Evaluation of the T25FW in minimally disabled people with multiple sclerosis.

BACKGROUND: Walking impairment is one of the most prevalent symptoms in people with multiple sclerosis (pwMS). In this study, we aimed to explore the usefulness of a simple walking test, the Timed 25 Foot Walk (T25FW), in detecting subtle differences in "fully ambulatory" pwMS compared to HC. METHODS: We therefore investigated retrospective data from a clinical real-life cohort of 650 pwMS. We first analyzed the amount of patients showing clinically relevant impairment in the T25FW (T25FW > 6 s) within different levels of disability according to the Expanded Disability Status Scale (EDSS). For detailed analysis in "fully ambulatory" pwMS, we formed four groups according to the respective levels of disability (EDSS 0, EDSS 1, EDSS 1.5-2, EDSS 2.5-3), and compared their walking speed to age- and sex-matched healthy controls (HC). RESULTS: In our cohort, the number of patients showing clinically relevant slowing in the T25FW ranged from 15% in "fully ambulatory" patients (EDSS 0-3) to 69% in patients with moderate (EDSS 3.5-5.5) and 100% in patients with severe impairment (EDSS ≥6). Further analyses in "fully ambulatory" patients revealed that all EDSS-subgroups showed significant slowing compared to HC. The mean difference to walking speed of HC became gradually more pronounced from 0.15 m/s in asymptomatic patients (EDSS 0) to 0.5 m/s in patients with EDSS 2.5-3. CONCLUSION: These findings underline the ability of the T25FW to detect slowing even in patients with minimal disability. While the difference to HC was slightly below clinical relevance in asymptomatic patients (EDSS 0), slowing gradually worsened from EDSS 1 onwards and exceeded published thresholds for clinical meaningfulness.

High serum neurofilament light chain levels correlate with brain atrophy and physical disability in multiple sclerosis.

BACKGROUND AND PURPOSE: Serum neurofilament light chain (sNfL) is a promising biomarker of neuroaxonal damage in persons with multiple sclerosis (pwMS). In cross-sectional studies, sNfL has been associated with disease activity and brain magnetic resonance imaging (MRI) changes; however, it is still unclear to what extent in particular high sNfL levels impact on subsequent disease evolution. METHODS: sNfL was quantified by an ultrasensitive single molecule array (Simoa) in 199 pwMS (median age = 34.2 years, 64.3% female) and 49 controls. All pwMS underwent 3-T MRI to assess global and compartmental normalized brain volumes, T2-lesion load, and cortical mean thickness. Follow-up data and serum samples were available in 144 pwMS (median follow-up time = 3.8 years). Linear and binary logistic models were used to estimate the independent contribution of sNfL for changes in MRI and Expanded Disability Status Scale (EDSS). Age-corrected sNfL z-scores from a normative database of healthy controls were used for sensitivity analyses. RESULTS: High sNfL levels at baseline were associated with atrophy measures of the whole brain (standardized beta coefficient ßj = -0.352, p < 0.001), white matter (ßj = -0.229, p = 0.007), thalamus (ßj = -0.372, p = 0.004), and putamen (ßj = -1.687, p = 0.012). pwMS with high levels of sNfL at baseline and follow-up had a greater risk of EDSS worsening (p = 0.007). CONCLUSIONS: Already single time point elevation of sNfL has a distinct effect on brain volume changes over a short-term period, and repeated high levels of sNfL indicate accumulating physical disability. Serial assessment of sNfL may provide added value in the clinical management of pwMS.

Abnormal pulmonary hemodynamics during exercise is associated with exercise capacity in COPD.

BACKGROUND: Pulmonary hypertension (PH) is a frequent complication in COPD and it is associated with decreased exercise capacity and poor prognosis. We hypothesized that even in COPD patients without significant PH at rest, abnormal pulmonary hemodynamics during exercise affect exercise capacity. METHODS: Consecutive COPD patients with clinically indicated right heart catheterization and resting mean pulmonary arterial pressure (mPAP) < 25 mmHg and age- and sex-matched controls with the same limits of pulmonary hemodynamics but no chronic lung disease who underwent clinical work-up including invasive hemodynamic assessment during exercise, were retrospectively analyzed. Chi-square tests were used to evaluate differences between groups for categorical data and Fisher's exact test or Mann-Whitney-U-tests for continuous variables. Associations were analyzed with Spearman rank correlation tests. RESULTS: We included n = 26 COPD patients (female/male: 16/10, 66 ± 11 yr, FEV1: 56 ± 25%predicted) and n = 26 matched controls (FEV1: 96 ± 22%predicted). At rest, COPD patients presented with slightly increased mPAP (21 (18-23) vs. 17 (14-20) mmHg, p = 0.022), and pulmonary vascular resistance (PVR) [2.5 (1.9-3.0) vs. 1.9 (1.5-2.4) WU, p = 0.020] as compared to controls. During exercise, COPD patients reached significantly higher mPAP [47 (40-52) vs. 38 (32-44) mmHg, p = 0.015] and PVR [3.1 (2.2-3.7) vs. 1.7 (1.1-2.9) WU, p = 0.028] values despite lower peak exercise level [50 (50-75) vs. 100 (75-125) Watt, p = 0.002]. The mPAP/cardiac output slope was increased in COPD vs. controls [6.9 (5.5-10.9) vs. 3.7 (2.4-7.4) mmHg/L/min, p = 0.007] and negatively correlated with both peak oxygen uptake (r = - 0.46, p = 0.007) and 6-min walk distance (r = - 0.46, p = 0.001). CONCLUSION: Even in the absence of significant PH at rest, COPD patients reveal characteristic abnormalities in pulmonary hemodynamics during exercise, which may represent an important exercise-limiting factor.

Pulmonary vascular disease and exercise hemodynamics in chronic liver disease.

BACKGROUND & AIMS: Portopulmonary hypertension (POPH) and hepatopulmonary syndrome (HPS) are severe pulmonary vascular complications of chronic liver disease and strongly associated with morbidity and mortality. The prevalence of these complications is relatively high in patients evaluated for liver transplantation, however it is virtually unknown in patients with stable chronic liver disease. METHODS: We assessed the pulmonary hypertension (PH) and HPS prevalence in a prospective registry study of our liver out-patient clinic in a tertiary center. Between 2011 and 2016, consecutive patients with cirrhosis or non-cirrhotic portal hypertension were prospectively enrolled after written informed consent. We excluded patients with acute decompensation of liver disease and other causes of PH like severe chronic heart or lung diseases and chronic thromboembolic PH. HPS was diagnosed using contrast enhanced echocardiography and blood gas analysis. Patients were screened for PH using an algorithm implementing severity of dyspnea, echocardiography, cardiopulmonary exercise testing and exercise echocardiography employing a threshold of systolic pulmonary arterial pressure (SPAP) = 50 mmHg at peak exercise. If the algorithm indicated an increased PH risk, patients were invited for invasive investigations by means of right heart and hepatic vein catheter. We defined POPH as resting mPAP≥21 mmHg and PVR>3WU and PAWP<15 mmHg, mild PH as resting mPAP = 21-24 mmHg, and exercise PH as mPAP>30 mmHg and TPR >3 WU at peak exercise. RESULTS: Two-hundred-five patients were enrolled (male 75%; cirrhosis 96%; median age 57 yrs). Sixty-seven patients (33%) fulfilled HPS criteria but only two (1.0%) for severe (PaO2:50-60 mmHg) or very severe HPS (PaO2<50 mmHg). In 18/77 patients (23%) undergoing exercise echocardiography, SPAP at peak exercise exceeded 50 mmHg. Finally, n = 3 (1.5%) patients were invasively diagnosed with POPH, n = 4 (2.9%) with mild PH and n = 2 with exercise PH. CONCLUSION: In chronic liver disease, excluding acute decompensation and other causes of PH, POPH and severe HPS are rare findings while mild to moderate HPS and mild PH or exercise PH are more frequent.

Relevance of Cognition and Emotion for Patient-Reported Quality of Life After Stroke in Working Age: An Observational Cohort Study.

Background: Patient-reported quality of life (QoL) may help to capture sequela of stroke more comprehensively. We aimed to investigate QoL in working age persons with ischemic stroke regarding impaired domains and identify factors associated with better QoL. Methods: We invited persons with stroke aged 18-55 years to participate in this prospective observational study. We assessed QoL and self-rated health using the EuroQol 5 Dimension questionnaire (EQ-5D) during hospital stay (baseline) and at 3-months follow-up (FU). Additionally, the National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), cognition (Montreal Cognitive assessment, MOCA), emotion (Hospital Anxiety and Depression Scale), and return to work were evaluated. We used hierarchical regression to identify predictors of QoL (self-rated health and QoL Index score) at FU. Results: We included 138 persons with stroke (mean age = 43.6 ± 10 years; 41% female; median admission NIHSS = 2), of whom 99 participated at FU. QoL Index and self-rated health were correlated with NIHSS, mRS, anxiety, and depression at both timepoints. Although 80% had favorable functional outcome at FU (mRS < 2), high proportions of these persons reported problems in the "Pain and/or Discomfort" (25.3%) and "Anxiety/Depression" (22.8%) dimensions. Only discharge NIHSS and baseline MOCA independently predicted self-rated health at FU. Female sex, higher discharge NIHSS, and higher baseline depression scores predicted worse QoL Index scores at FU. Conclusions: Three months post-stroke, working age persons with stroke frequently reported problems in dimensions not assessed by the routinely used mRS. Despite correlations between clinical scales and QoL, patient-reported outcomes and screening for cognition and emotion ensure a more comprehensive assessment of post-stroke consequences relevant for QoL.

Information processing speed as a prognostic marker of physical impairment and progression in patients with multiple sclerosis.

BACKGROUND: Prediction of disability progression in patients with MS (pwMS) is challenging. So far, scarce evidence exists suggesting knowledge about how cognitive performance may potentially improve prediction of physical impairment and disability progression in MS. Therefore, we wanted to assess the prognostic value of cognitive performance regarding physical impairment and disability progression in pwMS. METHODS: 85 patients (64% female; 60% relapse-remitting MS; mean age=36.78 ± 9.63 years) underwent clinical, neuropsychological (Brief Repeatable Battery for Neuropsychological Test (BRB-N)) and brain MRI (T1-weighted and T2-weighted FLAIR images) assessment at baseline and after an average of 7 years (SD=3.75) at follow-up. We assessed physical impairment and annualized disability progression (disability progression divided by follow-up duration) using the Expanded Disability Status Scale (EDSS). To compare patients with no or mild physical impairment (EDSS≤2.5) and patients with moderate to severe physical impairment (EDSS≥3.0), we used an EDSS score ≥3.0 as cut-off. Silent progression was defined by an EDSS worsening of at least 0.5 in the absence of relapses and inflammation in relapsing-remitting MS. RESULTS: In hierarchical regression models (method "STEPWISE", forward) performance in information processing speed was a significant and independent predictor of physical impairment (EDSS≥3.0) at follow-up (model R²=0.671, b=-1.46, OR=0.23, p=0.001) and annualized disability progression (adjusted model R²=0.257, ß=-0.26, 95% CI: -0.066, -0.008, p=0.012), in addition to demographics (age, education, individual follow-up time), clinical (EDSS, disease duration, clinical phenotype, annualized-relapse-rate) and MRI measures (brain volumes and T2-lesion load). In a MANCOVA controlled for age, disease duration and individual follow-up time, worse baseline performance in information processing speed was found in patients with higher EDSS at follow-up (m=-1.91, SD=1.18, p<0.001) and silent progression (m=-2.19, SD=1.01, p=0.038). CONCLUSION: Performance in information processing speed might help to identify patients at risk for physical impairment. Therefore, neuropsychological assessment should be integrated in clinical standard care to support disease management in pwMS.

Severe Pulmonary Hypertension in COPD: Impact on Survival and Diagnostic Approach.

BACKGROUND: Severe pulmonary hypertension (PH) is prognostically highly relevant in patients with COPD. The criteria for severe PH have been defined based on hemodynamic thresholds in right heart catheterization. RESEARCH QUESTION: Can noninvasive clinical tools predict severe PH in patients with COPD? How does the mortality risk change with increasing severity of airflow limitation and pulmonary vascular disease? STUDY DESIGN AND METHODS: We retrospectively analyzed all consecutive patients with COPD with suspected PH undergoing in-depth clinical evaluation, including right heart catheterization, in our PH clinic between 2005 and 2018. Clinical variables potentially indicative of severe PH or death were analyzed using univariate and stepwise multivariate logistic regression and Cox regression analysis adjusted for age and sex. RESULTS: We included 142 patients with median FEV1 of 55.0% predicted (interquartile range [IQR], 42.4%-69.4% predicted) and mean pulmonary arterial pressure of 35 mm Hg (IQR, 27-43 mm Hg). A multivariate model combining echocardiographic systolic pulmonary arterial pressure of ≥ 56 mm Hg, N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels of ≥ 650 pg/mL, and pulmonary artery (PA) to ascending aorta (Ao) diameter ratio on chest CT scan of ≥ 0.93 predicted severe PH with high positive and negative predictive values (both 94%). After correction for age and sex, both airflow limitation (P = .002; Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages 1-2 vs stage 3: hazard ratio [HR], 1.56 [95% CI, 0.90-2.71]; GOLD stages 1-2 vs stage 4: HR, 3.45 [95% CI, 1.75-6.79]) and PH severity (P = .012; HR, 1.85 [95% CI, 1.15-2.99]) remained associated independently with survival. The combination of GOLD stages 3 and 4 airflow limitation and severe PH showed the poorest survival (HR for death, 3.26 [95% CI, 1.62-6.57; P = .001] vs GOLD stages 1-2 combined with nonsevere PH). INTERPRETATION: In patients with COPD, the combination of echocardiography, NT-proBNP level, and PA to Ao diameter ratio predicts severe PH with high sensitivity and specificity. The contribution of severe PH and severe airflow limitation to impaired survival is comparable.

Decreased Cerebrospinal Fluid Antioxidative Capacity Is Related to Disease Severity and Progression in Early Multiple Sclerosis.

Background: Oxidative stress-induced neuronal damage in multiple sclerosis (MS) results from an imbalance between toxic free radicals and counteracting antioxidants, i.e., antioxidative capacity (AOC). The relation of AOC to outcome measures in MS still remains inconclusive. We aimed to compare AOC in cerebrospinal fluid (CSF) and serum between early MS and controls and assess its correlation with clinical/radiological measures. Methods: We determined AOC (ability of CSF and serum of patients to inhibit 2,2'-azobis(2-amidinopropane) dihydrochloride-induced oxidation of dihydrorhodamine) in clinically isolated syndrome (CIS)/early relapsing-remitting MS (RRMS) (n = 55/11) and non-inflammatory neurological controls (n = 67). MS patients underwent clinical follow-up (median, 4.5; IQR, 5.2 years) and brain MRI at 3 T (baseline/follow-up n = 47/34; median time interval, 3.5; IQR, 2.1 years) to determine subclinical disease activity. Results: CSF AOC was differently regulated among CIS, RRMS and controls (p = 0.031) and lower in RRMS vs. CIS (p = 0.020). Lower CSF AOC correlated with physical disability (r = -0.365, p = 0.004) and risk for future relapses (exp(ß) = 0.929, p = 0.033). No correlations with MRI metrics were found. Conclusion: Decreased CSF AOC was associated with increased disability and clinical disease activity in MS. While our finding cannot prove causation, they should prompt further investigations into the role of AOC in the evolution of MS.

Micro-RNA-125a mediates the effects of hypomethylating agents in chronic myelomonocytic leukemia.

BACKGROUND: Chronic myelomonocytic leukemia (CMML) is an aggressive hematopoietic malignancy that arises from hematopoietic stem and progenitor cells (HSPCs). Patients with CMML are frequently treated with epigenetic therapeutic approaches, in particular the hypomethylating agents (HMAs), azacitidine (Aza) and decitabine (Dec). Although HMAs are believed to mediate their efficacy via re-expression of hypermethylated tumor suppressors, knowledge about relevant HMA targets is scarce. As silencing of tumor-suppressive micro-RNAs (miRs) by promoter hypermethylation is a crucial step in malignant transformation, we asked for a role of miRs in HMA efficacy in CMML. RESULTS: Initially, we performed genome-wide miR-expression profiling in a KrasG12D-induced CMML mouse model. Selected candidates with prominently decreased expression were validated by qPCR in CMML mice and human CMML patients. These experiments revealed the consistent decrease in miR-125a, a miR with previously described tumor-suppressive function in myeloid neoplasias. Furthermore, we show that miR-125a downregulation is caused by hypermethylation of its upstream region and can be reversed by HMA treatment. By employing both lentiviral and CRISPR/Cas9-based miR-125a modification, we demonstrate that HMA-induced miR-125a upregulation indeed contributes to mediating the anti-leukemic effects of these drugs. These data were validated in a clinical context, as miR-125a expression increased after HMA treatment in CMML patients, a phenomenon that was particularly pronounced in cases showing clinical response to these drugs. CONCLUSIONS: Taken together, we report decreased expression of miR-125a in CMML and delineate its relevance as mediator of HMA efficacy within this neoplasia.

Exercise Pulmonary Resistances Predict Long-Term Survival in Systemic Sclerosis.

BACKGROUND: Pulmonary hemodynamics during exercise may reveal early pulmonary vascular disease and may be of clinical and prognostic relevance in systemic sclerosis (SSc). We aimed to assess the prognostic relevance of exercise pulmonary resistances in patients with SSc with no or mildly increased mean pulmonary arterial pressure (mPAP). RESEARCH QUESTION: Are pulmonary resistances at peak exercise independent predictors of mortality in systemic sclerosis? STUDY DESIGN AND METHODS: All SSc patients with resting mPAP < 25 mm Hg and at least one year of follow-up data who underwent symptom-limited exercise right heart catheterization between April 2005 and December 2018 were analyzed retrospectively. Age-adjusted Cox regression analysis was used to evaluate the association between pulmonary resistances and all-cause mortality. RESULTS: The cohort consisted of 80 patients: 73 women and 7 men with a mean age of 57 years (interquartile range [IQR], 47-67 years) and a mean follow-up time of 10.4 years (IQR, 8.5-11.8 years). At baseline, resting mPAP of ≤ 20 mm Hg and 21 to 24 mm Hg was found in 68 and 12 patients, respectively. Pulmonary vascular resistance (PVR) and total pulmonary resistance (TPR) at peak exercise were associated significantly with mortality (P = .006 [hazard ratio (HR), 2.20; 95% CI, 1.26-3.87] and P = .026 [HR, 1.56; 95% CI, 1.06-2.29]), whereas resting PVR and TPR were not (P = .087 [HR, 2.27; 95% CI, 0.89-5.83] and P = .079 [HR, 1.88; 95% CI, 0.93-3.80]). The mPAP per cardiac output (CO) and transpulmonary gradient (TPG) per CO slopes were associated significantly with mortality (P = .047 [HR, 1.14; 95% CI, 1.002-1.286] and P = .034 [HR, 1.34; 95% CI, 1.02-1.76]) as well. The area under the receiver operating characteristic curve for exercise PVR to predict 10-year mortality was 0.917 (95% CI, 0.797-1.000). INTERPRETATION: PVR and TPR at peak exercise, mPAP/CO slope, and TPG/CO slope are predictors of age-adjusted long-term mortality in SSc patients with no or mildly increased pulmonary arterial pressure.

The impact of vascular risk factors on brain volume and lesion load in patients with early multiple sclerosis.

BACKGROUND: Vascular risk factors (VRF) in multiple sclerosis (MS) patients have been associated with lower brain volumes. It is currently unknown if this association already exists in early MS and how it develops over time. METHODS: We identified 82 patients with clinically isolated syndrome (CIS) ( n = 61) or with early relapsing-remitting MS ( n = 21) and assessed their VRF including arterial hypertension, hyperlipidaemia, diabetes mellitus and smoking. We analysed T2-lesion load, normalized brain volume (NBV), cortical grey (cGMV) and white matter volumes (WMV), thalamic and basal ganglia volumes at baseline and follow-up magnetic resonance imaging (MRI) and assessed the percentage of brain volume change (PBVC) using SIENA. RESULTS: Patient mean age was 32.4 (±8.7) years and 54 (65%) were women. Median follow-up period was 42 (29-54) months. In total, 26 patients (31.7%) had one or more VRF (VRF+). At baseline, VRF+ patients had a lower NBV (1530.9 cm3 vs 1591.2 cm3, p = 0.001), a lower cGMV (628.5 cm3 vs 668.6 cm3, p = 0.002) and WMV (752.2 cm3 vs 783.9 cm3, p = 0.009) than VRF-negative patients. Similar results were obtained at follow-up. PBVC was comparable between patients with and without VRF. CONCLUSION: VRF are associated with lower brain volume already in early MS but do not lead to increased brain volume loss during 3.5 years of follow-up.

Longitudinal MRI dynamics of recent small subcortical infarcts and possible predictors.

We aimed to explore the morphological evolution of recent small subcortical infarcts (RSSIs) over 15 months. Moreover, we hypothesized that quantitative lesion apparent diffusion coefficient (ADC) values and serum neurofilament light (NfL) levels predict subsequent lacunar cavitation. We prospectively studied 78 RSSI patients, who underwent pre-defined follow-up investigations three and 15 months poststroke using 3 T MRI including high-resolution T1 sequences. To identify potential predictors of cavitation, we determined RSSI size and quantitative ADC values, and serum NfL using the SIMOA technique. The majority of RSSIs showed cavitation at three months (n = 61, 78%) with only minimal changes regarding cavitation status thereafter. The maximum axial lacunar diameter decreased from 8 mm at three to 7 mm at 15 months (p < 0.05). RSSIs which cavitated had lower lesional ADC values and were associated with higher baseline NfL levels compared to those without cavitation, but did not differ regarding lesion size. In logistic regression analysis, only baseline NfL levels predicted cavitation (p = 0.017). In this prospective study using predefined high-resolution MRI protocols, the majority of RSSIs evolved into lacunes during the first three months poststroke with not much change thereafter. Serum NfL seems to be a promising biomarker for more advanced subsequent tissue destruction in RSSIs.

Use of ECG and Other Simple Non-Invasive Tools to Assess Pulmonary Hypertension.

BACKGROUND: There is a broad consensus that pulmonary hypertension (PH) is to be diagnosed by right heart catheterization (RHC) and that the most important non-invasive tool is echocardiography. However, the role of simple non-invasive tools in the work-up of PH is not clearly defined. We hypothesized that the use of simple non-invasive techniques may help to guide important decisions in the diagnostics of pulmonary hypertension. OBJECTIVES: We aimed to develop an algorithm with the use of simple, non-invasive tools in order to identify patients with very high or very low likelihood of PH. METHODS: We retrospectively analyzed all consecutive patients undergoing RHC between 2005 and 2010 in our center and performed logistic regression of simple non-invasive parameters regarding detection and exclusion of PH and derived a two-step algorithm. In a prospective study we evaluated this algorithm between 2011 and 2013. RESULTS: The retrospective cohort consisted of n = 394 patients of which 49% presented with PH. Right axis deviation in the ECG was present in 90/394 patients and had a positive predictive value (PPV) of 93% for PH. The combination of non-right axis deviation, N-terminal pro brain natriuretic peptide (NT-proBNP)<333pg/ml, arterial oxygen saturation (SO2)≥95.5% and WHO functional class I-II was present in 69/394 patients and excluded PH with a negative predictive value (NPV) of 96%. The prospective study confirmed these results in a cohort of n = 168 patients (PPV:92%, NPV:97%). Taken together, simple non-invasive tools allowed a prediction regarding the presence or absence of PH in 42% of patients with suspected PH. CONCLUSION: ECG, NT-proBNP, SO2 and WHO functional class may predict the presence or absence of PH in almost half of the patients with suspected PH, suggesting an important role for these variables in the work-up of patients at risk for PH. CLINICAL TRIAL REGISTRATION: NCT01607502.

Dynamics of brain iron levels in multiple sclerosis: A longitudinal 3T MRI study.

OBJECTIVE: We investigated longitudinal changes in iron concentration in the subcortical gray matter (caudate nucleus, globus pallidus, putamen, thalamus) of patients with clinically isolated syndrome (CIS) and definite multiple sclerosis (MS) and their relation to clinical and other morphologic variables. METHODS: We followed 144 patients (76 CIS; median Expanded Disability Status Scale [EDSS] 1.0 [interquartile range (IQR) 0.0-2.0]; 68 MS; median EDSS 2.0 [IQR 1.0-3.3]) clinically and with 3T MRI over a median period of 2.9 (IQR 1.3-4.0) years. Iron concentration was determined by R2* relaxometry at baseline and last follow-up. RESULTS: At baseline, subcortical gray matter iron deposition was higher in MS compared to CIS. In CIS, R2* rates increased in the globus pallidus (p < 0.001), putamen (p < 0.001), and caudate nucleus (p < 0.001), whereas R2* rates in the thalamus decreased (p < 0.05). In MS, R2* rates increased in the putamen (p < 0.05), remained stable in the globus pallidus and caudate nucleus, and decreased in the thalamus (p < 0.01). Changes in R2* relaxation rates were unrelated to changes in the volume of respective structures, of T2 lesion load, and of disability. CONCLUSIONS: Iron accumulation in the basal ganglia is more pronounced in the early than later phases of the disease and occurs independent from other morphologic brain changes. Short-term changes in iron concentration are not associated with disease activity or changes in disability.

Characterization of patients with borderline pulmonary arterial pressure.

BACKGROUND: Resting mean pulmonary artery pressure (mPAP) values between 20 and 25 mm Hg are above normal but do not fulfill the criteria for pulmonary hypertension (PH). The clinical relevance of such borderline hemodynamics is a matter of discussion. METHODS: We focused on patients who underwent right-sided heart catheterization during rest and exercise for symptoms indicative of PH or due to underlying disease associated with an increased risk for pulmonary arterial hypertension and characterized the patients according to their resting mPAP. Patients with manifest PH (mPAP ≥ 25 mm Hg) were excluded. RESULTS: We included 141 patients, 32 of whom presented with borderline hemodynamics (20 < mPAP < 25 mm Hg). Borderline patients were older (65.8 ± 12.5 years vs 57.3 ± 12.5 years, P = .001) and more often had cardiac comorbidities (53% vs 15%, P < .001) or decreased lung function (47% vs 16%, P < .001) as compared with patients with resting mPAP < 21 mm Hg. After correction for age, borderline patients had significantly increased pulmonary vascular resistance (2.7 ± 0.7 Wood units vs 1.8 ± 0.8 Wood units, P < .001) and mPAP/cardiac output (CO) and transpulmonary gradient/CO slopes (both P < .001) as well as lower peak oxygen uptake (16.9 ± 4.6 mL/min/kg vs 20.9 ± 4.7 mL/min/kg, P = .009) and 6-min walk distance (383 ± 120 m vs 448 ± 92 m, P = .001). During follow-up (4.4 ± 1.4 years), the mortality rate of borderline patients vs patients with resting mPAP < 21 mm Hg was 19% vs 4%. CONCLUSIONS: In patients undergoing right-sided heart catheterization with exclusion of manifest PH, borderline elevation of pulmonary arterial pressure is associated with cardiac and pulmonary comorbidities, decreased exercise capacity, and a poor prognosis.

Proton pump inhibitors for reflux therapy in infants: effectiveness determined by impedance pH monitoring.

PURPOSE: To evaluate the influence of proton pump inhibitors (PPI) in predominantly milk-fed infants with symptoms of GERD by 24-h pH-multichannel intraluminal impedance (24-h pH-MII). METHODS: Ten infants (8 males and 2 females) with a mean gestational age of 39 weeks (28-40) were included. 24-h pH-MII was performed before prescription and during intake of PPI. Total acid exposure time, bolus exposure time (acidic/non-acidic/total) and the number of refluxes (acidic/non-acidic/total) were determined. Clinical symptoms were recorded and used to calculate the Reflux Symptom Index (RSI) and the Symptom Severity Index (SSI). RESULTS: There was a significant decrease in the number of acidic refluxes, total acid exposure and acidic bolus exposure time. However, this went along with a significant increase in non-acidic bolus exposure time. The total number of refluxes and the total bolus exposure time remained unchanged. Under PPI, a decrease of SSI and RSI for pain-related symptoms could be observed. For respiratory symptoms and vomiting however no significant changes could be demonstrated. CONCLUSIONS: Under PPI, an improvement of pain-related symptoms could be shown. The decrease of acid exposure went along with an increase of non-acidic refluxes resulting in almost constant total reflux numbers. This finding is interpreted as main reason for some persisting symptoms despite adequate PPI dosage. Concluding from our data PPI therapy should only be indicated in case of pain, but has no effect in case of vomiting or recurrent respiratory symptoms.