Hypotensive episodes at 24-h ambulatory blood pressure monitoring predict adverse outcomes in Parkinson's disease.

PURPOSE: Neurogenic orthostatic hypotension (nOH) is a frequent nonmotor feature of Parkinson's disease (PD), associated with adverse outcomes. Recently, 24-h ambulatory blood pressure monitoring (ABPM) showed good accuracy in diagnosing nOH. This study aims at evaluating the prognostic role of ABPM-hypotensive episodes in predicting PD disability milestones and mortality and comparing it to the well-defined prognostic role of bedside nOH. METHODS: Patients with PD who underwent ABPM from January 2012 to December 2014 were retrospectively enrolled and assessed for the development of falls, fractures, dementia, bed/wheelchair confinement, hospitalization, and mortality, during an up-to-10-year follow-up. Significant ABPM-hypotensive episodes were identified when greater than or equal to two episodes of systolic BP drop ≥ 15 mmHg (compared with the average 24 h) were recorded during the awakening-to-lunch period. RESULTS: A total of 99 patients (74% male, age 64.0 ± 10.1 years, and PD duration 6.4 ± 4.0 years) were enrolled. At baseline, 38.4% of patients had ABPM-hypotensive episodes and 46.5% had bedside nOH. On Kaplan-Meier analysis, patients with ABPM-hypotensive episodes showed earlier onset of falls (p = 0.001), fractures (p = 0.004), hospitalizations (p = 0.009), bed/wheelchair confinement (p = 0.032), dementia (p = 0.001), and shorter survival (8.0 versus 9.5 years; p = 0.009). At Cox regression analysis (adjusted for age, disease duration, Charlson Comorbidity Index, and Hoehn and Yahr stage) a significant association was confirmed between ABPM-hypotensive episodes and falls [odds ratio (OR) 3.626; p = 0.001), hospitalizations (OR 2.016; p = 0.038), and dementia (OR 2.926; p = 0.008), while bedside nOH was only associated with falls (OR 2.022; p = 0.039) and dementia (OR 1.908; p = 0.048). CONCLUSIONS: The presence of at least two ABPM-hypotensive episodes independently predicted the development of falls, dementia, and hospitalization, showing a stronger prognostic value than the simple bedside assessment.

Hypotensive episodes at 24-h Ambulatory Blood Pressure Monitoring predict adverse outcomes in Parkinson's Disease.

Purpose: Neurogenic orthostatic hypotension (nOH) is a frequent non-motor feature of Parkinson's disease (PD), associated with adverse outcomes. Recently, 24-hour ambulatory BP monitoring (ABPM) has been shown to diagnose nOH with good accuracy (in the presence of at least 2 episodes of systolic BP drop ≥ 15 mmHg compared to the average 24-h). This study aims at evaluating the prognostic role of ABPM-hypotensive episodes in predicting PD disability milestones and mortality and comparing it to well-defined prognostic role of nOH. Methods: PD patients who underwent ABPM from January 2012 to December 2014 were retrospectively enrolled and assessed for the development of falls, fractures, dementia, bed/wheelchair confinement, hospitalization, mortality, during an up-to-10-year follow-up. Results: Ninety-nine patients (male 74%; age: 64.0 ± 10.1 years; PD duration: 6.4 ± 4.0 years) were enrolled. At baseline, 38.4% of patients had ABPM-hypotensive episodes and 46.5% had bedside nOH.At Kaplan-Meier analysis patients with ABPM-hypotensive episodes had an earlier onset of falls (p = 0.001), fractures (p = 0.004), hospitalizations (p = 0.009), bed/wheelchair confinement (p = 0.032), dementia (p = 0.001), and showed a shorter survival (8.0vs9.5 years; p = 0.009). At Cox regression analysis (adjusted for age, disease duration, Charlson Comorbidity Index, and H&Y stage at baseline) a significant association was confirmed between ABPM-hypotensive episodes and falls (OR:3.626; p = 0.001), hospitalizations (OR:2.016; p = 0.038), and dementia (OR:2.926; p = 0.008), while bedside nOH was only associated with falls (OR 2.022; p = 0.039) and dementia (OR:1.908; p = 0.048). Conclusion: The presence of at least two ABPM-hypotensive episodes independently predicted the development of falls, dementia, and hospitalization, showing a stronger prognostic value than the simple bedside assessment.

Detection of Early Myocardial Dysfunction by Imaging Biomarkers in Cancer Patients Undergoing Photon Beam vs. Proton Beam Radiotherapy: A Prospective Study.

1. Background: We sought to determine acute and subacute changes in cardiac function after proton beam (PBT) and photon beam (PhT) radiotherapy (RT) using conventional and two-dimensional speckle tracking echocardiography (2D-STE) in patients with malignant breast and thoracic tumors. 2. Methods: Between March 2016 and March 2017, 70 patients with breast or thoracic cancer were prospectively enrolled and underwent transthoracic echocardiography with comprehensive strain analysis at pretreatment, mid-treatment, end of treatment, and 3 months after RT. 3. Results: PBT was used to treat 44 patients; PhT 26 patients. Mean ± SD age was 55 ± 12 years; most patients (93%) were women. The median (interquartile range) of the mean heart dose was lower in the PBT than the PhT group (47 [27-79] vs. 217 [120-596] cGy, respectively; p < 0.001). Ejection fraction did not change in either group. Only the PhT group had reduced systolic tissue Doppler velocities at 3 months. 2D-STE showed changes in endocardial and epicardial longitudinal, radial, and circumferential early diastolic strain rate (SRe) in patients undergoing PhT (global longitudinal SRe, pretreatment vs. end of treatment (p = 0.04); global circumferential SRe, pretreatment vs. at 3-month follow-up (p = 0.003); global radial SRe, pretreatment vs. at 3-month follow-up (p = 0.02) for endocardial values). Epicardial strain values decreased significantly only in patients treated with PhT. Patients in the PhT group had a significant decrease in epicardial global longitudinal systolic strain rate (GLSRs) (epicardial GLSRs, at baseline vs. at end of treatment [p = 0.009]) and in GCSRe and GRSRe (epicardial GCSRe, at baseline vs. at 3-month follow-up (p = 0.02); epicardial GRSRe, at baseline vs. at 3-month follow-up (p = 0.03)) during treatment and follow-up. No changes on 2D-STE were detected in the PBT group. 4. Conclusions: Patients who underwent PhT but not PBT had reduced tissue Doppler velocities and SRe values during follow-up, suggesting early myocardial relaxation abnormalities. PBT shows promise as a cardiac-sparing RT technology.

Ventricular strain analysis in patients with no structural heart disease using a vendor-independent speckle-tracking software.

BACKGROUND: Ventricular strain measurements vary depending on cardiac chamber (left ventricle [LV] or right ventricle [RV]), type of strain (longitudinal, circumferential, or radial), ventricular level (basal, mid, or apical), myocardial layer (endocardial or epicardial), and software used for analysis, among other demographic factors such as age and gender. Here, we present an analysis of ventricular strain taking all of these variables into account in a cohort of patients with no structural heart disease using a vendor-independent speckle-tracking software. METHODS: LV and RV full-thickness strain parameters were retrospectively measured in 102 patients (mean age 39 ± 15 years; 62% female). Within this cohort, we performed further layer-specific strain analysis in 20 subjects. Data were analyzed for global and segmental systolic strain, systolic strain rate, early diastolic strain rate, and their respective time-to-peak values. RESULTS: Mean LV global longitudinal, circumferential, and radial strain values for the entire cohort were - 18.4 ± 2.0%, - 22.1 ± 4.1%, and 43.9 ± 12.1% respectively, while mean RV global and free wall longitudinal strain values were - 24.2 ± 3.9% and - 26.1 ± 5.2% respectively. Women on average demonstrated higher longitudinal and circumferential strain and strain rate than men, and longer corresponding time-to-peak values. Longitudinal strain measurements were highest at the apex compared with the mid ventricle and base, and in the endocardium compared with the epicardium. Longitudinal strain was the most reproducible measure, followed closely by circumferential strain, while radial strain showed suboptimal reproducibility. CONCLUSIONS: We present an analysis of ventricular strain in patients with no structural heart disease using a vendor-independent speckle-tracking software.

Diagnostic and predictive value of speckle tracking echocardiography in cardiac sarcoidosis.

BACKGROUND: Sarcoidosis is a systemic granulomatous disease that may affect the myocardium. This study evaluated the diagnostic and prognostic value of 2-dimensional speckle tracking echocardiography in cardiac sarcoidosis (CS). METHODS: Eighty-three patients with extracardiac, biopsy-proven sarcoidosis and definite/probable diagnosis of cardiac involvement diagnosed from January 2005 through December 2016 were included. Strain parameters in early stages of CS, in a subgroup of 23 CS patients with left ventricular ejection fraction (LVEF) within normal limits (LVEF> 52% for men: > 54% for women, mean value: 57.3% ± 3.8%) and no wall motion abnormalities was compared with 97 controls (1:4) without cardiac disease. LV and right ventricular (RV) global longitudinal (GLS), circumferential (GCS), and radial (GRS) strain and strain rate (SR) analyses were performed with TomTec software and correlated with cardiac outcomes (including heart failure and arrhythmias). This study was approved by the Mayo Clinic Institutional Review Board, and all patients gave informed written consent to participate. RESULTS: Mean age of CS patients was 53.6 ± 10.8 years, and 34.9% were women. Mean LVEF was 43.2% ± 12.4%; LV GLS, - 12.4% ± 3.7%; LV GCS, - 17.1% ± 6.5%; LV GRS, 29.3% ± 12.8%; and RV wall GLS, 14.6% ± 6.3%. In the 23 patients with early stage CS with normal LVEF and RV systolic function, strain parameters were significantly reduced when compared with controls (respectively: LV GLS, - 15.9% ± 2.5% vs - 18.2% ± 2.7% [P = .001]; RV GLS, - 16.9% ± 4.5% vs - 24.1% ± 4.0% [P < .001]). A LV GLS value of - 16.3% provided 82.2% sensitivity and 81.2% specificity for the diagnosis of CS (AUC 0.91), while a RV value of - 19.9% provided 88.1% sensitivity and 86.7% specificity (AUC 0.93). Hospital admission and heart failure significantly correlated to impaired LV GLS (> - 14%). CONCLUSION: Reduced strain values in the LV GLS and RV GLS can be used in the diagnostic algorithm in patients with suspicion of cardiac sarcoidosis. These values also correlate with adverse cardiovascular events.

Cardiac organ damage in patients with Parkinson's disease and reverse dipping.

OBJECTIVE: Patients with autonomic neuropathy associated with Parkinson's disease often show reverse dipping pattern/nocturnal hypertension at 24-h ambulatory blood pressure (BP) monitoring (24-h ABPM) and diurnal orthostatic hypotension. The aim of the study was to evaluate cardiac alterations in Parkinson's disease patients with reverse dipping, in comparison with non-reverse dippers Parkinson's disease and essential hypertensive patients. METHODS: A total of 26 consecutive Parkinson's disease patients with reverse dipping at 24-h ABPM and no previous history of hypertension were compared with 26 non-reverse Parkinson's disease patients matched for age, sex and 24-h mean BP, and 26 essential hypertensive patients matched for nighttime mean BP. None of the Parkinson's disease patients suffered from cardiovascular diseases or were treated with antihypertensive or antihypotensive drugs. Reverse dipping was defined by a systolic day-night BP difference less than 0% at 24-h ABPM. Left ventricular (LV) hypertrophy was defined by a LV mass index at least 115 g/m in men and at least 95 g/m in women. RESULTS: LV mass, indexed for BSA, was significantly higher in reverse dipping than non-reverse Parkinson's disease patients (respectively 90.2 ±â€Š25.3 vs. 77.4 ±â€Š13.3 g/m, P = 0.04), and was similar to essential hypertensive patients (91.6 ±â€Š24.8, P = 0.92). LV hypertrophy was detected in five reverse dipping Parkinson's disease patients and four hypertensive patients, but was not present in non-reverse Parkinson's disease patients (P = 0.046). Nocturnal BP values, nocturnal BP load, weighted BP variability and age were found to correlate with the increased LV mass index. CONCLUSION: Reverse dipping and nocturnal hypertension are related to higher LV mass and increased prevalence of LV hypertrophy in Parkinson's disease patients.

Detection of orthostatic hypotension with ambulatory blood pressure monitoring in parkinson's disease.

We sought to test the accuracy of 24-hours ambulatory blood pressure (BP) monitoring (ABPM) for the detection of orthostatic hypotension (OH) in Parkinson's disease (PD). A total of 113 patients referred for autonomic testing between January 2015 and June 2017 underwent ABPM and office BP measurements in supine and standing positions. The study population consisted of 81 males and 32 females with PD duration of 6.5 ± 4.1 years and Hoehn and Yahr staging of 1 (13.3%), 1.5 (20.4%), 2 (27.4%), 2.5 (23.9%), 3 (13.3%), and 4 (1.8%). Motor fluctuations were present in 44% of patients. The data from office BP recordings were compared to selected ABPM parameters, and the results showed an association between OH and (a) ABPM-detected hypotensive episodes (Hypo-ep) and (b) ABPM-detected awakening hypotension (Hypo-aw). Having 2 or more Hypo-ep episodes ≤15 mmHg (systolic) compared to average 24-h systolic BP [Formula: see text] yielded 75% diagnostic accuracy for OH, while the presence of at least one [Formula: see text] within 90 min after getting up [Formula: see text] yielded 93% specificity for OH. A diagnostic accuracy of 87.6% was achieved when including daytime and nighttime ABPM values, weighted BP variability, systolic and diastolic BP loads, nocturnal dipping, and postprandial hypotension in a computerized prediction algorithm. In conclusion, our findings suggest that selected ABPM parameters, such as the number of hypotensive episodes and the presence of awakening hypotension, may be used to screen patients for OH, while using a computerized prediction algorithm that includes all ABPM parameters provides the greatest diagnostic accuracy.

Blood pressure circadian rhythm alterations in alpha-synucleinopathies.

INTRODUCTION: We sought to analyze the blood pressure (BP) circadian rhythm in Parkinson's disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF) and to evaluate the effect of vasoactive and dopaminergic medications on BP fluctuations during activities of daily living. METHODS: We analyzed data from patients with PD (n = 72), MSA (n = 18), and PAF (n = 17) evaluated with 24-h ambulatory BP monitoring (ABPM) at our Center between 1996 and 2015. Comparisons between groups were performed according to (a) clinical diagnosis and (b) pharmacological treatment. ABPM parameters included 24-h BP variability, BP load, nocturnal dipping, and awakening hypotension. RESULTS: The average BP was 121 ± 14/72 ± 8 mmHg during daytime and 133 ± 20/76 ± 13 mmHg during nighttime (p < 0.01), with BP load of 24 ± 22/15 ± 16% (daytime) vs. 61 ± 36/52 ± 36% (nighttime) (p < 0.01). In-office BP measurements were consistent with OH in 95 patients (89%) and SH in 63 (59%). ABPM demonstrated increased BP variability in 67 patients (63%), awakening hypotension in 63 (59%), "reverse dipping" in 85 (79.4%), "reduced dipping" in 13 (12.1%), and "normal dipping" in 9 (8.4%). No differences were observed between PD, MSA, and PAF, but a sub-analysis of PD patients revealed two distinct patterns of BP alterations. No significant differences were observed in relation to the use of vasoactive or dopaminergic medications. CONCLUSION: Regardless of the neurological diagnosis and pharmacological treatment, patients with alpha-synucleinopathies showed a BP circadian rhythm characterized by increased BP variability, reverse dipping, increased BP load, and awakening hypotension.

Reverse blood pressure dipping as marker of dysautonomia in Parkinson disease.

INTRODUCTION: We sought to evaluate if the presence of abnormal circadian loss of nocturnal blood pressure dipping (reverse dipping) is associated with cardiovascular dysautonomia, a major source of morbidity in Parkinson disease. METHODS: Consecutive Parkinson disease patients were enrolled in this cross-sectional study between January 2015 and June 2017. All subjects underwent same-day autonomic testing and 24-h ambulatory blood pressure monitoring. Cardiovascular dysautonomia was defined by the presence of at least one moderate or severe cardiovagal and adrenergic test abnormality. RESULTS: We recruited 114 PD patients (79 males; mean age 64 ±â€¯10 years; disease duration 6 ±â€¯4 years). Cardiovascular dysautonomia was present in 32% (36/114). The blood pressure patterns were normal dipping in 28.9% (n = 33), extreme dipping in 6.1% (n = 7), reduced dipping in 32.5% (n = 37), and reverse dipping in 32.5% (n = 37). Reverse dipping was disproportionately prevalent in subjects with cardiovascular dysautonomia (69% vs 15%, p < 0.001). The diagnostic accuracy of reverse dipping in discriminating cardiovascular dysautonomia (AUC 0.791, specificity 84%, sensitivity 69%) was higher than that of bedside blood pressure ascertainment of neurogenic orthostatic hypotension (0.681, 66%, 69%) and supine hypertension (0.641, 78%, 50%). CONCLUSIONS: Reverse nocturnal blood pressure dipping is a marker of cardiovascular dysautonomia in Parkinson disease, which can be screened for with ease and affordability using ambulatory blood pressure monitoring.

Risk factors for arterial hypertension after liver transplantation.

Arterial hypertension represents a common complication of immunosuppressive therapy after liver transplantation (LT). The aim of the study is to evaluate the prevalence and risk factors associated with hypertension after LT. From a cohort of 323 cirrhotic patients who underwent LT from 2008 to 2012, 270 patients were retrospectively evaluated, whereas 53 (16.4%) patients deceased. Hypertension was defined as blood pressure ≥140/90 mm Hg in at least two visits and/or the need for antihypertensive therapy. The prevalence of hypertension was 15% before LT and significantly increased up to 53% after LT (P < .001). Mean follow-up was 43 ± 19 months. In normotensive (NT) subjects at baseline, 35.9% developed sustained hypertension after LT, whereas 15.2% developed transient hypertension within the first month after LT, and then returned NT. The development of sustained hypertension after LT was related to the mammalian target of rapamycin inhibitor treatment (odds ratio [OR], 4.02; 95% confidence interval [CI], 1.26-13.48; P = .02), alcoholic cirrhosis before LT (OR, 3.38; 95% CI, 1.44-8.09; P = .005), and new-onset hepatic steatosis after LT (OR, 2.13; 95% CI, 1.10-4.11; P = .02). Tacrolimus, the etiology and severity of liver disease, and other immunosuppressive regimens were not related to the development of hypertension after LT. In our cohort, the prevalence of arterial hypertension has increased up to 53% after LT, and metabolic comorbidities and immunosuppressive treatment with mammalian target of rapamycin inhibitors are the risk factors for the development of hypertension after LT.

Peripheral Inflammatory Markers and Antioxidant Response during the Post-Acute and Chronic Phase after Severe Traumatic Brain Injury.

Traumatic brain injury (TBI) is a mechanical insult to the brain caused by external forces and associated with inflammation and oxidative stress. The patients may show different profiles of neurological recovery and a combination of oxidative damage and inflammatory processes can affect their courses. It is known that an overexpression of cytokines can be seen in peripheral blood in the early hours/days after the injury, but little is known about the weeks and months encompassing the post-acute and chronic phases. In addition, no information is available about the antioxidant responses mediated by the major enzymes that regulate reactive oxygen species levels: superoxide dismutase, catalase, peroxidases, and GSH-related enzymes. This study investigates the 6-month trends of inflammatory markers and antioxidant responses in 22 severe TBI patients with prolonged disorders of consciousness, consecutively recruited in a dedicated neurorehabilitation facility. Patients with a high degree of neurological impairment often show an uncertain outcome. In addition, the profiles of plasma activities were related to the neurological recovery after 12 months. Venous peripheral blood samples were taken blindly as soon as clinical signs and laboratory markers confirmed the absence of infections, 3 and 6 months later. The clinical and neuropsychological assessment continued up to 12 months. Nineteen patients completed the follow-up. In the chronic phase, persistent high plasma levels of cytokines can interfere with cognitive functioning and higher post-acute levels of cytokines [interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL1b, IL6] are associated with poorer cognitive recoveries 12 months later. Moreover, higher IFN-γ, higher TNF-α, and lower glutathione peroxidase activity are associated with greater disability. The results add evidence of persistent inflammatory response, provide information about long-term imbalance of antioxidant activity, and suggest that the over-production of cytokines and the alteration of the redox homeostasis in the post-acute phase might adversely affect the neurological and functional recovery. Inflammatory and antioxidant activity markers might offer a feasible way to highlight some of the processes opposing recovery after a severe TBI.

The role of autonomic dysfunction in cirrhotic patients before and after liver transplantation. Review of the literature.

In patients affected by hepatic cirrhosis, autonomic dysfunction is a common finding; usually it is asymptomatic but it may correlate with increased mortality and morbidity before, during and after liver transplant, due to hemodynamic instability in the course of stressful events like sepsis, gastrointestinal bleeding and reperfusion after transplantation surgery. Hyperdynamic circulation and hepatic dysfunction seem to play a role in the pathogenesis of autonomic dysfunction, even if pathophysiological mechanisms are not completely known. We present a revision of previous literature about prevalence, pathophysiological mechanisms, clinical features, and mortality and morbidity of autonomic dysfunction secondary to hepatic cirrhosis.

Neuropsychological changes and cranioplasty: A group analysis.

BACKGROUND: Cranioplasty is the surgical answer to cranial defect due to decompressive craniectomy in order to increase patient's safety and for cosmetic reasons. Two main neurological sequelae of skull breaches have been described and cranioplasty has been suggested as a way to treat these neurological symptoms, but its effects on cognitive and motor functions are still unclear. MATERIALS AND METHODS: In order to better elucidate if and to what extent the cranioplasty affects the whole array of cognitive functions or just some specific domains, 29 patients were studied pre- and post-cranioplasty, with structured assessments of memory, attention, language and executive functioning performed ~ 4 months and 1 month before cranioplasty and 1 month and 6 months after surgery. RESULTS AND CONCLUSION: Cranioplasty affects the cognitive profile with a non-specific pattern of change. Timing of the cranioplasty plays a key role to enucleate cognitive improvement, indeed greater cognitive changes were seen in patients who had cranioplasty within 6 months following the injury. Thus, cranioplasty must be considered a key factor in neuropsychological recovery and should be performed as soon as possible following the injury in order to take advantage of the window of opportunity for rehabilitation.

Cardiac Organ Damage and Arterial Stiffness in Autonomic Failure: Comparison With Essential Hypertension.

Autonomic failure (AF) is characterized by orthostatic hypotension, supine hypertension, and increased blood pressure (BP) variability. AF patients develop cardiac organ damage, similarly to essential hypertension (EH), and have higher arterial stiffness than healthy controls. Determinants of cardiovascular organ damage in AF are not well known: both BP variability and mean BP values may be involved. The aim of the study was to evaluate cardiac organ damage, arterial stiffness, and central hemodynamics in AF, compared with EH subjects with similar 24-hour BP and a group of healthy controls, and to evaluate determinants of target organ damage in patients with AF. Twenty-seven patients with primary AF were studied (mean age, 65.7±11.2 years) using transthoracic echocardiography, carotid-femoral pulse wave velocity, central hemodynamics, and 24-hour ambulatory BP monitoring. They were compared with 27 EH subjects matched for age, sex, and 24-hour mean BP and with 27 healthy controls. AF and EH had similar left ventricular mass (101.6±33.3 versus 97.7±28.1 g/m(2), P=0.59) and carotid-femoral pulse wave velocity (9.3±1.8 versus 9.2±3.0 m/s, P=0.93); both parameters were significantly lower in healthy controls (P<0.01). Compared with EH, AF patients had higher augmentation index (31.0±7.6% versus 26.1±9.2%, P=0.04) and central BP values. Nighttime systolic BP and 24-hour systolic BP predicted organ damage, independent of BP variability. AF patients develop hypertensive heart disease and increased arterial stiffness, similar to EH with comparable mean BP values. Twenty-four-hour and nighttime systolic BP were determinants of cardiovascular damage, independent of BP variability.

Cardiovascular complications in patients with autonomic failure.

Patients with autonomic failure are characterized by orthostatic hypotension, supine hypertension, high blood pressure variability, blunted heart rate variability, and often have a "non-dipping" or "reverse dipping" pattern on 24-h ambulatory blood pressure monitoring. These alterations may lead to cardiovascular and cerebrovascular changes, similar to the target organ damage found in hypertension. Often patients with autonomic failure are on treatment with anti-hypotensive drugs, which may worsen supine hypertension. The aim of this review is to summarize the evidence for cardiac, vascular, renal, and cerebrovascular damage in patients with autonomic failure.

Targeted metabolomics in the expanded newborn screening for inborn errors of metabolism.

Inborn errors of metabolism are genetic disorders due to impaired activity of enzymes, transporters, or cofactors resulting in accumulation of abnormal metabolites proximal to the metabolic block, lack of essential products or accumulation of by-products. Many of these disorders have serious clinical consequences for affected neonates, and an early diagnosis allows presymptomatic treatment which can prevent severe permanent sequelae and in some cases death. Expanded newborn screening for these diseases is a promising field of targeted metabolomics. Here we report the application, between 2007 and 2014, of this approach to the identification of newborns in southern Italy at risk of developing a potentially fatal disease. The analysis of amino acids and acylcarnitines in dried blood spots by tandem mass spectrometry revealed 24 affected newborns among 45,466 infants evaluated between 48 and 72 hours of life (overall incidence: 1 : 1894). Diagnoses of newborns with elevated metabolites were confirmed by gas chromatography-mass spectrometry, biochemical studies, and genetic analysis. Five infants were diagnosed with medium-chain acyl CoA dehydrogenase deficiency, 1 with methylmalonic acidemia with homocystinuria type CblC, 2 with isolated methylmalonic acidemia, 1 with propionic acidemia, 1 with isovaleric academia, 1 with isobutyryl-CoA dehydrogenase deficiency, 1 with beta ketothiolase deficiency, 1 with short branched chain amino acid deficiency, 1 with 3-methlycrotonyl-CoA carboxylase deficiency, 1 with formimino-transferase cyclodeaminase deficiency, and 1 with cystathionine-beta-synthase deficiency. Seven cases of maternal vitamin B12 deficiency and 1 case of maternal carnitine uptake deficiency were detected. This study supports the widespread application of metabolomic-based newborn screening for these genetic diseases.

Maternal vitamin B12 deficiency detected in expanded newborn screening.

OBJECTIVES: Besides the inherited form, vitamin B(12) deficiency may be due to diet restrictions or abnormal absorption. The spread of newborn screening programs worldwide has pointed out that non-inherited conditions are mainly secondary to a maternal deficiency. The aim of our work was to study seven cases of acquired vitamin B12 deficiency detected during our newborn screening project. Moreover, we aimed to evaluate vitamin B(12) and related biochemical parameters status on delivering female to verify the consequences on newborns of eventually altered parameters. DESIGN AND METHODS: 35,000 newborns were screened; those showing altered propionyl carnitine (C3) underwent second-tier test for methylmalonic acid (MMA) on dried blood spot (DBS). Subsequently, newborns positive to the presence of MMA on DBS and their respective mothers underwent further tests: serum vitamin B(12), holo-transcobalamin (Holo-TC), folate and homocysteine; newborns were also tested for urinary MMA content. A control study was conducted on 203 females that were tested for the same parameters when admitted to hospital for delivery. RESULTS: Approximately 10% of the examined newborns showed altered C3. Among these, seven cases of acquired vitamin B(12) deficiency were identified (70% of the MMA-positive cases). Moreover, our data show a high frequency of vitamin B(12) deficiency in delivering female (approximately 48% of examined pregnants). CONCLUSIONS: We suggest to monitor vitamin B(12) and Holo-TC until delivery and to reconsider the reference interval of vitamin B(12) for a better identification of cases at risk. Finally, newborns from mothers with low or borderline levels of vitamin B(12) should undergo second-tier test for MMA; in the presence of MMA they should be supplemented with vitamin B(12) to prevent adverse effects related to vitamin B(12) deficiency.

Arrhythmic syncope in neurogenic orthostatic hypotension: two case reports.

Patients with autonomic failure experience orthostatic hypotension (OH) often leading to syncope. Arrhythmias may cause severe syncope, characterized by an increased risk of mortality. We report two cases of patients with primary autonomic neuropathy suffering from both severe OH and arrhythmic syncope.