Chronic sodium depletion suppresses the area postrema pressor pathway

Sodium depletion in dogs is known to affect both the renin-angiotensin as well as the sympathetic nervous system. The effect of this dietary regime upon the area postrema pressor pathway, as evaluated by the cardiovascular responses to centrally acting angiotensin II, has not been determined previously. With this in mind, male mongrel dogs were maintained on either a normal or a sodium restricted diet supplemented with furosemide and dose-response curves for intravertebral and intravenous angiotensin II (range: 1-20 ng/kg/min) were obtained. Sodium depletion results in not only a blunted intravenous pressor response to angiotensin II but also the abolition of the centrally mediated pressor responses mediated by the area postrema. Because accumulating evidence indicates that in sodium depleted dogs sympathetic nerve activity is reduced while central noradrenergic inhibitory activity is increased the reduced effects of angiotensin II upon the central sympathetically mediated pressor response may in part be related to decreases in sympathetic nerve activity.     

Inhibition of angiotensin converting enzyme by the metalloendopeptidase 3.4.24.15 inhibitor c-phenylpropyl-alanyl-alanyl-phenylalanyl-p-aminobenzoate.

Inhibitors of metallopeptidases may represent new alternatives in the treatment of cardiovascular disease. Recent investigations have linked the hypotensive properties of the metalloendopeptidase 3.4.24.15 (MEP 24.15) inhibitor c-phenylpropyl-alanyl-alanyl-phenylalanyl-para-aminobenzoate (cFP-A-A-F-pAB) to the attenuation of bradykinin metabolism. However, since angiotensin converting enzyme (ACE) is widely recognized to contribute to the metabolic clearance of bradykinin, we characterized the specificity of cFP-A-A-F-pAB towards ACE. We also determined whether cFP-A-A-F-pAB inhibits the conversion of angiotensin I (Ang I) to Ang II by pulmonary ACE. The ACE activity toward the synthetic substrate hippuryl-histidine-leucine (Hip-His-Leu) was measured in vitro using both a purified lung preparation and pooled rat serum. The ACE activity was inhibited at increasing concentrations of the MEP 24.15 inhibitor. Kinetic analysis revealed that cFP-A-A-F-pAB competitively inhibited pulmonary ACE with a Ki of 0.19 microM. In rat serum, cFP-A-A-F-pAB also competitively inhibited ACE. The hydrolysis of Ang I into Ang II by pulmonary ACE was inhibited to a similar extent by both cFP-A-A-F-pAB and the ACE inhibitor MK 422. These findings are the first to show that the MEP 24.15 inhibitor cFP-A-A-F-pAB also inhibits ACE. We suggest that the reported hypotensive actions of cFP-A-A-F-pAB may be due to the reduction in both bradykinin metabolism and Ang II generation arising from the blockade of ACE.     

Role of area postrema pressor mechanisms in the regulation of arterial pressure

This article discusses the data which established that angiotensin II modulates the tonic and reflex control of cardiovascular function by actions on the nuclear regions of the dorsal medulla oblongata. Although physiological evidence for the modulatory actions of angiotensin II in structures of the lower brainstem has been gathered over the past 16 years, only the recent application of new neurobiological techniques has allowed a more definitive understanding of its role. The identification of high affinity angiotensin II binding sites within the parenchyma of the area postrema with the technique of in vitro receptor autoradiography has provided anatomical validity for a role of angiotensin II in the central nervous system. The added discovery of angiotensin II binding sites in subnuclear components of the nucleus tractus solitarii and the motor nucleus of the tenth cranial nerve provides additional information on the various mechanisms through which angiotensin II may affect the intrinsic activity of the brainstem neuronal circuits involved in the integration of baroreceptor and sensory visceromotor function.     

A chronomorphological structural model of rat thyroid gland

Circadian rhythmicity of the structural morphometric model of thyroid has been studied in 36 Wistar rats kept in LD 12:12. The parameters evaluated are: a. the volume fraction occupied by: 1. follicle epithelium, 2. colloid, 3. interstitium at 6 time points in 24h; b. the follicle size distribution; c. the number of follicles per unit tissue volume. The circadian rhythms of mean follicular diameter and of follicular cavity mean diameter have been demonstrated (p less than 0.03 and p less than 0.01 respectively) and show overlapping acrophases of -120 degrees (-64 degrees/-176 degrees) and -108 degrees (-99 degrees/-116 degrees). The synchronization between rhythms, shown for mean follicular diameter and for follicular cavity mean diameter, suggests a rhythmical pulsation of the whole follicle, while the thickness of the follicular epithelium does not undergo a statistically significant periodic variation.     

Effect of estrogen on neprilysin expression in uterus and kidney of Sprague-Dawley normotensive and heterozygous (mRen2)27-transgenic hypertensive rats

The present study was designed to determine whether estrogen modulates the angiotensin processing enzymes in membrane homogenates obtained from uterus and kidney cortex and medulla of Sprague-Dawley (SD) and heterozygous (mRen2)27-transgenic hypertensive (Tg(+)) female rats treated with or without 17beta-estradiol (E2). We evaluated estrogen's influence on neprilysin (NEP), an endopeptidase that forms angiotensin-(1-7) [Ang-(1-7)] and on aminopeptidase (AMP), which degrades Ang-(1-7). Renal tissue from normotensive and hypertensive male rats was also evaluated. E2 up-regulated NEP mRNA in the uterus of both SD and Tg(+) and this was associated with increased NEP activity in the uterus of SD (0.31+/-0.03 nmol/min/mg versus 0.18+/-0.04 nmol/min/mg of protein, p<0.05) and Tg(+) (0.26+/-0.04 nmol/min/mg versus 0.13+/-0.02 nmol/min/mg of protein, p<0.05) female). E2 had no significant effect on NEP activity in cortex and medulla of hypertensive and normotensive female. In female animals, cortical NEP activity is two-fold higher than medullary; in males there is a four-fold higher cortical NEP activity as compared to medulla. In male animals, medullary NEP was significantly lower than females with or without E2 treatment; no gender specific effect was found in cortex. E2 treatment also caused a two-fold increase in AMP activity in the uterus and 1.6-fold decrease in kidney cortex of SD and Tg(+) female (p<0.05). Our studies indicate that NEP may be a primary candidate for increased Ang-(1-7) processing in the uterus with estrogen treatment; kidney NEP, on the other hand, showed no modulation by estrogen, suggesting that down regulation of other processing enzymes, like AMP and ACE, may come into play in the kidney with estrogen replacement. In addition, these studies showed that there is tissue-specific regulation of NEP with estrogen treatment that is strain independent.     

Qualitative immune modulation by interleukin-2 (IL-2) adjuvant therapy in immunological non responder HIV-infected patients

Background

Treatment of HIV-infected patients with interleukin-2 (IL-2) produces significant increases in CD4 T cell counts; however an associated qualitative improvement in cells function has yet to be conclusively demonstrated. By measuring mycobacterial killing activity, we evaluated IL-2-mediated functional immune enhancement ex vivo in immunological non-responders (INRs).

Methods and Findings

PBMC from 12 immunological non-responders (INRs) (CD4+<200/µl, HIV-RNA<50 cp/ml) on combination antiretroviral treatment (cART) were collected at baseline, and after 3 IL-2 cycles. Eight INRs receiving only cART were studied as controls. After 21 days of PBMC incubation with a virulent M. avium suspension, counts of residual colony forming units (CFUs) and concentrations of TNF-α, IL-10 and IFN-γ were determined. In IL-2 treated patients, a significant reduction in mean residual CFUs of PBMC cultures was observed (p<0.01). Moreover, following IL-2 treatment, significant increases in PBMC''s IFNγ production (p = 0.02) and substantial reductions in IL-10 levels were observed.

Conclusions

IL-2 therapy restores the ability of the lympho-monocyte system in eliciting an effective response against mycobacterial infections. Our data indicate the possibility of a clinical role held by IL-2 in enhancing the immune function of subjects unable to achieve immune competence through cART alone.     

Diversity of the diatom genus Fragilariopsis in the Argentine Sea and Antarctic waters: morphology, distribution and abundance

Fragilariopsis species composition and abundance from the Argentine Sea and Antarctic waters were analyzed using light and electron microscopy. Twelve species (F. curta, F. cylindrus, F. kerguelensis, F. nana, F. obliquecostata, F. peragallii, F. pseudonana, F. rhombica, F. ritscheri, F. separanda, F. sublinearis and F. vanheurckii) are described and compared with samples from the Frenguelli Collection, Museo de La Plata, Argentina. F. peragallii was examined for the first time using electron microscopy, and F. pseudonana was recorded for the first time in Argentinean shelf waters. New information on the girdle view is included, except for the species F. curta, F. cylindrus and F. nana, for which information already existed. In the Argentine Sea, F. pseudonana was the most abundant Fragilariopsis species, and in Antarctic waters, F. curta was most abundant. Of the twelve species of Fragilariopsis documented, four occurred in the Argentine Sea, nine in the Drake Passage and twelve in the Weddell Sea. F. curta, F. kerguelensis, F. pseudonana and F. rhombica were present everywhere.     

Characterization of the Cardiac Renin Angiotensin System in Oophorectomized and Estrogen-Replete mRen2.Lewis Rats

The cardioprotective effects of estrogen are well recognized, but the mechanisms remain poorly understood. Accumulating evidence suggests that the local cardiac renin-angiotensin system (RAS) is involved in the development and progression of cardiac hypertrophy, remodeling, and heart failure. Estrogen attenuates the effects of an activated circulating RAS; however, its role in regulating the cardiac RAS is unclear. Bilateral oophorectomy (OVX; n = 17) or sham-operation (Sham; n = 13) was performed in 4-week-old, female mRen2.Lewis rats. At 11 weeks of age, the rats were randomized and received either 17 β-estradiol (E2, 36 µg/pellet, 60-day release, n = 8) or vehicle (OVX-V, n = 9) for 4 weeks. The rats were sacrificed, and blood and hearts were used to determine protein and/or gene expression of circulating and tissue RAS components. E2 treatment minimized the rise in circulating angiotensin (Ang) II and aldosterone produced by loss of ovarian estrogens. Chronic E2 also attenuated OVX-associated increases in cardiac Ang II, Ang-(1–7) content, chymase gene expression, and mast cell number. Neither OVX nor OVX+E2 altered cardiac expression or activity of renin, angiotensinogen, angiotensin-converting enzyme (ACE), and Ang II type 1 receptor (AT1R). E2 treatment in OVX rats significantly decreased gene expression of MMP-9, ACE2, and Ang-(1–7) mas receptor, in comparison to sham-operated and OVX littermates. E2 treatment appears to inhibit upsurges in cardiac Ang II expression in the OVX-mRen2 rat, possibly by reducing chymase-dependent Ang II formation. Further studies are warranted to determine whether an E2-mediated reduction in cardiac chymase directly contributes to this response in OVX rats.     

Probabilistic seasonal dengue forecasting in Vietnam: A modelling study using superensembles

BackgroundWith enough advanced notice, dengue outbreaks can be mitigated. As a climate-sensitive disease, environmental conditions and past patterns of dengue can be used to make predictions about future outbreak risk. These predictions improve public health planning and decision-making to ultimately reduce the burden of disease. Past approaches to dengue forecasting have used seasonal climate forecasts, but the predictive ability of a system using different lead times in a year-round prediction system has been seldom explored. Moreover, the transition from theoretical to operational systems integrated with disease control activities is rare.Methods and findingsWe introduce an operational seasonal dengue forecasting system for Vietnam where Earth observations, seasonal climate forecasts, and lagged dengue cases are used to drive a superensemble of probabilistic dengue models to predict dengue risk up to 6 months ahead. Bayesian spatiotemporal models were fit to 19 years (2002–2020) of dengue data at the province level across Vietnam. A superensemble of these models then makes probabilistic predictions of dengue incidence at various future time points aligned with key Vietnamese decision and planning deadlines. We demonstrate that the superensemble generates more accurate predictions of dengue incidence than the individual models it incorporates across a suite of time horizons and transmission settings. Using historical data, the superensemble made slightly more accurate predictions (continuous rank probability score [CRPS] = 66.8, 95% CI 60.6–148.0) than a baseline model which forecasts the same incidence rate every month (CRPS = 79.4, 95% CI 78.5–80.5) at lead times of 1 to 3 months, albeit with larger uncertainty. The outbreak detection capability of the superensemble was considerably larger (69%) than that of the baseline model (54.5%). Predictions were most accurate in southern Vietnam, an area that experiences semi-regular seasonal dengue transmission. The system also demonstrated added value across multiple areas compared to previous practice of not using a forecast. We use the system to make a prospective prediction for dengue incidence in Vietnam for the period May to October 2020. Prospective predictions made with the superensemble were slightly more accurate (CRPS = 110, 95% CI 102–575) than those made with the baseline model (CRPS = 125, 95% CI 120–168) but had larger uncertainty. Finally, we propose a framework for the evaluation of probabilistic predictions. Despite the demonstrated value of our forecasting system, the approach is limited by the consistency of the dengue case data, as well as the lack of publicly available, continuous, and long-term data sets on mosquito control efforts and serotype-specific case data.ConclusionsThis study shows that by combining detailed Earth observation data, seasonal climate forecasts, and state-of-the-art models, dengue outbreaks can be predicted across a broad range of settings, with enough lead time to meaningfully inform dengue control. While our system omits some important variables not currently available at a subnational scale, the majority of past outbreaks could be predicted up to 3 months ahead. Over the next 2 years, the system will be prospectively evaluated and, if successful, potentially extended to other areas and other climate-sensitive disease systems.