| 2021 | From Normal Cognition to Cognitive Impairment and Dementia: Impact of Orthostatic Hypotension. | Hypertension | The role of orthostatic hypotension (OH) in the continuum of cognitive aging remains to be clarified. We sought to investigate the associations of OH with dementia, cognitive impairment, no dementia (CIND), and CIND progression to dementia in older adults while considering orthostatic symptoms. This population-based cohort study included 2532 baseline (2001-2004) dementia-free participants (age ≥60 years; 62.6% women) in the SNAC-K (Swedish National Study on Aging and Care in Kungsholmen) who were regularly examined over 12 years. We further divided the participants into a baseline CIND-free cohort and a CIND cohort. OH was defined as a decrease by ≥20/10 mm Hg in systolic/diastolic blood pressure upon standing and further divided into asymptomatic and symptomatic OH. Dementia was diagnosed following the international criteria. CIND was defined as scoring ≥1.5 SDs below age group-specific means in ≥1 cognitive domain. Data were analyzed with flexible parametric survival models, controlling for confounding factors. Of the 2532 participants, 615 were defined with OH at baseline, and 322 were diagnosed with dementia during the entire follow-up period. OH was associated with an adjusted hazard ratio of 1.40 for dementia (95% CI, 1.10-1.76), 1.15 (0.94-1.40) for CIND, and 1.54 (1.05-2.25) for CIND progression to dementia. The associations of dementia and CIND progression to dementia with asymptomatic OH were similar to overall OH, whereas symptomatic OH was only associated with CIND progression to dementia. Our study suggests that OH, even asymptomatic OH, is associated with increased risk of dementia and accelerated progression from CIND to dementia in older adults. |
| 2021 | Sedative effects of acepromazine in combination with nalbuphine or butorphanol, intramuscularly or intravenously, in healthy cats: a randomized, blinded clinical trial. | J Feline Med Surg | The aim of this study was to compare the sedative effects in cats administered acepromazine-nalbuphine and acepromazine-butorphanol, intramuscularly (IM) and intravenously (IV), and the occurrence of adverse cardiorespiratory effects.Forty-six cats were randomly divided into four groups and administered acepromazine (0.05 mg/kg) combined with nalbuphine (0.5 mg/kg) or butorphanol (0.4 mg/kg), IV (ACP-NAL and ACP-BUT groups, respectively) or IM (ACP-NAL and ACP-BUT groups, respectively). Sedation scores, ease of intravenous catheter placement (simple descriptive scale [SDS] scores), physiologic variables, venous blood gases and the propofol dose required for anesthetic induction were recorded.Mild sedation was observed in all groups approximately 30 mins after treatment administration (timepoint T1, prior to propofol administration). Sedation scores at T1 increased above baseline in all groups ( <0.05), but no significant difference was observed among groups. Dynamic interactive visual analogue scale sedation scores (range 0-100 mm) recorded at T1 were (median [interquartile range]): ACP-NAL, 12 (10-12); ACP-NAL, 11 (6-16); ACP-BUT, 11 (7-14); and ACP-BUT, 12 (7-19). Overall, SDS scores did not change from baseline at T1 and there was no significant difference among groups. The propofol dose did not differ among groups. Blood gases remained within the reference intervals for cats. Significant decreases from baseline were detected for all groups in systolic arterial pressure (SAP). Mean ± SD values at T1 were (mmHg): ACP-NAL, 108 ± 13; ACP-NAL, 102 ± 10; ACP-BUT, 97 ± 13; and ACP-BUT, 98 ± 21. Arterial hypotension (SAP <90 mmHg) was recorded at T1 in 0/11, 1/13, 4/11 and 5/11 cats in groups ACP-NAL, ACP-NAL, ACP-BUT and ACP-BUT, respectively, and was further exacerbated after the induction of anesthesia with propofol.In healthy cats administered acepromazine-nalbuphine and acepromazine-butorphanol, IM and IV, the degree of sedation was mild regardless of the protocol and the route of administration. The main adverse effect observed was a reduction in arterial blood pressure. |
| 2020 | Differences in correlations of depression and anhedonia with cardiovascular sympathetic functions during a head-up tilt test in drug-naïve Parkinson's disease patients. | Neurol Sci | Depression is a symptom of Parkinson's disease (PD) and may be correlated with cardiovascular sympathetic function. Anhedonia is an element of depression, but these symptoms can emerge independently in PD. A correlation of anhedonia with cardiovascular sympathetic function has rarely been examined.To compare correlations of depression and anhedonia with cardiovascular sympathetic function in drug-naive PD patients.Assessments of depression (Self-rating Depression Scale; SDS), anhedonia (Snaith-Hamilton Pleasure Scale; SHAPS), myocardial I-MIBG (I-meta-iodobenzylguanidine) scintigraphy (heart to mediastinum (H/M) ratios in early and delayed images), and head-up tilt test (HUT) up to 60° for 10 min were performed in 45 drug-naïve PD patients. During the HUT, blood pressure was measured every minute and the maximum decrease in systolic blood pressure (SBP) was determined. Plasma noradrenaline (NA) and arginine vasopressin (AVP) levels were examined at baseline and 10 min after tilt, with subsequent calculation of increases in plasma NA and AVP levels in this 10 min. Correlation coefficients were calculated among these assessment parameters.SDS significantly correlated with % maximum decrease in SBP (r = 0.344, p = 0.02), but not with H/M ratios in both images and increases in plasma NA and AVP levels. SHAPS did not correlate with the change in SBP, H/M ratios in both images, or plasma NA and AVP levels.Depression was correlated with the % maximum decrease in SBP during a 10-min HUT, but anhedonia did not show this relationship. This suggests that depression and anhedonia may have different pathophysiological backgrounds in drug-naïve PD patients. |
| 2019 | Effect of midazolam on the quality and duration of anaesthetic recovery in healthy dogs undergoing elective ovariohysterectomy or castration. | Vet Anaesth Analg | To determine whether the use of a single dose of midazolam affects quality and duration of the recovery period in healthy dogs undergoing elective castration or ovariohysterectomy.Prospective, randomized, placebo-controlled, masked clinical trial.Seventy-four client-owned dogs undergoing neutering.Following cage demeanour scoring using a simple descriptive scale (SDS), dogs were premedicated with acepromazine (0.03 mg kg) and pethidine (3 mg kg) intramuscularly (quadriceps muscle). Twenty minutes later sedation was scored with an SDS. Male dogs were induced with midazolam (0.25 mg kg) (group M) or an equivalent amount of Hartmann's solution (group P) and propofol intravenously (IV). Female dogs were induced with propofol alone and were administered midazolam (group M) or Hartmann's solution (group P) 5 minutes before intraoperative manipulation of the first ovary. Anaesthesia was maintained with isoflurane in oxygen. Intraoperative analgesia was provided with morphine (0.3 mg kg IV) prior to the start of surgery. Male dogs were administered intratesticular lidocaine (1 mg kg). All dogs were administered meloxicam (0.2 mg kg IV) at the end of the procedure, and recovery was scored with an SDS following extubation and 30 minutes later. Time to extubation, head lift, sternal position and standing and complications during recovery were recorded. Data are presented as median (range).Time to standing was significantly longer in animals in group M [56 (13-179) minutes] than in group P [44 (4-137) minutes], and the early recovery score in group M [3 (2-6)] was overall worse than in group P [3 (1-5)]. Significantly more dogs in group M (n = 30) than in group P (n = 22) displayed hypotension.The administration of midazolam prolonged time to standing and had a mild negative effect on the quality of recovery in a pooled population of healthy male and female dogs undergoing neutering. |
| 2019 | Safety, Tolerability, and Pharmacokinetics of GDC-0276, a Novel Na1.7 Inhibitor, in a First-in-Human, Single- and Multiple-Dose Study in Healthy Volunteers. | Clin Drug Investig | Current pain therapies often do not provide adequate pain relief and have dose-limiting adverse effects. Genetic evidence indicates that Na1.7 sodium channels are required for pain transduction and therefore represent an important therapeutic target. GDC-0276 is a novel Na1.7 inhibitor developed for the treatment of pain. This first-in-human trial evaluated the safety, tolerability, and pharmacokinetics of orally administered GDC-0276 in healthy subjects.This phase I, randomized, double-blind, placebo-controlled study assessed GDC-0276 as powder-in-capsule (PIC) or cyclodextrin solution (CD) single doses (SDs) of 2-270 mg (seven cohorts) and 45-540 mg (five cohorts), respectively. Multiple (MD) PIC doses were administered as total daily doses of 15-540 mg divided into two or three doses/day, up to 10 or 14 days. Safety was assessed by monitoring adverse events (AEs), vital signs, physical examinations, electrocardiograms, and laboratory tests for up to 15 days after the last day of dosing. GDC-0276 plasma pharmacokinetics were also determined.Three stages included 183 randomized subjects. GDC-0276 plasma exposure increased with dose level for all stages. Exposure was higher in the SD-CD cohorts compared with the equivalent SD-PIC dose levels. SDs were adequately tolerated up to 270 mg (SD-PIC) and 360 mg (SD-CD). Hypotension limited tolerability in the 540-mg SD-CD cohort. Multiple PIC doses were tolerated up to 270 mg twice daily, however liver transaminase elevations were frequently observed. No deaths or serious AEs occurred.GDC-0276 exhibited a safety and pharmacokinetic profile that supports its future investigation as a potential therapeutic for pain. |
| 2018 | Association of orthostatic hypotension with incident dementia, stroke, and cognitive decline. | Neurology | To examine associations of orthostatic hypotension (OH) with dementia and long-term cognitive decline and to update previously published results in the same cohort for stroke with an additional 16 years of follow-up.We analyzed data from 11,709 participants without a history of coronary heart disease or stroke who attended the baseline examination (1987-1989) of the prospective Atherosclerosis Risk in Communities (ARIC) study. OH was defined as a drop in systolic blood pressure (BP) of at least 20 mm Hg or a drop in diastolic BP of at least 10 mm Hg on standing. Dementia was ascertained via examination, contact with participants or their proxy, or medical record surveillance. Ischemic stroke was ascertained via cohort surveillance of hospitalizations, cohort follow-up, and linkage with registries. Both outcomes were adjudicated. Cognitive function was ascertained via 3 neuropsychological tests administered in 1990 to 1992 and 1996 to 1998 and a full battery of tests in 2011 to 2013. Scores were summarized and reported as SDs. We used adjusted Cox regression and linear mixed models.Over ≈25 years, 1,068 participants developed dementia and 842 had an ischemic stroke. Compared to persons without OH at baseline, those with OH had a higher risk of dementia (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.20-1.97) and ischemic stroke (HR 2.08, 95% CI 1.65-2.62). Persons with OH had greater, although nonsignificant, cognitive decline over 20 years (SD 0.09, 95% CI -0.02 to 0.21).OH assessed in midlife was independently associated with incident dementia and ischemic stroke. Additional studies are needed to elucidate potential mechanisms for these associations and possible applications for prevention. |
| 2018 | The use of a perioperative supra-physiological dose of glucocorticoid is not supported by evidence - a systematic review. | Dan Med J | A supra-physiological dose of glucocorticoid (SDS) is administered routinely in the perioperative management of patients on long-term regular glucocorticoid therapy. The dose of glucocorticoid used in these regimens varies. The current treatment is based on two 60-year-old case reports. No data exist to document the required dose of glucocorticoid to prevent perioperative hypotension or the category of patients needing this dose. Having in mind that high doses of glucocorticoids have several potential side effects, this practice ought to be re-evaluated in the light of available evidence.We searched MEDLINE, Embase and the Cochrane Library for data about perioperative stress dose. The search was conducted by the two authors and repeated by a research librarian to ensure inclusion of all related studies. All original articles and reviews relating to the perioperative use of SDS in chronic glucocorticoid-treated patients were included. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were applied.A total of 21 studies met the inclusion criteria of which five were prospective studies, five retrospective studies, three randomised controlled trials and eight reviews (three systematic reviews, one Cochrane review, three treatment guidelines, and one meta-analysis). No data supported routine use of SDS. Patients who continued their normal glucocorticoid treatment throughout the perioperative period had no need for SDS.No evidence supports the preoperative use of SDS in patients receiving chronic glucocorticoid therapy. |
| 2017 | A Pharmacological Examination of the Cardiovascular Effects of Malayan Krait (Bungarus candidus) Venoms. | Toxins (Basel) | Cardiovascular effects (e.g., tachycardia, hypo- and/or hypertension) are often clinical outcomes of snake envenoming. Malayan krait () envenoming has been reported to cause cardiovascular effects that may be related to abnormalities in parasympathetic activity. However, the exact mechanism for this effect has yet to be determined. In the present study, we investigated the and cardiovascular effects of venoms from Southern (BC-S) and Northeastern (BC-NE) Thailand. SDS-PAGE analysis of venoms showed some differences in the protein profile of the venoms. venoms (50 µg/kg-100 µg/kg, i.v.) caused dose-dependent hypotension in anaesthetised rats. The highest dose caused sudden hypotension (phase I) followed by a return of mean arterial pressure to baseline levels and a decrease in heart rate with transient hypertension (phase II) prior to a small decrease in blood pressure (phase III). Prior administration of monovalent antivenom significantly attenuated the hypotension induced by venoms (100 µg/kg, i.v.). The sudden hypotensive effect of BC-NE venom was abolished by prior administration of hexamethonium (10 mg/kg, i.v.) or atropine (5 mg/kg, i.v.). BC-S and BC-NE venoms (0.1 µg/kg-100 µg/ml) induced concentration-dependent relaxation (EC = 8 ± 1 and 13 ± 3 µg/mL, respectively) in endothelium-intact aorta. The concentration-response curves were markedly shifted to the right by pre-incubation with L-NAME (0.2 mM), or removal of the endothelium, suggesting that endothelium-derived nitric oxide (NO) is likely to be responsible for venom-induced aortic relaxation. Our data indicate that the cardiovascular effects caused by venoms may be due to a combination of vascular mediators (i.e., NO) and autonomic adaptation via nicotinic and muscarinic acetylcholine receptors. |
| 2015 | Proteomic analysis of the rare Uracoan rattlesnake Crotalus vegrandis venom: Evidence of a broad arsenal of toxins. | Toxicon | The investigation of venoms has many clinical, pharmacological, ecological and evolutionary outcomes. The Crotalus spp. venom can cause hemorrhage, neurotoxicity, myotoxicity, coagulopathy and hypotension. Although neurotoxicity and hemorrhage usually does not occur for the same species, the rare Venezuelan species Crotalus vegrandis presents both characteristic. Different from the other species it has a restricted ecological niche and geographical distribution. Nevertheless, it has a raising medical importance as this rattlesnake population is increasing. Few works describe its neurotoxic and hemorrhagic features, but other toxins might play an important role in envenomation. We combined proteomic methods to identify for the first time the main components of it venom: 2D SDS-PAGE and gel-filtration chromatography for protein mixture decomplexation; LC-MS(2) of low molecular mass fractions and tryptic peptides; bioinformatic identification of toxin families and specific protein species based on unique peptide analysis and sequence database enriched with species-specific venom gland transcripts; and finally polyclonal anti-crotamine Western-blotting. Our results point to a broad arsenal of toxins in C. vegrandis venom: PIII and PII metalloproteases, crotoxin subunits, other phospholipases, isoforms of serine proteases and lectins, l-amino-acid oxidase, nerve growth factor, as well as other less abundant toxins. |
| 2015 | [Hemodynamic effects of succinate-containing dialyzing solution]. | Ter Arkh | To assess the results of using an acetate-free succinate-containing dialyzing solution (SDS) against natremia and blood pressure (BP) in patients on chronic hemodialysis (HD).Ninety-two patients were transferred from 3 Saint Petersburg HD centers to 3-month HD treatment using SDS. The investigators measured blood biochemical indicators immediately before and 1 and 3 months after the investigation, BP before and after a successive HD session, and the patients' weight and its gain in the period between HD sessions. Hypotensive and hypertensive episodes were recorded during HD sessions throughout the investigation.Following 3-month treatment using SDS, there were statistically significant decreases in blood sodium levels and systolic BP (SBP) prior to a HD session. At the same time, patients with a baseline pre-HD SBP of less than 100 mm Hg were observed to have a statistically significant increase in this indicator by the end of the investigation. Pre-dialysis diastolic BP (DBP) and post- dialysis SBP and DBP substantially unchanged. After 3 months of SDS use, there was a statistically significant reduction in weight gain in the period between HD sessions. When SDS was administered, the frequency of hypertensive episodes tended to decline after a HD session.The use of SDS causes a drop in pre-dialysis blood sodium levels, ensuring adequate dehydration in patients and improving hypertension control. In doing so, SDS prevents hypotension during a HD session. |
| 2015 | Association between Intraoperative Hypotension and Hypertension and 30-day Postoperative Mortality in Noncardiac Surgery. | Anesthesiology | Although deviations in intraoperative blood pressure are assumed to be associated with postoperative mortality, critical blood pressure thresholds remain undefined. Therefore, the authors estimated the intraoperative thresholds of systolic blood pressure (SBP), mean blood pressure (MAP), and diastolic blood pressure (DBP) associated with increased risk-adjusted 30-day mortality.This retrospective cohort study combined intraoperative blood pressure data from six Veterans Affairs medical centers with 30-day outcomes to determine the risk-adjusted associations between intraoperative blood pressure and 30-day mortality. Deviations in blood pressure were assessed using three methods: (1) population thresholds (individual patient sum of area under threshold [AUT] or area over threshold 2 SDs from the mean of the population intraoperative blood pressure values), (2). absolute thresholds, and (3) percent change from baseline blood pressure.Thirty-day mortality was associated with (1) population threshold: systolic AUT (odds ratio, 3.3; 95% CI, 2.2 to 4.8), mean AUT (2.8; 1.9 to 4.3), and diastolic AUT (2.4; 1.6 to 3.8). Approximate conversions of AUT into its separate components of pressure and time were SBP < 67 mmHg for more than 8.2 min, MAP < 49 mmHg for more than 3.9 min, DBP < 33 mmHg for more than 4.4 min. (2) Absolute threshold: SBP < 70 mmHg for more than or equal to 5 min (odds ratio, 2.9; 95% CI, 1.7 to 4.9), MAP < 49 mmHg for more than or equal to 5 min (2.4; 1.3 to 4.6), and DBP < 30 mmHg for more than or equal to 5 min (3.2; 1.8 to 5.5). (3) Percent change: MAP decreases to more than 50% from baseline for more than or equal to 5 min (2.7; 1.5 to 5.0). Intraoperative hypertension was not associated with 30-day mortality with any of these techniques.Intraoperative hypotension, but not hypertension, is associated with increased 30-day operative mortality. |
| 2015 | Pediatric patients with pheochromocytoma: Experience of a tertiary health center. | Pediatr Int | The aim of this retrospective study was to investigate pheochromocytoma (pheo), which is a rare endocrine tumor in the pediatric population.The medical records of five children with pheo were studied. The age, gender, clinical presentation, family history, physical findings, coexisting pathology, laboratory evaluation, surgical treatment, and postoperative course were investigated.The patients were four girls and one boy with a mean age of 13.2 years (range, 9.57-15.95 years). None of the patients had paroxysmal hypertension and one had normal blood pressure. No malign pheo was identified. Mean height and weight standard deviation scores (SDS), body mass index (BMI), and BMI SDS were -0.24, 0.04, 20.9 kg/m(2), and 0.20 at the time of diagnosis, and 0.03, 0.43, 23.8 kg/m(2) and 0.49 1 year after operation, respectively. BMI increased significantly after operation. Three patients had normal epinephrine and metanephrine, but elevated norepinephrine and normetanephrine on 24 h urine. Vanillylmandelic acid on 24 h urine sample was elevated in all patients. Ultrasonography failed to visualize tumors in two patients with bilateral pheo. One patient had postoperative severe hypotension. Insulin resistance associated with severe acanthosis nigricans observed in one patient regressed postoperatively.Pheo in children may present with different symptoms and findings. Decreased catecholamine in the postoperative period may lead to weight gain. |
| Prognostic factors in outcome of angioedema in the emergency department. | Allergy Asthma Proc | Angioedema is a transient, localized swelling caused by two distinct mechanisms, mediated by histamine and bradykinin, respectively, although a proportion of cases remain idiopathic. Studies that characterize undifferentiated angioedema presenting in emergency departments (EDs) are limited. This study investigates the presentation patterns of undifferentiated angioedema in the ED based on the presumed mechanism of swelling. Medical records from all ED visits to two tertiary care hospitals from July 2007 to March 2012 were electronically reviewed. Records with documented visible swelling on general inspection and/or fiberoptic laryngoscopy and a diagnostic code for anaphylactic shock, angioneurotic edema, allergy unspecified, defects in the complement system, or unspecified drug adverse effects were included. Demographic, clinical, and outcome data were collected via a standardized form. Data were analyzed descriptively, including frequencies and percentages for categorical data and means and SDs for continuous data. Predictors for admission were identified using multivariate logistic regression models. ED records from 527 visits for angioedema by 455 patients were included in the study. Annual rate of angioedema was 1 per 1000 ED visits. Urticaria was associated with peripheral (p = 0.008) and lip angioedema (p = 0.001), and the absence of urticaria correlated with tongue angioedema (p = 0.001) and trended toward correlation with pharyngeal angioedema (p = 0.056). Significant predictors of admission included nonsteroidal anti-inflammatory drug-induced angioedema (odds ratio [OR], 15.3), epinephrine treatment (OR, 8.34), hypotension (OR, 15.7), multiple-site angioedema (OR, 4.25), and pharyngeal (OR, 1.23) and tongue angioedema (OR, 4.62). Concomitant urticaria was associated with a significant longer stay in the ED (p < 0.001). The presence of urticaria correlated with the location of angioedema, need for airway management, length of ED visit, and recurrence. A detailed drug and family history, screening blood work for C1 esterase inhibitor deficiency when indicated, and prompt management of angioedema based on presumed mechanism of swelling are crucial steps in managing undifferentiated angioedema in ED. |
| 2014 | Combined venom gland cDNA sequencing and venomics of the New Guinea small-eyed snake, Micropechis ikaheka. | J Proteomics | The venom arsenal of the New Guinea small-eyed snake, Micropechis ikaheka, was investigated by a joint cDNA sequencing and venomics approach. Twenty-seven full-length DNA sequences encoding novel venom proteins were recovered in this study. Using this cDNA dataset we achieved locus-specific resolution for 19 out of the approximately 50 reverse-phase- and SDS-PAGE-separated venom proteins. The venom proteome of M. ikaheka is dominated by at least 29 D49-phospholipase A₂ (PLA₂) and 14 short and long neurotoxins of the three-finger toxin (3FTx) family. These protein classes represent, respectively, 80% and 9.2% of the total venom proteins. Two PIII-metalloproteinase (SVMP) molecules (7.6%), three CRISP isoforms (1.8%), and a single Kunitz-type inhibitor, vespryn, 5'-nucleotidase, serine proteinase and LAO molecules, none of which represents more than 0.7% of the total venom proteome, complete the protein arsenal of M. ikaheka. In concordance with clinical observations, this venom composition points to a central role for post-synaptically-acting neurotoxic toxins in the envenomation strategy developed by this species. PLA₂ molecules represent the main myotoxic components of M. ikaheka venom. In addition, the estimated LD₅₀ for mice of the reverse-phase-isolated 3FTx (0.22 mg/kg) and PLA₂ (1.62 mg/kg) enriched fractions, strongly suggests that these two toxin classes contribute synergistically to venom lethality, with the 3FTxs playing a dominant role. The high structural and functional conservation exhibited by M. ikaheka and Australian elapid venoms may underlay the positive clinical outcomes of envenoming resulting from bites by M. ikaheka that have been documented through the use of bioCSL polyvalent antivenom.The poorly understood venom proteome of the New Guinea small-eyed snake, Micropechis ikaheka, a large and powerfully built elapid endemic to Papua New Guinea and Indonesian West Papua province, was investigated through a combined venomics and venom gland transcriptomics approach. Although M. ikaheka accounts for only a small proportion of snakebites on the mainland, 40% of snakebites on Karkar Island are attributed to bites by this snake. Major effects of envenomings include life-threatening post-synaptic neuromuscular blockade resulting in respiratory paralysis, myotoxicity, severe bleeding, hypotension and cardiovascular abnormalities. We have investigated the contribution of 3FTxs and PLA₂ molecules in venom lethality, myotoxicity, and cardiovascular function. Our work provides important correlations between venom composition and its pharmacological activity. In conjunction with the antivenomics work reported in the companion paper, our study may contribute to improve treatment outcomes for snakebite victims of M. ikaheka. |
| 2014 | Ischemia-induced depolarizations and associated hemodynamic responses in incomplete global forebrain ischemia in rats. | Neuroscience | Spontaneous depolarizations around the core are a consistent feature of focal cerebral ischemia, but the associated regional hemodynamic changes are heterogeneous. We determined how the features of depolarizations relate to subsequent cerebral blood flow (CBF) changes in global forebrain ischemia. Forebrain ischemia was produced in halothane-anesthetized rats (n=13) by common carotid artery occlusion and hypovolemic hypotension. Mean arterial blood pressure (MABP) was monitored via a femoral catheter. Specific illuminations allowed the capture of image sequences through a cranial window to visualize: changes in membrane potential (voltage-sensitive dye method); CBF (laser speckle contrast imaging); cerebral blood volume (intrinsic optical signal, IOS at 540-550nm); and hemoglobin deoxygenation (IOS at 620-640nm). A depolarization occurred (n=9) when CBF fell below 43.4±5% of control (41±4mmHg MABP), and propagated with a distinct wave front at a rate of 2.8mm/min. Depolarizations were either persistent (n=4), intermediate (n=3) or short, transient depolarization (n=2). Persistent and intermediate depolarizations were associated with sustained hypoperfusion (-11.7±5.1%) and transient hypoperfusion (-17.4±5.2, relative to CBF before depolarization). Short, transient depolarizations did not generate clear CBF responses. Depolarizations during incomplete global ischemia occurred at the lower limit of CBF autoregulation, propagated similar to spreading depolarization (SD), and the hemodynamic responses indicated inverse neurovascular coupling. Similar to SDs associated with focal stroke, the propagating event can be persistent or transient. |
| 2012 | Children born small for gestational age (SGA). | Prilozi | SGA (small for gestational age) is a child born with birth weight and/or length (BW/BL) under two standard deviations (2 SDS) for the gestational age and sex of the population. ~5% of all newborn children are SGA. A broad spectrum of factors are found to be causative: maternal, placental, foetal, metabolic, and genetic. In the newborn period the SGA children are at greater risk of life-threatening conditions: hypoglycaemia, hypercoagulability, necrotic enterocolitis, direct hyperbilirubinemia, hypotension, etc. Approximately 10 percent of SGA children do not achieve catch-up growth and remain short (≥-2 SDS) into adulthood. SGA people have an increased incidence of metabolic syndrome, coronary artery disease, stroke, low bone density and osteoporosis. SGA children aged more than 4 years with no evidence of spontaneous catch-up and with a height≥2.5 SD are considered for growth hormone (GH) treatment. |
| 2010 | Perfusion pressure-dependent recovery of cortical spreading depression is independent of tissue oxygenation over a wide physiologic range. | J Cereb Blood Flow Metab | Spreading depression (SD) is a slowly propagating wave of transient neuronal and glial depolarization that develops after stroke, trauma and subarachnoid hemorrhage. In compromised tissue, repetitive SD-like injury depolarizations reduce tissue viability by worsening the mismatch between blood flow and metabolism. Although the mechanism remains unknown, SDs show delayed electrophysiological recovery within the ischemic penumbra. Here, we tested the hypothesis that the recovery rate of SD can be varied by modulating tissue perfusion pressure and oxygenation. Systemic blood pressure and arterial pO(2) were simultaneously manipulated in anesthetized rats under full physiologic monitoring. We found that arterial hypotension doubled the SD duration, whereas hypertension reduced it by a third compared with normoxic normotensive rats. Hyperoxia failed to shorten the prolonged SD durations in hypotensive rats, despite restoring tissue pO(2). Indeed, varying arterial pO(2) (40 to 400 mm Hg) alone did not significantly influence SD duration, whereas blood pressure (40 to 160 mm Hg) was inversely related to SD duration in compromised tissue. These data suggest that cerebral perfusion pressure is a critical determinant of SD duration independent of tissue oxygenation over a wide range of arterial pO(2) levels, and that hypotension may be detrimental in stroke and subarachnoid hemorrhage, where SD-like injury depolarizations have been observed. |
| 2009 | Chinese bellflower root anaphylaxis: IgE-binding components and cross-reactivity with mugwort and birch. | Korean J Intern Med | A 56-year-old man who had suffered from seasonal rhinitis in spring and autumn experienced recurrent generalized urticaria and an oral burning sensation after eating several cooked herbs for 3 months. A skin-prick test showed positive responses to various pollens, celery, Chinese bellflower, and arrowroot. The Chinese bellflower-specific IgE ELISA OD value was 1.547. Oral challenge with unprocessed raw Chinese bellflower root provoked oral burning sensation, eyelid swelling, generalized urticaria, and hypotension. In an ELISA inhibition test, IgE binding to Chinese bellflower was significantly inhibited by Chinese bellflower, mugwort, and birch pollen extract. SDS-PAGE and immunoblot assay revealed nine IgE-binding components, and common protein bands were detected in the range of 40~55 kDa (Chinese bellflower-mugwort-birch) and 14 kDa (Chinese bellflower-birch). Chinese bellflower root can cause anaphylaxis and may have cross-reactivity with mugwort and birch. |
| 2007 | Long-term prognostic value of blood pressure variability in the general population: results of the Pressioni Arteriose Monitorate e Loro Associazioni Study. | Hypertension | The hypothesis has been advanced that cardiovascular prognosis is related not only to 24-hour mean blood pressure but also to blood pressure variability. Data, however, are inconsistent, and no long-term prognostic study is available. In 2012 individuals randomly selected from the population of Monza (Milan), 24-hour ambulatory blood pressure (Spacelabs 90207) was measured via readings spaced by 20 minutes. Systolic and diastolic blood pressure variability was obtained by calculating the following: (1) the SD of 24-hour, day, and night mean values; (2) the day-night blood pressure difference; and (3) the residual or erratic blood pressure variability (Fourier spectral analysis). Fatal cardiovascular and noncardiovascular events were registered for 148 months. When adjusted for age, sex, 24-hour mean blood pressure, and other risk factors, there was no relationship between the risk of death and 24-hour, day, and night blood pressure SDs. In contrast, the adjusted risk of cardiovascular death was inversely related to day-night diastolic BP difference (beta coefficient=-0.040; P<0.02) and showed a significant positive relationship with residual diastolic blood pressure variability (beta coefficient=0.175; P<0.002). Twenty-four-hour mean blood pressure attenuation of nocturnal hypotension and erratic diastolic blood pressure variability all independently predicted the mortality risk, with the erratic variability being the most important factor. Our data show that the relationship of blood pressure to prognosis is complex and that phenomena other than 24-hour mean values are involved. They also provide the first evidence that short-term erratic components of blood pressure variability play a prognostic role, with their increase being accompanied by an increased cardiovascular risk. |
| 2006 | Left ventricular hypertrophy in patients with autonomic failure. | Am J Hypertens | In autonomic failure (AF), supine hypertension may predispose patients to end-organ damage. The pathophysiology of hypertensive heart disease in AF is not known. The aim of the present study was to evaluate the prevalence and predisposing factors of left ventricular hypertrophy (LVH) in patients with AF.We studied 25 patients with AF (67 +/- 8 years); 80% were being treated for orthostatic hypotension. Twenty patients with essential hypertension (68 +/- 6 years) were considered as the control group. All subjects underwent echocardiography for measurement of left ventricular mass (LVM). The patients with AF underwent a 24-h BP monitoring and long-term blood pressure (BP) variability was calculated as standard deviation (SD) of the average of the half-hour mean values.The LVM is comparable in patients with AF and hypertensive controls (145 +/- 35 g/m2 v 127 +/- 32 g/m2, P = .07). The proportion of patients with LVH is similar in both populations (AF 80%, hypertensive 70%). The patients with AF were divided into two groups, with and without LVH. The SDs are significantly higher in AF patients with LVH than in those with normal LVM (SD 24-h systolic BP: 22 +/- 4 v 14 +/- 1 mm Hg, P = .001).A high proportion of patients with AF show LVH. The LVM values are comparable with those of patients with essential hypertension. The development of LVH seems to depend on high BP variability, characteristic of AF patients. Detection of LVH may help in the choice of treatment for orthostatic hypotension and in the prevention of heart failure. |
| 2006 | Altered 24-hour blood pressure profiles in children and adolescents with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. | J Clin Endocrinol Metab | Children and adolescents with classical congenital adrenal hyperplasia have been shown to be at risk for obesity associated with higher insulin and leptin levels. Because these factors are also known to cause hypertension, the aim of this study was to analyze 24-h blood pressure profiles and their relation to different clinical and laboratory parameters.Fifty-five subjects, aged between 5.3 and 19.0 yr, were enrolled in a prospective, cross-sectional study. All patients had genetically proven 21-hydroxylase deficiency and underwent ambulatory 24-h blood pressure monitoring during a period off school/work. RESULTS (MEDIAN, RANGE): The median body mass index of the cohort was significantly elevated [1.09 sd score (SDS), -2.45 to 3.77]. Daytime and nighttime systolic blood pressures were also significantly elevated (0.67 SDS, -1.5-4.1; 0.63 SDS, -0.91 to 3.3), whereas daytime diastolic blood pressure was significantly lowered (-0.81 SDS, -2.6 to 3.2) and normal during the night (0.11 SDS, -2.0 to 2.0). Overall, there was a normal nocturnal drop of systolic (12.8%, 2.1-22.8) but not diastolic blood pressure (17.2%, 0.90-25.8). The different parameters of systolic and diastolic blood pressures were significantly correlated with body mass index and skinfold thickness (r(s) = 0.271-0.486). There was no correlation with equivalent hydrocortisone and fludrocortisone dosage and laboratory parameters except for serum leptin and insulin.Our data show altered 24-h blood pressure profiles with elevated systolic levels correlated with the degree of overweight and obesity, whereas normal-weight patients tended to diastolic hypotension. |
| 2005 | Minimal impact urethroplasty allows same-day surgery in most patients. | Urology | To present our evaluation of the safety and feasibility of decreasing the impact of anterior urethroplasty by minimizing the surgery time, maximizing adjuvant pain therapy, and using anesthetic agents that decrease the incidence and severity of side effects, which allows most patients to leave the hospital comfortably within 4 hours of surgery.A retrospective chart review of 54 consecutive anterior urethroplasty patients from August 2000 to August 2004 (34 anterior anastomotic and 20 ventral onlay buccal mucosal graft urethroplasty) was performed.Historically, 27% of patients had undergone same-day surgery (SDS). After the initiation of minimal impact surgery and early discharge, 85% did so. All but one admission was planned (1 patient [2%] had hypotension in the recovery room and was admitted). No postoperative readmissions or emergency room visits occurred. The admitted patients had comparable stricture length to, but slightly older age (49 years compared with 42 years) than, the SDS patients. The perioperative complications were mild (small wound gap, small scrotal hematoma) and were seen in 5% of SDS patients and 0% of admitted patients. Late complications (chordee, mild erectile dysfunction, and urinary tract infection) were seen in 19% of SDS patients and 18% of admitted patients. The incidence of recurrences after a mean follow-up of 27 months was comparable (3% for the SDS and 6% for the admitted group).Decreasing the impact of urethroplasty surgery allows safe early discharge for most patients. Unexpected admissions were uncommon, and we continue to plan for admission only for the extremely elderly, those with severe comorbidities, and those expected to undergo lengthy (longer than 5 hours) surgery. |
| Hemodynamic benefits of matrix metalloproteinase-9 inhibition by doxycycline during experimental acute pulmonary embolism. | Angiology | The authors examined whether acute pulmonary embolism (APE) increases lung matrix metalloproteinase (MMP)-2 and MMP-9 activities and whether inhibition of MMPs with doxycycline attenuates the hemodynamic changes associated with APE. Anesthetized male Wistar rats were monitored for mean arterial blood pressure (MAP) and heart rate (HR). Rats in the control group (n = 5) received only saline IV; rats in the embolism (Emb) group (n = 8) received saline IV followed 10 minutes later by an injection of Sephadex microspheres (9 mg/kg) IV; rats in the doxycycline (Doxy) group (n = 4) received only doxycycline (30 mg/kg) IV, followed 10 minutes later by an injection of saline IV; rats in the Doxy + Emb group (n = 8) received the same dose of doxycycline followed 10 minutes later by the same amount of microspheres described above. Lung samples were homogenized and assayed by SDS-polyacrilamide gel electrophoresis gelatin zymography to evaluate lung MMP-2 and MMP-9 activities. Saline or doxycycline produced no significant changes in MAP, HR, and in MMP-2 and MMP-9 activities. Conversely, lung embolization significantly reduced MAP by > 32 mm Hg and HR by > 90 bpm for more than 60 minutes, and increased MMP-9 activity by 43% (all p < 0.05). No significant differences were observed in MMP-2 activity. However, lung embolization produced only transient hypotension in rats pretreated with doxycycline. In this group, MAP returned to baseline values 5 to 10 minutes after embolization. In addition, pretreatment with doxycycline blunted the increase in lung MMP-9 activity after lung embolization (p < 0.05). This study demonstrates for the first time that MMP-9 inhibition with doxycycline attenuates APE-induced hemodynamic changes in the animal model examined. These findings indicate that MMP-9 activation plays a role in the pathophysiology of APE and suggest that pharmacologic strategies targeting specific MMPs with selective inhibitors may prevent the detrimental acute hemodynamic consequences of APE. |
| 2004 | Stress dose steroids in renal transplant patients undergoing lymphocele surgery. | Transplant Proc | The requirement for perioperative stress dose steroids (SDS) in patients on long-term steroid therapy is controversial, but SDS are given during perioperative care. Studies focusing on surrogate outcomes like cortisol levels indicate a possible requirement for SDS, but clinical results are sparse. We retrospectively compared outcomes of renal or pancreas/kidney transplant patients undergoing surgical lymphocele drainage who did (n=20) or did not (n=38) receive SDS. Patients had similar demographic characteristics (P=NS). No patient developed hypotension (SBP < 80 mmHg), mental status change, unexplained arthralgias, or ileus. Impaired wound healing occurred in one patient in each group (P=NS), and lymphocele recurrence occurred in 25% of the SDS group and 10.5% of the other group (P=.25). SBP decreased from baseline in both groups (P <.001) but did not differ between groups, and maximum blood glucose was higher in the SDS group (P=.04). No difference was observed in other measured parameters. These data indicate that SDS increased the risk of hyperglycemia and provided no apparent benefit. A prospective study is warranted to confirm these findings. |
| 2005 | The contribution of genetic and environmental factors to quantitative variability of erythrocyte membrane proteins in primary hypotension. | Ann Hum Genet | Our previous studies have shown that, compared with healthy individuals, patients with primary arterial hypotension (PAH) have significant quantitative changes in erythrocyte membrane proteins. The purpose of the present study was to evaluate the contribution made by genetic and environmental factors to quantitative variation of erythrocyte membrane proteins in PAH. We studied 109 hypotensive patients, 124 normotensive subjects, 222 of their first-degree relatives and 24 twin pairs by sodium dodecyl sulphate (SDS) polyacrylamide gel electrophoresis. The decomposition of total phenotypic variance of erythrocyte membrane proteins to genetic and environmental components was performed on the basis of correlations among first-degree relatives by the least squares method. The genetic dominance and shared environmental factors were found to influence the variability of cytoskeletal membrane proteins whose contents were changed in PAH. Furthermore, variations in alpha-spectrin, actin and anion exchanger in hypotensives were substantially influenced by major gene and maternal effects. Ankyrin 2.1 and actin content was under the control of common underlying genes. Variations in membrane-associated glutathione-S-transferase and tropomyosin were predominantly affected by polygenes. These findings suggest that the putative major genes with pleiotropic effects appear to be involved in the control of quantitative disorders of erythrocyte membrane proteins in primary hypotension. |
| 2004 | Antihypertensive and antiproteinuric efficacy of ramipril in children with chronic renal failure. | Kidney Int | While the antihypertensive and renoprotective potency of angiotensin-converting enzyme (ACE) inhibitors is well-established in adults with hypertension and/or chronic renal failure, little experience exists in pediatric chronic kidney disease.As part of a prospective assessment of the renoprotective efficacy of ACE inhibition and intensified blood pressure (BP) control, 397 children (ages 3 to 18 years) with chronic renal failure [CRF; glomerular filtration rate (GFR) 11 to 80 mL/min/1.73 m2] and elevated or high-normal BP received ramipril (6 mg/m2) following a 6-month run-in period including a two-month washout of any previous ACE inhibitors. Drug efficacy was assessed by two monthly office BP and proteinuria assessments, and by ambulatory BP monitoring at start and after 6 months of treatment.In the 352 patients completing six months of treatment, 24-hour mean arterial pressure (MAP) had decreased by a mean of 11.5 mm Hg (-2.2 SDS) in initially hypertensive subjects, but only by 4.4 mm Hg (-0.8 SDS) in patients with initially normal BP. A linear correlation was found between MAP at baseline and the change of MAP during treatment (r= 0.51; P < 0.0001). The antihypertensive response was independent of changes in concomitant antihypertensive medication or underlying renal disease. BP was reduced with equal efficacy during day- and nighttime. Urinary protein excretion was reduced by 50% on average, with similar relative efficacy in patients with hypo/dysplastic nephropathies and glomerulopathies. The magnitude of proteinuria reduction depended on baseline proteinuria (r= 0.32, P < 0.0001), and was correlated with the antihypertensive efficacy of the drug (r= 0.22, P < 0.001). The incidence of rapid rises in serum creatinine and progression to end-stage CRF during treatment did not differ from the pretreatment observation period. Mean serum potassium increased by 0.3 mmol/L. Ramipril was discontinued in three patients due to symptomatic hypotension or hyperkalemia. Hemoglobin levels decreased by 0.6 g/dL in the first two treatment months and remained stable thereafter.Ramipril appears to be an effective and safe antihypertensive and antiproteinuric agent in children with CRF-associated hypertension. The BP lowering and antiproteinuric effects are greatest in severely hypertensive and proteinuric children. |
| 2003 | Structures of neuropeptide gamma from goldfish and mammalian neuropeptide gamma, as determined by 1H NMR spectroscopy. | J Pept Res | Neuropeptide gamma belongs to tachykinin families which have a common C-terminal amino acid sequence (Phe-X-Leu-Met-NH2) and which induce various biological responses including salivation, hypotension, and contraction of gastrointestinal, respiratory, and urinary smooth muscle. In the present study, we present the solution structures of neuropeptide gamma (NPgamma) from gold fish (G-NPgamma) and mammalian NPgamma (M-NPgamma), as determined by nuclear magnetic resonance (NMR) spectroscopy in 50% trifluoroethanol (TFE)/water (1 : 1, v/v) solution and 200 mm sodium dodecyl sulfate (SDS) micelles. In aqueous TFE solution, G-NPgamma has a alpha-helical conformation in the region of His12-Met21 and a short helix in the N-terminal region, and has a beta-turn from Arg9 to Arg11 in between. In aqueous TFE solution, M-NPgamma also has alpha-helical conformations both in the C-terminal region and the N-terminal region and a beta-turn from His9 to Arg11 in between. In SDS micelle, the structure of G-NPgamma contains a stable alpha-helix from His12 to Met21 and a beta-turn from Arg9 to Arg11, while M-NPgamma has a short helix from Ser16 to Met21. The region from His12 to Met21 corresponds to the amino acid sequence of neurokinin A. Neuropeptide gamma may act as a precursor of neurokinin A and the post-translational processing of this peptide involves the enzymatic attack of the basic beta-turn region from residue 9 to residue 11 in the middle. From our relaxation study, it could be suggested that in fish system G-NPgamma induces the biological actions corresponding to those of substance P in mammalian system. The structures of G-NPgamma and M-NPgamma contain alpha-helical structures at the C-terminus and this helix seems to promote the affinity for NK1 and/or NK2 receptor. |
| 1997 | [Shy-Drager syndrome and multiple system atrophy]. | Nihon Rinsho | Shy-Drager syndrome (SDS) is a subtype of multiple system atrophy (MSA) with the clinical predominance of autonomic failure. The differential diagnosis between SDS and Parkinson's disease (PD) can sometimes be difficult clinically. The features favoring a clinical diagnosis of SDS are marked orthostatic hypotension, erectile impotence in males, urinary symptoms, nocturnal stridor, rigidity and akinesia without tremors, levodopa unresponsiveness, cerebellar signs, cerebellar atrophy on brain CT scans and MRI. |
| 1996 | Neurohumoral, peptidergic and biochemical responses to supine exercise in two groups with primary autonomic failure: Shy-Drager syndrome/multiple system atrophy and pure autonomic failure. | Clin Auton Res | The neurohumoral, peptidergic and biochemical responses to supine leg exercise were studied in two groups with primary autonomic failure: Shy-Drager syndrome (SDS, n = 15) and pure autonomic failure (PAF, n = 15), to determine if these accounted for exercise-induced hypotension and the greater blood pressure (BP) fall in PAF. Responses were compared to normal subjects (controls, n = 15), in whom BP rose with exercise. Resting plasma noradrenaline (NA) was higher in controls than SDS, and was lowest in PAF. With exercise, NA increased in controls, with a small rise in SDS, but no change in PAF. Resting plasma adrenaline (A) was higher in controls and SDS than PAF, with no change during exercise. Plasma dopamine was unrecordable at all stages in all groups. Resting plasma renin activity (PRA) was higher in controls than SDS and PAF, and was unchanged with exercise in all groups. Plasma insulin, C-peptide and serum growth hormone (GH) were similar at rest and with exercise in the three groups. Plasma glucose was higher at rest in SDS and PAF, and increased with exercise in all three groups. In conclusion, neither exercise-induced hypotension, nor the differences between SDS and PAF could be related to abnormalities in the release of A, PRA, insulin, glucose or GH. The abnormal NA response to exercise was consistent with the BP fall being due to inadequate compensatory sympathetic activity. In SDS, the small NA increase, in the presence of supersensitivity, may have reduced their BP fall as compared to PAF. These results suggest that impaired sympathetic neural activity is a key factor in exercise-induced hypotension. |
| 1996 | Differences in cardiovascular responses to supine exercise and to standing after exercise in two clinical subgroups of Shy-Drager syndrome (multiple system atrophy). | J Neurol Neurosurg Psychiatry | In chronic autonomic failure of varying aetiologies, there are differences in the cardiovascular responses to supine leg exercise and to standing after exercise. Whether this occurs between the different subgroups with Shy-Drager syndrome (SDS) is unknown.Fourteen patients with the cerebellar form (SDS-C) and 11 patients with parkinsonian features (SDS-P) were studied.Both groups had a similar degree of autonomic failure and postural hypotension. Their responses were compared with nine patients with idiopathic Parkinson's disease (IPD) and 15 normal subjects (controls), all with normal autonomic function. With supine exercise, blood pressure and heart rate rose similarly in controls and patients with IPD and there was no fall in blood pressure on standing after exercise. In both SDS groups there were abnormal responses to exercise: blood pressure fell in SDS-C, but did not fall or rise in SDS-P. Heart rate increased similarly in both SDS groups, calculated systemic vascular resistance fell similarly, but cardiac index rose more in SDS-P than SDS-C. Resting plasma noradrenaline concentrations were subnormal in both forms of SDS, and did not increase with exercise. Postural hypotension was enhanced after exercise to the same extent in SDS-C and SDS-P.The greater cardiovascular abnormalities in response to exercise in SDS-C suggests that cerebellar or brain stem autonomic pathways are impaired to a greater extent in SDS-C than in SDS-P. Pooling SDS subgroups, therefore, may obscure pathophysiological differences to certain stimuli. Clinically when postural hypotension is being assessed, separation of the subgroups may not be essential, as they responded similarly. |
| 1996 | Purification and characterization of a fibrinogen-clotting enzyme from the venom of jararacuçu (Bothrops jararacussu). | Toxicon | A clotting enzyme of the venom of Bothrops jararacussu, denoted FC-Bj, was purified by gel chromatography on Sephadex G-100 followed by HPLC on DEAE-5PW-PAK and gel filtration on Sephacryl S-200HR. The enzyme was identified as an acidic glycoprotein which probably consists of a single polypeptide chain with isoelectric point values in the range 3.3-4.4 and containing approx. 19% carbohydrates. On polyacrylamide gel electrophoresis (PAGE) at pH 8.3, the enzyme presented a diffuse protein band. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), the enzyme showed two protein bands corresponding to mol. wts of 50,600 and 60,000. After treatment of the enzyme with neuraminidase, a strongly stained band and a band weaker in staining intensity were observed on SDS-PAGE, thereby reducing the mol. wts to 44,500 and 56,300, respectively. The clotting factor possessed N-alpha-benzoyl-DL-arginine p-nitroanilide hydrolysing activity and coagulated fibrinogen to fibrin. These activities were 0.548 units/mg and 50.55 NIH thrombin units/mg, respectively. The proteinase was of the serine type, as indicated by sensitivity to phenylmethanesulfonyl fluoride and benzamidine. However, the amidolytic activity of this enzyme was resistant to inhibitors such as heparin, aprotinin, agmatine, EDTA, I-2581 and TLCK. The importance of disulfide bridges for the structural integrity of the purified enzyme was indicated by the loss of amidolytic activity in the presence of beta-mercaptoethanol and dithiothreitol. SDS-PAGE of fibrinogen degraded with this enzyme revealed the disappearance of the A alpha and B beta chains and the appearance of lower mol. wt fragments. The enzyme was able to hydrolyse synthetic chromogenic substrates with arginine as the C-terminal residue, and the kinetic parameters were determined. It hydrolysed the plasma kallikrein substrate H-D-Pro-Phe-Arg-pNA (S-2302) and produced kinin-releasing activity causing ileum contraction. In addition, hypotension and bradycardia were observed in urethane-anesthetized rats upon i.v. injection of the enzyme. |
| 1996 | Specific adrenomedullin binding sites and hypotension in the rat systemic vascular bed. | Regul Pept | The potent vasodilator peptide, adrenomedullin, has been shown to be present in plasma, suggesting a physiological role in cardiovascular control. Here we investigated the hypotensive action of adrenomedullin in vivo, using the anaesthetised rat as the bioassay model, and adrenomedullin binding sites using ligand binding assays on rat blood vessel membranes. Rat alpha CGRP and both human and rat adrenomedullins induced dose-dependent, powerful and long-lasting hypotensive effects. At peptide doses used in this study (0.02-2 nmol/kg), the efficacy of both human and rat adrenomedullins was lower than that of rat alpha CGRP. The CGRP1-receptor antagonist, human CGRP(8-37) (200 nmol/kg) was able to completely inhibit the hypotensive effect of rat alpha CGRP (0.2 nmol/kg) but not that of rat adrenomedullin (2 nmol/kg), implying that the adrenomedullin action is independent of CGRP1-receptors. Ligand binding assays confirmed the presence of both CGRP and adrenomedullin binding sites in rat blood vessels. The 125I-rat adrenomedullin binding site has a Kd = 0.32 +/- 0.12 nM (n = 4) for rat adrenomedullin but has a Ki > 10(-6) M for rat alpha CGRP. Chemical cross-linking and SDS-PAGE analysis revealed theadrenomedullin binding protein to have a M(r) of 83000 with a minor band of M(r) = 99000. The results suggest that the hypotensive effect of adrenomedullin may be mediated via specific adrenomedullin binding sites, in vivo. |
| 1995 | Postural hypotension enhanced by exercise in patients with chronic autonomic failure. | QJM | The effect of supine exercise on blood pressure (BP), measured while recumbent and after head-up postural change, was investigated in three groups with marked postural hypotension due to chronic autonomic failure: 15 with associated neurological impairment (Shy-Drager syndrome, SDS, multiple system atrophy); 15 with pure autonomic failure (PAF) and two with a deficiency of the enzyme dopamine beta hydroxylase (DBH deficiency). Fifteen normal subjects were controls. In controls, exercise increased supine BP, and there was no postural fall before or after exercise. In SDS and PAF, however, exercise produced a substantial fall in BP, which was greater in PAF. In both groups, BP fell to a lower level on standing after than before exercise. In DBH deficiency, there was little change in BP with exercise, but BP fell to a lower level on standing after exercise. In all three groups with autonomic failure, there were more symptoms of postural hypotension on standing after exercise. The influence of exercise on both supine and postural BP, therefore, should be considered in the clinical and laboratory assessment of autonomic dysfunction. |
| 1995 | [Multivariate analysis of spinal automatism in neurological diseases]. | Rinsho Shinkeigaku | We investigated the relationship between spinal automatism (SA) and other neurological signs and symptoms (pyramidal, extrapyramidal, cerebellar, autonomic) by multivariate analysis in cervical spondylotic myelopathy (CSM) 112 cases, amyotrophic lateral sclerosis (ALS) 121 cases, and multiple system atrophy (MSA) 115 cases (olivo-ponto-cerebellar atrophy (OPCA) 55 cases, Shy-Drager syndrome (SDS) 42 cases, striato-nigral degeneration (SND) 18 cases). SA elicitation maneuver we used was pinprick stimulation at the dorsal pedal skin, and all cases showed twitched or phasic triple flexion pattern. As SA was elicited in 19 cases in CSM (17.0%), 23 cases (19.0%) in ALS, 36 cases (31.3%) in MSA, SA was more elicited in MSA than in ALS and CSM (p < 0.05, p < 0.01 by chi-squared test). In MSA, SA tended to be elicited more likely in SDS (21 cases, 50.0%) and in SND (8 cases, 44.4%) than in OPCA (7 cases, 12.7%) (p < 0.01 by chi-squared test). In MSA, the longer the duration of the disease became, the more SA was elicited, but not in ALS and CSM. Multivariate analysis (quantification method type II) showed that clinical signs as a statistical contribution factor for SA elicitation ranked Babinski's sign, micturition disturbance in ALS and CSM and Babinski's sign, orthostatic hypotension in MSA in order: In all 3 diseases, Babinski's sign and autonomic disturbance ranked higher. This conclusion suggested that SA was not always related to the pyramidal tract damage and was associated with the damage of small myelinated fibers in and/or around the pyramidal tract. |
| 1994 | [A case of anaphylaxis caused by sunflower seed]. | Arerugi | A 14 years old boy experienced an anaphylactic reaction of dyspnea, vomiting, urticaria and hypotension after he ate sunflower seeds. Specific IgE-mediated hypersensitivity to sunflower seen extract was demonstrated by skin tests and radioallergosorbent test (RAST). By immunoblotting test analysis (SDS-PAGE, Western blotting method), the allergenic activity of sunflower seem were shown to be in the MW range of 13.5 Kd. |
| 1993 | Midodrine in neurogenic orthostatic hypotension. A new treatment. | Int Angiol | Neurogenic orthostatic hypotension is a severely disabling condition due to deficient peripheral vasoconstrictor tone in response to the upright position and is characterized by a decrease in blood pressure upon standing associated with symptoms of lightheadedness, dizziness, visual "white-out", weakness, lack of energy, near syncope or even syncope. Previous pharmacologic treatment of neurogenic orthostatic hypotension has been problematic. Midodrine, a new specific alpha-1-agonist has been shown to produce arteriolar constriction and decrease in venous pooling via a constriction of venous capacitance vessels. Therefore, a recent multicenter study evaluated the safety and efficacy of midodrine therapy in 97 patients with neurogenic orthostatic hypotension due to various etiologies: Shy Drager syndrome (No. 18); Bradbury Eggleston syndrome (idiopathic orthostatic hypotension) (No. 20); diabetic autonomic neuropathy (No. 27); Parkinson's disease (No. 22); and miscellaneous (No. 10). Following one week of placebo therapy, the patients were randomized into 4 groups for a 4 week period of time; placebo, 2.5 mg, 5 mg, or 10 mg three times daily. The BE/SDS subgroup demonstrated a 27 +/- 8% (22 mmHg) increase in standing systolic blood pressure for the 10 mg dose. Diabetics achieved a significant increase at 5 mg. Similar increases were observed for the entire group on the 10 mg dose (p < 0.001). Symptoms or fainting, blurred vision, improved energy level, standing time, and depressed feelings were also significantly improved even at lower doses (p < 0.05 or less). Side effects were mild. Therefore, midodrine is an effective and safe agent for the treatment of neurogenic orthostatic hypotension. |
| 1993 | [Hyperthermia in a Shy-Drager syndrome patient--pathophysiological effects of body temperature and L-DOPS on orthostatic hypotension]. | Rinsho Shinkeigaku | A 65-year-old man was admitted to our hospital because of syncope, hyperthermia and urinary disturbance. Neurological examination revealed cerebellar ataxia, muscular rigidity, hyperreflexia with Babinski sign in both sides, and various autonomic dysfunctions including anisocoria, orthostatic hypotension and neurogenic bladder. He was diagnosed as having Shy-Drager syndrome (SDS). Oral administration of L-threo-3,4-dihydroxyphenyl-serine (L-DOPS) (300 mg/day) was started for orthostatic hypotension. After discharge he suffered from pneumonia at his house, and he kept himself warm because of a chill. The patient then fell into hyperthermia (44.0 degrees C), resulting in unconsciousness and a state of shock. He was transferred to our hospital again and was treated by body cooling and drip infusion of dopamine after which he recovered completely within one day. Control of body temperature and blood pressure was examined by heat loading and head-up tilt after heat loading, with or without administration of L-DOPS. These examinations showed that his rectal body temperature rose easily during heat loading and that this phenomenon was enhanced by the administration of L-DOPS. Moreover as his body temperature became higher, he more easily developed syncope due to orthostatic hypotension. It is suggested that in SDS patients, L-DOPS facilitates orthostatic hypotension and syncope in high temperature conditions. |
| 1992 | Effect of xamoterol in Shy-Drager syndrome. | Circulation | Xamoterol, a cardioselective beta 1-adrenoceptor partial agonist, has been reported to be effective on postural hypotension. We investigated the effect of xamoterol in five patients with Shy-Drager syndrome (SDS) in relation to their prevailing sympathetic nerve activity and sensitivity of beta-adrenoceptors and the change in circadian variation of blood pressure.Ambulatory blood pressure over 24 hours was monitored by noninvasive sphygmomanometer (model 5200, Spacelab). Plasma norepinephrine levels of SDS patients were significantly lower than that of normal subjects (n = 5) both at rest (54 +/- 15 versus 178 +/- 83 pg/ml) and after 10-minute standing (74 +/- 24 versus 318 +/- 143 pg/ml). Infusion of isoproterenol (0.02 micrograms/kg/min) produced a mild rise of systolic blood pressure and tachycardia in normal subjects but resulted in marked hypotension and tachycardia in SDS subjects. After xamoterol administration (200 mg b.i.d.), systolic blood pressure and heart rate were significantly increased in the averages during the day; however, increases were more pronounced at night. In two of the five patients, the improvement in dizziness was large enough to enable them to increase their daily activities.Our observations suggest that 1) beta 1-selective, high intrinsic sympathomimetic activity of xamoterol increases blood pressure and heart rate in patients with SDS as a consequence of their prevailing beta 1-adrenoceptor hypersensitive state, and 2) blood pressure monitoring over 24 hours appears to have important advantages in evaluating the therapeutic effects on postural hypotension. |
| 1991 | Abnormally increased iron concentration in basal ganglia in Shy-Drager syndrome. MR imaging and autonomic study. | Arq Neuropsiquiatr | Report of an early case of Shy-Drager syndrome in a 67 year-old woman patient. Autonomic failure was diagnosed by functional evaluation as well as laboratory tests. MR imaging disclosed a prominent putamina hypodensity in T2-weighted images at high field strength due to iron increased depositing in this basal ganglia. MR imaging evidences confirm Shy-Drager syndrome diagnosis, and contributes for differential diagnosis of idiopathic hypotension (pure autonomic failure) in special in SDS early cases. |
| 1991 | Anaphylaxis to annatto dye: a case report. | Ann Allergy | Annatto dye is an orange-yellow food coloring extracted from the seeds of the tree Bixa orellana. It is commonly used in cheeses, snack foods, beverages, and cereals. Previously reported adverse reactions associated with annatto dye have included urticaria and angioedema. We present a patient who developed urticaria, angioedema, and severe hypotension within 20 minutes following ingestion of milk and Fiber One cereal, which contained annatto dye. Subsequent skin tests to milk, wheat, and corn were negative. The patient had a strong positive skin test to annatto dye, while controls had no response. The nondialyzable fraction of annatto dye on SDS-PAGE demonstrated two protein staining bands in the range of 50 kD. Immunoblotting demonstrated patient IgE-specific for one of these bands, while controls showed no binding. Annatto dye may contain contaminating or residual seed proteins to which our patient developed IgE hypersensitivity. Annatto dye is a potential rare cause of anaphylaxis. |
| 1991 | [Shy-Drager syndrome: its autonomic function, alpha 2 receptor density and mechanism of postprandial hypotension]. | J Cardiol | The autonomic function, platelet alpha 2 receptor (alpha 2R) density, and mechanism of postprandial hypotension were examined in a 58-year-old man with Shy-Drager syndrome (SDS). His chief complaints were orthostatic syncope and impotence. His blood pressure was kept within normal limits in a supine position, but severe hypotension and fainting occurred when he assumed an upright posture. There were diminished sweating response to warm stress, abnormal pupil reactions to drugs, lack of blood pressure elevation at phase IV during the Valsalva maneuver, and a lack of pressor response to hyperventilation and cold stress. The plasma norepinephrine levels (pNE) were very low in a supine position at rest and in a head-up tilt position. Severe blood pressure fall (hypotension) associated with a lack of pNE elevation occurred during an oral glucose tolerance test (oGTT). Platelet alpha 2R density increased and the pressor response to infused norepinephrine (NE-R) was pronounced. The heart rate response to injected atropine was clearly attenuated. The coefficient of the R-R interval variation in the ECG (CVRR), which may reflect parasympathetic activity, was markedly low at rest. In addition, a decrease in a head-up tilt position and increase during oGTT also resolved. These results indicate that a dysfunction of the parasympathetic and sympathetic nervous systems and the up-regulation in the alpha 2R system that leads to an increase in alpha 2R density in SDS are involved in this disease and that the mechanism of postprandial hypotension in SDS may be different from that in normal elderly subjects. |
| 1990 | Mirtazapine vs. amitriptyline vs. placebo in the treatment of major depressive disorder. | Psychopharmacol Bull | Patients (n = 150) were randomized to a 6-week, double-blind study to evaluate the relative efficacy and safety of mirtazapine, amitriptyline, and placebo in the treatment of major depressive disorder symptoms. Average daily modal doses were mirtazapine, 18 mg; amitriptyline, 111 mg; and placebo, 4.6 capsules. Mirtazapine- and amitriptyline-treated patients had statistically significantly greater mean Hamilton Rating Scale for Depression (HAM-D) score reductions (weekly visits 1, 2, 4, and endpoint) compared to placebo. These findings were supported by the Montgomery-Asberg Depression Rating Scale (MADRS); the Zung Self-rating Depression Scale (SDS); and the Clinical Global Impressions (CGI) scales. Somnolence and weight gain were the only adverse clinical experiences (ACEs) reported substantially more often by mirtazapine-treated patients than by those in the placebo group. However, more amitriptyline-treated patients reported decreased visual accommodation, dry mouth, dyspepsia, constipation, tachycardia, hypertension, hypotension, discoordination, dizziness, and tremor than mirtazapine- or placebo-treated patients. Results of this study indicate that mirtazapine is more effective than placebo in the treatment of these patients, and superior to amitriptyline in respect to anticholinergic and cardiovascular effects. |
| 1989 | Cardiovascular reflex responses in patients with unexplained syncope. | Clin Sci (Lond) | 1. This study was undertaken to determine whether, in a group of patients complaining of recurrent syncopal attacks but with no apparent cause, there was evidence of abnormal cardiovascular reflex control. 2. The steady-state responses of blood pressure, heart rate and cardiac output to head-up tilting were determined in 67 patients using entirely 'non-invasive' methods. In some patients we also studied the immediate response of pulse interval to carotid baroreceptor stimulation by neck suction. 3. Two of the patients developed vasovagal attacks during the 20 min test period of head-up tilting. Eighteen others showed postural hypotension, defined as a fall in blood pressure to outside the limits of two SDS from the mean values of age-related control subjects. 4. Patients who showed postural hypotension had a mean fall in cardiac output significantly larger than that in age-related control subjects. Responses in the nonhypotensive patients did not differ significantly from controls. 5. Stimulation of carotid baroreceptors resulted in significantly smaller responses of pulse interval in the patients defined as having postural hypotension compared with the non-hypotensive patients and with the age-related control subjects. 6. In some of the patients who did not show postural hypotension during the standard test, the duration of tilt was prolonged for up to 1 h. Five out of 26 patients developed vasovagal attacks. All the vasovagal patients showed an initial tachycardia and the response of pulse interval to neck suction was significantly larger than in the controls.(ABSTRACT TRUNCATED AT 250 WORDS) |
| 1989 | The biological and immunological properties of fractionated atrial extracts from young and old rats. | Life Sci | We have previously reported that the biological activity of rat atrial extract declines with age. The present study was undertaken to further evaluate the natriuretic, hypotensive and immunological properties of fractionated and HPLC purified atrial extracts prepared from young and old rats. Acetic acid extracts were prepared and subsequently fractionated by gel permeation chromatography. The high (greater than 10,000 daltons) and low (less than or equal to 10,000 daltons) molecular weight fractions were collected, lyophilized and assayed. Radioimmunoassay competitive binding curves of the initial and fractionated extracts were parallel (p greater than 0.05) to the synthetic ANP standard. No differences in parallelism (p greater than 0.05) were observed in the natriuretic activity of the initial extracts, the low molecular weight (LMW) fractions from both age groups, the 290 day high molecular weight (HMW) fraction or the synthetic ANP standard. However, the natriuretic activity of the 15 day HMW fraction was significantly attenuated compared to the other treatment groups (p less than 0.05). The initial 15 day extract was also significantly more hypotensive than the 290 day extract (p less than 0.05). HMW extracts were subjected to HPLC and the resulting immunoreactive ANP peak was reassayed. Based on SDS-PAGE and immuno blot analysis, the HPLC purified fraction was found to contain only immunoreactive proANP. Subsequent bioassay revealed greater hypotension and reduced natriuretic activity in the 15 day proANP fraction in comparison to a similarly prepared extract from older animals. Thus, we conclude that qualitative differences in the biological properties of atrial extracts may be ascribable to age-related changes in the composition of proANP or to other undefined biologically active atrial substance(s). |
| 1986 | Multiple system atrophy (Shy-Drager syndrome): MR imaging. | Radiology | The Shy-Drager syndrome (SDS) is a form of progressive autonomic nervous system failure (PAF) with orthostatic hypotension and associated extrapyramidal involvement that is often mistaken for Parkinson disease. SDS includes olivopontocerebellar atrophy and striatonigral degeneration which is attended by PAF. Eight patients with SDS were studied on a 0.5-T superconducting system utilizing T1-weighted inversion recovery (IR) and T2-weighted spin-echo pulse sequences and also on a 1.5-T system using spin-echo sequences. With IR sequences, atrophy of the putamina was demonstrated in patients with SDS that is consistent with findings of neuronal loss in these nuclei reported on postmortem examinations. An abnormal decrease in signal intensity of the putamina, particularly along their lateral and posterior portions, was also detected, predominantly on T2-weighted sequences, and in three cases on T1-weighted spin-echo sequences. Abnormalities were detected on both imagers but were shown with greater clarity on the 1.5-T device. SDS is the first disease in which convincing basal ganglia changes have been shown in vivo exclusively by MR imaging. |
| 1985 | [Neuropathological background of spinocerebellar degeneration--with special reference to autonomic nervous system lesions in olivopontocerebellar atrophy, Shy-Drager syndrome and multiple system atrophy]. | No To Shinkei | For elucidation of actual status of olivopontocerebellar atrophy (OPCA) in nosological relation to Shy-Drager syndrome (SDS) and multiple system atrophy (MSA), neuropathological examination with morphometric survey on the intermediolateral column of the spinal cord was performed. The materials were 13 cases registered in our laboratory. Clinically, they consisted of 9 sporadic OPCA including 2 cases with prominent autonomic failure, and 4 hereditary spinocerebellar degeneration. In the autonomic nervous system of CNS, degeneration of the intermediolateral column was found in the sporadic cases without exception, irrespective of presence or absence of orthostatic hypotension, while the hereditary cases showed neither orthostatic hypotension nor neuronal loss in the nucleus. The autonomic centers in the brain-stem and cerebellum were systematically affected in both the sporadic and the hereditary cases. It was particularly remarked that the fastigial nucleus, tractus and nucleus solitarius, which have been suggested to be related to cardiovascular control, was severely affected. The locus coeruleus, on the other hand, was less severely affected in the hereditary cases. The most remarkable finding was that there was no case with neuropathological change restricted only to the olivo-ponto-cerebellar (OPC) and/or autonomic nervous systems. The sporadic cases had OPC system degeneration with striato-nigral degeneration (SND) and autonomic nervous system degenerations, irrespective of differences in clinical features from case to case. It should be emphasized that the actual neuropathological status of our sporadic cases could be regarded as a multisystemic degeneration inevitably combined with OPC system degeneration, apart from whether such cases are designated as MSA or not. Finally it was remarked that the hereditary cases were different from the sporadic cases in that there occurred far less severe involvement of the locus coeruleus and intermediolateral column, and primary degeneration of the substantia nigra different obviously from SND. |
| 1984 | Fulminating haemophilus influenzae b meningitis. | Can J Neurol Sci | Haemophilus influenzae type b (HIb) is the most common cause of bacterial meningitis in children with a mortality rate ranging from 1.6% to 14%. Most patients have a 2-3 day history of symptoms prior to admission. A few have fulminating disease with rapid neurological deterioration. Review of 191 cases of HIb meningitis revealed a mortality rate of 2.1% but all who died had fulminating meningitis (FM). Four of six patients with FM died. FM patients had symptoms for less than 24 hours before rapid neurological deterioration with increased ICP, seizures, coma and/or respiratory arrest. Review of 10 FM cases revealed that on admission, 5 had hypotension, 3 had thrombocytopenia, and 8 had coma. Typical CSF changes were seen in only 7. All fatal cases died within 24 hours. Brain swelling and tonsillar herniation were found at autopsy. SDS-PAGE outer membrane protein subtyping did not show one "killer strain". Animal and autopsy data suggest that diminished CSF outflow and cerebral edema contribute to increased ICP. To improve survival of FM patients, initial treatment must (1) decrease ICP below levels impairing cerebral perfusion, (2) maintain adequate ventilation and blood pressure, and include (3) LP when stable, (4) antibiotics, and (5) close monitoring. Utilizing these principles, two FM patients survived without major sequelae. |
| Vocal fold paresis in Shy-Drager syndrome. | Ann Otol Rhinol Laryngol | Twelve patients with Shy-Drager syndrome (SDS) presenting symptoms of multiple nervous system atrophy and orthostatic hypotension were examined for laryngeal movement disorders and vocal impairment in speech. Vocal fold abductor paresis was found in 11 patients and was bilateral in 10. Speech task performance was recorded in SDS patients, Parkinson patients and age- and sex-matched controls. Trained listeners with inter-rated reliability greater than or equal to .85 judged each recording on 20 attributes while blind to speaker identity. SDS patients had a breathy and strained voice quality, reduced loudness, monopitch and monoloudness, imprecise consonants, variations in rate and rate-slowing, suggesting a flaccid type of dysarthria. In comparison with Parkinson patients, SDS patients had excess vocal hoarseness, intermittent glottal fry and a slow and deliberate speaking rate. Orthostatic hypotension, laryngeal stridor, hoarseness, intermittent glottal fry and slow speech rate were found to be discriminating symptoms of SDS. |
| 1978 | The splanchnic autonomic outflow in Shy-Drager syndrome and idiopathic orthostatic hypotension. | Ann Neurol | Since splanchnic outflow is important in the maintenance of postural normotension in man, we performed a quantitative analysis of preganglionic autonomic neuron cell bodies of the seventh thoracic spinal cord segment and their corresponding axons in 2 patients with Shy-Drager syndrome (SDS) and 1 with idiopathic orthostatic hypotension (IOH) and compared these values to control data. The intermediolateral column (ILC) neuron cell body counts were reduced to 17% of control levels in SDS and 52% of control levels in IOH. The B fiber counts in the corresponding ventral spinal root were reduced to 21% and 41% in SDS and IOH, respectively. From the present study and our previous results of ILC counts with age, we infer that orthostatic hypotension does not develop until half or more of the preganglionic autonomic neurons have degenerated. An additional finding in SDS is that there is involvement beyond autonomic neurons. |