Major Neurological Disease and Occupational Exposure to Organic Solvents

Five patients are described who presented with major organicbrain disease affecting one or more of pyramidal and extrapyramidaltracts, cerebellum, and higher cortical functions. All had ahistory of 10 years or more of regular occupational exposureto solvents in confined spaces, three in painting inside shipsand the others in weapons maintenance and printing. All hadbeen regularly exposed to high air vapour peaks as well as toskin contamination. Four showed some evidence of improvementafter the exposure ceased. None was initially suspected of havinga toxic encephalopathy by the consultant to whom he was referred.The spectrum of neurological disease presented by these menmirrors closely that described in solvent abusers. All wereforced by illness to retire from their work, a circumstancewhich might have in the past have led to such conditions beingmissed in cross-sectional studies, which in general have notshown evidence of major disease. We suggest that when such diseaseoccurs nowadays, its cause is usually not suspected. Furtherepidemiological study of the problem is necessary.     

Diverticulite solitaire du c?lon droit

Diverticula of the right colon are a rare clinical entity. Diverticulitis can occur with these lesions, but the diagnosis is frequently missed as the presentation is similar to that of acute appendicitis and can mimic other acute intraabdominal infections such as cholecystitis. The authors report a case of solitary diverticulitis of the right colon in a young woman, an incidental discovery during surgery for suspected appendicitis, with emphasis on the diagnostic and therapeutic modalities.     

A methodology for the real-time measurement of distal extremity temperature

The real-time measurement of distal extremity temperature may have a wide variety of uses, from assessing occupational cold exposure to determining the impact of autonomic dysfunction on normal thermoregulation. In this study, we describe a novel approach to the measurement of this physiologic parameter by the use of datalogger iButtons affixed to the foot and outer clothing, the latter serving as an approximate measure of ambient temperature, in conjunction with the measurement of foot movement via actigraphy. This approach was piloted in 20 individuals, all of whom were also requested to maintain a diary of activities during the measurement period. The technique was found to be reliable and well tolerated amongst the group of subjects, with no individual suffering an adverse reaction (e.g. skin breakdown) while wearing the device. However, periods of ambient temperature data were suspect in at least 25% of the recordings, presumably due to misplacement of the sensor. Several approaches to data analysis suggested themselves, including separate analysis of the nocturnal/sleep and awake data sets. The use of datalogger iButtons in conjunction with actigraphy appears to be a potential useful approach for the acquisition of real-time distal extremity temperature and movement data and has the potential of serving a variety of clinical and research purposes.     

Calmodulin antagonists inhibit and phorbol esters enhance transferrin endocytosis and iron uptake by immature erythroid cells

Seven antagonists of the calcium-binding protein calmodulin were found to inhibit iron and transferrin uptake by reticulocytes. This inhibition could be completely accounted for by inhibition of the endocytosis and exocytosis of transferrin. When four of the antagonists were tested with the nucleated erythroid cells from the liver of the fetal rat, inhibition of iron uptake was also observed but at higher concentrations than required for the same degree of inhibition with reticulocytes. The tumor promoters phorbol 12-myristate 13-acetate (PMA) and phorbol 12,13-dibutyrate (PDB) were shown to increase the rates of iron and transferrin uptake by reticulocytes and fetal liver erythroid cells by accelerating the rates of transferrin endocytosis and exocytosis. Since these substances are known to stimulate the calcium-activated enzyme protein kinase C while calmodulin antagonists are inhibitory, it is concluded that this enzyme plays an important role in the endocytosis and intracellular cycling of transferrin, and iron uptake by immature erythroid cells. However, the possibilities that calmodulin is also involved or that the inhibitory effects of the calmodulin antagonists are due to nonspecific actions on the cell membrane cannot be excluded.     

Gender Differences in Platelet Reactivity in Patients Receiving Dual Antiplatelet Therapy

Background

Cardiovascular risk is still underestimated in women, experiencing higher mortality and worse prognosis after acute cardiovascular events. Gender differences have been reported in thrombotic and hemorrhagic risk during dual antiplatelet therapy (DAPT), thus suggesting a potential variability in platelet reactivity according to sex. The aim of the present study was to assess the role of gender on platelet function and the prevalence of high-on treatment residual platelet reactivity (HRPR) during DAPT in patients with recent acute coronary syndrome or percutaneous coronary revascularization.

Methods

Patients treated with DAPT (ASA and clopidogrel or ticagrelor) were scheduled for platelet function assessment at 30–90 days post-discharge. By whole blood impedance aggregometry, HRPR was considered for ASPI test >862 AU*min (for ASA) and ADP test values ≥417 AU*min (for ADP-antagonists).

Results

We included 541 patients on DAPT, 122 (22.6 %) of whom were females. Females were older (p < 0.001), displayed more frequently hypercholesterolemia (p = 0.003), renal failure (p = 0.04), acute presentation (p < 0.001), higher cholesterol levels and platelets count (p < 0.001). Inverse association was demonstrated with smoking (p < 0.001), previous PCI (p = 0.04) and statin use (p = 0.03), creatinine and haemoglobin (p < 0.001). Female gender did not influence mean platelet reactivity or the prevalence of HRPR for ASA (1.7 % vs 1.4 %, OR[95%CI] = 1.14[0.17–4.36], p = 0.99, adjusted OR[95%CI] = 1.54[0.20–11.6], p = 0.68) or ADP-antagonists (26.3 % vs 22.8 %, OR[95%CI] = 1.17[0.52–1.34], p = 0.45, adjusted OR[95%CI] = 1.05[0.59–1.86], p = 0.87). Results did not change when considering separately the 309 patients treated with clopidogrel (34 % vs 31.3 %, OR[95%CI] = 1.13[0.62–2.07], p = 0.76, adjusted OR[95%CI] = 1.35[0.63–2.9], p = 0.44 for females vs males), or patients (n = 232) on ticagrelor (20.4 % vs 11.1 %, OR[95%CI] = 2.27[0.99–5.17], p = 0.06 for females vs males), confirmed after correction for baseline differences (adjusted OR[95%CI] = 1.21[0.28–2.29], p = 0.68).

Conclusion

In patients receiving dual antiplatelet therapy, gender does not impact on the prevalence of high-on treatment residual platelet reactivity (HRPR) with the major antiplatelet agents ASA, clopidogrel or ticagrelor.

     

Safety and immunogenicity of a recombinant sporozoite malaria vaccine against Plasmodium vivax.

A recombinant Plasmodium vivax circumsporozoite (CS) antigen representing approximately 70% of the CS protein was expressed in yeast and adsorbed onto aluminum hydroxide for use as a malaria vaccine. In a study of safety and immunogenicity, 30 volunteers were divided into four groups of 5, 5, 10, and 10 individuals, and inoculated intramuscularly with 50, 100, 200, or 400 micrograms of vaccine, respectively. Primary vaccinations were followed by two booster immunizations at six weeks and six months. Overall, the vaccine was well tolerated. Following the third vaccination, one volunteer developed acute hepatitis of uncertain etiology that resolved without sequelae. All volunteers in the 400-micrograms group, and six of 10 in the 200-micrograms group generated IgG against P. vivax CS protein, as determined by Western blot using recombinant CS protein. However, the magnitude of the antibody response measured by indirect immunofluorescence of intact sporozoites or enzyme-linked immunosorbent assay against the recombinant protein was low, and responses could not be boosted. Antigen-driven replication studies using peripheral blood lymphocytes failed to detect proliferative responses specific to peptide sequences represented in the recombinant vaccine, except in one volunteer. Minimal humoral and cell-mediated immune responses developed in most recipients who received this recombinant CS vaccine.     

Vitamin D levels and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor

Background: Suboptimal platelet inhibition still represents an important challenge, especially for patients undergoing percutaneous coronary interventions (PCIs). However, very few are known so far on the predictors of high-residual platelet reactivity (HRPR) despite antiplatelet strategies. Increasing attention has been paid in the last years to the role of vitamin D in atherothrombosis. Therefore, the aim of our study was to evaluate the impact of vitamin D levels on platelet function in patients treated with dual antiplatelet therapy (DAPT). Patients treated with DAPT (ASA and clopidogrel or ticagrelor) after a recent acute coronary syndrome (ACS) or elective PCI were scheduled for platelet function assessment at 30–90 days post-discharge. Platelet function was assessed by whole blood impedance aggregometry (Multiplate®-Roche Diagnostics AG), HRPR was considered for ASPI test values > 862 AU*min (for ASA) and adenosine diphosphate (ADP) test values ≥417 AU*min (for ADP-antagonists). Fasting samples were obtained for main chemistry parameters and vitamin D level assessment.

Our population is represented by 503 patients, who were divided according to vitamin D quartiles (≤9.1; 9.2–14.4; 14.5–21.7; >21.7 ng/ml). Lower vitamin D levels related with age (p = 0.04), diabetic status (p = 0.05), and previous coronary surgery (p = 0.007), therapy with beta-blockers and statins (p = 0.01 and p = 0.02). Vitamin D inversely related to the levels of total cholesterol (p = 0.01), triglycerides (p < 0.001), hemoglobin (p = 0.05), and HbA1c (p < 0.001). Significantly higher platelet reactivity was observed after platelet stimulation with ADP (p = 0.01), but not with other platelet activators. The prevalence of HRPR for ASA was low (1.2%) and not conditioned by Vitamin D levels (adjusted OR[95%CI] = 1.56[0.71–3.5], p = 0.27). HRPR with ADP-antagonists was observed in 26% of patients, and the rate increased with lower vitamin D quartiles (37.3% vs 22.2% vs 24.4% vs 20.2%, p = 0.005, adjusted OR[95%CI] = 1.23[1.02–1.49], p = 0.04).

An absolute increase in HRPR with lower vitamin D levels was similarly observed among patients receiving ticagrelor (adjusted OR[95% CI] = 1.40[0.95–2.06], p = 0.08), and those on clopidogrel (adjusted OR[95%CI] = 1.31[0.99–1.75], p = 0.06).

Thus, lower vitamin D levels are associated with higher platelet reactivity and impaired effectiveness of ADP-antagonists, while not influencing the effectiveness of ASA. Future studies will tell whether vitamin D supplementation can reduce platelet reactivity, overcoming the phenomenon of resistance to antiplatelet agents.