Blood pressure variability and cognitive function in older hypertensives.

Several studies have shown that cerebrovascular organ damage can related not only to average blood pressure (BP) levels, but also to BP variability. The aim of this study was to investigate the relationship between 24 hr BP variability and cognitive function in older hypertensives. Forty older, never treated hypertensives were submitted to 24 hr ambulatory BP monitoring (ABPM) and subdivided, according to the variability of the systolic BP (SBP), in two groups: 23 with higher (> PV) and 17 with lower (< PV) SBP variability, defined as the standard deviation (SD) of the mean 24 hr SBP values and as coefficient of variation (CV). They underwent a cognitive assessment by mini mental state examination (MMSE) and a recording of the brain event-related potentials (ERPs). ERPs record neuronal electric activity when the patients are submitted to frequent and rare acoustic stimuli and must recognize and count rare (target) stimuli. The two groups with statistically different 24 hr SBP variability, did not show significant differences in MMSE scores or in N2 and P300 ERP latencies, thus indicating a lack of difference in the cognitive ability between the two groups. Our results show that cognitive function is not related to 24 hr SBP variability in older hypertensives.

Circadian blood pressure pattern and cognitive function in newly diagnosed older hypertensives.

Hypertensive subjects can be subdivided in two groups, dippers and non-dippers, according to the presence or the lack of a nocturnal fall of blood pressure (BP) of over 10%. Several studies have investigated cardiovascular and cerebrovascular organ damage in the two groups with discordant results, but fewer of them analysed the relationship between circadian BP pattern and cognitive function, and none in the early phases of hypertension. To this purpose, we selected 40 older hypertensives, 23 dippers and 17 non-dippers, with newly diagnosed hypertension, never treated, who underwent to 24-h ambulatory BP monitoring (ABPM), Mini-Mental State Examination (MMSE) and recording of event-related potentials (ERPs). No significant differences between dippers and non-dippers were found in the MMSE scores and P300 latency values, as we expected, and not even in N2 wave latency values, showing that the non-dipping pattern is not associated with lower cognitive function in the early phases of hypertension.

Susceptibility to Leishmania mexicana infection is due to the inability to produce IL-12 rather than lack of IL-12 responsiveness.

Almost all inbred mice are highly susceptible to parasites of the Leishmania mexicana complex that includes L. amazonensis and L. mexicana. Recent studies have reported that T cells from L. amazonensis-infected mice fail to respond to IL-12 due to impaired IL-12R expression. Here, we demonstrate that lymph node cells from L. mexicana-infected C57BL/6 and 129Sv/Ev mice respond efficiently to exogenous IL-12 in vitro and produce IFN-gamma. Moreover, we also show that deletion of signal transducer and activator of transcription (STAT)4 gene in resistant STAT6-/- mice renders them susceptible to L. mexicana. These findings indicate that an inability to produce IL-12 rather than unresponsiveness to this cytokine is responsible for susceptibility to L. mexicana. Moreover, the data also demonstrate that the STAT4-mediated pathway is critical for the development of protective immunity against cutaneous leishmaniasis, regardless of the species of Leishmania and/or genetic background of the mice.

Event-related potentials in the elderly with new mild hypertension.

Hypertension is a risk factor for cerebrovascular diseases (CVD) and cognitive impairment and the relative risk of CVD at every level of blood pressure (BP) is greater among the elderly. We submitted 20 elderly affected by new mild hypertension and 10 elderly normotensives to 24-hour ambulatory BP monitoring (ABPM), to evaluate their cognitive state using the Mini-Mental-State-Examination and to the recording of related acoustic evoked potentials (P300 and N2). We did not find significant differences for P300 latency between hypertensives and normotensives, while N2 latency recording showed a statistically significant protracted value in elderly hypertensives. In these patients we found a significant correlation between the N2 latency and systolic blood pressure values recorded by ABPM. These results demonstrated early functional alterations of cognitive state in elderly hypertensives, that are related to systolic blood pressure and future data might point to an earlier use of therapy.

Genetically resistant mice lacking IL-18 gene develop Th1 response and control cutaneous Leishmania major infection.

IL-18 has been shown to play a critical role in the development of a Th1 response and immunity against intracellular pathogens. To determine the role of IL-18 in the development of protective immunity against Leishmania major, we have analyzed the course of cutaneous L. major in IL-18-deficient C57BL/6 mice (IL-18-/-) compared with similarly infected wild-type mice (IL-18+/+). After L. major infection, IL-18-/- mice may develop larger lesions during early phase of infection but eventually will resolve them as efficiently as IL-18+/+ mice. By 2 wk after infection, although Ag-stimulated lymph node cells from L. major-infected IL-18+/+ and IL-18-/- mice produced similar levels of IFN-gamma, those from IL-18-/- mice produced significantly more IL-12 and IL-4. By 10 wk after infection, both IL-18+/+ and IL-18-/- mice had resolved L. major infection. At this time, lymph node cells from both IL-18+/+ and IL-18-/- mice produced IL-12 and IFN-gamma but no IL-4. Furthermore, administration of anti-IFN-gamma Abs to IL-18-/- mice rendered them susceptible to L. major. These results indicate that despite the role IL-18 may play in early control of cutaneous L. major lesion growth, this cytokine is not critical for development of protective Th1 response and resolution of L. major infection.

Interleukin-4-deficient BALB/c mice develop an enhanced Th1-like response but control cardiac inflammation following Borrelia burgdorferi infection.

Interleukin-4 has been reported to critically modulate Borrelia burgdorferi infection and Lyme arthritis in experimental murine models. To determine the in vivo role of IL-4 in controlling Lyme carditis, we compared immunological responses and the severity of cardiac inflammation in wild-type BALB/c (IL-4 +/+) and IL-4 deficient BALB/c (IL-4 -/-) mice infected with B. burgdorferi by tick-bite. At day 15 and 30 post-infection IL-4 -/- mice produced significantly greater titers of spirochete-specific IgG2a than the wild-type IL-4 +/+ mice, which produced significantly more spirochete-specific IgG1. Following in vitro antigenic stimulation with B. burgdorferi antigen, splenocytes from infected IL-4 -/- and IL-4 +/+ mice displayed similar magnitudes of proliferative responses at day 15 and 30 post-infection. At day 30 antigen-stimulated splenocytes from infected IL-4 -/- mice, however, produced significantly more IFN-gamma than those derived from similarly infected IL-4 +/+ mice, suggesting that Th1-influenced responses predominated in IL-4 -/- mice. Moreover, inflamed hearts from IL-4 -/- mice displayed higher levels of IFN-gamma and TNF-alpha transcripts as compared to IL-4 +/+ mice. At both time points antigen-stimulated splenocytes from IL-4 +/+ and IL-4 -/- mice produced significant amounts of IL-10 but those from IL-4 +/+ mice produced either no or little IL-4. Histopathology demonstrated typical Lyme carditis in both IL-4 +/+ and IL-4 -/- mice at day 15 and day 30. Although Borrelia-infected IL-4 -/- mice developed a more severe carditis on day 30, the carditis resolved by day 50, as it did in IL4 +/+ mice. These results indicate that although IL-4 may help limit the severity of Lyme carditis, its absence does not preclude resolution of cardiac lesions.

Baroreflex sensitivity in the elderly with silent myocardial ischemia.

In order to assess high-pressure baroceptor sensitivity and parasympathetic function in elderly patients with silent myocardial ischemia, we selected 45 inpatients in our geriatric unit for a prospective cohort study of patients with coronary heart disease. All patients were over 65 years of age (37 men and 8 women) and had coronary heart disease, documented by an angiographic study and electrocardiographic evidence of myocardial ischemia during exercise stress testing, performed according to the Bruce protocol. The subjects were divided in three subgroups: group 1 (22 patients) with electrocardiographic and echocardiographic history of myocardial infarction but no angina chest pain during exercise testing; group 2 (13 patients) with no exercise induced chest pain; and group 3 (10 patients) with exercise-induced chest pain. Baroceptor sensitivity was assessed in all subjects, by evaluating heart rate changes expressed in RR interval on the basis of changes in the mean arterial pressure during intravenous infusion of stepwise doses (50-100 and 150 microg) of phenylephrine hydrochloride. Heart rate changes were also evaluated during overshoot of the Valsalva maneuver (Valsalva max.), providing an index of parasympathetic activity. Our results showed that group two patients (only silent ischemia) had significantly (P>0.001) greater baroceptor sensitivity than the other two groups (group 2; 15.2+/-1.9 ms/mmHg; group 1: 10.0+/-1.7 ms/mmHg; and group 3: 9.8+/-1.7 ms/mmHg). Group two also showed a significant positive correlation (r=0.58; P<0.05) between baroceptor sensitivity and end-diastolic pressure and a significant inverse correlation (r=-0.672; P<0.05) between baroceptor sensitivity and the ejection fraction. Group 2 patients had a significantly longer RR interval than group 1 (P<0.05) and group 3 (P<0.05); a significant positive correlation (r=0.620; P<0.05) between Valsalva max. and end-diastolic pressure; and a significant inverse correlation (r=0.694; P<0.05) between Valsalva max. and the ejection fraction. Valsalva max. and baroceptor sensitivity correlated significantly in all three groups (group 1, r=0.707; P<0.001; group 2, r=0.94; P<0.001; and group 3; r=0.833; P<0.05). In conclusion our data suggest that elderly patients with silent ischemia appear to have an increased capacity for evoking parasympathetic reflexes that could inhibit pain perception.

Power spectral analysis of heart rate in elderly hypertensive subjects with or without silent coronary disease.

Much evidence indicates an involvement of the sympathetic nervous system in the genesis of silent myocardial ischemia. The authors assessed autonomic system activity by power spectrum analysis of heart rate variability in 21 elderly hypertensive men with and without angiographically confirmed coronary artery disease and compared the results with those from an age-matched control group. In the analysis an autoregressive algorithm was used to determine the power spectrum from an electrocardiographic recording of 512 consecutive RR intervals. The autonomic nervous system induces two distinct sinusoids: a low-frequency signal attributable to sympathetic activity and a high-frequency vagal response. In the hypertensive patients with coronary disease the authors also evaluated sympathetic activation after double-blind, placebo-controlled administration of metoprolol (100 mg/day), followed by amlodipine (10 mg/day), quinapril (20 mg/day), and amlodipine (5 mg/day) plus quinapril (10 mg/day).

The effects of antihypertensive drugs on the autonomic nervous system in elderly hypertensive patients with silent myocardial ischemia.

To seek further evidence for the participation of sympathetic nervous system in the onset of transient episodes of painless ischemia, we compared the behavior of the autonomic nervous system by means of power spectrum analysis of heart rate variability in 15 elderly hypertensive men with angiographically confirmed painless coronary artery disease, and in 10 similar patients without coronary artery disease. An autoregressive algorithm was used to calculate the power spectrum density from an electrocardiographic (ECG) recording of 512 consecutive RR intervals. The power spectrum comprised two main bandwidths: a high-frequency band reflecting parasympathetic and a low-frequency band reflecting sympathetic activity. In the hypertensives with painless coronary disease sympathetic tone was also assessed after double-blind placebo-controlled administration of metoprolol (100 mg/day), amlodipine (10 mg/day), quinapril (20 mg/day), and amlodipine (5 mg/day) plus quinapril (10 mg/day). The hypertensives with painless coronary disease had significantly higher sympathetic activity than those without (low frequency: 58.0 +/- 2.0 vs 25.0 +/- 1.0, p < 0.001) but significantly lower parasympathetic activity (high frequency: 39.0 +/- 2.0 vs 60.0 +/- 2.0, p < 0.001). Treatment with metoprolol, quinapril and amlodipine plus quinapril significantly depressed sympathetic activity (p < 0.05).