Structure and dynamics of major histocompatibility class Ib molecule H2-M3 complexed with mitochondrial-derived peptides.

Presentation of antigenic peptides to T-cell receptors is an essential step in the adaptive immune response. In the mouse the class Ib major histocompatibility complex molecule, H2-M3, presents bacterial- and mitochondrial-derived peptides to T-cell receptors on cytotoxic T cells. Four mitochondrial heptapeptides, differing only at residue 6, form complexes with H2-M3 which can be distinguished by T cells. No structures of relevant receptors are available. To investigate the structural basis for this distinction, crystal structures were determined and molecular dynamics simulations over one microsecond were done for each complex. In the crystal structures of the heptapeptide complexes with H2-M3, presented here, the side chains of the peptide residues at position 6 all point into the H2-M3 binding groove, and are thus inaccessible, so that the very similar structures do not suggest how recognition and initiation of responses by the T cells may occur. However, conformational differences, which could be crucial to T-cell discrimination, appear within one microsecond during molecular dynamics simulations of the four complexes. Specifically, the three C-terminal residues of peptide ligands with alanine or threonine at position 6 partially exit the binding groove; this does not occur in peptide ligands with isoleucine or valine at position 6. Structural changes associated with partial peptide exit from the binding groove, along with relevant peptide binding energetics and immunological results are discussed. Communicated by Ramaswamy H. Sarma.

Successfully treating 90 patients with obsessive compulsive disorder in eight days: the Bergen 4-day treatment.

BACKGROUND: Oslo University Hospital, Norway, had by autumn 2016, accumulated a waiting list of 101 patients with obsessive-compulsive disorder (OCD) who had a legal right to receive treatment by a specialized OCD team. In this challenging situation, the Bergen OCD-team suggested to solve the problem by offering all patients an option for the rapid Bergen 4-day treatment (B4DT). The B4DT is an individual treatment delivered during four consecutive days in a group of six patients with the same number of therapists. The approach has previously shown a post-treatment response rate of 90% and a 3-month remission rate of 70%. METHODS: Ninety-seven of the wait-list patients were available for the scheduled time slots, and 90 received the 4-day format during 8 days (45 patients each week). The therapists were recruited from 22 different specialized OCD-teams from all over Norway, and 44 (68%) had not previously delivered the 4-day format. RESULTS: Post-treatment; 91.1% of the patients were classified as responders, and 72.2% were in remission. At 3-month follow-up; 84.4 were classified as responders and the remission rate was 67.7%. Oslo University Hospital now offers the 4-day treatment as standard treatment for OCD. CONCLUSIONS: We conclude that the B4DT is an acceptable and potentially effective OCD-treatment.

Prevention of atrial fibrillation in hypertension.

Hypertensive patients have an increased risk of developing atrial fibrillation (AF), which increases cardiovascular morbidity and mortality in this population. Primary prevention is a new strategy in treating AF; previously, it was more common to focus on preventing adverse outcomes and controlling the arrhythmia's rate and rhythm. In this review, we consider the possible preventive effects of antihypertensive treatment on new-onset AF seen in recent trials, especially with blockers of the renin-angiotensin system (RAS). Several secondary analyses of large, randomized trials regarding hypertension and heart failure have shown promising results with benefits beyond the expected blood pressure-lowering effect. A few prospective studies on prevention of AF recurrence with RAS blockade have been published, and more studies are expected to be published in the near future.

Do screening blood pressure and plasma catecholamines predict development of hypertension? Twenty-year follow-up of middle-aged men.

OBJECTIVES: The sympathetic nervous system is implicated in the development and maintenance of hypertension. However, the predictive impact of arterial plasma catecholamines has never been reported. We investigated arterial catecholamines and blood pressures (BPs) prospectively over 20 years in a group of well-characterized middle-aged men. METHODS: Fifty-six of original 79 men were available for the follow-up. Multiple regression analysis was done with mean BP at follow-up as a dependent variable, and arterial plasma catecholamines and BP at baseline as independent variables. RESULTS: Half of the originally normotensive men developed hypertension during follow-up. There were significant differences in the screening BP values measured at baseline between the new hypertensives and the sustained normotensives. Multiple regression analysis revealed arterial adrenaline at baseline as an independent predictor of mean BP at follow-up in the new hypertensives (beta = 0.646, R2 = 0.42, p = 0.007). Furthermore, arterial noradrenaline at baseline was a negative independent predictor of mean BP at follow-up in the sustained normotensives (beta = -0.578, R2 = 0.334, p = 0.020). Noradrenaline increased with age in the group as a whole (1318+/-373 vs 1534+/-505 pmol/l, p = 0.010) while adrenaline did not change. CONCLUSION: Our data suggest that arterial adrenaline is involved in the development of hypertension over 20 years in middle-aged men. Men with sustained normotension may have an inherent protection against sympathetic overactivity. Furthermore, screening BP at baseline in normotensive men differentiated between those who developed hypertension and those who remained normotensive at follow-up.

Serum phosphate, blood pressure, and the metabolic syndrome--20-year follow-up of middle-aged men.

The authors investigated the relationship between serum phosphate (S-phosphate) and the metabolic syndrome in a group of middle-aged hypertensive and normotensive men during 20-year follow-up. Fifty-six men participated. Of the original 34 normotensive men, hypertension developed in 17. In the group as a whole and in those in whom hypertension developed, there was a significant negative relationship between S-phosphate at baseline and mean blood pressure (MBP) at follow-up. A significant relationship was observed between S-phosphate at baseline and components of the metabolic syndrome in the group as a whole, in individuals with hypertension, and in individuals with the lowest S-phosphate levels at follow-up. S-phosphate at baseline predicted MBP 20 years later in a group of hypertensive and normotensive men. When grouped according to the number of components of the metabolic syndrome, individuals with the lowest serum phosphate levels had the highest number of risk factors. These findings may suggest a role of low S-phosphate in the development of hypertension and the metabolic syndrome.

Arterial plasma vasopressin and aldosterone predict left ventricular mass in men who develop hypertension over 20 years.

Left ventricular (LV) hypertrophy is related to blood pressure level and neurohormonal factors. The authors previously demonstrated that arterial norepinephrine levels predict LV mass in middle-aged men who developed hypertension through 20 years. The aim of this 20-year prospective study was to investigate arterial vasopressin, aldosterone, and renin as long-term predictors of LV mass. Normotensives (n=17), subjects who developed hypertension (n=17), and sustained hypertensives (n=22) were compared at baseline (42 years) and at follow-up (62 years). There were no significant differences in baseline vasopressin, aldosterone, or renin levels. The group with sustained hypertension had more LV hypertrophy (P=.025) at follow-up. Among new hypertensives, multiple regression analysis demonstrated that baseline arterial vasopressin (beta-0.53; P=.041) and aldosterone (beta-0.56;P=.032) independently explained LV mass index (R(2)=0.85; P=.035). In conclusion, baseline arterial vasopressin and aldosterone, but not renin, appear to predict LV mass in middle-aged men who developed hypertension over a 20-year period.

Complications of hypertension and the role of angiotensin receptor blockers in hypertension trials.

Hypertension is a high-prevalence disease that may affect several organs. In recent years, data have accumulated indicating that angiotensin II receptor blockers (ARBs) may have a supplementary effect beyond lowering blood pressure. The aim of this review is to evaluate the impact of ARBs on the most important complications of hypertension--heart, cerebrovascular and renal diseases, and metabolic complications--based on the findings from large clinical hypertension trials. The results may indicate that ARBs have a superior effect compared with placebo or other antihypertensive drugs in order to prevent left ventricular hypertrophy, atrial fibrillation, stroke, renal disease and diabetes mellitus, while there appears to be no blood pressure-independent superior effect of ARBs regarding prevention of myocardial infarction or heart failure.

Prevention of new-onset atrial fibrillation and its predictors with angiotensin II-receptor blockers in the treatment of hypertension and heart failure.

Atrial fibrillation is the most frequent occurring sustained cardiac arrhythmia and it is related to common cardiac disease conditions. Hypertension increases the risk of atrial fibrillation by approximately two-fold and, because of the high prevalence of hypertension, it accounts for more cases of atrial fibrillation than any other risk factor. In recent years, there are two large hypertension trials (LIFE and VALUE) and two large heart failure trials (CHARM and Val-HeFT) reporting the beneficial effect of angiotensin II-receptor blockers (ARBs) on new-onset atrial fibrillation, beyond the blood pressure-lowering effect. Blockade of the renin-angiotensin system may prevent left atrial dilatation, atrial fibrosis, dysfunction and conduction velocity slowing. Some studies also indicate direct anti-arrhythmic properties. This review aims to consider the preventive effect of ARBs on new-onset atrial fibrillation observed in recent reports from these trials, and to discuss possible mechanisms of the beneficial effect of angiotensin II-receptor blockade.

Increased hematocrit before blood pressure in men who develop hypertension over 20 years.

We have previously demonstrated that neurohormonal activity can predict left ventricular (LV) mass in men who developed hypertension over 20 years. The aim of the study was to investigate early markers of cardiac and hemorheological changes at baseline in these men, i.e., before a rise in blood pressure. Fifty-six middle-aged men were followed for 20 years; 22 were sustained hypertensives, 17 developed hypertension, and 17 were sustained normotensives. They were compared at baseline (42 years) and follow-up (62 years). We investigated Cornell voltage product and Sokolow-Lyon voltage, hematocrit (Hct), and echocardiographic LV parameters. There was no sign of LV hypertrophy by electrocardiography (ECG) at baseline. Baseline Hct discriminated between the groups (P= .015) and correlated to diastolic blood pressure (DBP) at baseline (r = 0.37, P= .006) and follow-up (r = 0.31, P= .020). Regression analysis identified baseline Hct as an independent correlate of DBP in the cohort at baseline when they were untreated (beta = .33, P= .013, R(2) = 0.25), and of borderline significance at follow-up (beta = .26, P= .060, R(2) = 0.12) despite possible interference by antihypertensive drugs. Hct was elevated at baseline compatible with the hypothesis that pathogenic hemorheological processes could be activated at the outset and prior to cardiac changes in men who later develop hypertension.

Mechanism of angiotensin II type 1 receptor blocker action in the regression of left ventricular hypertrophy.

Left ventricular hypertrophy refers to a pathologic increase in left ventricular mass and is associated with an increased risk of subsequent cardiovascular morbidity and mortality from any cause. In the development of left ventricular hypertrophy there is growth of cardiomyocytes and accumulation of extracellular matrix and fibrosis. The actions are partly induced by angiotensin II, the principal effector of the renin-angiotensin-aldosterone system, binding to the AT1 receptor. Biochemical markers, some implicated in inflammatory changes, correlate with changes in left ventricular mass. The reduction in left ventricular mass brought about with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ARB) therapy correlates with a reduction in these inflammatory changes, monitored by brain natriuretic peptide. Recent studies incorporating trials of ARBs have found ARBs to be more effective in reducing left ventricular mass than beta blockers and possibly more effective than calcium antagonists. Initial studies suggest that ARBs and angiotensin-converting enzyme inhibitors may have similar effects in terms of reducing left ventricular hypertrophy, and the combination of angiotensin-converting enzyme inhibitors and ARBs is thought to be synergistic due to a more complete inhibition of the renin-angiotensin-aldosterone system. In conclusion, these agents are efficacious in antihypertensive therapy and can play an important role in the prevention or regression of left ventricular hypertrophy due to hypertension.

Arterial plasma noradrenaline predicts left ventricular mass independently of blood pressure and body build in men who develop hypertension over 20 years.

BACKGROUND: Increased sympathetic activity may be an underlying mechanism in cardiovascular disease. It has been hypothesized that the degree of left ventricular (LV) hypertrophy is partly related to the blood pressure level, and partly to neurohormonal factors. The aim of this study was to investigate predictors of LV mass, including arterial plasma noradrenaline as an index of sympathetic activity, with particular emphasis on subjects who developed hypertension over a period of 20 years. METHODS: In a 20-year prospective study of middle-aged men, sustained hypertensives (n = 22), new hypertensives (crossovers) (n = 17) and sustained normotensives (controls) (n = 17) were examined both at baseline and after 20 years of follow-up (at ages 42.1 +/- 0.5 and 62.3 +/- 0.6 years, respectively). Relationships between arterial plasma catecholamines, blood pressure and body mass index at baseline to left ventricular parameters by echocardiography at follow-up were investigated. RESULTS: Groups were homogeneous regarding age, gender, race and body build. The group of sustained hypertensives had significantly more LV hypertrophy (P = 0.025) and diastolic dysfunction (P = 0.010). Among the crossovers, LV mass index was positively correlated to arterial plasma noradrenaline (r = 0.50, P = 0.043) and body mass index (BMI) (r = 0.51, P = 0.039) and showed a positive trend with systolic blood pressure (SBP) at baseline. Arterial plasma noradrenaline (beta = 0.47) was found to predict LV mass index after 20 years independently of BMI (beta = 0.45) and SBP (beta = 0.22) at baseline (R adjusted = 0.345, P = 0.037). Such a relationship was not found in the controls or in the sustained hypertensives, of which 16 were treated with antihypertensive drugs. CONCLUSIONS: Arterial plasma noradrenaline at baseline, as an index of sympathetic activity, predicts LV mass at follow-up independently of systolic blood pressure and body build in middle-aged men who developed hypertension over a period of 20 years.