[Vitamin D as a cardiovascular risk factor in workers]. / La vitamina D come fattore di rischio cardiovascolare nei lavoratori.

Numerous evidence suggests that vitamin D deficiency is implicated in the development of cardiovascular risk. It has been investigated the relationship between cardiovascular risk factors and vitamin D concentrations in 264 consecutive workers from Centro Obesità e Lavoro della Clinica del Lavoro di Milano. For these studies, glicometaboliche analysis, anthropometric measurements and impedance evalutation were performed and questionnaires to estimate nutrient levels in the diet were administered. The levels of vitamin D are found to be deficient in 166 patients (less than 20 ng/mL), insufficient in 63 patients (less than 30 ng/mL) and optimal for the remaining 35 patients. A significant negative association was observed between the concentrations of vitamin D and cardiovascular risk factors (HOMA ratio and TG/HDL) ratios and BMI. Vitamin D is a cardiovascular risk factor "corrected" for example by changing the eating habits of workers.

[Comparison of indexes for assessing insulin resistance for the health surveillance among workers]. / Confronto tra indici per la valutazione dell'insulinoresistenza nella sorveglianza sanitaria dei lavoratori.

Night shift workers present a high risk to develop metabolic and cardiovascular disorders for alterations that involve effects on circadian rhythms at the level of insulin resistance (IR). Monitor such parameter in this category of workers, therefore, is a crucial step in health surveillance. To this aim, the currently in use test consists in the calculation of the HOMA index [basal insulin (MU/ml) x basal glycemy(mmol/l)/22.5], a measurement with a considerable cost (about 13 Euros). Recent studies demonstrated that the measurement of TyG index calculated as Ln[Triglycerids (mg/dl) x Glucose(mg/dl)/2] and of the triglycerids/HDL-cholesterol ratio correlates with HOMA index. These analyses cost altogether about 5 Euros, allowing a clear decrease of expenses. Our study, carried out on 217 workers at Centre for Obesity and Occupational Medicine of the Occupational Medicine Clinic of Milan, confirmed such correlation and identified the TyG as the index with the best cost/performance ratio. Our future goal is to establish cut-off values, necessary to adopt the TyG as first choice index.

Analysis of inflammatory and immune response biomarkers in sputum and exhaled breath condensate by a multi-parametric biochip array in cystic fibrosis.

Cystic Fibrosis (CF) lung disease is characterized by high levels of cytokines and chemokines in the airways, producing chronic inflammation. Non-invasive biomarkers, which are also specific for the inflammatory and immune responses, are urgently needed to identify exacerbations and evaluate therapeutic efficacy. The aim of this study is to evaluate the association of sputum and exhaled breath condensate (EBC) biomarker changes with clinical exacerbation and response to therapy. We studied the simultaneous presence and concentration of twelve cytokines and growth factors (EGF, IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-gamma, MCP-1, TNF-alpha and VEGF) by a multi-parametric biochip array in sputum and EBC of 24 CF patients before, after 6 and 15 days of therapy, and 15 days after the end of treatment for an acute exacerbation. Correlations with functional respiratory tests (FEV1, FVC) and the systemic marker C-reactive protein (CRP) were looked for. In sputum, before therapy, VEGF and IL-1beta levels positively correlated with the respiratory function and CRP. Sputum IL-1alpha, IL-1beta IL-4, IL-10, TNF-alpha, and VEGF significantly decreased, while EGF increased, during therapy. IL-8 and IL-4 levels negatively correlated with the respiratory function at 15 and 30 days from the start of therapy, respectively. IL-4, IL-6, IL-10 and TNF-alpha positively correlated with CRP during therapy. Although some EBC biomarkers correlated with respiratory function and CRP, no significant associations with these clinical parameters were found. Sputum IL-1beta and VEGF might be considered biomarkers of an acute exacerbation in CF patients. A panel of sputum cytokines and growth factors may better describe the response to intravenous antibiotic treatment of CF than one single systemic marker.

Acute pyelonephritis as a cause of hyponatremia/hyperkalemia in young infants with urinary tract malformations.

Obstructive uropathy causes tubular resistance to aldosterone and severe metabolic imbalance may be precipitated by an episode of pyelonephritis. In the last 3 years we investigated 52 episodes of pyelonephritis (positive urine culture, elevated C reactive protein, fever, elevated neutrophil count) in 50 children between 15 days and 15 months of age. Ultrasonography voiding cystography and renal scintiscan were performed in all cases and i.v. urography in some. A salt-losing syndrome with hyponatremia and hyperkalemia (Na < 125 meq/liter; K > 6.3 meq/liter) was observed in 17 infants < 3 months, accompanied by plasma aldosterone concentration of 5000 to 23,000 pg/ml (normal value, < 1000 pg/ml). All these children had a severe urinary tract (UT) malformation (ureteropelvic junction stenosis in 7 cases, vesicoureteral reflux in 7, posterior urethral valves in 2, double system in 1). Thirteen infants < 3 months, 7 with no urinary tract malformations, did not have electrolyte imbalance. Pyelonephritis was diagnosed in 20 other patients ages 4 to 15 months, including 16 with severe UT malformations; 4 had normal UTs. We conclude that a salt-losing syndrome with tubular resistance to aldosterone can occur during pyelonephritis in young infants with congenital UT malformation, that the risk diminishes considerably or disappears after 3 months of age and that in the absence of UT malformation pyelonephritis does not cause acute sodium loss of clinical relevance.

Studies on the indirect feedback inhibition of cholinergic neurons triggered by oxotremorine in striatum.

Oxotremorine produced 30-75% increases in rat striatal acetylcholine content and 10-15% decreases in choline content at the subtremorogenic doses of 0.34-1.34 mumol/kg, without affecting choline acetyltransferase and acetylcholinesterase activities and the sodium-dependent high affinity uptake of choline. The increase in acetylcholine was blocked by atropine and by reserpine indicating that oxotremorine indirectly influences the intrinsic striatal cholinergic neurons through a monoamine-mediated negative feedback loop. Experiments designed to interfere with neurotransmitter function indicated that noradrenaline and not dopamine or serotonin, mediated the response to oxotremorine.

L-arginine supplementation in young renal allograft recipients with chronic transplant dysfunction.

AIMS: L-arginine (LA), the precursor of nitric oxide (NO), was suggested to be beneficial in many forms of renal disease: hypertension, ureteral obstructive nephropathy and cyclosporin A (CsA) nephrotoxicity. METHODS: Thus, we investigated the effects of LA supplementation on renal function, proteinuria and blood pressure (BP) in young renal allograft recipients with chronic renal transplant dysfunction treated with CsA. Eleven CsA-treated renal allograft recipients with chronic transplant dysfunction, aged 11-22 years, were randomly assigned to a 6-week treatment period with placebo (P), followed by 2 subsequent 6-week periods with LA supplementation (0.1 g/kg body weight/day) or a 6-week treatment period with LA, followed by 2 subsequent 6-week periods with P. At the end of each treatment period 24-hour BP recordings were made, and GFR (Inutest), RPF (PAH clearance) and the urinary excretion of protein, albumin, nitrate, cGMP and urea were evaluated. RESULTS: In comparison to placebo, LA treatment did not significantly change GFR, RPF, proteinuria and albuminuria, mean systolic or diastolic BP. The urinary excretion of urea and NO3 increased after LA supplementation (uUrea: LA 26.3 +/- 4.6 compared to P 23.5 +/- 4.7 g/day/1.73 m3, p < 0.05, uNO3: LA 514 +/- 152 compared to P 95 +/- 41 mM/day/1.73 m3, p < 0.05), whereas urinary excretion of cGMP remained unchanged. CONCLUSION: LA supplementation did not improve renal function and did not decrease proteinuria in CsA-treated renal allograft recipients with chronic transplant dysfunction possibly because of inhibition of NO-cGMP forming mechanism.

Renal and metabolic effects of L-arginine infusion in kidney transplant recipients.

AIM AND METHODS: In order to investigate the role of kidney damage on renal response to L-arginine (L-Arg) infusion in transplant patients receiving cyclosporine A (CsA) treatment, we assessed systemic and glomerular hemodynamic variables, the fraction excretion of urinary sodium, albumin, cyclic GMP (as an index of nitric oxide (NO) production from L-Arg) and urea excretion (as an index of ureagenesis), and glucoregulatory hormone levels in five normal volunteers and 21 renal allograft recipients (aged 10-20 years) treated with CsA, 10 with normal renal function and 11 with chronic renal insufficiency. RESULTS: In the normal subjects, L-Arg infusion (290 mg/min/1.73 m2 for 1 h) significantly reduced mean arterial pressure (MAP) (76+/-7 to 70+/-5 mmHg) and renal vascular resistance (RVR), and increased GFR (103+/-9 to 122+/-7 min/1.73 m2), RPF, urinary cyclic GMP excretion (0.40+/-0.1 to 0.60+/-0.1 nmol/100 ml glomerular filtrate (GF)), and sodium and albumin excretion. Neither the patients with chronic graft dysfunction nor those with a normal graft responded to L-Arg infusion: RVR remained high, and MAP, GFR, RPF, fractional excretion of sodium and urinary excretion of albumin and cyclic GMP were unchanged in both groups of patients. Glucagon, insulin and urinary urea excretion rose significantly in controls and both patient groups. CONCLUSION: The hemodynamic effects of L-Arg infusion were inhibited in the patients, regardless of their degree of renal function, possibly because L-Arg-NO production was blunted.

Comparison of the effects of the stereoisomers of fenfluramine on the acetylcholine content of rat striatum, hippocampus and nucleus accumbens.

The (+)- and (-)- isomeric forms of fenfluramine were compared for their effects on rat brain area acetylcholine (ACh) content. The drugs showed similar patterns in increasing ACh content in the accumbens and hippocampus and in being ineffective in the brainstem. The actions differed in the striatum where the (+)-form markedly increased ACh content while the (-)-form produced no change. Both isomer-induced increases in ACh in the accumbens were prevented when 5-HT synthesis was blocked by p-chlorophenylalanine, thus denoting 5-hydroxytryptaminergic mediation of these effects. In striatum, the increase in ACh induced by (+)-fenfluramine was summated with the increase in ACh induced by dopamine receptor stimulation with apomorphine and was not prevented by dopamine receptor blockade with pimozide. On the other hand, apomorphine's effect was blocked by (-)-fenfluramine while pimozide pretreatment unmasked an increase in ACh induced by (-)-fenfluramine. The results favour the notion that there is a population of cholinergic neurons intrinsic to the striatum which is under inhibitory 5-HT regulation and independent of inhibitory dopamine regulation.

A randomized placebo-controlled study on high-dose oral algal docosahexaenoic acid supplementation in children with cystic fibrosis.

Low plasma concentrations of docosahexaenoic acid (DHA) are reported in unsupplemented cystic fibrosis (CF) patients. Forty-one CF patients aged from 6 to 12 years were randomized to receive high-dose DHA (100 mg/kg/day in the first month and 1g per day thereafter through a 12-month supplementation) or placebo (germ oil). Primary outcome was percentage change in plasma AA:DHA ratio. Secondary outcomes were changes in the number of pulmonary exacerbations compared to previous year, lung function, BMI, skinfold thicknesses, and body composition assessed by DXA and in serum concentrations of C-reactive protein, cytokines and vitamin (α-tocopherol and retinol). Compared to the control group plasma AA:DHA ratio decreased in the intervention group after 6 months (median percentage changes: -73% in the intervention group vs. -10% in the control group, P=0.001). No differences were detected between groups for secondary outcomes. Despite a decrease of the AA/DHA ratio, DHA supplementation for one year did not induce any significant biochemical and clinical improvement in CF patients.

Multicenter evaluation of the first automated Elecsys sFlt-1 and PlGF assays in normal pregnancies and preeclampsia.

OBJECTIVES: Performance evaluation of Elecsys sFlt-1 and PlGF assays. DESIGN AND METHODS: Within-, between-run, total imprecision, functional sensitivity, inter-laboratory comparison, method comparison and lot-to-lot reproducibility were evaluated. RESULTS: Within- and between-run CVs were below 4% for sFlt-1 >60 and PlGF > 20 pg/mL. Total imprecision CVs were below 4.3%. Functional sensitivity was < 5 pg/mL. Inter-laboratory CVs were <5%. Elecsys correlated well with Quantikine VEGF-R1 (r=0.960) and PlGF (r=0.968). Lot-to-lot comparisons yielded highly correlated results (r>0.999). In healthy pregnancies, the median levels of sFlt-1 remained constant in first (1107 pg/mL) and second trimesters (1437 pg/mL) but increased in the third trimester (2395 pg/mL), while median PlGF levels increased in the first (30 pg/mL) and second trimesters (279 pg/mL) and peaked at 29 to 32 weeks (626 pg/mL) and decreased thereafter (340 pg/mL). The sFlt-1/PlGF ratio is highest in the first trimester (median: 28) but remained constant in the second (median: 4.7) and third trimesters (median: 5.1). In PE/HELPP samples matched for gestational age the sFlt-1 levels were significantly higher (6894-34,624 pg/mL), whereas PlGF levels were lower (9.2-80 pg/mL) and the median sFlt-1/PlGF ratio is much higher (461; range: 121-2614) than in apparently healthy pregnancies (3.6; range: 0.3-105). CONCLUSION: The new Roche Elecsys sFlt-1 and PlGF immunoassay showed excellent precision and reliability. There was a clear difference in the Elecsys sFlt-1/PlGF ratio between samples obtained from women with apparently normal pregnancy at the time of blood collection and those diagnosed with PE/HELLP at the same age of gestation.

Sodium excretion and hyperfiltration during glucose infusion in man.

The relations between renal hemodynamics (Inutest, CPAH) and sodium excretion were studied in 7 nondiabetics in whom a similar expansion was induced (1) with a 3-hour 5% glucose infusion and (2) with a 0.9% saline load. With both infusions the body weight increased, hematocrit fell, and the plasma renin activity was suppressed. During glucose infusion, blood glucose rose from 3.9 mmol/l to a plateau of around 13 mmol/l; glycosuria was absent during the 1st h, then appeared and stabilized during the following 2h. Glucose infusion caused a progressive increase in glomerular filtration rate and in renal blood flow in both absence and presence of glycosuria, without significant changes in sodium excretion despite volume expansion and increase of filtered sodium load. When saline was infused, there was a sustained increase of fractional sodium excretion, and no hemodynamic modifications were observed. We suggest that a primary glucose-induced metabolic stimulation of sodium reabsorption may play a role in the genesis of glucose-induced hyperfiltration.

Lack of glomerular hemodynamic stimulation after infusion of branched-chain amino acids.

Renal hemodynamics (Inutest. CPAH) were studied in five adult volunteers infused on separate occasions with branched-chain amino acids (BCAA), a mixture of nonessential and essential amino acids of the same volume, osmolality and nitrogen content, and 0.9% saline solution. BCAA infusion caused moderate renal vasoconstriction, a slight increase of GFR and a progressive rise of the filtration fraction (FF), whereas the amino acids mixture induced a significantly higher increase of GFR and a state of renal vasodilatation without altering the FF. The volume expansion with 0.9% saline did not cause any notable hemodynamic modification except for reduced FF. This study demonstrates that whereas a state of hyperfiltration and hyperemia is specifically induced by an amino acid mixture independently of volume expansion and osmolar load, the administration of BCAA provides nitrogen without renal hemodynamic stimulation.

Follow-up study of enzymuria and beta 2 microglobulinuria during cis-platinum treatment.

Twenty patients with epithelian ovarian cancer treated with DDP (cis-diammine-dichloroplatinum II) 50 mg/m2 were followed for 24 weeks in order to assess the nephrotoxicity of the drug. Ten patients received the total dose in one day with heavy osmotic hydration (Group A), and for the other 10 the dose was subdivided over 3 consecutive days (Group B). The renal tubular toxicity of DDP treatment was evaluated over a total of 120 courses. After the first DDP administration, there was a prompt, reversable and dose-dependent increase in the urinary excretion of beta 2 microglobulin with no difference between the two groups: Group A from 405 to 990 and Group B from 109 to 585 ng/mg creatinine. An increase always occurred during subsequent courses, but it was significantly lower in Group B after the sixth course, from 125 to 331 ng/mg creatinine. A similar pattern was found for the urinary excretion of N-acetyl-glucosaminidase (NAG), a lysosomal enzyme of tubular origin. The percentage fraction of urinary sodium excretion (FeNa%) increased after each dose of DDP; Group A from 0.82 to 2.30 and Group B from 0.68 to 2.53. This effect was reversible and it occurred to the same extent during the subsequent courses. There was no impairment of the glomerular filtration rate. Thus, enzymuria and beta 2 microglobulin excretion are a sensitive tool to reveal minor tubular damage. Their use to predict serious renal dysfunction in longitudinal studies, however, seems questionable.

Serum beta 2-microglobulin in fetuses with urinary tract anomalies.

OBJECTIVE: Our purpose was to establish a reference range of fetal serum beta 2-microglobulin, an index of glomerular filtration rate, and to compare the values obtained in fetuses with urinary tract anomalies with this range. STUDY DESIGN: Serum beta 2-microglobulin was measured in 53 control fetuses at 18 to 39 weeks' gestation and in 14 fetuses with urinary tract anomalies, 9 of which had simultaneous urine sampling. RESULTS: In controls fetal serum beta 2-microglobulin had a mean value of 3.4 mg/L (95% data intervals 2.0 to 4.9) and did not correlate with gestational age. In the 14 fetuses with urinary tract anomalies beta 2-microglobulin levels were increased overall compared with controls (median Z score 1.7, range -0.1 to 9.2), and this was also the case in the five fetuses with unilateral renal disorders (median Z score 1.7, range -0.1 to 3.8) and in a fetus who underwent vesicoamniotic shunting and had normal renal function at birth. Serum beta 2-microglobulin was normal in 4 fetuses with bilateral urinary tract obstruction and normal function at postnatal follow-up and also in 1 of 5 fetuses with renal failure. In fetuses with bilateral uropathy urinary sodium correlated with serum beta 2-microglobulin levels. CONCLUSIONS: Increased values of serum beta 2-microglobulin in fetuses with urinary tract anomalies indicate an impaired glomerular filtration rate. The finding of raised concentrations in fetuses with unilateral damage suggests that the compensatory role of the normal kidney is not complete during intrauterine life. Larger series are required to ascertain whether fetal blood sampling is warranted in the antenatal investigation of renal function, especially in view of the close correlation between urinary sodium and serum beta 2-microglobulin levels in fetuses with bilateral obstruction.

In fetuses with isolated hydronephrosis, urinary beta 2-microglobulin and N-acetyl-beta-D-glucosaminidase (NAG) have a limited role in the prediction of postnatal renal function.

Seventy-one fetal urine samples were taken from the bladder or renal pelvis of 33 fetuses at 13-36 weeks' gestation with a diagnosis of urinary tract anomaly. Severe isolated hydronephrosis in the absence of an enlarged bladder was the indication for sampling in 12/33 fetuses (26 samples), who were retrospectively classified into three groups: normal, intermediate, and dysplastic, based on the evaluation of postnatal renal function or histology. For all samples, urinary sodium (Na+), calcium (Ca2+), creatinine, beta 2-microglobulin, and N-acetyl-beta-D-glucosaminidase (NAG) were measured. Among the 71 fetal urine samples, both beta 2-microglobulin and NAG correlated inversely with gestational age, Na+, and Ca2+, but not with creatinine concentrations. However, the correlation of urinary beta 2-microglobulin with gestational age was dependent on the Na+ and Ca2+ concentrations, whereas urinary NAG correlated significantly with urinary Na+ and Ca2+, and also with gestational age. In fetuses with isolated hydronephrosis, only Na+, and not Ca2+, was significantly related to both beta 2-microglobulin and NAG. Only Na+ and beta 2-microglobulin were significantly, and similarly, higher in both dysplastic and intermediate kidneys when compared with fetuses with normal postnatal function. If only the last urine sampled was considered, there was overlapping of all parameters in the three groups. In isolated hydronephrosis, only the most extreme forms of renal failure might be suggested by elevated levels of Na+, Ca2+, beta 2-microglobulin, and NAG, without an obvious superiority of any of these parameters.

Use of the concomitant serum dosage of CA 125, CA 19-9 and interleukin-6 to detect the presence of endometriosis. Results from a series of reproductive age women undergoing laparoscopic surgery for benign gynaecological conditions.

BACKGROUND: Recent studies have proposed the measurement of CA 19-9 and IL-6 as an alternative to CA 125 as markers for endometriosis. This study was performed in order to verify the clinical value of serum CA 125, CA 19-9 and IL-6 levels, either by themselves or combined, in the detection of the disease. METHODS: In a prospective cohort study, serum concentrations of CA 125, CA 19-9 and IL-6 were measured in a consecutive series of 80 women of reproductive age who underwent laparoscopy for benign gynaecological pathologies. RESULTS: Endometriosis was documented in 45 women (stage I-II in 14 cases and stage III-IV in 31 cases). Patients with endometriosis had significantly higher levels of CA 125 than controls [23.4 IU/ml (13.3-37.6) versus 11.4 IU/ml (9.1-18.5), P < 0.001)]. Conversely, women with and without the disease were shown to have similar levels of both IL-6 pg/ml [0.6 (undetectable-1.4) versus 1.0 pg/ml (0.4-1.9), P = 0.09] and CA 19-9 [9.8 IU/ml (4.5-20.8) versus 7.4 IU/ml (2.8-11.5), P = 0.11]. The area under the receiver operating characteristics curve resulted in a statistically significant difference from the null hypothesis only for CA 125 (P < 0.001). Sensitivity and specificity of CA 125 were 27 and 97% respectively and were higher than those related to CA 19-9 and IL-6. Concomitant use of the three dosages led to a sensitivity and a specificity of 42 and 71% respectively. CONCLUSIONS: The concomitant dosage of CA 125, CA 19-9 and IL-6 does not add significant information in respect to the CA 125 test alone in diagnosing either early or advanced stages of endometriosis.

Proximal tubular function and hyperfiltration during amino acid infusion in man.

The relations between renal hemodynamics (Inutest, CPAH) and sodium segmental handling (sodium distal delivery, distal reabsorption, and fractional excretion) were studied in 9 healthy adults infused with an isotonic amino acid solution and in 6 subjects infused with 0.9% saline for 3 h at 0.2 ml/min/kg. During all tests maximal water diuresis was induced and maintained to effect analysis of sodium segmental transport. Both types of infusion produced a similar expansion of extracellular volume (weight increase, hematocrit fall, suppressed plasma renin activity and plasma aldosterone). The amino acid infusion increased the glomerular filtration rate (GFR) and renal blood flow without modifying the filtration fraction. With saline no hemodynamic modifications were observed. The expansion with saline depressed proximal and distal sodium reabsorption whereas during amino acid infusion sodium distal delivery was unaltered and the significantly increased sodium fractional excretion was sustained only by depressed distal reabsorption. Therefore, in parallel with the GFR increase, closely dependent on renal vasodilatation, the well-known stimulation of sodium cotransport by amino acids is able to antagonize the effects of expansion on the proximal sodium reabsorption. An explanation of glomerular hyperfiltration based on a primary metabolic stimulation of the proximal tubular function is suggested.