectively selected to develop a pharmacogenetic algorithm to identify the individual maintenance dose. MATERIALS & METHODS: The variables that were entered into the algorithm were: VKORC1, CYP2C9 and CYP4F2 polymorphisms, body surface area and age. RESULTS: The percentage of cases whose predicted mean weekly warfarin dose was within 20% of the actual maintenance dose was 51.8% considering patients overall, and were 36.2, 66.2 and 55.4%, respectively, taking into account patients requiring low (≤25 mg/week), intermediate (25-45 mg/week) and high (≥45 mg/week) doses. The algorithm could correctly assign 73.8 and 63.2% of patients to the low- and high-dose regimens, respectively. We developed and validated a pharmacogenetic algorithm in a series of Italian patients, we then tested, in the same series of italian patients, the formulas of three published algorithms. These three algorithms were developed and validated by their authors in a series of patients different from our own. The performance of our algorithm in our patients series was slightly higher than that achieved when using the three other algorithms in our patients series. CONCLUSION: The high predictive accuracy of low and high warfarin requirements of our algorithm warrants its application in prospective studies for clinical validation.