Relationship between Urinary AD7c-NTP with Cerebral Microbleeds Based on APOE Genotype.

OBJECTIVE: This study was performed to investigate the association between urinary Alzheimer-associated neuronal thread protein (AD7c-NTP) with cerebral microbleeds (CMBs) based on the apolipoprotein E (APOE) genotypes. METHODS: A total of 471 patients with acute cerebral infarction screened by magnetic sensitive imaging were enrolled in this study. Among them, twenty-seven cases of mixed CMBs were excluded. A total of 444 patients were divided into two groups according to the presence or absence of CMBs: CMBs group (n = 92) and noncerebral microbleeds group (nCMBs) (n = 352). Urine AD7c-NTP levels were measured using a human enzyme immunoassay kit. RESULTS: In patients with lobar CMBs, there was an interaction between urine AD7c-NTP levels and APOE genotypes (p = 0.01). In patients with APOE ε3/ε3 allele, the odds ratio of lobar CMBs per standard deviation of urinary AD7c-NTP levels was 0.92 (95% CI: 0.70-1.19). In patients with APOE ε2+ or ε4+ allele, the multivariate-corrected odds ratio of lobar CMBs per standard deviation of urinary AD7c-NTP levels was 2.95 (95% CI: 1.38-6.27). CONCLUSION: A higher level of urinary AD7c-NTP is involved in lobar CMBs, not deep CMBs.

Targeted urine metabolomics in preterm neonates with intraventricular hemorrhage.

Intraventricular hemorrhage (IVH) is a major cause of morbidity and mortality in preterm neonates. Elucidation of the mechanisms underlying IVH and/or development of disease biomarkers is essential. The aim of the study was to investigate the urine metabolic profile of preterm neonates (gestational age < 32 weeks) IVH and explore the role of metabolomics in understanding pathophysiological mechanisms of the disease from which novel biomarkers could be derived. In this single-center, prospective, case-control study, urine samples were collected from seven preterm infants with early IVH (IVH group) and from 11 preterm ones without IVH (control group) on days 1, 3 and 9 of life. Urine metabolites were evaluated using targeted liquid chromatography-tandem mass spectrometry. Demographic and perinatal-clinical characteristics were recorded. Univariate and multivariate statistical analyses were performed. Orthogonal Partial Least Squares-Discriminant Analysis showed that the study groups differed significantly due to alternation in 20 out of the 40 metabolites detected in the urine. Elevated differentiated metabolites included energy intermediates and other important compounds, whereas reduced ones various amino acids, hypoxanthine and nicotinamide. A set of metabolites showed high performance as indicators of IVH, especially during day 1. As evidenced by metabolomics, preterm neonates with IVH demonstrate significant metabolism perturbations. Potentially, a selected panel of metabolites could be used as urine biomarkers of IVH development and/or progression in high-risk preterm infants.

Disparities and guideline adherence in drugs of abuse screening in intracerebral hemorrhage.

OBJECTIVE: To characterize the pattern of urine drug screening in a cohort of intracerebral hemorrhage (ICH) patients at our academic centers. METHODS: We identified cases of primary ICH occurring from 2009 to 2011 in our academic centers. Demographic data, imaging characteristics, processes of care, and short-term outcomes were ascertained. We performed logistic regression to identify predictors for screening and evaluated preguideline and postguideline reiteration screening patterns. RESULTS: We identified 610 patients with primary ICH in 2009-2011; 379 (62.1%) were initially evaluated at an outside hospital. Overall, 142/610 (23.3%) patients were screened, with 21 positive for cocaine and 3 for amphetamine. Of patients <55 years of age, only 65/140 (46.4%) were screened. Black patients <55 years of age were screened more than nonblack patients <55 years of age (38/61 [62.3%] vs 27/79 [34.2%]; p = 0.0009). In the best multivariable model, age group (p = 0.0001), black race (p = 0.4529), first Glasgow Coma Scale score (p = 0.0492), current smoking (p < 0.0001), and age group × black race (p = 0.0097) were associated with screening. Guideline reiteration in 2010 did not improve the proportion <55 years of age who were screened: 42/74 (56.8%) were screened before and 23/66 (34.9%) after (p = 0.01). CONCLUSIONS: We found disparities in drugs of abuse (DOA) screening and suboptimal guideline adherence. Systematic efforts to improve screening for DOA are warranted. Improved identification of sympathomimetic exposure may improve etiologic classification and influence decision-making and prognosis counseling.

Urinary Allantoin Is Elevated in Severe Intraventricular Hemorrhage in the Preterm Newborn.

Germinal matrix intraventricular hemorrhage (IVH) is the most common type of intracranial hemorrhage observed in preterm neonates. It is a precursor of poor neurocognitive development, cerebral palsy, and death. The pathophysiology is not well defined, but damage to the fragile germinal matrix vasculature may be due to free radicals generated during inflammation and as a consequence of ischemia followed by reperfusion. Assessment of the oxidative stress status in these infants is therefore important. Urinary allantoin concentration was measured in preterm neonates as a marker of oxidative stress associated with IVH. Urine was collected from 44 preterm neonates at four time points between 24 and 72 hours of life (HOL), and the allantoin content was determined by gas chromatography mass spectrometry (GCMS). Records were retrospectively reviewed, and the incidence and severity of IVH was categorized as follows: no IVH (n = 24), mild (grade 1-2) IVH (n = 13), and severe (grade 3-4) IVH (n = 7). Neonates with severe IVH showed significantly elevated allantoin levels vs subjects with no IVH from 36 HOL (0.098 ± 0.013 µmol and 0.043 ± 0.007 µmol, respectively, p = 0.002). The allantoin concentration remained elevated even at 72 HOL (0.079 ± 0.014 µmol and 0.033 ± 0.008 µmol, respectively, p = 0.021). There were no significant differences in allantoin levels in the no IVH and mild IVH groups. IVH was diagnosed by head imaging on average at about 11th postnatal day. Urinary allantoin levels were significantly elevated during the first 3 days of life in the neonates subsequently diagnosed with severe IVH, suggesting that oxidative stress might be a crucial factor in IVH pathogenesis. Further studies are needed to assess the usefulness of urinary allantoin in early identification of preterm infants at risk for or with severe IVH and monitoring of the response to interventions designed to prevent or treat it.

Kidney function and cerebral small vessel disease in the general population.

BACKGROUND: Anatomic and hemodynamic similarities between renal and cerebral vessels suggest a tight link between kidney disease and brain disease. Although several distinct markers are used to identify subclinical kidney and brain disease, a comprehensive assessment of how these markers link damage at both end organs is lacking. AIM: To investigate whether measures of kidney function were associated with cerebral small vessel disease on MRI. METHODS: In 2526 participants of the population-based Rotterdam Study, we measured urinary albumin-to-creatinine ratio, and estimated glomerular filtration rate based on serum creatinine and cystatin C. All participants underwent brain magnetic resonance imaging. We assessed presence of cerebral small vessel disease by calculating white matter lesion volumes and rating the presence of lacunes and cerebral microbleeds. We used multivariable linear and logistic regression to investigate the association between kidney function and cerebral small vessel disease. RESULTS: Worse kidney function was consistently associated with a larger white matter lesion volume (mean difference per standard deviation increase in albumin-to-creatinine ratio: 0.09, 95% confidence interval 0.05; 0.12; per standard deviation decrease in creatinine-based estimated glomerular filtration rate: -0.04, 95% confidence interval -0.08;-0.01, and per standard deviation decrease in cystatin C-based estimated glomerular filtration rate: -0.09, 95% confidence interval -0.13;-0.05). Persons with higher albumin-to-creatinine ratio or lower cystatin C-based estimated glomerular filtration rate levels had a higher prevalence of lacunes (odds ratio per standard deviation increase in albumin-to-creatinine ratio: 1.24, 95% confidence interval 1.07; 1.43). Only participants in the highest quartile of albumin-to-creatinine ratio had a higher frequency of microbleeds compared to the lowest quartile. CONCLUSIONS: Worse kidney function is associated with cerebral small vessel disease. Of all measures of kidney function, in particular albumin-to-creatinine ratio is related to cerebral small vessel disease.

Elevated Activin A urine levels are predictors of intraventricular haemorrhage in preterm newborns.

AIM: Intraventricular haemorrhage (IVH) is the most common variety of cerebral haemorrhage and cause of neurological disabilities in preterm newborns. We evaluated the usefulness of urine Activin A concentrations for the early detection of perinatal IVH. METHODS: We conducted a case-control study on 100 preterm newborns (20 with IVH and 80 without IVH) in whom urine Activin A was measured at five predetermined time-points in the first 72 h after birth. IVH diagnosis and the extension of the lesion were performed by ultrasound scanning within the first 72 h and at 1 week after birth, respectively. RESULTS: Urine Activin A in infants who developed IVH was significantly higher than in controls at all monitoring time-points (p < 0.01 for all), increasing progressively from first urination to 24 h when it reached the highest peak (p < 0.001). At a cut-off 0.08 ng/L, at the first void, Activin A sensitivity and specificity were 68.7% (CI: 41.3-89%) and 84.5% (CI: 75-91.5%). CONCLUSION: Activin A measurements in urine soon after birth can constitute a promising tool for identifying preterm infants at risk of IVH.

Strong independent correlation of proteinuria with cerebral microbleeds in patients with stroke and transient ischemic attack.

OBJECTIVE: To assess the association of proteinuria with the frequency and number of cerebral microbleeds (CMB), a harbinger of future hemorrhagic stroke. DESIGN: Cross-sectional analysis. Patients Patients with consecutive ischemic stroke and transient ischemic attack admitted to a university hospital during a 22-month period. INTERVENTIONS: Presence and number of CMB were evaluated using gradient-echo T2*-weighted magnetic resonance imaging. Multivariable models were generated to determine the contribution of proteinuria to the frequency and number of CMB after adjusting for confounders. RESULTS: Of 236 patients (mean age, 70 years; 53% female), 72 (31%) had CMB present on gradient-echo imaging and 89 (38%) had evidence of proteinuria. In multivariable analyses with presence of CMB as the outcome, higher urinary protein (odds ratio [OR], 2.33; 95% confidence interval [CI], 1.10-4.95), being female (OR, 2.29; 95% CI, 1.19-4.49), history of atrial fibrillation (OR, 2.49; 95% CI, 1.14-5.44), elevated serum homocysteine (OR, 1.19; 95% CI, 1.09-1.29), and small-vessel disease subtype (OR, 2.95 95% CI, 1.43-6.10) were all significantly associated with presence of CMB. Logistic regression analysis by number of CMB showed similar findings. CONCLUSIONS: Proteinuria is strongly associated with both the frequency and number of CMB in patients with recent cerebral ischemia. Urinary protein excretion may be a CMB risk marker or potential therapeutic target for mitigating the untoward clinical sequela of CMB.

Thromboxane and prostacyclin biosynthesis in patients with acute spontaneous intracerebral hemorrhage.

OBJECTIVE: Elevated levels of 11-dehydrothromboxane B2 (11-dehydro-TXB2) excreted in urine have been observed in acute ischemic stroke. This marker of platelet activation has not been investigated in patients with acute spontaneous intracerebral hemorrhage (ICH). METHODS: We examined 43 patients with spontaneous ICH and 23 controls. Urinary excretion rates of 11-dehydro-TXB2, 2,3-dinor-thromboxane B2 (2,3 dinor-TXB2) and 2,3-dinor-6-ketoprostaglandin F(1alpha) (2,3-dinor-PGF(1alpha)) during the first week and at 3 months after ICH were compared between patients who had or had not used aspirin and controls. RESULTS: On admission, ICH patients without aspirin use had significantly higher urinary levels of 11-dehydro-TXB2 (p<0.001), 2,3-dinor-TXB2 (p<0.001) and 2,3-dinor-PGF(1alpha) (p=0.019) than controls. Aspirin users had significantly lower urinary levels of these metabolites than nonusers. The metabolite levels of aspirin users on admission did not significantly differ from those of controls. The differences between aspirin users and nonusers leveled off during the following 3-5 days, however, as the blocking effect of aspirin on the production of TXA2 and PGI2 ceased. Three months after ICH, the metabolite excretion levels in all the patients were similar to those in nonusers of aspirin on admission. On admission, aspirin users had longer bleeding times (p=0.032) than nonusers, but aspirin use did not associate with impaired recovery or hematoma enlargement. CONCLUSIONS: Urinary excretion levels of 11-dehydro-TXB2, 2,3-dinor-TXB2 and 2,3-dinor-PGF1alpha were higher in patients with acute ICH than in controls. The levels in aspirin users were equally low as in controls but rose to the levels of the other patients within a few days. The metabolite levels remained high 3 months after ICH in all patients. Prior use of aspirin did not seem to cause hematoma enlargement.

Increased platelet activation in the chronic phase after cerebral ischemia and intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Enhanced thromboxane (TX) biosynthesis has previously been reported in the acute phase after ischemic stroke. We investigated whether enhanced urinary excretion of 11-dehydro-TXB2, a noninvasive index of platelet activation, was present in the chronic phase after a transient ischemic attack (TIA) or stroke, including intracerebral hemorrhage. METHODS: We obtained a single urinary sample from 92 patients between 3 and 9 months after onset of stroke or TIA. The urinary excretion of the major enzymatic metabolite of TXA2, 11-dehydro-TXB2, was measured by a previously validated radioimmunoassay. The excretion rates were compared with those of 20 control patients with nonvascular neurological diseases. RESULTS: Urinary 11-dehydro-TXB2 averaged 294+/-139, 413+/-419, and 557+/-432 pmol/mmol creatinine for patients with TIA, ischemic stroke, and intracerebral hemorrhage, respectively; the values were higher in all subgroups (P<0.01) than that in control patients (119+/-66 pmol/mmol). Increased 11-dehydro-TXB2 excretion was present in 59% of all patients, in 60% (P<0.001) of patients with TIA, in 56% (P<0.001) of patients with ischemic stroke, and in 73% (P<0.001) of patients with intracerebral hemorrhage. Atrial fibrillation, no aspirin use, and severity of symptoms at follow-up contributed independently to the level of 11-dehydro-TXB2 excretion in a multiple linear regression analysis. CONCLUSIONS: Platelet activation is often present in patients in the chronic phase after stroke, including those with intracerebral hemorrhage. Persistent platelet activation, which is associated with atrial fibrillation and poor stroke outcome, can be substantially suppressed by aspirin treatment.

Hyponatremia and osmoregulation of vasopressin secretion in patients with intracranial bleeding.

To clarify the cause and pathophysiology of hyponatremia after intracranial bleeding, we analyzed the possible causative factors, and examined the response of vasopressin (AVP) secretion to osmotic stimulus in six patients. Despite hyponatremia, urinary sodium excretion persisted, with urinary osmolality exceeding plasma osmolality. Serum levels of urea nitrogen, creatinine, and uric acid were not elevated in any of them. PRA was normal or subnormal in four patients, and all had normal adrenocortical and thyroid functions. Although these laboratory findings may support the diagnosis of the syndrome of inappropriate antidiuretic hormone secretion, the cause of hyponatremia in our patients was attributed to excessive renal excretion of sodium, because water load performed in an euvolemic state showed no impairment in diuresis, and replenishment of sodium without water restriction improved hyponatremia as well as clinical conditions. Plasma AVP levels relative to plasma osmolality in these patients were constantly elevated. When challenged by an osmotic stimulus, AVP secretion increased with increasing plasma osmolality in one patient, but no consistent pattern of AVP secretion was observed in others. The potentiating effect of hypovolemia on osmotic secretion of AVP was not demonstrated in any of the patients. These results show that hyponatremia after intracranial bleeding with clinical features almost indistinguishable from those of syndrome of inappropriate antidiuretic hormone secretion may result from an impaired renal sodium-conserving mechanism of unknown cause. Persistent AVP secretion without an alteration in the sensitivity of the osmostat in this pathological state may be due to an incomplete suppression by plasma hypotonicity per se of the baroreceptor-mediated stimulation of AVP release.

Abnormal alpha-aminoadipic acid excretion in a newborn with a defect in platelet aggregation and antenatal cerebral haemorrhage.

alpha-Aminoadipic acid (alpha AA) is an intermediate in lysine metabolism. We report a new case with alpha AA excess in urine and plasma, without alpha-ketoadipic acid, in a full-term male child born to unrelated parents; he presented at 24h of life with seizures that failed to respond to phenobarbital, clonazepam, and Vigabatrin and death occurred on the 38th day of life. Brain imaging suggested antenatal haemorrhage. Small quantities of alpha AA were also detected in the blood and urine of both parents and a healthy brother, all three of whom exhibited the same defect in platelet aggregation as the deceased child. Both parents had decreased levels of plasma neopterin, a finding that might be related to the immunodeficiency described in other cases.

Intraventricular haemorrhage and the renin-angiotensin-aldosterone system in very low birthweight infants.

Blood volume, plasma renin activity (PRA) and urine aldosterone excretion (UAE) were measured in ten very low birthweight infants who had a Grade 3 or 4 intraventricular haemorrhage (IVH) during the first 2 days after birth. Mean (range) birthweight was 950 (630-1500) g and gestational age was 27 (23-31) weeks. Nine infants were receiving assisted ventilation and one was breathing spontaneously. Eight IVH occurred on the first postnatal day and two on the second; seven were symptomatic and three asymptomatic. PRA was significantly higher than control values on Day 1 only; median 244 (range 91-654) ng/ml per h vs. 64 (4-259) ng/ml per h (P less than 0.01). Infants with symptomatic IVH in the preceding 8 h (n = 6) all had PRA greater than 300 ng/ml per h; none of these infants had received transfusions or volume expansion between IVH and PRA measurement. PRA was less than 100 ng/ml per h in the three infants with asymptomatic IVH and one infant with greater than 24 h interval between IVH and PRA measurement; three of these four had received transfusions prior to PRA measurement. UAE was not significantly different from control values on either Day 1 or Day 2. Blood volume at 22 +/- 3 h postnatal age ranged from 75 to 107 ml/kg. There was an inverse logarithmic correlation between PRA and blood volume (r = 0.883; P less than 0.005), with PRA values exceeding 300 ng/ml per h when blood volume was less than 90 ml/kg. UAE did not correlate with either PRA or blood volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary arginine vasopressin: pattern of excretion in the neonatal period.

The pattern of arginine vasopressin (AVP) secretion in the immediate neonatal period is unclear. Plasma concentrations of AVP are reflected by its urinary excretion, thus providing a noninvasive method for studying the pattern of AVP release in the neonate. In these studies, we determined the pattern of urinary AVP excretion (microU/mg creatinine) during the first 2-4 days after birth in 78 neonates, 53 of whom had various prenatal and/or neonatal complications. In well term (n = 12) and preterm (n = 13) infants mean urinary AVP excretion decreased gradually during the first 24-36 h after birth. Although term and preterm infants with perinatal asphyxia had highest initial levels of urinary AVP (greater than 200 microU/mg creatinine) and a significant negative correlation with the 1-min Apgar score was obtained, their pattern of excretion was similar to respective controls. After delivery, elevated values for urinary AVP excretion were found among infants with neonatal courses complicated by intracranial hemorrhage, hypoxic encephalopathy, and pneumothorax. Urine osmolality did not correlate linearly with urinary AVP levels, but rather attained a maximum value of approximately 400 mosmol/kg at urinary AVP levels less than 200 microU/mg creatinine and then plateaued. It is concluded that the decrease in urinary AVP excretion observed soon after birth generally reflects diminution of the hypersecretion of AVP during parturition; neonates with evidence of intrapartum asphyxia initially have increased urinary AVP excretion; however, the pattern of excretion is similar to normal infants. During the neonatal period insults such as pneumothorax and intracranial hemorrhage may cause hypersecretion of this hormone.

Urinary excretion rate of antithrombin III related antigen in cerebral stroke.

The urinary excretion rate of antithrombin III related antigen (AT III RA) was examined in cerebral stroke. The excretion rate of AT III RA in cerebral hemorrhage (CH) was 12.33 +/- 1.61 X 10(-4) ml/min. The patients with CH were further classified into two groups: in group CH-I, whose consciousness state was stupor or further deteriorated including coma on admission, the excretion rate of AT III RA was 18.08 +/- 2.50 X 10(-4) ml/min. In group CH-II, whose consciousness state was clear on admission, the excretion rate of AT III RA was significantly lower than that in CH-I (6.20 +/- 1.56 X 10(-4) ml/min). The excretion rate in cerebral thrombosis (CT) was 1.96 +/- 0.25 X 10(-4) ml/min, which was significantly lower than that in CH. The excretion rate of AT III RA in both CH and CT was significantly higher than that in the healthy control group (0.29 +/- 0.04 X 10(-4) ml/min). Thus, AT III may change dynamically in cerebral stroke.

Hyponatraemia in the first week of life in preterm infants. Part I. Arginine vasopressin secretion.

Continuous sequential urinary arginine vasopressin measurements in 14 preterm, ventilated infants suggest that both osmoreceptor and volume receptor systems are able to stimulate the prolonged secretion of arginine vasopressin from 26 weeks' gestation. The kidney is able to respond to arginine vasopressin stimulation from the first day of life and from 26 weeks' gestation. A maximum urine osmolality not exceeding 550 mOsm/kg was reached which varied with hydration of the infant. Excretion of arginine vasopressin and urine osmolality increased during deterioration of respiratory illness, mask ventilation, bilateral pneumothoraces, and severe intraventricular haemorrhage. The data show that inappropriate arginine vasopressin secretion is common during illness in the first week of life in preterm infants and that strict attention must be paid to water balance during this time.

Abnormal catecholamine urinary excretion after emotional stimulus in patients with cerebral hemorrhage.

The epinephrine (E) and norepinephrine (NE) urinary excretion before and after a mild "emotional stimulus" (ES) was determined in 22 patients with cerebral infarction and 30 patients with cerebral hemorrhage, as well as in 18 normotensive and 18 hypertensive controls. In patients with cerebral infarction, the majority normotensive, the "emotional stimulus" induced a significant increase in NE excretion, but non-significant alterations in E excretion. Similar changes were noted in normotensive controls. In patients with cerebral hemorrhage, almost all hypertensive, and in hypertensive controls, ES brought about a consistent rise in E excretion without influencing significantly the NE excretion. The presence of a constant increase in E excretion after a mild emotion not only in patients with cerebral hemorrhage but also in subjects with uncomplicated essential hypertension, suggests that the E release found in patients with cerebral hemorrhage is related to the hypertensive state pre-existing the stroke rather than to hemorrhagic stroke itself. The pattern of catecholamine discharge in hypertensive patients might play a part in the occurrence of cerebral hemorrhagic accidents. The epinephrine discharges induce sudden increases in systolic blood pressure which could lead to the rupture of cerebral vessels with hyalinotic or atherosclerotic alterations.

Catecholamine-associated refractory hypertension following acute intracranial hemorrhage: control with propranolol.

Seven patients (4 with subarachnoid hemorrhage, 2 with intracerebral hemorrhage, and 1 with massive cerebral infarction) had acute arterial hypertension refractory to control by several antihypertensive drugs (hydralazine, sodium nitroprusside, alpha-methyldopa, and trimethaphan camsylate) used singly or in combination. In each case, catecholamine excretion--measured by urinary norepinephrine plus epinephrine--was markedly elevated, averaging 218 microgram/day. Patients without the acute refractory hypertension had normal or only slightly elevated urinary catecholamine levels (mean, 72 microgram/day). The beta-adrenergic blocking agent propranolol, in doses between 20 and 40 mg every 6 hours, successfully controlled blood pressure, while other agents failed. The intense sympathetic nervous system discharge resulting in acute refractory hypertension may be due to injury to the diencephalon or brainstem (or both) or to diffuse brain dysfunction from increased intracranial pressure or intracranial blood.

[Urinary uropepsin activity in patients with different forms of stroke]. / Aktywnosc uropepsyny w moczu chorych z róznymi postaciami udaru mózgu.

The investigations were carried out in 30 control cases, in 20 patients with acute transient cerebral circulatory failure, 20 patients with intracerebral haemorrhage, and 22 patients with thrombotic encephalomalacia. The determinations of uropepsin activity were done on the 1st, 3rd, 7th and 14th days of the disease. Uropepsin activity in 24-hour urine was determined by the method of West, Ellis and Scott. In the group of patients with acute transient cerebral circulatory failure abnormalities in urinary uropepsin activity were not significant. The mean activity of uropepsin in 24-hour urine in patients with intracerebral haemorrhage and brain infarction on the 1st day of the disease was significantly higher than in controls. The rise in the activity of this enzyme in patients with encephalomalacia was lower in relation to patients with intracerebral haemorrhages. During improvement of the condition of patients with brain stroke the uropepsin activity in 24-hour urine decreased.