The management of patients with acute ischemic stroke while on direct oral anticoagulants (DOACs): data from an Italian cohort and a proposed algorithm.

Approximately 1-2% of patients with non-valvular atrial fibrillation have an acute ischemic stroke (AIS) while on direct oral anticoagulant (DOAC) treatment every year. However, current evidence on stroke subtypes, pathophysiology and factors leading to the failure of DOAC preventive therapy in a "real world" setting is still scanty. This study aimed at investigating whether there is any relationship between DOAC plasma levels and the stroke occurrence, on the basis of the phenotypic classification and pathophysiology of the stroke, in a cohort of DOAC-treated patients admitted to our hospital for AIS over 1-year period. A total of 28 patients had DOAC plasma levels determined in emergency and were included in the study, nine patients receiving dabigatran, 11 rivaroxaban and 8 apixaban. The DOAC levels were low in 8/28 patients (28.6% of the sample), intermediate in 4 (14.3%) and high in 16 (57.1%). The most prevalent stroke subtype was the small vessel disease, according to the A-S-C-O phenotypic classification, in 53.6% of our sample. The most common clinical presentation was "minor stroke" in 71.4% of the cases. There was a significantly higher proportion of patients with high DOAC levels in the small vessel group, compared to the cardioembolic group without other phenotypes. The question arises as to the most suitable clinical management of AIS in these patients on DOACs. In the current absence of clear evidence, taking into account the DOAC levels (low/intermediate/high) and the underlying stroke pathophysiology, we present a flowchart of our proposed clinical management of ischemic stroke in patients while on DOAC.

Hypoadiponectinemia in lipodystrophic HIV individuals: a metabolic marker of subclinical cardiac damage.

BACKGROUND AND AIM: To evaluate cardiovascular abnormalities in highly active antiretroviral therapy (HAART) treated HIV patients with no signs or symptoms of cardiovascular impairment, and to assess the relative role of multiple concomitant risk factors. METHODS AND RESULTS: Forty-four consecutive HIV subjects (mean age 41+/-6 yrs) were enrolled. Inclusion criteria were HIV infection, CD4+cell count>150/ml, HAART treatment for at least 4 years. Metabolic serum levels, morphological and functional echocardiographic parameters were assessed in all subjects. Sixteen healthy age and sex matched subjects with no cardiovascular risk factors were recruited as controls. HIV patients showed increased left ventricular mass index with reduced mid-wall fractional shortening (mFS) when compared to controls (50.2+/-10.5 vs. 38.6+/-14.4, p=0.05 and 18.3+/-0.6 vs. 21.9+/-0.7, p<0.05, respectively). Twenty-nine patients were lipodystrophic (LD) and showed a longer HAART period (p=0.0004) and greater use of protease inhibitors (PI) (p=0.001). Coronary flow reserve (CFR) was significantly reduced in HIV patients as compared to controls (p<0.0001), as it was in LD subjects when compared to non-lipodystrophic ones (NLD) (p<0.001). Adiponectin concentrations were found to be significantly lower in LD subjects than in NLD ones (7.8+/-0.8 vs. 13.8+/-1.2 microg/ml, p=0.01), and showed a direct correlation with CFR. In multiple regression analysis, insulin, HDL and adiponectin accounted for 63% of CFR variations. CONCLUSIONS: Left ventricular hypertrophy, depressed mFS and reduced CFR represent the main signs of subclinical cardiac damage in HIV subjects treated with HAART. Hypoadiponectinemia in these subjects seems to be a metabolic risk factor of cardiovascular impairment.

Primary percutaneous transluminal coronary angioplasty in the setting of multivessel disease.

Primary percutaneous coronary intervention of the culprit lesion is the treatment of choice for acute myocardial infarction, while treatment of the severe non culprit lesion is not indicated in the guidelines (Class III indication). More aggressive strategies that include initial treatment of the severe non culprit lesion may reduce the incidence of delayed occlusions in specific clinical settings. The two cases we describe support our point of view.

Molecular analysis of atypical beta-thalassemia heterozygotes.

This paper reviews the molecular pathology of a heterogeneous group of beta-thalassemia heterozygotes which may be referred to as atypical beta-thalassemia. This group includes four different categories of heterozygous beta-thalassemia, which are characterized, respectively, by (1) normal MCV and MCH; (2) normal Hb A2; (3) normal MCV, MCH, and Hb A2 and imbalanced globin chain synthesis only or, (4) the presence of clinical manifestations. The first group is represented by a limited proportion of double heterozygotes for alpha- and beta-thalassemia. The second group includes two categories. One category is double heterozygotes for delta- and beta-thalassemia with the delta-thalassemia mutation in cis or in trans to beta-thalassemia. A number of delta-thalassemia mutations which produce this phenotype by interacting with beta-thalassemia have been described. The other category within the second group is heterozygotes for some mild beta(+)-thalassemia mutations. Within the third group, conclusive evidence for a mutation within the beta-globin gene cluster producing the silent beta-thalassemia phenotype has been obtained solely for a C----T substitution at -101 within the CACCC box of the beta-globin gene. Possible candidates are the complex rearrangements (-T, +ATA; -T, +ATATA) found at position -530 from the cap site. In the group of thalassemic hemoglobinopathies, a series of mutations mostly located in the third exon and producing elongated or truncated molecules have been recently reported. Most of the mutations are silent at the protein level, produce inclusion bodies in peripheral erythrocytes, and show a dominant transmission pattern or occur sporadically.

A rapid electrochemical assay of lecithin in amniotic fluid using a fluoride ion-sensitive electrode.

An electrochemical method is described for the determination of lecithin in rat and human amniotic fluid. Choline is released from lecithin enzymatically by phospholipase D and the hydrogen peroxide released by the action of choline oxidase is quantitatively determined by peroxidase-catalyzed rupture of the covalent C-F bond of 4-fluorophenol. The concentration of F- ions in solutions is determined by a fluoride sensitive electrode from the resulting cell potential difference recorded before and 10 min after addition of a solution containing phospholipase D, choline oxidase and horseradish peroxidase. Lecithin levels in rat amniotic fluid increased from about 10 mumol/l on the 20th day of gestation to 80 mumol/l on day 21, which corresponds to the time of spontaneous delivery. In human amniotic fluid the lecithin concentrations determined with this new method parallel those already reported. They were approximately 10 to 50 mumol/l between the 15th and 18th weeks of gestation and increased from 5- to 7-fold between the 37th and 41st weeks of pregnancy. This method was only slightly influenced by the presence of blood or meconium contamination in the amniotic fluid.

The lysosomal beta-D-N-acetylglucosaminidase isozymes in human plasma during pregnancy: separation and quantification by a simple automated procedure.

beta-D-N-Acetylglucosaminidase isozymes were separated and assayed in the plasma of control healthy individuals and pregnant women by an automated method consisting in chromatofocusing on polybuffer exchanger PBE-94 column, flow-through fluorimetric determination of activity and computer assisted quantification. Under the established optimal conditions the method fractionated beta-D-N-acetylglucosaminidase into four isozymes. A, I2, I1 and B, with the analytical coefficients of variation of 1.8, 2.2, 6.4 and 4.1%, respectively. Duration of a single analysis was 25 min including washing, and 10-15 successive runs could be performed on the same column with good reproducibility. A linear activity response was observed from 1-5 microliters of plasma (depending on the individual isozyme) to 50 microliters, and the detection limit was 0.016 mUnits. Isozyme A was heat labile. Upon sialidase treatment, isozymes A, I2 and I1 released sialic acid and were eluted from the column at less acidic pHs. In healthy individuals isozymes A, I2, I1 and B covered about 62.8, 6.9, 15.0 and 15.1% of the total beta-D-N-acetyl-glucosaminidase activity, respectively. During pregnancy the plasma concentration of all isozymes increased. Isozyme I2 showed the highest enhancement (30-fold), followed by I1 (8-fold), B (5.6-fold) and A (3-fold). Interruption of pregnancy by either physiological delivery or ambulatory abortion was followed by a sharp fall of the concentration of all isozymes reaching, in a few days, the control levels.

Behaviour of several enzymes of lysosomal origin in human plasma during pregnancy.

The following enzymes of lysosomal origin were fluorimetrically determined in maternal plasma from the second to the ninth month of pregnancy at 1-mth intervals: beta-D-N-acetylglucosaminidase (EC 3.2.1.30), beta-D-glucuronidase (EC 3.2.1.31), beta-D-glucosidase (EC 3.2.1.21), beta-D-galactosidase (EC 3.2.1.22), alpha-D-galactosidase (EC 3.2.1.23), alpha-L-fucosidase (EC 3.2.1.51) and alpha-D-mannosidase (EC 3.2.1.24) (pH 4.0). As reference microsomal alpha-D-mannosidase (pH 5.7) was also studied. Thirty-eight healthy women, aged 18-37 yr, who had a normal pregnancy followed by normal parturition, were studied. All enzymes, with the only exception of beta-D-galactosidase, showed a progressive and statistically significant increase of activity throughout pregnancy. At the end of pregnancy, the increase ranged from a maximum of 5.6-fold for beta-D-N-acetylglucosaminidase to a minimum of 0.55-fold for alpha-D-mannosidase, pH 5.7. In the case of beta-D-N-acetylglucosaminidase, the level at the fifth month of pregnancy was significantly higher than that at the third month, and from the sixth to the ninth month each level significantly differed from that of the month immediately preceding.

N-acetyl-beta-D-glucosaminidase (NAG) levels in amniotic fluid or urine in prenatal and postnatal life.

The isoenzyme pattern of N-acetyl-beta-D-glucosaminidase (NAG) was determined in the amniotic fluid of 75 women undergoing amniocentesis for genetic indications. In the amniotic fluid and in the newborn's urine the NAG was completely different from that in adult urine, indicating the presence of a fetal isoenzymatic form also present in the first stage of life.

Blood biochemical characteristics of cattle at sea level and at moderately high altitude (3,000 m).

We investigated the biochemical composition of blood from Holstein cows, native breed (criollas), and cows descended from fighting bulls (Vacas de lidia) raised at an altitude of 3,000 m (moderately high altitude, MHA), and compared the results with those from Holsteins and cows of similar genetic ancestry as the criollas (scrub cows), both raised at sea level (SL), to determine blood biochemical values characteristic of adaptation to high altitude. Only potassium and calcium concentrations were similar among groups. Glucose concentration was lower in MHA cows, with the exception of Vacas de lidia. Serum bicarbonate concentration was lower in MHA cows; this finding can be explained by hyperventilation in the hypoxic environment. Serum magnesium concentration was lower in SL and MHA Holsteins than in other groups. Serum phosphate concentration was lower in scrub cows, MHA Holsteins, and criollas than in other groups. Cholesterol concentrations were lower in SL Holsteins, whereas triglycerides were higher in scrub cows and MHA Vacas de lidia. Concentration of high-density lipoprotein was significantly greater in Vacas de lidia and less in MHA criollas than in the other groups. Uric acid and total protein were higher in MHA groups. Using radioimmunoassay for human proteins, thyroxine-binding globulin was undetectable. Total and free thyroxine and free triiodothyronine were higher in scrub cows, followed by Vacas de lidia; lower values were detected in SL and MHA Holsteins and MHA criollas.

Salt loading test in a population adapted to moderately high altitude living (3,000 m).

The sodium excretory capacity of normal subjects acutely mobilized from sea level to moderately high altitude was compared to native subjects adapted to high altitude living (3,000 meters). This study was conducted in order to provide insights into hormonal adaptations associated with acute mobilization to a hypoxemic environment and to try to determine how these variables could influence the renal handling of a salt load. A standard amount of 5% NaCl solution at a volume of 100 ml/m2 BSA was infused over a 30-min period to all subjects. Urine collections were obtained periodically over the next 3 h. Subjects adapted to moderately high altitude living were able to excrete a salt load faster than unadapted subjects (57.1 vs. 32.9 mmol.m-2.h-1, respectively). No change in plasma atrial natriuretic factor (ANF) concentration in either group of subjects was observed during the salt administration period. Adapted individuals had significantly higher baseline levels of antidiuretic hormone (ADH). The high altitude natives enhanced excretory response to a salt load was not explained by any observed hormonal changes and their lack of increased ADH release to serum osmolar changes was unexplained.

Effects of hypoxemia at sea level and high altitude on sodium excretion and hormonal levels.

Acute hypoxemia at sea level is associated with decreased aldosterone secretion. This inhibition is thought to be mediated through secretion of atrial natriuretic factor (ANF). The interaction of these two hormones should result in enhanced renal salt excretion during hypoxemic conditions. This hypothesis was tested by administration of a standardized salt load to seven normal subjects during normoxemia at sea level (SL), acute hypoxemia (AH) at sea level, and high altitude (HA) (3,000 m). Urine and venous blood samples were collected and analyzed. A natriuresis and diuresis was observed only under AH conditions. It was accompanied by a decrease in plasma aldosterone levels, but did not correlate with changes in plasma aldosterone levels, ANF, or other hormones. Increased plasma renin activity (PRA) and increased norepinephrine levels were encountered at HA, suggesting sympathetic nervous system activation. No change in anti-diuretic hormone (ADH) levels with increased plasma osmolality was seen at HA. We conclude that excretion of a salt load during normobaric hypoxemia is enhanced by a decrease in plasma aldosterone levels, unrelated to changes in ANF or other hormones. The differences observed in norepinephrine, PRA, and ADH levels during HA versus AH conditions suggest that hypobaria or chronic hypoxemia may influence these hormonal responses.

Salt excretory capacity in natives adapted to moderate high altitude living after acute mobilization to sea level.

The sodium excretory capacity of six normal subjects born and raised at moderately high altitude (2600 m) was evaluated at high altitude (HA), and after acute mobilization to sea level (SL). The ability of these individuals to respond to an acute salt load was evaluated by infusing a volume of 100 ml.m-2 body surface area (BSA) of 5% sodium chloride solution over a 30-min time period in both experimental conditions. HA natives were able to excrete a significantly greater salt load at HA than at SL (41.8% vs. 31.6%, respectively, p < 0.05) in 3 h. No changes in plasma atrial natriuretic factor (ANF) concentration were found in either experimental condition. Despite an increase in serum osmolality, no vasopressin (AVP) response was noted either at HA or SL. No correlation between serum AVP levels and urine c-AMP concentrations was found. The enhanced excretory response to a salt load at HA was not explained by the measured hormonal changes. The lack of AVP response to increased serum osmolality, both at HA and SL, in high altitude adapted subjects is presently unexplainable.

Analytical validity of electrochemical determination of lecithin for establishing foetal lung maturity in normal and complicated pregnancies.

An electrochemical assay of lecithin for the prediction of foetal lung maturity in normal and complicated pregnancies has been analytically evaluated. The method is based on sequential enzymatic reactions causing the stoichiometric transformation of lecithin to hydrogen peroxide, which reacts with an organo-fluoro compound in the presence of peroxidase. The rupture of the C-F bond releases fluoride ions, that are detected by a selective electrode. The correlation between the lecithin concentration in amniotic fluid, measured electrochemically, and the fluorescence polarization (FP) value, chosen as reference method, was determined. Correlation studies were performed on rat amniotic fluids, on 67 samples from human normal pregnancies, and on seven samples from complicated pregnancies. The relationships between the FP value and the lecithin concentration were linear, and the correlation coefficients were 0.987 for rat and 0.884 for human amniotic fluids. Concordance was good for predicting foetal lung maturity in complicated pregnancies.

A less aggressive therapeutic option for electrical storm.

Electrical storm (ES) describes the rapidly clustering ventricular fibrillation (VF) that requires multiple cardioversions. Emerging evidence suggests that Purkinje arborization and sympathetic nerve regeneration play a major role in initiating malignant arrhythmias. We report the case of two patients who, after having survived an acute myocardial infarction (MI), developed repetitive episodes of polymorphic ventricular tachycardia and VF one week after percutaneous revascularization, triggered by monomorphic premature ventricular contractions (PVCs). Owing to repetitive and drug-refractory VF episodes, temporary atrial overdrive pacing was attempted with complete suppression of VF. In the following month, recurrence of ventricular arrhythmia was inversely related to the atrial pacing rate. Although antiarrhythmic drugs other than beta-blockers had been discontinued, neither PVCs nor ventricular arrhythmias recurred at one-month follow-up when the lower pacing rate was set at 60 bpm. In conclusion in these patients, ES was likely related to nerve sprouting after ischemic injury. This chaotic phenomenon occurs early after tissue damage and shows a peak seven days after acute MI with degeneration of superfluous axon branches. High pacing rates can reduce early after depolarizations and suppress PVCs, thus preventing ES. On these grounds, ES patients may be treated with temporary overdrive pacing rather than early radiofrequency ablation.

[Selection of candidates for cardiac resynchronisation therapy and prediction of their response.]. / Selezione dei candidati alla terapia di resincronizzazione cardiaca e predizione della loro risposta.

AIMS: Cardiac resynchronization therapy is currently used in selected patients with end-stage heart failure. However, 30% of patients do not respond to CRT. The aim of our study was to find echocardiographic (TDI), electrocardiographic (QRS interval and electric distance between right and left catheter), clinical (6MW test) or autonomical (HRV) parameters able to predict responsiveness to CRT. MATERIALS AND METHODS: 47 patients (mean age 74+/-10 years) with end-stage heart failure, symptomatic, with left ventricular (LV) ejection fraction less than 35% and QRS 120 ms, underwent CRT. RESULTS: At thirteen months follow up, all clinical and echocardiographic parameters significantly improves (EF p<0.001; LVED volume p<0.001; 6MWT p<0.001; max delay TDI p<0.001; HRV p<0.05; Right-left distance p<0.05). A positive response was documented in 31/47 (67.4%) patients who presented an increase in LVEF > or = 5 units. There was a significant difference of LVED diameter (p<0.05) and HRV (p<0.05) between responders and non responders. Receiver-operating curve analysis showed that a positive response to CRT may be predicted in patients with LVED diameter <67 mm (with a sensitivity of 77% and a specificity of 88%). CONCLUSIONS: Our results confirm the clinical improvement obtained by CRT in end-stage heart failure patients as well as the limited value of QRS duration and intraventricular dyssynchrony as predictor of clinical recovery after CRT. While a most-advanced clinical stage of disease (HRV) without an advance left ventricular remodeling (LVED diameter) demonstrated to predict response to CRT, with sensitivity of 77% and specificity of 88%.

Haemolytic disease of the newborn due to anti-Fya (first case reported in Italy).

A new case of haemolytic disease of the newborn due to anti-Fya antibodies is described. The maternal alloimmunization was related to a previous blood transfusion. The patient, her previous child and the donor of the blood transfused were tested. Foetal condition was monitored by measuring bilirubin in amniotic fluid on three different occasions during pregnancy. The infant developed a mild haemolytic disease that required treatment only with phototherapy.

Metastatic ependymoma manifested by pancytopenia.

We present the case of a 32-year-old white man seen for evaluation of pancytopenia 12 years after thoracolumbar myeloresection of intramedullary ependymoma. Bone marrow examination revealed extensive marrow fibrosis and tumor infiltrate compatible with metastatic ependymoma. Myelophthisic anemia due to metastatic ependymoma, though not previously reported, should be entertained in the differential workup for pancytopenia.