In the Era of mRNA Vaccines,Is There Any Hope for HIV Functional Cure?

Over 36 million people worldwide are infected with HIV. Antiretroviral therapy (ART) has proven to be highly effective to prevent HIV-1 transmission, clinical progression and death. Despite this success, the number of HIV-1 infected individuals continues increasing and ART should be taken for life. Therefore, there are two main priorities: the development of preventive vaccines to protect from HIV acquisition and achieve an efficient control of HIV infection in the absence of ART (functional cure). In this sense, in the last few years, there has been a broad interest in new and innovative approaches such as mRNA-based vaccines. RNA-based immunogens represent a promising alternative to conventional vaccines because of their high potency, capacity for rapid development and potential for low-cost manufacture and safe administration. Some mRNA-based vaccines platforms against infectious diseases have demonstrated encouraging results in animal models and humans. However, their application is still limited because the instability and inefficient in vivo delivery of mRNA. Immunogens, design, immunogenicity, chemical modifications on the molecule or the vaccine delivery methods are all crucial interventions for improvement. In this review we, will present the current knowledge and challenges in this research field. mRNA vaccines hold great promises as part of a combined strategy, for achieving HIV functional cure.     

Cibenzoline for high-frequency ventricular arrhythmias: a short-term comparison with quinidine and a long-term follow-up

Cibenzoline, a new class I antiarrhythmic drug, was compared with quinidine in an open crossover study of 20 patients with frequent (greater than 30/hr) premature ventricular depolarizations (PVDs). Eight patients treated with cibenzoline experienced more than 75% reduction in PVD frequency. Cibenzoline completely suppressed ventricular couplets in eight of 17 patients and inhibited ventricular tachycardia (VT) in four of 13 patients. Only four patients (20%) responded to quinidine with a similar reduction in PVDs. Quinidine completely suppressed ventricular couplets in eight of 17 patients and episodes of VT in six of 13 patients. Cibenzoline prolonged PR, QRS, and QTc intervals. Eight patients who had shown more than a 75% reduction of PVDs were treated with cibenzoline for an extended period. At the end of three months, only five of eight patients continued to have 75% or greater reduction of PVDs. At the end of six and 12 months, four of five patients continued to have 75% or greater reduction of PVDs. Cibenzoline was similarly effective in suppressing complex arrhythmias. Thus, cibenzoline was only slightly superior to quinidine in suppressing ventricular arrhythmias. With long-term use of cibenzoline, significant PVD suppression was noted at the end of three months but not afterward.     

Neurotensin injected into the nucleus accumbens blocks the psychostimulant effects of cocaine but does not attenuate cocaine self-administration in the rat

The neuropeptide neurotensin (NT) has been shown to modulate mesolimbic dopaminergic activity. Neurotensin injected into the VTA produces motor stimulation and release of dopamine in the nucleus accumbens. In contrast, when neurotensin is administered into the nucleus accumbens, it produces neuroleptic-like effects such as attenuation of the locomotor activity elicited by psychostimulants. In the present study, the hypothesis that neurotensin injected into the nucleus accumbens might modulate the psychostimulant and reinforcing actions of cocaine was tested. In experiment one, rats were trained to self-administer cocaine intravenously on an FR5 schedule of reinforcement. Following the establishment of baseline responding, rats were implanted with bilateral cannulae in the nucleus accumbens. One week later, rats were injected into the nucleus accumbens with various doses of neurotensin (4.2, 8.4 and 16.7 μg, total doses bilaterally) immediately prior to the self-administration session. No significant effects were found with any of the doses of neurotensin tested on the self-administration of cocaine. However, in experiment 2, neurotensin at doses of 4.2 and 16.7 μg injected into the nucleus accumbens significantly reduced the locomotor activation induced by an acute injection of cocaine (15 mg/kg i.p.) and a dose of 16.7 μg attenuated the locomotor activation induced by amphetamine (0.75 mg/kg i.p.). Thus, neurotensin in the nucleus accumbens appears to specifically modulate the acute locomotor activating properties of cocaine but not cocaine self-administration. Different mechanisms by which NT interacts with dopamine in the nucleus accumbens may provide a means of selectively altering psychostimulant motor actions without affecting psychostimulant reinforcement.     

Modulation of arterial stiffness with intensive competitive training.

BACKGROUND: Aerobic exercise training has been associated with beneficial effects on the cardiovascular system, improving arterial compliance, possibly related to a positive impact on the endothelium. The effects of competitive aerobic exercise are not so well documented. This prompted us to evaluate the possible modulation of arterial properties in a group of athletes and their response to the aging process. METHODS: 423 healthy males were enrolled in a cross-sectional study, 212 of whom were competitive athletes and 211 were controls. All underwent carotid-femoral pulse wave velocity (PWV) evaluation, and casual blood pressure and other relevant anthropometric data were evaluated. RESULTS: To control the effects of age, each group was divided into two subgroups with an age cut-point of 20 years. PWV was 6.3 +/- 0.9 m/s (athletes) vs. 7.0 +/- 1.0 m/s (controls) for ages <20 years, and 7.6 +/- 1.2 m/s (athletes) vs. 8.1 +/- 0.9 m/s (controls) for ages >20 years, with statistically significant differences in both comparisons. A linear regression model with logarithmic tendency analysis with age as the independent determinant of PWV revealed a different progression of age-related deterioration of aortic compliance between the two groups (athletes and controls). CONCLUSIONS: Our data documented better compliance indices in competition athletes compared with controls, which may reflect optimization of endothelial function. This improvement was age-dependent, being less pronounced as the athletes grow older, which could be due partially to sustained stretching effects on the arterial walls in long-term competitors.     

Estimation of salt intake by urinary sodium excretion in a Portuguese adult population and its relationship to arterial stiffness.

BACKGROUND: Portugal has one of the highest mortality rates from stroke, a high prevalence of hypertension and probably a high salt intake level. AIM: To evaluate Portuguese salt intake levels and their relationship to blood pressure and arterial stiffness in a sample of four different adult populations living in northern Portugal. METHODS: A cross-sectional study evaluating 24-hour urinary excretion of sodium (24 h UNa+), potassium and creatinine, blood pressure (BP), and pulse wave velocity (PWV) as an index of aortic stiffness in adult populations of sustained hypertensives (HT), relatives of patients with previous stroke (Fam), university students (US) and factory workers (FW), in the context of their usual dietary habits. RESULTS: We evaluated a total of 426 subjects, mean age 50 +/- 22 years, 56% female, BMI 27.9+/-5.1, BP 159/92 mmHg, PWV 10.4+/-2.2 m/s, who showed mean 24h UNa+ of 202 +/- 64 mmol/d, corresponding to a daily salt intake of 12.3 g (ranging from 5.2 to 24.8). The four groups were: HT: n = 245, 49 +/- 18 years, 92% of those selected, 69% treated, BP 163/94 mmHg, PWV 11.9 m/s, 24 h UNa+ 212 mmol/d, i.e. 12.4 g/d of salt); Fam: n = 38, 64 +/- 20 years, 57 % of those selected, BP 144/88 mmHg, PWV 10.5 m/s, 24 h UNa+ 194 mmol/d, i.e. 11.1 g/d of salt; US: n = 82, 22 +/- 3 years, 57% of those selected, BP 124/77 mmHg, PWV 8.7 m/s, 24h UNa+ 199 mmol/d, i.e. 11.3 g/d of salt; FW: n = 61, 39 9 years, 47% of those selected, BP 129/79 mmHg, PWV 9.5 m/s, 24 h UNa+ 221 mmol/d, i.e. 12.9 g/d of salt. The ratio of urinary sodium/potassium excretion (1.9 (0.4) was significantly higher in HT than the other three groups. In the 426 subjects, 24h UNa+ correlated significantly (p < 0.01) with systolic BP (r = 0.209) and with PWV (r=0.256) after adjustment for age and BP. Multivariate analysis showed that BP, age and 24h UNa+ correlated independently with PWV taken as a dependent variable. CONCLUSIONS: Four different Portuguese populations showed similarly high mean daily salt intake levels, almost double those recommended by the WHO. Overall, high urinary sodium excretion correlated consistently with high BP levels and appeared to be an independent determining factor of arterial stiffness. These findings suggest that Portugal in general has a high salt intake diet, and urgent measures are required to restrict salt consumption in order to prevent and treat hypertensive disease and to reduce overall cardiovascular risk and events.