Performance of homeostasis model assessment and serum high-sensitivity C-reactive protein for prediction of isolated post-load hyperglycaemia.

AIMS: To evaluate whether homeostasis model assessment and high-sensitivity C-reactive protein improve the prediction of isolated post-load hyperglycaemia. METHODS: The subjects were 1458 adults without self-reported diabetes recruited between 2006 and 2010. Isolated post-load hyperglycaemia was defined as fasting plasma glucose < 7 mmol/l and 2-h post-load plasma glucose ≥ 11.1 mmol/l. Risk scores of isolated post-load hyperglycaemia were constructed by multivariate logistic regression. An independent group (n = 154) was enrolled from 2010 to 2011 to validate the models' performance. RESULTS: One hundred and twenty-three subjects (8.28%) were newly diagnosed as having diabetes mellitus. Among those with undiagnosed diabetes, 64 subjects (52%) had isolated post-load hyperglycaemia. Subjects with isolated post-load hyperglycaemia were older, more centrally obese and had higher blood pressure, HbA(1c), fasting plasma glucose, triglycerides, LDL cholesterol, high-sensitivity C-reactive protein and homeostasis model assessment of insulin resistance and lower homeostasis model assessment of ß-cell function than those without diabetes. The risk scores included age, gender, BMI, homeostasis model assessment, high-sensitivity C-reactive protein and HbA(1c). The full model had high sensitivity (84%) and specificity (87%) and area under the receiver operating characteristic curve (0.91), with a cut-off point of 23.81; validation in an independent data set showed 88% sensitivity, 77% specificity and an area under curve of 0.89. CONCLUSIONS: Over half of those with undiagnosed diabetes had isolated post-load hyperglycaemia. Homeostasis model assessment and high-sensitivity C-reactive protein are useful to identify subjects with isolated post-load hyperglycaemia, with improved performance over fasting plasma glucose or HbA(1c) alone.

Multi-tissue proteogenomic analysis for mechanistic toxicology studies in non-model species.

New approach methodologies (NAM), including omics and in vitro approaches, are contributing to the implementation of 3R (reduction, refinement and replacement) strategies in regulatory science and risk assessment. In this study, we present an integrative transcriptomics and proteomics analysis workflow for the validation and revision of complex fish genomes and demonstrate how proteogenomics expression matrices can be used to support multi-level omics data integration in non-model species in vivo and in vitro. Using Atlantic salmon as an example, we constructed proteogenomic databases from publicly available transcriptomic data and in-house generated RNA-Seq and LC-MS/MS data. Our analysis identified ∼80,000 peptides, providing direct evidence of translation for over 40,000 RefSeq structures. The data also highlighted 183 co-located peptide groups that supported a single transcript each, and in each case, either corrected a previous annotation, supported Ensembl annotations not present in RefSeq, or identified novel previously unannotated genes. Proteogenomics data-derived expression matrices revealed distinct profiles for the different tissue types analyzed. Focusing on proteins involved in defense against xenobiotics, we detected distinct expression patterns across different salmon tissues and observed homology in the expression of chemical defense proteins between in vivo and in vitro liver systems. Our study demonstrates the potential of proteogenomic analyses in extending our understanding of complex fish genomes and provides an advanced bioinformatic toolkit to support the further development of NAMs and their application in regulatory science and (eco)toxicological studies of non-model species.

A comprehensive 4-year survey of adverse drug reactions using a network-based hospital system.

WHAT IS KNOWN AND OBJECTIVE: Spontaneous Adverse Drug Reaction Reporting Systems (ADRRS) provide early warnings or 'signals' for adverse drug reactions (ADRs). Our aim was to survey reports of ADRs made through our teaching-hospital-based pharmacovigilance system to identify the drugs most commonly associated with allergies and the types of immunological reactions reported. METHODS: Adverse drug reactions records were retrieved from our network-based electronic notification system. RESULTS AND DISCUSSION: Four hundred and seventy four reports of adverse drug effects were studied. 37.3% of the reactions were immune-mediated drug hypersensitivity reactions. True drug hypersensitivity reactions involving IgE-mediated drug allergies accounted for 15% of all reactions. Of the drug hypersensitivity reactions, more than half (67%) were morbilliform skin eruptions, whereas cases of urticaria accounted for 20%. Antibiotics (33% of cases) were the most commonly reported drug allergies, followed by non-steroidal anti-inflammatory drugs (13%) and anti-epileptic agents (10%). WHAT IS NEW AND CONCLUSIONS: A hospital-based ADR reporting system can generate useful data. In our study, antibiotics accounted for the majority of drug allergies, particularly anaphylactic reactions. More cases of drug allergies were owing to cephalosporin allergies than penicillins. Anti-epileptic agents caused most of the severe drug hypersensitivity syndromes.

Centric fusion, satellite DNA, and DNA polarity in mouse chromosomes.

A fluorescent staining technique has demonstrated a contralateral arrangement of fluorescent spots in the centromeric region of mouse metacentric chromosomes which have resulted from centric fusion. The results suggest that centric fusion involves the maintenance of DNA polaritv through the centromere and that the thymidine-rich chain of satellite DNA in the centromeric region is associated with the same DNA chain in every mouse autosome.

Time-dependent benefit of initial thrombosuction on myocardial reperfusion in primary percutaneous coronary intervention.

BACKGROUND: In ST-segment elevation acute myocardial infarction (STEMI), dislodgement of thrombus within the culprit artery during primary percutaneous coronary intervention (PCI) may cause distal embolisation and impaired myocardial reperfusion. Clinical results of thromboembolic protection strategies have been controversial. We conducted this study to investigate whether the benefit of thrombus removal is time dependent. METHODS: Seventy-four STEMI patients within 12 h from onset were randomised to receive either primary PCI with initial thrombosuction (IT) or standard strategy. Results were analysed in subgroups according to the onset-to-lab time intervals (subgroup 1: 0-240 min, subgroup 2: 241-480 min and subgroup 3: 481-720 min). RESULTS: The primary end-points were improvements in thrombolysis in myocardial infarction flow (DeltaTIMI) and myocardial blush grade (DeltaMBG) postprocedure. Better DeltaTIMI (2.2 +/- 1.1 vs. 1.5 +/- 1.3, p = 0.014) and DeltaMBG (2.3 +/- 1.1 vs. 1.0 +/- 1.5, p < 0.001) were observed in IT patients, compared with standard PCI patients. In onset-to-lab time subgroup analysis, the difference between IT and standard PCI is significant only in subgroup 2 (DeltaTIMI 2.6 +/- 1.0 vs. 1.3 +/- 1.2, p = 0.007; DeltaMBG 2.6 +/- 0.9 vs. 1.0 +/- 1.1, p = 0.010), but not in the other two subgroups. CONCLUSIONS: This prospective randomised study shows that primary PCI with IT may improve epicardial flow and myocardial reperfusion in patients with STEMI, and this benefit is the most significant in patients treated within 4-8 h after symptom onset.

Innovative technique to reconstruct two branches of the right hepatic artery in living donor liver transplantation.

Hepatic arterial thrombosis is a critical complication in living donor liver transplantation (LDLT). Two separate branches of the right hepatic artery (RHA) are sometimes observed and addressed by anastomosis of the larger branch first, then checking backflow from the smaller branch. If not good, the smaller branch must be reconstructed. We used the cystic artery as a conduit for the reconstruction. Meticulous dissection was performed to identify all branches of the hepatic artery in the donor operation. The length of cystic artery preserved was as long as possible. The cystic arterial stump was anastomosed to the stump of the posterior branch the of RHA under microscopic guidance on the back table. Patency was checked through the stump of the anterior branch of the RHA. With this technique, only one orifice, the stump of right anterior hepatic artery, was used for hepatic artery reconstruction. We have performed this technique in two patients. Both had good arterial flow after living donor liver transplantation. This innovative technique is easy and safe, and requires only one anastomosis, which, in theory, decreases the adds of developing hepatic arterial thrombosis.

Hypofractionated CyberKnife stereotactic radiosurgery for acoustic neuromas with and without association to neurofibromatosis Type 2.

CyberKnife stereotactic radiosurgery (CKSRS) has been proved effective in treating intra-cranial lesions. To treat acoustic neuroma (AN) patients with or without neurofibromatosis Type 2 (NF2) associations, the functional preservation of hearing, trigeminal nerve, and facial nerve are important. Twenty-one patients were treated with hypofractionated CKSRS. Fourteen non-NF2 and seven NF2 patients were enrolled. Cranial nerve function, audiograms, and magnetic resonance images (MRI) were monitored. Mean follow-up was 15 month. Tumors with volumes ranging from 0.13 to 24.8 cm3 (mean 5.4 cm3) were irradiated with the marginal dose 1800-2000 cGy/3 fractions. Tumors were treated with an 80 to 89% isodose line (mean 83%) and mean 97.9% tumor coverage. Two patients experienced hearing deterioration (16.7%) in the non-NF2 group, and 3 patients (50%) in the NF2 group. No facial or trigeminal dysfunction, brain stem toxicity, or cerebellar edema occurred. Tumor regression was seen in 9 patients (43%) and stable in 12 patients (57%). 100% tumor control rate was achieved. Hypofractionated CKSRS was not only effective in tumor control but also excellent in hearing preservation for non-NF2 AN. But for NF2 patients, although the tumor control was remarkable, hearing preservation was modest as in non-NF2 patients.

The Angio-Seal arterial closure device for early ambulation after elective percutaneous coronary intervention in patients receiving low-dose enoxaparin.

This study evaluated the efficacy and safety of use of the Angio-Seal vascular closure device deployment for early ambulation (2 h) after elective percutaneous coronary intervention in 143 consecutive patients receiving either intravenous low-dose enoxaparin (0.5 mg/kg) or unfractionated heparin (UFH). The initial success rate of Angio-Seal(trade mark) deployment was 98.6%, with no significant difference between the UFH group (98.9%) and the enoxaparin group (98.0%). In-hospital and clinic outcomes were evaluated in the 141 patients with successful Angio-Seal deployment. During hospitalization, there were no deaths, myocardial infarction, urgent target vessel revascularization or bleeding events in either group; three patients in the UFH group and none in the enoxaparin group had minor vascular complications (differences not significant). In clinic follow-up, two patients in the UFH group and none in the enoxaparin group had major vascular complications (differences not significant). Routine use of the Angio-Seal(trade mark) for early ambulation in patients receiving intravenous low-dose enoxaparin compared with UFH provides promising efficacy and safety for daily practice.

Kinetics of amino acid transport across bone marrow cell membranes.

Dog bone marrow nucleated cells were incubated in media containing labeled L-amino acids, and the cellular accumulation of radioactivity as a function of time was measured and analyzed according to a three-compartment model.(a) The turnover half-time of intracellular histidine arising from extracellular sources was 6.0 +/-0.7 (SEM) min. Similar turnover half-time for serine was 10 +/-2 (SEM) min; for tryptophan, 6.5 +/-1.2 (SEM) min; and for methionine, 4.4 +/-0.6 (SEM) min. Loss of the intracellular amino acids to the extracellular space accounted for the major portion of their turnover.(b) Each of the four amino acids noted above appeared to be actively transported into the cell.(c) At physiologic extracellular histidine concentrations, histidine entered the cell predominantly by a facilitated process with an apparent Michaelis constant of 0.28 mmole/liter and a limiting flux of 14 x 10(-8) mmumole/min per cell. Loss of histidine from the cell appeared to be substantially facilitated with an apparent Michaelis constant greater than that for histidine entry.(d) Insulin and glucagon had no measurable effect on histidine transport across the bone marrow cell membrane.(e) Methionine depressed the influx and the fractional turnover rate of the intracellular pool of both histidine and serine.(f) The extent of cellular accumulation of alpha-N-formiminoglutamate and alpha-N-formylglutamate was about 1/100 that of histidine. alpha-N-formiminoglutamate added to the culture was about (1/4) as effective as histidine in providing monocarbon fragments for DNA thymine synthesis.

Development and characterization of desmoglein-3 specific T cells from patients with pemphigus vulgaris.

Pemphigus vulgaris (PV) is a cutaneous autoimmune disease characterized by blister formation in the suprabasilar layers of skin and mucosae and anti-desmoglein-3 (Dsg3) autoantibodies bound to the surface of lesional keratinocytes and circulating in the serum of patients. This disease can be reproduced in neonatal mice by passive transfer of patients' IgG, indicating that humoral immunity plays an important role in the pathogenesis of PV. Currently, the role of T lymphocytes in the development of PV is not clear. Here, we report that three immunoreactive segments of the ectodomain of Dsg3 specifically induced proliferation of T cells from PV patients. We found that T lymphocytes from 13 out of 14 patients responded to at least one of three Dsg3 peptides. T cells from controls and other patient groups did not respond to these Dsg3 peptides. The major T cell population stimulated by these Dsg3 peptides was CD4 positive. Dsg3-specific T cell lines and clones were developed and were shown to express a CD4 positive memory T cell phenotype. Upon stimulation, these cell lines and clones secreted a Th2-like cytokine profile. The Dsg3 responses of these T cells were restricted to HLA-DR, and not -DQ and -DP, of the major histocompatibility complex. This information will help to elucidate the cellular immune abnormalities leading to production of pathogenic IgG autoantibodies in patients with PV.

Desmoglein-1-specific T lymphocytes from patients with endemic pemphigus foliaceus (fogo selvagem).

Fogo selvagem (FS), the endemic form of pemphigus foliaceus, is a cutaneous autoimmune disease characterized by subcorneal blistering of the epidermis and the production of autoantibodies against the desmosomal antigen desmoglein-1 (Dsg1). Previously, we showed that mice injected with autoantibodies from FS patients develop a skin disease that reproduces the clinical, histological, and immunological features of FS, indicating that autoantibodies play an essential role in the development of this disease. The purpose of this study was to characterize the autoimmune T-cell response associated with FS. We provide here the first evidence, to our knowledge, that the great majority of FS patients have circulating T lymphocytes that specifically proliferate in response to the extracellular domain of Dsg1. Long-term T cells developed from these patients also responded to Dsg1, and this antigen-specific response was shown to be restricted to HLA-DR molecules. These Dsg1-reactive FS T cells exhibited a CD4-positive memory T-cell phenotype and produced a T helper 2-like cytokine profile. These findings represent the initial steps in defining the role of T cells in FS autoimmunity.

Vascular effects on ciliary tissue from endoscopic versus trans-scleral cyclophotocoagulation.

AIM: To determine the acute and chronic vascular effects of endoscopic cyclophotocoagulation (ECP) versus trans-scleral cyclophotocoagulation (TCP) in a rabbit model. METHODS: 20 rabbits underwent ECP in one eye and another 20 rabbits had unilateral TCP. Five treated eyes from each group underwent endoscopic fluorescein angiography (EFA) of the treated ciliary processes at each of the following time points: immediate, 1 day, 1 week, and 1 month. Five untreated rabbits were used as controls. The NIH Image software program was used to trace ciliary processes in order to determine their mean intensity, as a measure of their perfusion. Histopathology was also performed on eyes from each time point. RESULTS: Immediately and 1 day after laser, both TCP and ECP eyes demonstrated severely reduced or non-existent blood flow in the areas of treatment. TCP treated processes essentially remained non-perfused at the 1 week and 1 month time points. ECP treated processes showed some reperfusion at 1 week and greater reperfusion by 1 month. Histopathology confirmed the overall greater vascular occlusion seen with TCP. CONCLUSIONS: Chronic poor perfusion of the ciliary body after TCP may account, in part, for its efficacy, as well as the significant complications including hypotony and phthisis. Late reperfusion of this region after ECP may provide some insight into the differences in efficacy and complication rates compared to TCP.

Idiopathic syringomyelia: case report and review of the literature.

Syringomyelia is an uncommon disease that is caused most often by type I Chiari malformation, which develops in the hindbrain, and less frequently by other factors which are not limited to the hindbrain, including trauma, infection, or scoliosis. Idiopathic syringomyelia is rare. We present in this article a patient with idiopathic syringomyelia characterized by hypoesthesia and progressive weakness in the left lower limb. Decompression was attempted by means of laminectomy and a syringoarachnoid shunt. Motor, sensory, and bladder functions were monitored by the change in Japanese Orthopedic Association scores, which increased from 10 points preoperatively to 14 points 30 days postoperatively. This case demonstrates the effectiveness of surgical decompression in a patient with remarkable neurological deficit.

Evaluation of the pylorus with concurrent intraluminal pressure and EndoFLIP in patients with nausea and vomiting.

BACKGROUND: Nausea and vomiting occurs in gastroparesis due to diabetes mellitus or unknown causes. The aim of this study was to compare (i) pyloric distensibility to pyloric manometric pressure in patients with nausea and vomiting and (ii) to correlate distensibility with delays in gastric emptying. METHODS: Sleeve manometry and EndoFLIP were performed sequentially during the same endoscopy on 114 patients with nausea and vomiting (47 with diabetes mellitus and 67 with idiopathic cause) after a standardized gastric emptying study. The sleeve manometer was positioned fluoroscopically, and the EndoFLIP was placed endoscopically. Manometric pressure using a water-perfused catheter and distensibility using an EndoFLIP filled with 40 cc of saline were measured from the pylorus. KEY RESULTS: The basal pyloric pressure was elevated (>10 mmHg) in 34 patients and was normal in 80 patients. The basal and peak pressures were similar in patient with normal and delayed gastric emptying (p > 0.05). There was a significant decrease in distensibility (8.0 ± 1.0 mm(2) /mmHg) in patients with gastric retention (>20% at 4 h) compared with patients (12.4 ± 1.4 mm(2) /mmHg) (p < 0.01) with normal gastric retention (<10%). Pressure measurements from the sleeve manometer and the EndoFLIP correlated (r = 0.29) (p < 0.002), and increased EndoFLIP balloon pressure (19.4 ± 1.4 mmHg) (p < 0.01) was associated with a severe delay in gastric emptying. CONCLUSIONS & INFERENCES: Elevated basal pyloric pressure occurs in 42% of patients with nausea and vomiting and delayed emptying. Decreased pyloric distensibility occurs with nausea, vomiting, and delayed gastric emptying. The EndoFLIP is a useful tool in the evaluation of pyloric function in symptomatic patients.

Reduction in lipopolysaccharide-induced thrombocytopenia by triflavin in a rat model of septicemia.

BACKGROUND: Thrombocytopenia frequently occurs early in the course of Gram-negative bacterial infections. Triflavin, an Arg-Gly-Asp-containing disintegrin, has been suggested to interfere with the interaction of fibrinogen with the glycoprotein IIb/IIIa complex. The present study was undertaken to determine whether triflavin could prevent thrombocytopenia in lipopolysaccharide (LPS)-treated rats. METHODS AND RESULTS: In this study, 51Cr-labeled platelets were used to assess blood and tissue platelet accumulation after LPS challenge. The administration of LPS (4 mg/kg IV bolus) for 4 hours induced a reduction in radiolabeled platelets in blood and an obvious accumulation of platelets in liver. Triflavin (500 microg/kg) but not GRGDS (20 mg/kg) significantly prevented the alteration of radiolabeled platelet distribution in blood and liver when induced by LPS. Furthermore, triflavin but not GRGDS markedly suppressed the elevation in plasma thromboxane B2 concentration within the 4-hour period of LPS administration. In LPS-treated rats, the 5-hydroxytryptamine level was lower in the blood and higher in the liver compared with levels in normal saline-treated rats. Pretreatment with triflavin (500 microg/kg) significantly reversed the 5-hydroxytryptamine concentration in blood and liver of LPS-treated rats. In histological examinations and platelet adhesion assay, triflavin markedly inhibited the adhesion of platelets to subendothelial matrixes in vivo and in vitro. CONCLUSIONS: The results indicate that triflavin effectively prevents thrombocytopenia, possibly through the following 2 mechanisms: (1) Triflavin markedly inhibits platelet aggregation, resulting in decreased thromboxane A2 formation. (2) It inhibits the adhesion of platelets to subendothelial matrixes, thereby leading to a reversal in the distribution of platelets in blood and liver in LPS-treated rats.

Effect of anti-hypertensive drug dose frequency on the clinic-home blood pressure difference in patients with stage 1 treated hypertension.

Clinic blood pressure (CBP) is generally used for diagnosis and treatment monitoring in hypertension, but target organ damage correlates more closely with home blood pressure (HBP). Eliminating the clinic-home blood pressure difference (CHBPD) would make conventional CBP a more accurate alternative to HBP. This prospective, randomized, open trial compared the effect of a once-daily versus a twice-daily regimen of anti-hypertensive therapy on CHBPD. After a 2-week wash-out period, 85 confirmed stage 1 hypertensive patients were randomized to receive 2 mg trichlormethiazide daily in one (40 subjects) or two (45 subjects) daily doses for 3 weeks. CBP and HBP measurements were taken during the third week of treatment and the CHBPD calculated. After treatment, the systolic and diastolic CHBPD values were significantly greater in the once-daily regimen than in the twice-daily regimen. Conventional CBP should not be used as an alternative to HBP for evaluating prognosis and monitoring anti-hypertensive therapy when using a once-daily regimen.

T lymphocytes from a subset of patients with pemphigus vulgaris respond to both desmoglein-3 and desmoglein-1.

Pemphigus vulgaris and pemphigus foliaceus are cutaneous autoimmune diseases characterized by intraepithelial blisters and autoantibodies to desmosomal glycoproteins. The antigens recognized by pemphigus vulgaris and pemphigus foliaceus autoantibodies are desmoglein-3 (Dsg3) and desmoglein-1 (Dsg1), respectively. Dsg3 and Dsg1 are members of the desmoglein subfamily of the cadherin supergene family of cell adhesion molecules. It has been well documented that a subset of pemphigus vulgaris sera have IgG reactivity to both Dsg1 and Dsg3, suggesting that Dsg1 may also participate in the autoimmune response of these patients. The cellular mechanisms of T cell autoimmunity in these patients, however, are completely unknown. In this study, we tested the proliferative responses of T lymphocytes from eight pemphigus vulgaris patients after incubation with Dsg3 and Dsg1 fusion proteins. The sera of four of these PV patients showed reactivity with both Dsg1 and Dsg3, whereas the remaining four reacted only with Dsg3. We found that T cells obtained from those patients that exhibited the combined Dsg1/Dsg3 autoantibody reactivity showed a proliferative response after exposure to either Dsg1 or Dsg3 fusion proteins. The cellular responses to both of these recombinant proteins were highly specific and restricted to the CD4-positive T cell population. T cells from pemphigus vulgaris patients with no anti-Dsg1 serum reactivity showed a proliferative response to Dsg3, but not to Dsg1. The Dsg1 fusion protein used in this study has minimal sequence homology with Dsg3. Thus, this study provides the first evidence that T cells from a subset of pemphigus vulgaris patients respond to both Dsg1 and Dsg3.

Epitopes targeted by bullous pemphigoid T lymphocytes and autoantibodies map to the same sites on the bullous pemphigoid 180 ectodomain.

Bullous pemphigoid is a blistering skin disease characterized by autoantibodies directed against the NC16A domain of bullous pemphigoid 180 (collagen XVII), a transmembrane protein of epidermal basal cells. Passive transfer studies in mice have shown that antibodies that bind to this immunodominant region of bullous pemphigoid 180 are capable of inducing a skin disease that closely mimics bullous pemphigoid, supporting the hypothesis that epitopes within NC16A are involved in the pathogenesis of bullous pemphigoid. In this study, we examined the autoimmune T cell response in bullous pemphigoid patients. T cells from eight of 12 bullous pemphigoid patients, all of whom had circulating anti-bullous pemphigoid 180 autoantibodies, showed a specific proliferative response to recombinant forms of NC16A. T cell lines and clones developed from four of these patients recognize the same NC16A peptides as those targeted by autoantibodies from the corresponding individuals. These NC16A-responding T lymphocytes express alpha/beta T cell receptors and CD4 memory T cell surface markers and exhibited a Th1/Th2 mixed cytokine profile that may support the production of antibodies. This new information will aid in defining the key steps involved in the development of the autoimmune response in bullous pemphigoid.

The role of subclass switching in the pathogenesis of endemic pemphigus foliaceus.

Endemic pemphigus foliaceus, like the sporadic form seen in the developed world, is mediated by IgG antibodies to desmoglein-1. We studied an endemic focus in Limao Verde, Brazil, where disease prevalence is 3.4%. We previously detected IgG antibodies to desmoglein-1 in 97% of patients, but also in 55% of normal subjects in the endemic focus, with progressively lower levels in normal subjects in surrounding areas. An environmental trigger is hypothesized to explain these and other findings. In this study we sought to determine if patients and enzyme-linked-immunosorbent-assay-positive normal subjects in Limao Verde differ in IgG subclass response to desmoglein-1. We developed a sensitive and specific subclass enzyme-linked immunosorbent assay using recombinant desmoglein-1 and standardized the assay to enable comparability between the four subclasses. We found that normal subjects have an IgG1 and IgG4 response, whereas patients have similar levels of IgG1 but a mean 19.3-fold higher IgG4 response. Patients in remission have a weak IgG4 response, and a 74.3-fold higher IgG4 response is associated with active disease. Finally, in five patients in whom we had blood samples from both before and after the onset of clinical disease, a mean 103.08-fold rise in IgG4 was associated with onset of clinical disease, but only a mean 3.45-fold rise in IgG1. These results suggest that the early antibody response in normal subjects living in the endemic area and in patients before the onset of clinical disease is mainly IgG1. Acquisition of an IgG4 response is a key step in the development of clinical disease.

Increased plasma norepinephrine accompanies persistent tachycardia after hydralazine.

To determine the role of the peripheral sympathetic nervous system in the persistent tachycardia caused by the antihypertensive drug hydralazine, we examined the temporal relationships between the changes in heart rate and plasma norepinephrine concentration and the reduction in blood pressure produced by a range of doses of hydralazine administered intravenously to five hypertensive patients. Significant linear correlations were found between the increases in heart rate and plasma norepinephrine concentration and the reduction in blood pressure at 15 and 30 minutes after injection. However, at 240 minutes after injection, changes in heart rate and plasma norepinephrine were not correlated with changes in blood pressure and were disproportionately elevated relative to the reduction in blood pressure. A significant linear correlation between changes in heart rate and plasma norepinephrine concentration was noted at 15, 30, and 240 minutes after injection. The temporal discordance of the changes of both heart rate and plasma norepinephrine relative to the reduction in blood pressure and the significant linear correlation between the increases in heart rate and plasma norepinephrine concentration suggest that continued activation of the peripheral sympathetic nervous system contributes to the persistent tachycardia seen after the administration of hydralazine.