Patrick Dicker

Aliskiren Reduces Blood Pressure and Suppresses Plasma Renin Activity in Combination With a Thiazide Diuretic, an Angiotensin-Converting Enzyme Inhibitor, or an Angiotensin Receptor Blocker

Thiazide diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers all cause reactive rises in plasma renin activity. We hypothesized that renin inhibition with aliskiren would prevent this reactive rise and also enhance blood pressure lowering. In 3 open-label studies in which blood pressure was assessed with ambulatory measurement, aliskiren was administered to patients with mild-to-moderate hypertension in combination with hydrochlorothiazide (n=23), ramipril (n=21), or irbesartan (n=23). In the diuretic combination study, the addition of 25 mg of hydrochlorothiazide to 150 mg of aliskiren daily for 3 weeks significantly lowered daytime pressure, compared with aliskiren monotherapy (systolic/diastolic mean change from baseline [SEM]: daytime: −18.4 [2.1]/ −10.6 [1.7] versus −10.4 [1.8]/−5.8 [1.4]; nighttime: −15.6 [2.7]/−8.1 [1.8] versus −8.8 [2.9]/−5.0 [2.2]). In the angiotensin-converting enzyme inhibitor combination study, the addition of 75 or 150 mg of aliskiren to 5 mg of ramipril alone for 3 weeks further lowered both daytime and nighttime pressures compared with ramipril monotherapy (daytime: −10.5 [2.9]/−8.1 [2.1] and −14 [3.7]/−8.7 [2.3] versus −6.1 [2.4]/−5.9 [1.5]; nighttime: −8.1 [2.6]/−5.3 [2.4] and −9.6 [3.4]/−5.3 [2.4] versus −2 [2.3]/−0.7 [2.2]). In the angiotensin receptor blocker combination study, the addition of 75 or 150 mg of aliskiren to 150 mg of irbesartan alone, for 3 weeks, resulted in significantly lower nighttime pressures compared with irbesartan monotherapy (daytime: −14.8 [2]/−8.2 [1.3] and −13.3 [1.6]/−6.8 [0.9] versus −11.4 [1.6]/−6.5 [1.1]; nighttime: −16.1 [2.4]/−8.6 [1.7] and −13.2 [2.7]/−7.2 [1.9] versus −9.0 [2.5]/−4.7 [1.9]). Aliskiren (150 mg) alone significantly inhibited plasma renin activity by 65% (P<0.0001). Ramipril and irbesartan monotherapy caused 90% and 175% increases in plasma renin activity, respectively. By contrast, when aliskiren was coadministered with hydrochlorothiazide, ramipril, or irbesartan, plasma renin activity did not increase but remained similar to baseline levels or was decreased (combination therapy versus untreated; median [interquartile range]; aliskiren and hydrochlorothiazide: 0.4 [0.2 to 1.1] versus 0.7 [0.5 to 1.3]; ramipril and aliskiren: 0.5 [0.3 to 0.9] versus 0.6 [0.5 to 0.8]; irbesartan and aliskiren: 0.4 [0.2 to 0.9] versus 0.6 [0.4 to 0.9]). These results suggest that renin inhibition with aliskiren in these combinations increases renin-angiotensin system suppression, improves 24-hour blood pressure control, and may ultimately provide better end-organ protection in patients with hypertension.

Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder

There is evidence for both similarity and distinction in the presentation and molecular characterization of schizophrenia and bipolar disorder. In this study, we characterized protein abnormalities in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder using two-dimensional gel electrophoresis. Tissue samples were obtained from 35 individuals with schizophrenia, 35 with bipolar disorder and 35 controls. Eleven protein spots in schizophrenia and 48 in bipolar disorder were found to be differentially expressed (P<0.01) in comparison to controls, with 7 additional spots found to be altered in both diseases. Using mass spectrometry, 15 schizophrenia-associated proteins and 51 bipolar disorder-associated proteins were identified. The functional groups most affected included synaptic proteins (7 of the 15) in schizophrenia and metabolic or mitochondrial-associated proteins (25 of the 51) in bipolar disorder. Six of seven synaptic-associated proteins abnormally expressed in bipolar disorder were isoforms of the septin family, while two septin protein spots were also significantly differentially expressed in schizophrenia. This finding represented the largest number of abnormalities from one protein family. All septin protein spots were upregulated in disease in comparison to controls. This study provides further characterization of the synaptic pathology present in schizophrenia and of the metabolic dysfunction observed in bipolar disorder. In addition, our study has provided strong evidence implicating the septin protein family of proteins in psychiatric disorders for the first time.

Optimizing the definition of intrauterine growth restriction: the multicenter prospective PORTO Study

OBJECTIVE The objective of the Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction (IUGR) (PORTO Study), a national prospective observational multicenter study, was to evaluate which sonographic findings were associated with perinatal morbidity and mortality in pregnancies affected by growth restriction, originally defined as estimated fetal weight (EFW) <10th centile. STUDY DESIGN Over 1100 consecutive ultrasound-dated singleton pregnancies with EFW <10th centile were recruited from January 2010 through June 2012. A range of IUGR definitions were used, including EFW or abdominal circumference <10th, <5th, or <3rd centiles, with or without oligohydramnios and with or without abnormal umbilical arterial Doppler (pulsatility index >95th centile, absent or reversed end-diastolic flow). Adverse perinatal outcome, defined as a composite outcome of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, and death was documented for all cases. RESULTS Of 1116 fetuses, 312 (28%) were admitted to neonatal intensive care unit and 58 (5.2%) were affected by adverse perinatal outcome including 8 mortalities (0.7%). The presence of abnormal umbilical Doppler was significantly associated with adverse outcome, irrespective of EFW or abdominal circumference measurement. The only sonographic weight-related definition consistently associated with adverse outcome was EFW <3rd centile (P = .0131); all mortalities had EFW <3rd centile. Presence of oligohydramnios was clinically important when combined with EFW <3rd centile (P = .0066). CONCLUSION Abnormal umbilical artery Doppler and EFW <3rd centile were strongly and most consistently associated with adverse perinatal outcome. Our data call into question the current definitions of IUGR used. Future studies may address whether using stricter IUGR cutoffs comparing various definitions and management strategies has implications on resource allocation and pregnancy outcome.

2-D DIGE analysis implicates cytoskeletal abnormalities in psychiatric disease.

The mechanisms underlying white matter changes in psychiatric disease are not known. We aimed to characterise the differential protein expression in deep white matter from the dorsolateral prefrontal cortex from 35 schizophrenia, 35 bipolar disorder, and 35 control subjects, from the Stanley Array Collection. We used 2‐D DIGE to profile for protein expression changes in the brain. We found 70 protein spots to be significantly differentially expressed between disease and control subjects (ANCOVA, p<0.05), 46 of which were subsequently identified by LC‐MS/MS. The proteins identified included novel disease candidates as well as proteins that have previously been reported as abnormal in schizophrenia, thus reinforcing their association with the disease. Furthermore, we confirmed the direction of change for three proteins using ELISA, namely neurofilament‐light, amphiphysin II, and Rab‐GDP‐α, in a subset of the Stanley Array Collection. In addition, altered expression of neurofilament‐light, amphiphysin II, and Rab‐GDP‐α was not observed in the cortex of mice chronically treated with haloperidol, making it less likely that these alterations are a consequence of neuroleptic medication. The data presented here strongly suggest disruption of the cytoskeleton and its associated signal transduction proteins in schizophrenia, and to a lesser extent in bipolar disorder.

Ambulatory blood pressure monitoring predicts cardiovascular events in treated hypertensive patients--an Anglo-Scandinavian cardiac outcomes trial substudy.

Background Results of the Anglo-Scandinavian cardiac outcomes trial-blood pressure lowering arm (ASCOT-BPLA) showed significantly lower rates of coronary and stroke events in individuals allocated an amlodipine–perindopril combination drug regimen than in those allocated an atenolol–thiazide combination drug regimen. The aims of the ambulatory blood pressure (ABP) substudy of ASCOT were to examine the impact of the two blood pressure (BP)- lowering regimens on ambulatory pressures, test to what extent the between-treatment differences in cardiovascular outcome could be attributed to differences in ABP and assess whether ABP provides predictive information additional to that of clinic blood pressure (CBP) in treated hypertensive patients. Methods and results One thousand, nine hundred and five patients from four ASCOT centres had repeated ABPs performed over a median follow-up period of 5.5 years. As in the whole ASCOT population, CBP values were lower in amlodipine–perindopril-treated patients compared with those treated with atenolol–thiazide [between-regimen difference {95% confidence intervals (CIs)}]: [−1.5 (−2.4 to −0.5)/−1.2 (−1.8 to +0.5) mmHg]. Daytime BP during follow-up was higher in patients treated with amlodipine–perindopril therapy [+1.1 (0.1–2.1)/+1.6 (0.8–2.3) mmHg]; night-time systolic, but not diastolic BP, was lower in patients treated with amlodipine–perindopril therapy [−2.2 (−3.4 to +0.9)/+0.8 (0.0–1.6) mmHg]. The relative risk of a cardiovascular event associated with a 1 SD increment in accumulated mean BP was 1.35 (1.18–1.53) for clinic systolic BP, 1.30 (1.14–1.49) for daytime systolic BP and 1.42 (1.24–1.62) for night-time systolic BP. With adjustment for baseline variables, treatment regimen and clinic systolic BP, the hazard ratios were 1.17 (1.00–1.36) and 1.25 (1.08–1.47) for daytime and night-time systolic BP, respectively. The between-regimen adjusted hazard ratio for cardiovascular events (amlodipine–perindopril therapy versus atenolol–thiazide therapy) was 0.74 (0.55–1.01) and increased to 0.81 (0.60–1.10) after further adjustment for clinic systolic BP. Further, adjustment for night-time systolic BP increased the hazard ratio to 0.85 (0.62–1.16). Conclusion The amlodipine–perindopril and atenolol–thiazide regimens had different effects on daytime and night-time ABP, which may have contributed to the lower rates of events in patients treated with amlodipine–perindopril therapy. Both CBP and ABP were significantly associated with rates of cardiovascular events. ABP nocturnal pressures provided complimentary and incremental utility over CBP in the prediction of cardiovascular risk in treated hypertensive patients. These data support the use of ABP to assess the effect of antihypertensive treatment in clinical practice.

Common Proteomic Changes in the Hippocampus in Schizophrenia and Bipolar Disorder and Particular Evidence for Involvement of Cornu Ammonis Regions 2 and 3

CONTEXT The hippocampus is strongly implicated in schizophrenia and, to a lesser degree, bipolar disorder. Proteomic investigations of the different regions of the hippocampus may help us to clarify the basis and the disease specificity of the changes. OBJECTIVE To determine whether schizophrenia and bipolar disorder are associated with distinct patterns of differential protein expression in specific regions of the hippocampus. DESIGN, SETTING, AND PATIENTS A postmortem comparative proteomic study, including validation of differential expression, was performed. Midhippocampus samples from well-matched groups of 20 subjects with schizophrenia, 20 subjects with bipolar disorder, and 20 control cases from the Stanley Medical Research Institute Array Collection were analyzed. MAIN OUTCOME MEASURES We used laser-assisted microdissection to enrich for tissue from the hippocampal regions and 2-dimensional difference gel electrophoresis to compare protein profiles. Levels of differentially expressed proteins were confirmed by enzyme-linked immunosorbent assay and Western blotting. Hippocampi from haloperidol-treated mice were used to help discriminate drug-associated from disease-associated protein changes. RESULTS Across all hippocampal regions, 108 protein spots in schizophrenia and 165 protein spots in bipolar disorder were differentially expressed compared with controls. Sixty-one proteins were differentially expressed in both disorders. One hundred fifty-two of these proteins were identified by mass spectrometry, and they implicated a range of different processes including cytoskeletal and metabolic functions. In both disorders, cornu ammonis regions 2 and 3 were affected to a significantly greater degree than other hippocampal regions. Additionally, numerous proteins showed expression changes in more than 1 region and more than 1 disorder. Validation work confirmed changes in septin 11 and in the expression of proteins involved in clathrin-mediated endocytosis in both schizophrenia and bipolar disorder. CONCLUSIONS Overall, similar protein changes were observed in schizophrenia and bipolar disorder and for the first time indicate that the most prominent proteomic changes occur within the hippocampus in cornu ammonis regions 2 and 3. The cytoskeletal protein septin 11 and the cellular trafficking process of clathrin-mediated endocytosis are implicated by our study.

Proteomic analysis reveals protein changes within layer 2 of the insular cortex in schizophrenia

Abnormalities in the size and activity of the insular cortex (IC), a brain region involved in auditory hallucinations and language, have been previously found in brain imaging studies in schizophrenia. In addition, cortical layer 2 has been shown to be abnormal in many brain regions in schizophrenia. In this study, 2‐D DIGE was used to quantitatively analyse protein expression in schizophrenia and control cases (n = 15/group) in microdissected layer 2 IC tissue. Proteomic analyses revealed 57 significantly differentially expressed (p<0.05) protein spots in schizophrenia. Validation of differential expression of two of the proteins differentially expressed was subsequently confirmed using Western blotting. This work provides evidence of abnormal protein expression in layer 2 of the IC in schizophrenia, supporting previous work of reduced neuronal size in this cortical layer in the IC. Over half of proteins abnormally expressed in this study have not been reported previously in proteomic studies investigating schizophrenia or neurodegenerative disorders. Proteins found to be abnormally expressed appear to collectively impact on neuronal plasticity through roles in neurite outgrowth, cellular morphogenesis and synaptic function.

Proteomic and genomic evidence implicates the postsynaptic density in schizophrenia

The postsynaptic density (PSD) contains a complex set of proteins of known relevance to neuropsychiatric disorders, and schizophrenia specifically. We enriched for this anatomical structure, in the anterior cingulate cortex, of 20 schizophrenia samples and 20 controls from the Stanley Medical Research Institute, and used unbiased shotgun proteomics incorporating label-free quantitation to identify differentially expressed proteins. Quantitative investigation of the PSD revealed more than 700 protein identifications and 143 differentially expressed proteins. Prominent among these were altered expression of proteins involved in clathrin-mediated endocytosis (CME) (Dynamin-1, adaptor protein 2) and N-methyl-D-aspartate (NMDA)-interacting proteins such as CYFIP2, SYNPO, SHANK3, ESYT and MAPK3 (all P<0.0015). Pathway analysis of the differentially expressed proteins implicated the cellular processes of endocytosis, long-term potentiation and calcium signaling. Both single-gene and gene-set enrichment analyses in genome-wide association data from the largest schizophrenia sample to date of 13 689 cases and 18 226 controls show significant association of HIST1H1E and MAPK3, and enrichment of our PSD proteome. Taken together, our data provide robust evidence implicating PSD-associated proteins and genes in schizophrenia, and suggest that within the PSD, NMDA-interacting and endocytosis-related proteins contribute to disease pathophysiology.

Definition of intertwin birth weight discordance.

OBJECTIVE: To establish the level of birth weight discordance at which perinatal morbidity increases in monochorionic and dichorionic twin pregnancy. METHODS: This prospective multicenter cohort study included 1,028 unselected twin pairs recruited over a 2-year period. Participants underwent two weekly ultrasonographic surveillance from 24 weeks of gestation with surveillance of monochorionic twins two-weekly from 16 weeks. Analysis using Cox proportional hazards compared a composite measure of perinatal morbidity (including any of the following: mortality, respiratory distress syndrome, hypoxic–ischemic encephalopathy, periventricular leukomalacia, necrotizing enterocolitis, or sepsis) at different degrees of birth weight discordance with adjustment for chorionicity, gestational age, twin–twin transfusion syndrome, birth order, gender, and growth restriction. RESULTS: Perinatal outcome data were recorded for 977 patients (100%) who continued the study with both fetuses alive beyond 24 weeks, including 14 cases of twin–twin transfusion syndrome. Adjusting for gestation at delivery, twin order, gender, and growth restriction, perinatal mortality, individual morbidity, and composite perinatal morbidity were all seen to increase with birth weight discordance exceeding 18% for dichorionic pairs (hazard ratio 2.2, 95% confidence interval [CI] 1.6–2.9, P<.001) and 18% for monochorionic twins without twin–twin transfusion syndrome (hazard ratio 2.6, 95% CI 1.6–4.3, P<.001). A minimum twofold increase in risk of perinatal morbidity persisted even when both twin birth weights were appropriate for gestational age. CONCLUSION: The threshold for birth weight discordance established by this prospective study is 18% both for dichorionic twin pairs and for monochorionic twins without twin–twin transfusion syndrome. This threshold is considerably lower than that defined by many retrospective series as pathologic. We suggest that an anticipated difference of 18% in birth weight should prompt more intensive fetal monitoring. LEVEL OF EVIDENCE: II

Predictable progressive Doppler deterioration in IUGR: does it really exist?

OBJECTIVE An objective of the Prospective Observational Trial to Optimize Pediatric Health in IUGR (PORTO) study was to evaluate multivessel Doppler changes in a large cohort of intrauterine growth restriction (IUGR) fetuses to establish whether a predictable progressive sequence of Doppler deterioration exists and to correlate these Doppler findings with respective perinatal outcomes. STUDY DESIGN More than 1100 unselected consecutive ultrasound-dated singleton pregnancies with estimated fetal weight (EFW) less than the 10th centile were recruited between January 2010 and June 2012. Eligible pregnancies were assessed by serial Doppler interrogation of umbilical (UA) and middle cerebral (MCA) arteries, ductus venosus (DV), aortic isthmus, and myocardial performance index (MPI). Intervals between Doppler changes and patterns of deterioration were recorded and correlated with respective perinatal outcomes. RESULTS Our study of 1116 nonanomalous fetuses comprised 7769 individual Doppler data points. Five hundred eleven patients (46%) had an abnormal UA, 300 (27%) had an abnormal MCA, and 129 (11%) had an abnormal DV Doppler. The classic pattern from abnormal UA to MCA to DV existed but no more frequently than any of the other potential pattern. Doppler interrogation of the UA and MCA remains the most useful and practical tool in identifying fetuses at risk of adverse perinatal outcome, capturing 88% of all adverse outcomes. CONCLUSION In contrast to previous reports, we have demonstrated multiple potential patterns of Doppler deterioration in this large prospective cohort of IUGR pregnancies, which calls into question the usefulness of multivessel Doppler assessment to inform frequency of surveillance and timing of delivery of IUGR fetuses. These data will be critically important for planning any future intervention trials.