The return of increased blood pressure after discontinuation of antihypertensive treatment is associated with an impaired post-ischemic skin blood flow response.

OBJECTIVE: To assess the post-ischemic skin blood flow response after withdrawal of antihypertensive therapy in hypertensive patients with normal blood pressure during treatment. DESIGN AND METHODS: Twenty hypertensive patients (group A) with a normal clinic blood pressure (<140/ 90 mmHg) receiving antihypertensive treatment (any monotherapy; one pill per day for at least 6 months) had their treatment discontinued. Before medication withdrawal and 2, 4, 12 and 24 weeks thereafter, the following measurements were made: clinic blood pressure, home blood pressure (three times per week, morning and evening) and skin blood flow response to a 5 min forearm arterial occlusion (using laser Doppler flowmetry). The patients were asked to perform an ambulatory blood pressure recording at any time if home blood pressure was > or =160/95 mmHg on two consecutive days, and treatment was initiated again, after determination of the skin hyperemic response, if daytime ambulatory blood pressure was > or =140/90 mmHg. The same studies were performed in 20 additional hypertensive individuals in whom antihypertensive treatment was not withdrawn (group B). The allocation of patients to groups A and B was random. RESULTS: The data fom 18 patients in group A who adhered strictly to the procedure were available for analysis. Seven of them had to start treatment again within the first 4 weeks of follow-up; four additional patients started treatment again during the next 8 weeks (group A1). The seven other patients remained untreated (group A2). The skin hyperemic response decreased significantly in patients in group A1 and returned to baseline values at the end of the study, when there were again receiving antihypertensive treatment. In patients in group A2 a significant attenuation of the hyperemic response was also observed. This impaired response was present even at the end of the 6 month follow-up, at which time the patients were still untreated but exhibited a significantly greater blood pressure than before drug discontinuation. The hyperemic response of patients who did not stop treatment (group B) did not change during the course of the study. CONCLUSIONS: Our findings show a decrease in the postischemic skin blood flow response after withdrawal of antihypertensive treatment in hypertensive patients. This impaired response may be due to the development of endothelial dysfunction, vascular remodeling, or both, and might contribute to the return of blood pressure to hypertensive values after withdrawal of antihypertensive therapy.

Actualités en gastroentérologie et hépatologie [Highlights in gastroenterology and hepatology 2010].

This review highlights recent advances in gastroenterology and hepatology, including the treatment of Crohn's disease, of eosinophilic esophagitis, of chronic hepatitis C, and of hepatic encephalopathy as well as the role of high resolution manometry in the investigation of esophageal motility disorders. These new developments will be summarized and discussed critically, with a particular emphasis on their potential implications for current and future clinical practice.

Isolated office hypertension: a prehypertensive state?

OBJECTIVE AND METHOD: Isolated office hypertension, defined as hypertensive blood pressure values in a medical setting but normal self-measured or ambulatory-recorded blood pressures, is frequently encountered in clinical practice. Yet, whether this condition represents a transient state in the development of a sustained ambulatory hypertension is still unknown as no long-term analysis of the evolution of ambulatory blood pressure has been carried out in patients with isolated office hypertension. To evaluate whether such patients should be considered as truly normotensive or hypertensive, we have studied the long-term changes in office and ambulatory blood pressures in 81 patients in whom isolated office hypertension was observed between 1982 and 1988. RESULTS: After a 5-6 year follow-up, 60 of the 81 patients had a mean 12 h daytime ambulatory blood pressure greater than 140/90 mmHg, suggesting an evolution towards ambulatory hypertension. The development of hypertension could not be predicted on the basis of the follow-up office blood pressures as these tended to decrease during the follow-up period. CONCLUSIONS: The results of this study suggest that patients with isolated office hypertension should not be considered as truly normotensive individuals. Hence, these patients require a careful medical follow-up. Office blood pressure readings alone, however, do not appear to provide a good indicator of the long-term outcome of isolated office hypertension.

The renin-angiotensin system and arterial wall behavior.

To assess the behavior of the arterial wall in hypertensive patients, we developed a noninvasive ultrasonic device. Simultaneous recordings of internal diameter and blood pressure over the whole cardiac cycle are used to establish compliance-pressure curves. Blood pressure, which is a co-determinant of compliance, is thus taken into account. This method allows one to compare arteries from patients with different blood pressures. Arterial compliance and distensibility were first investigated in healthy young volunteers administered either lisinopril (20 mg), atenolol (100 mg) or nitrendipine (20 mg) once a day. After 8 days of treatment, only lisinopril was found to increase arterial compliance. Subsequently, we compared arterial diameter- and distensibility-pressure curves from newly diagnosed and untreated hypertensive patients with those of matched normotensive control patients. Diameter-pressure curves did not differ significantly between the groups and distensibility was not reduced. Similar findings were later obtained in an animal model, when mechanical properties of carotid arteries were compared between spontaneously hypertensive rats and normotensive counterparts (Wistar-Kyoto rats). These results, although interesting by providing noninvasive information on the elastic response of the wall, call for further development of the technique to be able to measure arterial wall thickness. Stress-strain relationship could ultimately be established to thoroughly characterize physical properties of blood vessel walls.

Recurrent de novo mitochondrial DNA mutations in respiratory chain deficiency.

Starting from a cohort of 50 NADH-oxidoreductase (complex I) deficient patients, we carried out the systematic sequence analysis of all mitochondrially encoded complex I subunits (ND1 to ND6 and ND4L) in affected tissues. This approach yielded the unexpectedly high rate of 20% mutation identification in our series. Recurrent heteroplasmic mutations included two hitherto unreported (T10158C and T14487C) and three previously reported mutations (T10191C, T12706C and A13514G) in children with Leigh or Leigh-like encephalopathy. The recurrent mutations consistently involved T-->C transitions (p<10(-4)). This study supports the view that an efficient molecular screening should be based on an accurate identification of respiratory chain enzyme deficiency.

Blood pressure loci identified with a gene-centric array.

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.

Connexin40 regulates renin production and blood pressure.

Renin secretion is regulated by coordinated signaling between the various cells of the juxtaglomerular apparatus. The renin-secreting cells (RSC), which play a major role in the control of blood pressure, are coupled to each other and to endothelial cells by Connexin40 (Cx40)-containing channels. In this study, we show that Cx40 knockout (Cx40-/-) mice, but not their heterozygous littermates, are hypertensive due to the increase in the number of RSC, renin biosynthesis, and plasma renin. Treatment with the angiotensin II receptor AT1 antagonist candesartan or the angiotensin II-converting enzyme inhibitor ramipril reduced the blood pressure of the Cx40-/- mice to the same levels seen in wild-type (WT) mice. The elevated blood pressure of the knockout mice was not affected by clipping one renal artery (2K1C, renin-dependent model of hypertension) or after a high salt diet. Under these conditions, however, Cx40-/- mice showed an altered production and release of renin. The renin mRNA ratio between the clipped and the non-clipped kidney was lower in the knockout than in the WT 2K1C mice. This indicates that the response to a change in blood pressure was altered. The RSC of the Cx40-/- mice did not have a compensatory increase in the levels of either Cx43 or Cx37. Our data show that renin secretion is dependent on Cx40 and suggest the Cx40-/- mice may be a genetic model of renin-dependent hypertension.

Hypertension. Effets du traitement antihypertenseur sur les fonctions cognitives [Hypertension. Effects of antihypertensive therapy on cognitive functions].

A cause and effect relationship between arterial hypertension and decline of cognitive function has long been suspected. In middle-age subjects indeed, an abnormally high blood pressure is a risk factor for the long-term development of dementia. Presently, it seems crucial to treat hypertensive patients in order to better protect them against cognitive decline. However, in the elderly patients the risk of mental deterioration may also be enhanced when diastolic pressure becomes too low, for example below 70 mmHg. Further studies are required to better define the antihypertensive drug regimen and target blood pressure which would be optimal for the prevention of cerebral small vessel disease.

Not so disadvantaged: Portuguese migrants in Switzerland have a better access to healthcare and health status than Portuguese residents

Background: Most migrant studies have compared health characteristics between migrants and nationals of the host country. We aimed at comparing health characteristics of migrants with nationals from their home country. Methods: Portuguese national health survey (2005-6; 30,173 participants aged 18-75 years) and four national health surveys conducted in Switzerland (2002, 2004, 2007 and 2011, totalling 1,170 Portuguese migrants of the same age range). Self-reported data on length of stay, cardiovascular risk factors, healthcare use and health status were collected. Results: Resident Portuguese were significantly older and more educated than migrants. Resident Portuguese had a higher mean BMI and prevalence of obesity than migrants. Resident Portuguese also reported more frequently being hypertensive and having their blood pressure screened within the last year. On the contrary, migrant Portuguese were more frequently smokers, had a medical visit in the previous year more frequently and self-rated their health higher than resident Portuguese. After adjustment for age, gender, marital status and education, migrants had a higher likelihood smoking, of having a medical visit the previous year, and of self-rating their current health as good or very good than resident Portuguese. Compared to Portuguese residents, cholesterol screening in the previous year was more common only among migrants living in Switzerland for more than 17 years. Conclusion: Portuguese migrants in Switzerland do not differ substantially from resident Portuguese regarding most cardiovascular risk factors. Migrants appear to benefit from higher healthcare accessibility and consider themselves healthier than Portuguese residents.

Role of comorbidities in outcome prediction after status epilepticus.

Status epilepticus (SE) is associated with significant mortality and morbidity. A reliable prognosis may help better manage medical resources and treatment strategies. We examined the role of preexisting comorbidities on the outcome of patients with SE, an aspect that has received little attention to date. We prospectively studied incident SE episodes in 280 adults occurring over 55 months in our tertiary care hospital, excluding patients with postanoxic encephalopathy. Different models predicting mortality and return to clinical baseline at hospital discharge were compared, which included demographics, SE etiology, a validated clinical Status Epilepticus Severity Score (STESS), and comorbidities (assessed with the Charlson Comorbidity Index) as independent variables. The overall short-term mortality was 14%, and only half of patients returned to their clinical baseline. On bivariate analyses, age, STESS, potentially fatal etiologies, and number of preexisting comorbidities were all significant predictors of both mortality and return to clinical baseline. As compared with the simplest predictive model (including demographics and deadly etiology), adding SE severity and comorbidities resulted in an improved predictive performance (C statistics 0.84 vs. 0.77 for mortality, and 0.86 vs. 0.82. for return to clinical baseline); comorbidities, however, were not independently related to outcome. Considering comorbidities and clinical presentation, in addition to age and etiology, slightly improves the prediction of SE outcome with respect to both survival and functional status. This analysis also emphasizes the robust predictive role of etiology and age.

Neurological complications of infective endocarditis: risk factors, outcome, and impact of cardiac surgery: a multicenter observational study.

BACKGROUND The purpose of this study was to assess the incidence of neurological complications in patients with infective endocarditis, the risk factors for their development, their influence on the clinical outcome, and the impact of cardiac surgery. METHODS AND RESULTS This was a retrospective analysis of prospectively collected data on a multicenter cohort of 1345 consecutive episodes of left-sided infective endocarditis from 8 centers in Spain. Cox regression models were developed to analyze variables predictive of neurological complications and associated mortality. Three hundred forty patients (25%) experienced such complications: 192 patients (14%) had ischemic events, 86 (6%) had encephalopathy/meningitis, 60 (4%) had hemorrhages, and 2 (1%) had brain abscesses. Independent risk factors associated with all neurological complications were vegetation size ≥3 cm (hazard ratio [HR] 1.91), Staphylococcus aureus as a cause (HR 2.47), mitral valve involvement (HR 1.29), and anticoagulant therapy (HR 1.31). This last variable was particularly related to a greater incidence of hemorrhagic events (HR 2.71). Overall mortality was 30%, and neurological complications had a negative impact on outcome (45% of deaths versus 24% in patients without these complications; P<0.01), although only moderate to severe ischemic stroke (HR 1.63) and brain hemorrhage (HR 1.73) were significantly associated with a poorer prognosis. Antimicrobial treatment reduced (by 33% to 75%) the risk of neurological complications. In patients with hemorrhage, mortality was higher when surgery was performed within 4 weeks of the hemorrhagic event (75% versus 40% in later surgery). CONCLUSIONS Moderate to severe ischemic stroke and brain hemorrhage were found to have a significant negative impact on the outcome of infective endocarditis. Early appropriate antimicrobial treatment is critical, and transitory discontinuation of anticoagulant therapy should be considered.

Cerebrospinal fluid biomarkers of central nervous system dysfunction in HIV-infected patients

Background :¦In addition to opportunistic infections of the central nervous system (CNS), which are due to immunosuppression related to HIV, the latter virus, itself, can cause neuropathological abnormalities which are located mainly in the basal ganglia and are characterized by microglial giant cells, reactive astrocytosis and perivascular monocytes. This HIV encephalopathy is characterized, clinically, by psycho-motor slowing, memory loss, difficulties in complex tasks requiring executive functions, as well as motor disorders .These cognitive deficits are grouped under the acronym of HIV-associated neurocognitive disorders (HAND). In fact, HANDs are subdivided in three groups in accordance with the severity of the cognitive impairment: Asymptomatic Neurocognitive Impairment (ANI), Mild/moderate Neurocognitive Disorders (MND) and HIV Associated Dementia (HAD).¦While the incidence of HAD has significantly decreased in the era of combined antiretrobiral therapy (cART), the prevalence of milder forms of HIV-associated neurocognitive disorders HAND seem to have increased. There are many potential reasons to explain this state of facts.¦An important question is to understand how soon the brain may be affected by HIV. Since performing a biopsy in these patients is not an issue, the study of the CSF represents the best available way to look at putative biomarkers of inflammation/neurodegeneration in the CNS. Here, we wanted to examined the putative usefulness of different biomarkers as early indicators of anti-retroviral failure at the level of the CNS. We chose to study the CSF levels of:¦Amyloid-β 1-42 (Aβ42), Tau total (tTau), phosphorylated Tau (pTau), Neopterin and S100-β.¦Indeed, these molecules are representative biomarkers of the major cells of the CNS, i.e. neurons,¦macrophages/microglia and astrocytes.¦To examine how sensitive were these CSF biomarkers to indicate CNS insults caused by HIV, we proposed to take advantage of the MOST (Monotherapy Switzerland/Thailand study) study, recently published in AIDS. Thus, we collaborated with Prof. Pietro Vernazza in St-Gall. In MOST study, monotherapy (MT) consisting in ritonavir-boosted lopinavir (LPV/r) was compared to continuous conventional antiretroviral therapy including several molecules, hereafter referred as CT¦Methods :We tested 61 cerebrospinal fluid (CSF) samples from 52 patients enrolled in MOST, including 34 CSF samples of CT and 27 of MT (mean duration on MT: 47+20 weeks) in patients who maintained full VL suppression in blood (<50cps/ml). Using enzyme-linked immunosorbent assay (ELISA), we determined the CSF concentration of S100-beta (astrocytosis), neopterin (microglia, inflammation), total Tau (tTau), phosphorylated Tau (pTau), and amyloid-beta 1-42 (Abeta), the latter three markers indicating neuronal damages. The CSF samples of 37 HIV-negative patients with Alzheimer dementia (AD) served as controls. Results are expressed in pg/ml and reported as median ± interquartile range. Mann Whitney-U test was used to compare the results of a given biomarker between two groups and the Fisher test to compare frequencies.¦Results: We found a higher concentration of S100-beta (570±1132) and neopterin (2.5±2.9) in the CSF of MT versus CT (0±532, p=0.002 and 1.2±2.5, p=0.058, respectively). A cutoff of 940 pg/ml for S100-beta allowed to discriminate MT (11 above versus 16 below) from CT (1 vs 33, p=0.0003). At a lesser extent, a cutoff of 11 pg/ml for neopterin separated MT (4 above versus 23) from CT (0 vs 34, p=0.034) (Figure).¦In AD, tTau was higher (270±414) and Abeta lower (234±328) than in CT (150±153, p=0.0078, and 466±489, p=0.007, respectively). Such as for CT, Abeta was lower in AD than in MT (390±412, p=0.01). However, contrasting with CT, the levels of tTau were not different between AD and MT (199±177, p=0.11). S100b (173±214; p=0.0006) and neopterin (1.1±0.9; p=0.0014) were lower in AD than MT.¦Conclusions: Despite full VL-suppression in blood, HIV monotherapy is sufficient to trigger inflammation and, especially, astrocytosis. CSF markers of patients on CT have the same profile as reported for healthy subjects, suggesting that CT permits a good control of HIV in the brain. Finally, the levels of tTau, which are relatively similar between AD and MT patients, suggest that neurons are damaged during monotherapy.

Main objectives and new aspects of combination treatment of hypertension

AIM: To review the various pharmacological approaches currently proposed for the treatment of hypertension. RESULTS: With the evolution of pharmacological treatment of hypertension, various classes of agent (diuretics, beta-blockers, angiotensin converting enzyme inhibitors, calcium antagonists and alpha 1-blockers) have become available for the initiation of antihypertensive therapy. As monotherapy, each type of agent will normalize blood pressure in about half of all hypertensive patients. Replacing one drug with another that acts through a different mechanism improves the probability of controlling blood pressure. Another way to increase the number of responders is to increase the dose; however, this often results in more side effects. A preferable way of improving efficacy is to combine low doses of drugs that have different impacts on the cardiovascular system, thus opposing the compensatory responses that tend to limit the blood pressure drop. CONCLUSION: Low-dose drug combinations are generally well tolerated and the treatment of hypertension can be simplified by using fixed-dose combinations. These combinations have the potential to become a valuable alternative in the initiation of antihypertensive therapy.

The Effect of Valsartan versus Non-RAAS Treatment on Autoregulation of Cerebral Blood Flow.

Background: Cerebral autoregulation (CA) is a protective mechanism which maintains the steadiness of the cerebral blood flow (CBF) through a broad range of systemic blood pressure (BP). Acute hypertension has been shown to reduce the cerebrovascular adaptation to BP variations. However, it is still unknown whether CA is impaired in chronic hypertension. This study evaluated whether a strict control of BP affects the CA in patients with chronic hypertension, and compared a valsartan-based regimen to a regimen not inhibiting the renin-angiotensin-aldosterone system (non-RAAS). Methods: Eighty untreated patients with isolated systolic hypertension were randomized to valsartan 320 mg or to a non-RAAS regimen during 6 months. The medication was upgraded to obtain BP <140/90 mm Hg. Continuous recordings of arterial BP and CBF velocity (transcranial Doppler) were performed during periods of 5 minutes, at rest, and at different levels of alveolar CO(2) pressure provided by respiratory maneuvers. The dominant frequency of CBF oscillations was determined for each patient. Dynamic CA was measured as the mean phase shift between BP and CBF by cross-spectral analysis in the medium frequency and in the dominant CBF frequency. Results: Mean ambulatory 24-hour BP fell from 144/87 to 127/79 mm Hg in the valsartan group and from 144/87 to 134/81 mm Hg in the non-RAAS group (p = 0.13). Both groups had a similar reduction in the central BP and in the carotido-femoral pulse wave velocity. The average phase shift between BP fluctuations and CBF response at rest was normal at randomization (1.82 ± 0.08 s), which is considered a preserved autoregulation and increased to 1.91 ± 0.12 s at the end of study (p = 0.45). The comparison of both treatments showed no significant difference (-0.01 ± 0.17 s vs. 0.16 ± 0.16 s, p = 0.45) for valsartan versus non-RAAS groups. The plasmatic level of glycosylated hemoglobin decreased in the valsartan arm compared to the non-RAAS arm (-0.23 ± 0.06 vs. -0.08 ± 0.07%, p = 0.07). Conclusions: In elderly hypertensive men with isolated chronic systolic hypertension, CA seems efficient at baseline and is not significantly affected by 6 months of BP-lowering treatment. This suggests that the preventive effects of BP medication against stroke are not mediated through a restoration of the CA.

Recurrent mutations in the CDKL5 gene: Genotype-phenotype relationships.

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been described in epileptic encephalopathies in females with infantile spasms with features that overlap with Rett syndrome. With more than 80 reported patients, the phenotype of CDKL5-related encephalopathy is well-defined. The main features consist of seizures starting before 6 months of age, severe intellectual disability with absent speech and hand stereotypies and deceleration of head growth, which resembles Rett syndrome. However, some clinical discrepancies suggested the influence of genetics and/or environmental factors. No genotype-phenotype correlation has been defined and thus there is a need to examine individual mutations. In this study, we analyzed eight recurrent CDKL5 mutations to test whether the clinical phenotype of patients with the same mutation is similar and whether patients with specific CDKL5 mutations have a milder phenotype than those with other CDKL5 mutations. Patients bearing missense mutations in the ATP binding site such as the p.Ala40Val mutation typically walked unaided, had normocephaly, better hand use ability, and less frequent refractory epilepsy when compared to girls with other CDKL5 mutations. In contrast, patients with mutations in the kinase domain (such as p.Arg59X, p.Arg134X, p.Arg178Trp/Pro/Gln, or c.145 + 2T > C) and frameshift mutations in the C-terminal region (such as c.2635_2636delCT) had a more severe phenotype with infantile spasms, refractory epileptic encephalopathy, absolute microcephaly, and inability to walk. It is important for clinicians to have this information when such patients are diagnosed. © 2012 Wiley Periodicals, Inc.