Exploring novel circulating biomarkers for liver cancer through extracellular vesicle characterization with infrared spectroscopy and plasmonics.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common form of liver cancer, with cirrhosis being a major risk factor. Traditional blood markers like alpha-fetoprotein (AFP) demonstrate limited efficacy in distinguishing between HCC and cirrhosis, underscoring the need for more effective diagnostic methodologies. In this context, extracellular vesicles (EVs) have emerged as promising candidates; however, their practical diagnostic application is restricted by the current lack of label-free methods to accurately profile their molecular content. To address this gap, our study explores the potential of mid-infrared (mid-IR) spectroscopy, both alone and in combination with plasmonic nanostructures, to detect and characterize circulating EVs. RESULTS: EVs were extracted from HCC and cirrhotic patients. Mid-IR spectroscopy in the Attenuated Total Reflection (ATR) mode was utilized to identify potential signatures for patient classification, highlighting significant changes in the Amide I-II region (1475-1700 cm-1). This signature demonstrated diagnostic performance comparable to AFP and surpassed it when the two markers were combined. Further investigations utilized a plasmonic metasurface suitable for ultrasensitive spectroscopy within this spectral range. This device consists of two sets of parallel rod-shaped gold nanoantennas (NAs); the longer NAs produced an intense near-field amplification in the Amide I-II bands, while the shorter NAs were utilized to provide a sharp reflectivity edge at 1800-2200 cm-1 for EV mass-sensing. A clinically relevant subpopulation of EVs was targeted by conjugating NAs with an antibody specific to Epithelial Cell Adhesion Molecule (EpCAM). This methodology enabled the detection of variations in the quantity of EpCAM-presenting EVs and revealed changes in the Amide I-II lineshape. SIGNIFICANCE: The presented results can positively impact the development of novel laboratory methods for the label-free characterization of EVs, based on the combination between mid-IR spectroscopy and plasmonics. Additionally, data obtained by using HCC and cirrhotic subjects as a model system, suggest that this approach could be adapted for monitoring these conditions.

Compact and tunable focusing device for plasma wakefield acceleration.

Plasma wakefield acceleration, either driven by ultra-short laser pulses or electron bunches, represents one of the most promising techniques able to overcome the limits of conventional RF technology and allows the development of compact accelerators. In the particle beam-driven scenario, ultra-short bunches with tiny spot sizes are required to enhance the accelerating gradient and preserve the emittance and energy spread of the accelerated bunch. To achieve such tight transverse beam sizes, a focusing system with short focal length is mandatory. Here we discuss the development of a compact and tunable system consisting of three small-bore permanent-magnet quadrupoles with 520 T/m field gradient. The device has been designed in view of the plasma acceleration experiments planned at the SPARC_LAB test-facility. Being the field gradient fixed, the focusing is adjusted by tuning the relative position of the three magnets with nanometer resolution. Details about its magnetic design, beam-dynamics simulations, and preliminary results are examined in the paper.

Investigating the CVD Synthesis of Graphene on Ge(100): toward Layer-by-Layer Growth.

Germanium is emerging as the substrate of choice for the growth of graphene in CMOS-compatible processes. For future application in next generation devices the accurate control over the properties of high-quality graphene synthesized on Ge surfaces, such as number of layers and domain size, is of paramount importance. Here we investigate the role of the process gas flows on the CVD growth of graphene on Ge(100). The quality and morphology of the deposited material is assessed by using µ-Raman spectroscopy, X-ray photoemission spectroscopy, scanning electron microscopy, and atomic force microscopy. We find that by simply varying the carbon precursor flow different growth regimes yielding to graphene nanoribbons, graphene monolayer, and graphene multilayer are established. We identify the growth conditions yielding to a layer-by-layer growth regime and report on the achievement of homogeneous monolayer graphene with an average intensity ratio of 2D and G bands in the Raman map larger than 3.

Self-assembling of large ordered DNA arrays using superhydrophobic patterned surfaces.

In this paper we present a simple and robust method to realize highly ordered arrays of stretched and suspended DNA molecules over the millimeter length scale. To this end we used an ad hoc designed superhydrophobic surface made of high aspect-ratio silicon pillars, where we deposited a droplet containing genomic DNA. A precise positioning of DNA strands was achieved by shaping the silicon pillars so that sharpened features resembling tips were included. Such features allowed us to accurately control the droplet de-wetting dynamics, pinning DNA strands in a well-defined position above pillars. The proposed technique has the potential to positively impact on the development of novel DNA chips for genetic analysis.

Effects of regular exercise on blood pressure and left ventricular hypertrophy in African-American men with severe hypertension.

BACKGROUND: The prevalence of hypertension and its cardiovascular complications is higher in African Americans than in whites. Interventions to control blood pressure in this population are particularly important. Regular exercise lowers blood pressure in patients with mild-to-moderate hypertension, but its effects in patients with severe hypertension have not been studied. We examined the effects of moderately intense exercise on blood pressure and left ventricular hypertrophy in African-American men with severe hypertension. METHODS: We randomly assigned 46 men 35 to 76 years of age to exercise plus antihypertensive medication (23 men) or antihypertensive medication alone (23 men). A total of 18 men in the exercise group completed 16 weeks of exercise, and 14 completed 32 weeks of exercise, which was performed three times per week at 60 to 80 percent of the maximal heart rate. RESULTS: After 16 weeks, mean (+/- SD) diastolic blood pressure had decreased from 88 +/- 7 to 83 +/- 8 mm Hg in the patients who exercised, whereas it had increased slightly, from 88 +/- 6 to 90 +/- 7 mm Hg, in those who did not exercise (P = 0.002). Diastolic blood pressure remained significantly lower after 32 weeks of exercise, even with substantial reductions in the dose of antihypertensive medication. In addition, the thickness of the interventricular septum (P = 0.03), the left ventricular mass (P = 0.02), and the mass index (P = 0.04) had decreased significantly after 16 weeks in the patients who exercised, whereas there was no significant change in the nonexercisers. CONCLUSIONS: Regular exercise reduced blood pressure and left ventricular hypertrophy in African-American men with severe hypertension.

Importance of obesity, race and age to the cardiac structural and functional effects of hypertension. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

OBJECTIVES: The purpose of this study was to determine the effects of obesity and its interaction with age, race and the magnitude of blood pressure elevation in a large cohort of patients with mild to moderate hypertension and a high prevalence of left ventricular hypertrophy. BACKGROUND: Obesity, race and age each have important effects on the incidence and severity of hypertension and may contribute to the effects of blood pressure elevation on the cardiac manifestations of hypertension. METHODS: Left ventricular structure and function were assessed with two-dimensional targeted M-mode echocardiography in 692 men with mild to moderate hypertension (average blood pressure 153/100 mm Hg), and the data were compared in relation to obesity (determined from body mass index), age, race, blood pressure, physical activity, plasma renin activity, urinary sodium excretion, hematocrit, heart rate and serum lipids. RESULTS: Left ventricular hypertrophy was common (63% with increased left ventricular mass, 22% with left ventricular hypertrophy on the electrocardiogram [ECG]). On multivariable regression analysis, body mass index was the strongest predictor of left ventricular mass and magnified the slope relation of blood pressure to left ventricular mass. Despite a greater prevalence of ECG left ventricular hypertrophy in blacks (31%) than in whites (10%), left ventricular mass and echocardiographic prevalence of left ventricular hypertrophy did not differ by race. However, septal, posterior left ventricular and relative wall thickness were greater in black than in white men. CONCLUSIONS: Obesity is the strongest clinical predictor of left ventricular mass and left ventricular hypertrophy in men, even in those with mild to moderate hypertension of sufficient severity to be associated with a high prevalence of left ventricular hypertrophy. Moreover, independent effects of systolic blood pressure on left ventricular mass are amplified by obesity. Although race does not affect left ventricular mass or the prevalence of left ventricular hypertrophy, black race is associated with greater relative wall thickness, itself a predictor of unfavorable cardiovascular outcome.

Diuretic therapy and exercise in patients with systemic hypertension.

Twenty patients with uncomplicated systemic hypertension underwent treadmill testing twice during placebo treatment and twice during hydrochlorothiazide treatment. Data were collected at rest, at peak exercise and 10 min after exercise. Serum potassium, magnesium and plasma catecholamines increased significantly with exercise. There was no rebound hypokalaemia during the recovery period. Occasional ventricular premature complexes were recorded in all phases of the study. However, there was no difference in the frequency or complexity of arrhythmias between the placebo and the treatment periods.

Effects of diuretic therapy and exercise-related arrhythmias in systemic hypertension.

The effect of aerobic exercise on cardiac arrhythmias, plasma catecholamines, potassium and magnesium in patients with systemic hypertension was assessed. Twenty patients (age 54 +/- 8 years) with uncomplicated hypertension underwent exercise treadmill testing twice while receiving placebo and twice while receiving hydrochlorothiazide 100 mg daily. Blood samples for electrolytes and catecholamines were obtained at rest, at peak exercise and 10 minutes after exercise. There were no substantial differences comparing the first to the second placebo phase or the first to the second treatment period. As expected, hydrochlorothiazide treatment caused a significant decrease in serum potassium (4.00 +/- 0.44 to 3.32 +/- 0.49 mEq/liter, p less than 0.001). Serum magnesium did not change with treatment. Serum potassium, serum magnesium and plasma catecholamines increased significantly with exercise. No rebound hypokalemia occurred during recovery. Occasional ventricular premature contractions were noted at rest during all phases of the study, with only a slight increase in frequency during exercise. Couplets were noted only rarely. No difference in the frequency or complexity of arrhythmias was noted between placebo and treatment periods. Diuretic therapy or diuretic-induced hypokalemia has no profound effect on cardiac arrhythmias during or after exercise in patients with uncomplicated systemic hypertension.

Exercise blood pressure response and left ventricular hypertrophy.

Although hypertension is the major cause of left ventricular hypertrophy (LVH), numerous studies failed to demonstrate a close correlation between resting blood pressure (BP) and degree of LVH. Some authors have shown better correlation between BP at work and left ventricular mass (LV mass), whereas other studies supported an association between catecholamines or angiotensin II and LV mass. In this study we investigated the relationship of resting and exercise BP and catecholamines to the degree of LVH. Nineteen patients with established mild to moderate hypertension were studied. Blood pressure was measured following a ten-minute rest and every three minutes during exercise using a Bruce protocol. Electrolytes, epinephrine (EP), and norepinephrine (NE) were measured at rest, at peak exercise, and at ten-minutes postexercise. Resting BP averaged 154 +/- 24/99 +/- 9 mm Hg and at three minutes of exercise 195 +/- 30/101 +/- 6 (P less than .001). Resting EP was 51 +/- 20 pg/mL, NE 314 +/- 187, and at peak exercise EP was 107 +/- 61 (P less than .001) and NE 1016 +/- 566 (P less than .001). The average LV mass was 277 +/- 85 g. A significant correlation was found only between systolic BP at three minutes of exercise and LV mass (r = .479, P less than .04). No other variable correlated significantly with LV mass. These data suggest that systolic BP achieved at low level of exercise (5 mets), corresponding to usual daily activities, may be the most important determinant of LVH in patients with hypertension.

Thiazide therapy is not a cause of arrhythmia in patients with systemic hypertension.

Forty-four patients with uncomplicated systemic hypertension underwent 48-hour electrocardiographic monitoring before and after four weeks of treatment with hydrochlorothiazide, 100 mg daily. Plasma potassium concentration decreased from 4.07 +/- 0.26 mmol/L (4.07 +/- 0.26 mEq/L) to 3.36 +/- 0.44 mmol/L (3.36 +/- 0.44 mEq/L). The average number of premature ventricular contractions, couplets, or ventricular tachycardia episodes did not change significantly. Twenty patients had more than minimal ventricular ectopy (class 2 to 5) before and 17 after diuretic therapy. Further analysis revealed that following diuretic therapy, neither patients with plasma potassium levels of 3.4 mmol/L or less (less than or equal to 3.4 mEq/L) nor patients with left ventricular hypertrophy had increased ectopy as compared with baseline. At baseline, patients with left ventricular hypertrophy had more arrhythmias than patients without. We conclude that the results of this study provide no evidence that diuretic therapy or diuretic-induced hypokalemia results in increased ventricular ectopy, and that patients with left ventricular hypertrophy may have more ventricular ectopy than patients without, but these arrhythmias are not adversely effected by diuretic therapy.

Incidence and cardiac effects of systemic venous air embolism. Echocardiographic evidence of arterial embolization via noncardiac shunt.

Central nervous system dysfunction in venous air embolism may result from air entering the arterial circulation. Using two-dimensional and pulsed-wave Doppler echocardiography, this study not only documented the frequent presence of air in the right heart chambers of patients undergoing upright neurosurgery or pacemaker insertion, but also documented the presence of air in the left atrium and left ventricle of one patient via noncardiac shunt. Studies in dogs confirmed paradoxical air embolism in the absence of anatomic communications between right and left heart chambers. Systemic venous air also produced a dose-dependent increase in pulmonary artery pressure and diastolic flattening of the ventricular septum with increase in left ventricular filling pressure despite preserved systolic function.

Effect of diuretic therapy on ventricular arrhythmias in hypertensive patients with or without left ventricular hypertrophy.

Recent studies have suggested that hypertensive patients with ECG evidence of left ventricular hypertrophy (LVH) may have increased risk of sudden death when treated with diuretics. In the present study echocardiography was used as a more sensitive index for the presence of LVH. Thirty-one patients with uncomplicated hypertension underwent 48-hour ambulatory ECG monitoring both before any treatment and after 4 weeks of hydrochlorothiazide, (HCTZ), 100 mg daily. In 18 patients with left ventricular posterior wall thickness (LVPWT) greater than or equal to 13 mm (average = 14.4 +/- 0.2 mm) on echocardiogram, plasma potassium decreased from 4.1 +/- 0.3 to 3.3 +/- 0.4 mEq/L with HCTZ (p less than 0.01). Premature ventricular contractions (PVCs) averaged 5.7 +/- 9.9/hr at baseline and 7.1 +/- 16.6/hr following HCTZ (p = NS). The total number of couplets was 29 before and 13 after HCTZ, while four brief runs of ventricular tachycardia occurred only before treatment. In the remaining 13 patients with LVPWT less than or equal to 12 mm (average = 11.2 +/- 0.1 mm), plasma potassium decreased from 4.1 +/- 0.3 to 3.4 +/- 0.5 mEq/L with HCTZ (p less than 0.01). The average number of PVCs was 4.3 +/- 8.0/hr after HCTZ (p = NS). One couplet and one 3-beat run of ventricular tachycardia occurred before and one 3-beat run of ventricular tachycardia after HCTZ. Although more complex arrhythmias were noted in the LVH group, the differences were not statistically significant. These results indicate that thiazide therapy does not increase ventricular arrhythmias either in patients with or without LVH.

Initial and long-term effects of prazosin on sympathetic vasopressor responses in essential hypertension.

In 10 untreated hypertensive patients who received an initial dose of 3 to 5 mg prazosin, supine blood pressure (BP) decreased significantly, from an average of 171 +/- 24/96 +/- 10 to 157 +/- 22/90 +/- 10 mm Hg (p less than 0.025). The Valsalva overshoot, response to cold pressor test and digital vasoconstrictor response to a deep breath were not inhibited. However, during 55 degrees passive headup tilt there was a significant decrease in BP. Seven patients received prazosin for a period of 3 months. After long-term therapy BP returned to baseline levels and a dose of prazosin similar to that given initially produced an average decrease in BP from 174 +/- 20/101 +/- 8 to 167 +/- 23/99 +/- 7 mm Hg. Upright tilting no longer resulted in a decrease in BP. The Valsalva overshoot, cold pressor test and digital vasoconstrictor responses remained unchanged. Orthostatic hypotension after the first dose of prazosin without blockade of the other sympathetic reflex responses suggests that the drug has a greater blocking effect on capacitance vessels than on resistance vessels. Prazosin showed a loss of antihypertensive effectiveness during long-term treatment.

Treatment of severe hypertension with intravenous labetalol.

The effectiveness of repeated intravenous injections of labetalol in reducing blood pressure (BP) was evaluated in patients with severe hypertension. The subjects were 10 patients who were 29 to 61 yr old and who had diastolic blood pressure (DBP) of 125 mm Hg or higher. Repeated injections titrated from 20 to 80 mg were given at 15-min intervals until there was a reduction in DBP of 30 mm Hg or until 300 mg had been administered. The average reduction of BP ranged from 201 +/- 5/132 +/- 1 to 157 +/- 6/108 +/- 4 mm Hg (mean +/- SEM). Four patients responded with a reduction in DBP of 30 mm Hg or more with total doses of 60 to 220 mg. Of the remaining six who received the full dose, in four there was a 20 to 29 mm Hg reduction in DBP, in one there was a 10 mm Hg fall, and in one there was no reduction. There was a positive correlation between age and response to intravenous labetalol. No severe side effects were encountered. Intravenous labetalol is useful and well tolerated in patients with severe hypertension.

Acute and short-term effects of new calcium antagonist in hypertension.

Nitrendipine (Bay e 5009) is a new calcium antagonist antihypertensive agent similar in structure and function to nifedipine. Nitrendipine was tested in a range of single and repeated doses in 10 adult males with uncomplicated mild to moderate hypertension. The treatment goal was reduction of diastolic blood pressure to 90 mm Hg or less. The dose that achieved goal blood pressure ranged between 10 and 30 mg. Systolic and diastolic blood pressure began to fall within 15 minutes following ingestion of single oral doses of nitrendipine. The maximum effect of the drug was achieved in 60 to 90 minutes and remained at approximately this level for 6 to 8 hours. The average reduction in supine diastolic was more than twice as great as the fall in systolic blood prere began to fall within 15 minutes following ingestion of single oral doses of nitrendipine. The maximum effect of the drug was acheived in 60 to 90 minutes and remained at approximately this level for 6 to 8 hours. The average reduction in supine diastolic was more than twice as great as the fall in systolic blood pressure. With continuous doses given three times daily, all patients' blood pressures were as low or lower than the maximal effect observed after single doses. The reduction in blood pressure was sustained for the full 3 weeks of treatment. There was a sustained small increase in pulse rate averaging 6 beats/min. The drug was generally well tolerated by most patients. Mild to moderate headache that resolved with continued treatment was the most frequent side effect. This preliminary trial indicates that nitrendipine is an effective antihypertensive agent that merits further study.

Effect of therapy on left ventricular function in hypertension.

1. Twelve untreated hypertensive patients whose blood pressure was 171.8 +/- 5.5 mmHg systolic and 119.7 +/- 3.4 mmHg diastolic (mean +/- SEM) were treated aggressively with diuretics plus other antihypertensive agents. Echocardiograms were performed before, and 2 weeks, 3 months and 6 months after therapy. Blood pressures were lowered to an average of 142/98 mmHg over the 6 month period. 2. Mean velocity of circumferential fibre shortening rose from 1.1 +/- 0.09 to 1.3 +/- 0.06 diameters/s at 2 weeks and remained elevated at the end of 3 months (1.3 +/- 0.03 diameters/s) (P < 0.025), but returned to the control level in 6 months. Similarly, ejection fraction increased significantly during the same period from a control value of 65.1 +/- 4.4 to 73.4 +/- 1.8% (P < 0.025) and persisted in this range at 3 months. At 6 months the ejection fraction had returned to pretreatment levels. There were significant reductions in left ventricular end-systolic and end-diastolic dimensions. Left ventricular mass index decreased from 182.3 +/- 18.3 to 163.8 +/- 12.4 g/m2 after 6 months of therapy. 3. These results indicate that in the early stages of blood pressure reduction there is a temporary increase in ejection phase indices, probably related to afterload reduction. The reduction in the left ventricular mass index suggests that increased cardiac muscle mass due to elevated blood pressure may be partially reversible after long-term reduction in blood pressure.

Comparative haemodynamic and metabolic effects of vasodilator and inotropic agents in experimental myocardial infarction.

Following coronary embolisation and onset of left ventricular failure 27 awake dogs were randomly assigned to infusion of saline (controls), nitroprusside, or dobutamine (a new inotropic agent). Nitroprusside and dobutamine both increased cardiac output and lowered left ventricular filling pressure while raising coronary sinus flow. Dobutamine, however, increased myocardial oxygen consumption whereas nitroprusside reduced it. Therefore vasidilators may be more beneficial than inotropic agents in acute myocardial infarction.