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Effect of sleep deprivation on driving safety in housestaff.

Sleep deprivation is known to affect driving safety. Housestaff (HS) are routinely sleep-deprived when on call. We hypothesized that this would affect their driving. We therefore administered questionnaires regarding driving to 70 pediatric HS, who were on call every fourth night, and to 85 faculty members (FAC), who were rarely disturbed at night. HS were questioned about events during their residency, and FAC were questioned about events during the preceding three years. There was an 87% response rate for each group. HS slept 2.7 +/- 0.9 (SD) hours when on call vs 7.2 +/- 0.8 hours when not on call (p < 0.001). 44% of HS had fallen asleep when stopped at a light, vs 12.5% FAC (p < 0.001). 23% of HS had fallen asleep while driving vs. 8% FAC (ns). A total of 49% of HS had fallen asleep at the wheel; 90% of these events occurred post-call. In contrast, only 13% of FAC had fallen asleep at the wheel (p < 0.001). HS had received a total of 25 traffic citations for moving violations vs. 15 for FAC and were involved in 20 motor vehicle accidents vs. 11 for FAC. One traffic citation clearly resulted from HS falling asleep at the wheel vs. none for FAC. We conclude that HS frequently fall asleep when driving post-call. We speculate that current HS work schedules may place some HS at risk for injury to themselves and others. Further study, using prospectively objective measures is indicated.

Accidents, Traffic↗

Comparison of the acute hemodynamic effects of hypertonic or colloid infusions immediately after mitral valve repair.

OBJECTIVE: To determine the acute hemodynamic effect of hypertonic saline and/or colloid solutions as volume resuscitation in postoperative mitral valve repair patients. DESIGN: Prospective, randomized trial. SETTING: Postoperative cardiac intensive care unit of Broussais Hospital. PATIENTS: Twenty-six patients who underwent mitral valve repair were prospectively studied. Two patients were excluded during the study. INTERVENTIONS: During the immediate postoperative period, when wedge pressure decreases to <8 mm Hg, patients were randomly assigned to receive 250 mL of either hypertonic saline 7.2%-hydroxyethyl starch 6% (molecular weight, 200,000; hydroxyethylation ratio, 0.5) solution (HS-HES group), hypertonic saline 7.2% solution (HS group), or hydroxyethyl starch 6% solution (HES group). The infusion was completed within 15 mins. No additional volume was infused throughout the study. MEASUREMENTS AND MAIN RESULTS: Standard hemodynamic measurements and echocardiographic data demonstrated that HS-HES and HS induced a higher increase in left ventricular end-diastolic area than HES. In the HS-HES and HS groups, systemic vascular resistances decreased significantly and end-systolic area tended to decrease. In the HES group, systemic vascular resistances did not change and end-systolic area tended to increase. Accordingly, ejection fraction increased significantly by 21% and 18% with HS-HES (from 50.5 +/- 5.5 to 61.2 +/- 4.8) and HS (from 49.7 +/- 3.6 to 58.8 +/- 3.3), respectively, and did not change with HES. A major increase in cardiac index was observed after hypertonic solutions infusion, from 2.9 +/- 0.3 to 4.1 +/- 0.4 L/min/m2 in the HS-HES group and from 2.7 +/- 0.3 to 3.8 +/- 0.4 L/min/m2 in the HS group. Then, cardiac index progressively returned to baseline values within the 3 hrs after the infusion. No significant difference was observed between HS-HES and HS. In these groups, plasma sodium increased significantly after the infusion and remained higher than baseline values throughout the study. Adverse events were observed only with hypertonic solution administration: hypotensive episodes, sudden increases in pulmonary capillary wedge pressure, and ventricular arrhythmias. These side effects are likely attributable to a too-high dose and/or rate of infusion. All patients included in the study were discharged from the hospital before the 10th postoperative day. CONCLUSION: We conclude that in patients who have undergone mitral valve repair, postoperative infusion of hypertonic saline solutions increases left ventricular preload and left ventricular ejection fraction. The use of these hypertonic solutions may be of interest in patients with valvular cardiomyopathy. A titrated dose and a low rate of infusion may substantially improve the safety.

Cardiac Surgical Procedures↗

Decompensation characterized by decreased perfusion of the heart and brain during hemorrhagic shock: role of endothelin-1.

BACKGROUND: Endothelin-1 (ET-1), a 21-amino-acid peptide produced by vascular endothelium, is a potent vasoconstrictor and a component of local regulation of vascular tone through its effect on underlying vascular smooth muscle. Hemorrhagic shock (HS) is characterized by compensatory regional vasoconstriction to decrease peripheral tissue perfusion and to maintain core organ perfusion. Decompensation occurs with prolonged duration of HS. In the present study, we hypothesized that systemic and vital organ tissue ET-1 concentrations would correlate with changes in systemic and vital organ perfusion associated with compensatory and decompensatory states of HS. METHODS: After surgical instrumentation, HS was induced in male Sprague-Dawley rats by withdrawing blood via femoral artery to a mean arterial pressure of 35 to 40 mm Hg that was maintained for either 30 minutes or 90 minutes in separate groups of male Sprague-Dawley rats. Systemic hemodynamics and regional blood flow were measured using a radioactive microsphere technique. In separate groups of animals, sham, 30 minutes of HS, or 90 minutes of HS, plasma and tissue concentrations of ET-1 were determined using a radioimmunoassay technique. RESULTS: HS maintained for 90 minutes was associated with increased arterial base deficit from 3.6 +/- 0.53 mEq/L to 13 +/- 0.37 mEq/L, decreased cardiac output from 79 +/- 18 mL/min to 18 +/- 5 mL/min, and increased systemic vascular resistance from 1,004 +/- 102 mm Hg/L. min to 2,392 +/- 447 mm. Hg/L min as compared with baseline values. With 90 minutes of HS as compared with 30 minutes of HS, perfusion was significantly decreased in brain (72 +/- 11 vs. 29 +/- 6 mL/min. 100 g tissue) and heart (483 +/- 30 vs. 173 +/- 38 mL/min. 100 g tissue) and kidney perfusion was decreased (from 114 +/- 28 mL/min/100 g tissue to 29 +/- 2 mL/min. 100 g tissue), and ET-1 concentration was increased significantly in brain (cerebral cortex, 89 +/- 14 pg/100 g tissue to 144 +/- 19 pg/100 g tissue; midbrain, 172 +/- 15 pg/100 g tissue to 211 +/- 10 pg/100 g tissue), heart (left ventricle, 312 +/- 11 pg/100 g tissue to 360 +/- 14 pg/100 g tissue), kidney (medulla, 857 +/- 61 pg/100 g tissue to 1,277 +/- 41 pg/100 g tissue), and plasma (5.31 +/- 0.6 pg/100 g tissue to 21.26 +/- 2.9 pg/mL). CONCLUSION: Decreased vital organ and peripheral tissue perfusion, a primary decompensation effect of HS, was apparent with 90 minutes of HS but not with 30 minutes, and was associated with increased vital organ tissue and plasma ET-1 concentrations. These data suggest a role for ET-1 in control mechanisms of progressive vasoconstriction that occurs with prolonged duration of HS.

Animals↗

Hypertonic saline resuscitation diminishes lung injury by suppressing neutrophil activation after hemorrhagic shock.

UNLABELLED: Hypertonic saline (HS) resuscitation after hemorrhage and sepsis has been shown to markedly reduce the development of lung injury in animals, compared with traditional resuscitation with lactated Ringer's (LR). These experiments examined the effect of HS on lung injury after hemorrhage without sepsis. The effects of HS and LR resuscitation on neutrophil trafficking, neutrophil adhesion, and neutrophil oxidative burst were studied. METHODS: BALB/c mice were hemorrhaged to a mean arterial pressure of 40 torr for 1 h. Animals were resuscitated with shed blood and either 4 mL/kg of 7.5% HS or LR in twice the volume of the shed blood. Lung histology was examined 24 h after hemorrhage. Lung myeloperoxidase content and bronchoalveolar lavage fluid neutrophil counts were obtained. Peripheral blood smears were obtained to determine the neutrophil percentage. Peripheral blood neutrophil CD11b expression and neutrophil H2O2 production were assayed by flow cytometry. RESULTS: HS animals had less lung injury than LR animals. The mean myeloperoxidase activity in HS versus LR animals was 1.79+/-1.33 U/100 mg versus 3.0+/-1.33 U/100 mg, respectively. The percentage of neutrophils in the bronchoalveolar lavage fluid of HS animals (3.8%+/-.8) was significantly less than that of LR animals (10.8%+/-2.1). This corresponded to a significantly higher peripheral blood neutrophil count in HS animals compared with LR animals, 41% vs. 20%, respectively. There was no difference in neutrophil expression of the CD11b integrin between the HS and LR groups. The neutrophils of LR animals had basal H2O2 production that was 107% greater than that of controls; HS suppressed this hemorrhage-induced activation by > 60%. HS resuscitation after hemorrhagic shock protects against the development of lung injury. This protection is due, in part, to suppression of the hemorrhage-induced neutrophil oxidative burst. HS resuscitation offers immunomodulatory potential after hemorrhagic shock.

Animals↗

The effect of hypertonic (3%) saline with and without furosemide on plasma osmolality, sodium concentration, and brain water content after closed head trauma in rats.

Adding furosemide (F) to mannitol causes a greater decrease of brain volume, intracranial pressure, and brain water content (BW) as compared with mannitol alone. We examined whether adding F to hypertonic saline (HS) causes less increase of BW early after closed head trauma (CHT) as compared with HS alone. With institutional approval, 125 rats underwent sham surgery or CHT and then immediately received no treatment, HS (1.2 g/kg, 3% solution), or HS + F (2 mg/kg). In groups 1-10 (n = 8/group), the percent BW content was determined at 30, 60, or 120 minutes. In groups 11-14 (n = 8/group), physiologic values were determined at 0, 30, 60, and 120 minutes. At 120 minutes, the increase of BW caused by CHT (sham = 78.9 +/- 0.6% and CHT = 81.5 +/- 2.2%, mean +/- SD) was prevented by HS + F (78.0 +/- 0.8%) but not by HS (80.7 +/- 2.2%). Both HS and HS + F similarly increased plasma osmolality and sodium concentration. Post-CHT hypotension and acidosis (30 and 60 minutes) and decrease of hemoglobin concentration (120 minutes) were less with HS + F than with HS. We conclude that adding F to HS decreases BW without causing more increase of osmolality and Na than that caused by HS alone.

Animals↗

Erythropoietin levels in the different clinical forms of hereditary spherocytosis.

Erythropoietin (EPO), the main growth factor responsible for the regulation of red blood cell production, may be overproduced when blood loss or haemolysis occurs. Patients with mild hereditary spherocytosis (HS) are able to maintain normal haemoglobin concentration, whereas typical and severe HS patients develop an anaemic state. Splenectomy usually reverses anaemia. We aimed to clarify the role of EPO in the response to enhanced spherocyte destruction, and to look for a linkage with the broad clinical spectra of HS. EPO levels, reticulocyte count and production index (RPI), other parameters used to classify HS and the protein deficiencies underlying HS were evaluated in previously diagnosed unsplenectomised (n = 24) and splenectomised (n = 10) patients presenting mild, typical or severe HS. A significant increase in EPO was observed in all unsplenectomised HS patients. In the mild form, a significant correlation of EPO with reticulocyte count and RPI was observed; however, this correlation disappeared in typical HS patients. Splenectomised HS patients presented a correction in EPO levels in all forms of HS, although the reticulocyte count and RPI sustained slightly higher values. Our data show HS as a disease linked to an overproduction of EPO, according to the severity of the disease; however, a disturbance in erythropoiesis seems to occur in typical HS. Moreover, splenectomy leads to a correction in the EPO levels.

Adult↗

New insight into the signalling pathways of heat stress-induced myocardial preconditioning: protein kinase Cepsilon translocation and heat shock protein 27 phosphorylation.

1. Heat stress (HS) is known to induce delayed preconditioning against myocardial infarction 24 h later, but the exact signalling pathway of this response remains to be elucidated. In previous studies, we have shown evidence for the implication of protein kinase C (PKC) and p38 mitogen-activated protein kinase (MAPK) in the HS-induced reduction in infarct size. Furthermore, in their phosphorylated state, small heat shock proteins (Hsp27) seem to confer cytoskeletal protection. In the present study, we sought to determine the effect of HS on the subcellular distribution of PKC isoforms and on Hsp27 phosphorylation. 2. Rats were subjected to either HS (42 degrees C for 15 min; HS group) or sham anaesthesia (sham group) before their hearts were excised. Myocardial tissue extracts obtained 20 min or 24 h after HS were processed for western blot analysis. 3. In the HS group, PKCepsilon translocated from the cytosolic to the particulate fraction (4426 +/- 128 vs 6258 +/- 316 arbitrary units; P = 0.002). Chelerythrine (5 mg/kg, i.p.), a PKC inhibitor, abolished this translocation. Western blot analysis of Hsp27 24 h after HS showed a marked increase in protein expression and phosphorylation in the particulate fraction. 4. In the present study, we have shown that HS induces the translocation of PKCepsilon from the cytosolic to the particulate fraction. Along with our previous observation that PKC is a trigger of HS-induced myocardial preconditioning, the results of the present study suggest an important role of the epsilon isoform of PKC in this cardioprotective mechanism. Furthermore, we have also demonstrated that the cytoprotective protein Hsp27 is phosphorylated following HS. Therefore, we can conclude that PKC and MAPK/Hsp27 are involved in the signalling pathway of HS-induced cardioprotection.

Animals↗

Hemicranial volume deficits in patients with temporal lobe epilepsy with and without hippocampal sclerosis.

PURPOSE: In patients with refractory temporal lobe epilepsy, studies have suggested volume deficits measured by MRI of brain structures outside the epileptogenic hippocampus. Hippocampal sclerosis (HS) is a frequent, but not obligate, finding in such patients. The present study examines the influence of the presence of HS on quantitative magnetic resonance imaging (MRI) measurements. METHODS: We analyzed 47 patients and 30 controls by quantitative MRI, including intracranial volume (ICV), hemicranial volume, hippocampal volume (HCV), and T2 relaxometry. MRI results were compared with histological findings in the resected temporal lobe. RESULTS: Histology documented HS in 35 patients (HS group) and other findings in 12 patients (no-HS group). In both groups, the hemicranial volume ipsilateral to the epileptogenic focus was significantly smaller than on the contralateral side (p < 0.004). The HCV on both sides was smaller in the HS group compared with patients without HS (p < or = 0.004). Unilateral hippocampal atrophy and increased T2 value were found in 71% of patients with HS, and bilaterally normal HCV and T2 value were found in 67% of patients without HS. CONCLUSIONS: The smaller hemicranial volume on the focus side, irrespective of the presence or absence of HS suggests a different pathogenic mechanism for the additional hemicranial volume deficit, compared to HS itself. The contralateral HCV deficit depends on the presence of HS, indicating a pathogenic connection between damage to both hippocampi.

Adult↗

The association of early childhood caries and race/ethnicity among California preschool children.

OBJECTIVES: This paper explores the role of race/ethnicity in the occurrence of early childhood caries (ECC) among California Head Start (HS) and non-HS preschool children. METHODS: Using oral examination and questionnaire data from the 1993-94 California Oral Health Needs Assessment of Children, we computed the prevalence of ECC using various definitions and fitted logistic regression models to explore the effect of race/ethnicity on ECC, separately for HS and non-HS children, adjusting for bedtime feeding habits and other covariates. RESULTS: Among 2,520 children, the largest proportion with a history of falling asleep sipping milk/sweet substance was among Latinos/Hispanics (72% among HS and 65% among non-HS) and HS Asians (56%). HS Asians and Latinos/Hispanics had the largest prevalence of ECC (30%-33%) and untreated caries (49%-54%). The estimated risk for ECC was more than three times higher in HS Asians compared to HS whites and among non-HS African Americans and Asians compared to non-HS whites controlling for socioeconomic status variables. The risk of ECC was also significantly higher among children who fell asleep while sipping milk or any sweet substance compared to those who did not. CONCLUSION: Studies of the cultural/behavioral patterns that may be specific to ethnic subgroups with the highest risk for ECC seem essential to the development of effective prevention strategies.

Black or African American↗

Some Immunochemical Properties of Dextransucrase and Invertase from Streptococcus mutans.

Dextransucrase and invertase of some strains of Streptococcus mutans were examined by immunodiffusion with antisera against enzymes purified from strain HS-6 (Bratthall's serotype a). Both antisera cross-reacted with crude enzyme preparations from the other serotype a (strains HS-1 and AHT) and d organisms (strains KIR, OMZ176, and OMZ65) but not with those from serotype b (strains FA-1 and BHT) or c organisms (strains GS-5, Ingbritt, and NCTC 10449). Based upon the antiserum used, the orders of antigenic similarity of the cross-reacting enzymes to the HS-6 enzymes were HS-6 > HS-1 > AHT = KIR = OMZ176 = OMZ65 for dextransucrase and HS-6 = HS-1 > AHT = KIR = OMZ176 = OMZ65 for invertase. It was found that the enzymes from serotype a organisms were not always antigenically homogeneous, as seen between strains HS-6, HS-1, or AHT for dextransucrase, and between the HS group and strain AHT for invertase. Antiserum against the HS-6 dextransucrase markedly inhibited the heterologous dextransucrases of serotype a organisms with the exception of strain HS-1 and d organisms, with or without the addition of dextran.

Journal Article↗

Interaction of classical swine fever virus with membrane-associated heparan sulfate: role for virus replication in vivo and virulence.

Passage of native classical swine fever virus (CSFV) in cultured swine kidney cells (SK6 cells) selects virus variants that attach to the surface of cells by interaction with membrane-associated heparan sulfate (HS). A Ser-to-Arg change in the C terminus of envelope glycoprotein E(rns) (amino acid 476 in the open reading frame of CSFV) is responsible for selection of these HS-binding virus variants (M. M. Hulst, H. G. P. van Gennip, and R. J. M. Moormann, J. Virol. 74:9553-9561, 2000). In this investigation we studied the role of binding of CSFV to HS in vivo. Using reverse genetics, an HS-independent recombinant virus (S-ST virus) with Ser(476) and an HS-dependent recombinant virus (S-RT virus) with Arg(476) were constructed. Animal experiments indicated that this adaptive Ser-to-Arg mutation had no effect on the virulence of CSFV. Analysis of viruses reisolated from pigs infected with these recombinant viruses indicated that replication in vivo introduced no mutations in the genes of the envelope proteins E(rns), E1, and E2. However, the blood of one of the three pigs infected with the S-RT virus contained also a low level of virus particles that, when grown under a methylcellulose overlay, produced relative large plaques, characteristic of an HS-independent virus. Sequence analysis of such a large-plaque phenotype showed that Arg(476) was mutated back to Ser(476). Removal of HS from the cell surface and addition of heparin to the medium inhibited infection of cultured (SK6) and primary swine kidney cells with S-ST virus reisolated from pigs by about 70% whereas infection with the administered S-ST recombinant virus produced in SK6 cells was not affected. Furthermore, E(rns) S-ST protein, produced in insect cells, could bind to immobilized heparin and to HS chains on the surface of SK6 cells. These results indicated that S-ST virus generated in pigs is able to infect cells by an HS-dependent mechanism. Binding of concanavalin A (ConA) to virus particles stimulated the infection of SK6 cells with S-ST virus produced in these cells by 12-fold; in contrast, ConA stimulated infection with S-ST virus generated in pigs no more than 3-fold. This suggests that the surface properties of S-ST virus reisolated from pigs are distinct from those of S-ST virus produced in cell culture. We postulate that due to these surface properties, in vivo-generated CSFV is able to infect cells by an HS-dependent mechanism. Infection studies with the HS-dependent S-RT virus, however, indicated that interaction with HS did not mediate infection of lung macrophages, indicating that alternative receptors are also involved in the attachment of CSFV to cells.

Animals↗

Genes for low-molecular-weight heat shock proteins of soybeans: sequence analysis of a multigene family.

Soybeans, Glycine max, synthesize a family of low-molecular-weight heat shock (HS) proteins in response to HS. The DNA sequences of two genes encoding 17.5- and 17.6-kilodalton HS proteins were determined. Nuclease S1 mapping of the corresponding mRNA indicated multiple start termini at the 5' end and multiple stop termini at the 3' end. These two genes were compared with two other soybean HS genes of similar size. A comparison among the 5' flanking regions encompassing the presumptive HS promoter of the soybean HS-protein genes demonstrated this region to be extremely homologous. Analysis of the DNA sequences in the 5' flanking regions of the soybean genes with the corresponding regions of Drosophila melanogaster HS-protein genes revealed striking similarity between plants and animals in the presumptive promoter structure of thermoinducible genes. Sequences related to the Drosophila HS consensus regulatory element were found 57 to 62 base pairs 5' to the start of transcription in addition to secondary HS consensus elements located further upstream. Comparative analysis of the deduced amino acid sequences of four soybean HS proteins illustrated that these proteins were greater than 90% homologous. Comparison of the amino acid sequence for soybean HS proteins with other organisms showed much lower homology (less than 20%). Hydropathy profiles for Drosophila, Xenopus, Caenorhabditis elegans, and G. max HS proteins showed a similarity of major hydrophilic and hydrophobic regions, which suggests conservation of functional domains for these proteins among widely dispersed organisms.

Amino Acid Sequence↗

ET(A) receptor blockade prevents renal dysfunction in salt-sensitive hypertension induced by sensory denervation.

To test the hypothesis that activation of the endothelin type A (ET(A)) receptor contributes to decreased renal excretory function and increased blood pressure in sensory nerve-degenerated rats fed a high-salt diet, neonatal Wistar rats were given vehicle or capsaicin (CAP, 50 mg/kg s.c.) on the first and second day of life. After being weaned, vehicle or CAP-treated rats were fed a normal (NS, 0.5%) or a high- (HS, 4%) sodium diet for 2 wk with or without ABT-627 (5 mg x kg(-1) x day(-1), a selective ET(A) receptor antagonist). Systolic blood pressure increased in CAP-treated rats fed a HS diet (CAP-HS) compared with vehicle-treated rats fed a HS diet (CON-HS, 145 +/- 7 vs. 89 +/- 5 mmHg, P < 0.05). Creatinine clearance and fractional sodium excretion (FE(Na)) decreased in CAP-HS rats compared with CON-HS rats (creatinine clearance, 0.54 +/- 0.05 vs. 0.81 +/- 0.09 ml x min(-1) x 100 g body wt(-1); FE(Na), 8.68 +/- 0.99 vs. 12.53 +/- 1.47%, respectively; P < 0.05). Water and sodium balance increased in CAP-HS rats compared with CON-HS (water balance, 20.2 +/- 1.5 vs. 15.5 +/- 1.9 ml/day; sodium balance, 11.9 +/- 3.1 vs. 2.4 +/- 0.3 meq/day, respectively; P < 0.05). The endothelin (ET)-1 levels in plasma and isolated glomeruli increased by about twofold in CAP-HS rats compared with CON-HS rats (P < 0.05). ABT-627 prevented the decrease in creatinine clearance and FE(Na), the increase in water and sodium balance, and the increase in blood pressure in CAP-HS rats (P < 0.05). Therefore, the blockade of the ET(A) receptor ameliorates the impairment of renal excretory function and prevents the elevation in blood pressure in salt-sensitive hypertension induced by degeneration of sensory nerves, indicating that the activation of the ET(A) receptor impairs renal function and contributes to the development of a salt-induced increase in blood pressure in this model.

Animals↗

Heat stress protects aged hypertrophied and nonhypertrophied rat hearts against ischemic damage.

To explore the effects of heat stress (HS) in aged hypertrophied and nonhypertrophied rat hearts, postischemic recovery was investigated 15 mo after aortic constriction (AoB) or sham operation (Sham). Twenty-four hours after HS (42 degrees C; 15 min) or control treatment (normothermia), global ischemia was induced for 20 min in isolated AoB hearts and for 20 or 30 min in Sham hearts. After HS, postischemic recovery after 20-min ischemia in AoB hearts and 30-min ischemia in Sham hearts, respectively, was significantly better than in corresponding controls. In AoB hearts, cardiac output (CO), left ventricular developed pressure (LVDP), and the positive maximal first derivative of left ventricular pressure (+dP/dtmax) recovered to 33 +/- 26 (means +/- SD), 87 +/- 5, and 72 +/- 12%, respectively, after HS and to 5 +/- 8, 22 +/- 39, and 17 +/- 29% of preischemic values, respectively, in controls. Postischemic arrhythmias were significantly reduced in HS hypertrophied hearts, but creatine kinase (CK) loss was not reduced. In Sham hearts subjected to 30 min ischemia, CO, LVDP, and +dP/dtmax recovered to 20 +/- 20, 75 +/- 8, and 59 +/- 15%, respectively, after HS and to 3 +/- 8, 21 +/- 32, and 16 +/- 32% of preischemic values, respectively, in controls. Duration of arrhythmias and CK loss were not reduced in the heated hearts. When Sham hearts were subjected to only 20-min ischemia, functional recovery was not different in HS and control hearts, indicating that HS pretreatment extends the ischemic interval before irreversible injury occurs in the heart. In all HS Sham hearts, the myocardial 72-kDa HS protein (HSP 70) content was significantly increased. However, in HS AoB hearts, HSP 70 levels were not significantly different from the values in the control hearts. These results indicate that HS pretreatment induces cardioprotection in aged hypertrophied and nonhypertrophied rat hearts, which, however, cannot be unequivocally related to increased HSP 70 tissue contents.

Animals↗

The safety and efficacy of inhaled dry powder mannitol as a bronchial provocation test for airway hyperresponsiveness: a phase 3 comparison study with hypertonic (4.5%) saline.

BACKGROUND: Inhaled mannitol is a new bronchial provocation test (BPT) developed to improve portability and standardisation of osmotic challenge testing. Osmotic challenge tests have an advantage over the traditional methods of measuring airway hyperresponsiveness using methacholine as they demonstrate higher specificity to identify asthma and thus the need for treatment with inhaled corticosteroids (ICS). The safety and the efficacy of mannitol (M) as a BPT to measure airway hyperresponsiveness were compared to hypertonic (4.5%) saline (HS) in people both with and without signs and symptoms of asthma. METHODS: A phase III, multi-centre, open label, operator-blinded, crossover design, randomised trial, with follow-up. Asthmatics and non-asthmatics (6-83 yr) were recruited and 592 subjects completed the study. Mannitol was delivered using a low resistance dry powder inhaler and HS was delivered using an ultrasonic nebuliser. The FEV1 was measured 60 seconds after each dose of mannitol (5,10,20,40,80,160,160,160 mg) and after each exposure to HS (0.5,1.0,2.0,4.0,8.0 minutes). A 15% fall in FEV1 defined a positive test. Adverse events were monitored and diaries kept for 7 days following the tests. RESULTS: Mean pre-test FEV1 (mean +/- SD) was 95.5 +/- 14% predicted. 296 were positive to mannitol (M+) and 322 positive to HS (HS+). A post study physician conducted clinical assessment identified 82.3% asthmatic (44% classified mild) and 17.7% non-asthmatic. Of those M+, 70.1% were taking ICS and of those mannitol negative (M-), 81.1 % were taking ICS. The % fall in FEV1 for mannitol in asthmatics was 21.0% +/- 5.7 and for the non-asthmatics, 5.5% +/- 4.8. The median PD15 M was 148 mg and PD15 HS 6.2 ml. The sensitivity of M to identify HS+ was 80.7% and the specificity 86.7%. The sensitivity of M compared with the clinical assessment was 59.8% and specificity 95.2% and increased to 88.7% and 95.0% respectively when the M- subjects taking ICS were excluded. Cough was common during testing. There were no serious adverse events. The diarised events were similar for mannitol and HS, the most common being headache (17.2%M, 19%HS), pharyngolaryngeal pain (5.1%M, 3%HS), nausea (4.3%M, 3%HS), and cough (2.2%M, 2.4%HS). CONCLUSION: The efficacy and safety of mannitol was demonstrated in non-asthmatic and clinically diagnosed asthmatic adults and children.

Administration, Inhalation↗

Role of endogenous atrial natriuretic peptide in chronic anemia in the ovine fetus: effects of a non-peptide antagonist for atrial natriuretic peptide receptor.

Chronic fetal anemia causes polyhydramnios and fetal hydrops and is associated with increased fetal diuresis and natriuresis. To determine the role of atrial natriuretic peptide (ANP) in the renal adaptation to chronic fetal anemia we studied the effects of HS-142-1 (HS), a specific inhibitor of the guanylate cyclase-linked ANP receptor (ANP-GC), in two groups of chronically instrumented unanesthetized sheep fetuses. Seven fetuses were made anemic by serial isovolemic hemorrhage over 1 wk, and five fetuses served as nonanemic controls. Over the 7 d of hemorrhage ANP concentrations increased (45 +/- 7 to 234 +/- 15 fmol/mL). Hematocrit and arterial blood oxygen content were significantly lower in the anemic compared with the nonanemic fetuses (13.8 +/- 0.7 versus 34.6 +/- 2.3% and 0.7 +/- 0.1 versus 2.6 +/- 0.2 mmol/L). Before HS urine flow rate, urinary sodium excretion, fractional excretion of sodium, and renal blood flow were increased in the anemic fetuses, and the extracellular fluid volume (inulin space) was increased (674 +/- 94 versus 497 +/- 71 mL/kg). However, GFR was not different between the groups. HS caused a significant increase in the central venous pressure of the anemic fetuses (0.49 +/- 0.03 to 0.70 +/- 0.05 kPa). Urinary excretion of cGMP was considered to be a marker of endogenous ANP renal effect and was measured before and after a single bolus of HS (5.2 +/- 0.30 mg/kg). HS decreased urinary cGMP excretion to 50 and 37% of baseline levels in anemic and nonanemic fetuses, respectively. Urine flow decreased in both nonanemic and anemic fetuses (0.48 +/- 0.13 to 0.25 +/- 0.06 and 1.30 +/- 0.66 +/- 0.06 mL/min). Sodium excretion decreased in both groups after HS (19 +/- 5 to 9 +/- 2 and 83 +/- 16 to 39 +/- 5 mumol/min). GFR decreased after HS (3.0 +/- 0.8 to 2.4 +/- 0.5 and 3.6 +/- 0.3 to 2.6 +/- 0.2 mL/min. Fraction excretion of sodium also decreased in both groups after HS (4.6 +/- 2.7 to 2.7 +/- 0.5 and 16.1 +/- 2.4 to 11 +/- 1.6). Percent decreases in urine flow, sodium excretion, GFR, and fractional excretion of sodium observed in the anemic fetuses were not statistically different from the nonanemic fetuses. Urine flow and sodium excretion did not decrease to control levels after HS, suggesting that factors in addition to ANP contribute to the natriuresis seen with chronic anemia. After HS a transient increase in renal blood flow was observed in the nonanemic fetuses. An immediate and sustained further increase in renal blood flow was observed in the anemic fetuses (336 +/- 37 to 436 +/- 58 mL/min/100 g of kidney). Decreasing GFR and increasing renal blood flow suggests HS may alter the renal microcirculation by reversing ANP-induced constriction of the glomerular efferent arteriole. We conclude that sustained increases of the central venous pressure suggest that ANP inhibition results in decreased fluid movement into perivascular tissue. Endogenous ANP may help to maintain basal renal function in the normal fetal kidney and participates in the renal adaptation to chronic fetal anemia. ANP may promote urine flow and sodium excretion by its effects on both the renal microcirculation and the sodium reabsorptive capacity of the nephron.

Anemia↗

Highly sensitive serum thyroglobulin and circulating thyroglobulin mRNA evaluations in the management of patients with differentiated thyroid cancer in apparent remission.

We studied the potential role of innovative diagnostic tools for the management of patients with differentiated thyroid cancer (DTC). Several methods for the detection of the tumor marker thyroglobulin (Tg) have been employed in 36 patients in apparent remission at the moment of the study. All patients had negative anti-Tg antibodies and were evaluated during L-T(4) suppressive therapy before and after stimulation with recombinant human TSH (rhTSH). Serum Tg was measured by means of conventional [nonhighly sensitive (nhs)] or highly sensitive (hs) immunoassays with positive cut-off values set at 1.0 and 0.18 microg/liter, respectively. The RT-PCR conditions for the qualitative determination of Tg mRNA from peripheral blood were optimized to prevent interference by illegitimate transcription. The patients have been classified on the basis of a hs-basal Tg testing by taking into account the results of their baseline samples in hs immunoassay and RT-PCR method; hs-basal Tg testing was considered positive when the marker was detectable in at least one of the two tests. The predictive value of hs-basal Tg testing was estimated on the basis of a global clinical evaluation, including serum Tg response after rhTSH stimulation and reports of contemporary (131)I scan and neck ultrasound. The clinical evaluation was considered positive when at least one of these criteria yielded positive results. Although nhs-Tg measurement was poorly predictive of the clinical status, basal hs-Tg evaluation was found to be concordant with the clinical evaluation in 71% of cases. Results of basal Tg mRNA detection did not vary after rhTSH stimulation and were concordant with the clinical evaluation in 66% of cases. Tg mRNA evaluation alone showed 10 apparently false-positive results, and serum basal hs-Tg was falsely negative in 11 additional cases, suggesting that a suitable predictability could be obtained by the association of these 2 parameters. Indeed, the combination of hs-Tg assay and mRNA detection in the hs-basal Tg testing allowed the identification of 22 patients with a positive persistent/recurrent disease or normal thyroid residue, as well as identification of all 6 patients with a negative clinical evaluation. In conclusion, the combined evaluation of circulating Tg mRNA and serum Tg by means of hs noncompetitive immunoassay (hs-basal Tg testing) can give useful information on the clinical status of patients with DTC who are apparently disease-free, even on L-T(4) TSH-suppressive therapy. Therefore, these combined evaluations retain a potential role in the clinical monitoring of DTC patients. In particular, a negative hs-basal Tg testing would indicate disease remission and the opportunity to lengthen the intervals between rhTSH stimulations and/or to shift patients to a less profound TSH suppression with L-T(4).

Adenocarcinoma, Follicular↗

Pure hippocampal sclerosis: a rare cause of dementia mimicking Alzheimer's disease.

OBJECTIVES: To identify patients with pure hippocampal sclerosis (HS) as a cause of dementia, to determine whether they have had histories of hypotension or hypoxia, and to compare the clinical features of patients with pure HS with a control group of AD patients without HS. METHODS: In a retrospective study, the authors reviewed all 1771 cases received in their dementia brain bank from 1978 through 1996 to identify those patients with pure HS, defined as severe degeneration and gliosis of the CA1 sector and subiculum of the hippocampal formation in the absence of other significant dementing disease such as Alzheimer's changes. The control group included all patients received during the same period with severe AD without HS, infarcts, or other dementing disease. RESULTS: Seven pure HS cases (0.4%) were identified. None had any episodes of syncope, hypotension, or hypoxia reported in association with dementia onset. Six had memory loss as the primary presenting symptom, and all became progressively demented. Forty-five AD patients without HS were identified for the control group. There were no clear clinical differences between the two groups with regard to sex, age at onset, risk factors for vascular disease, symptoms of cerebrovascular disease, treatment with tranquilizing medications, treatment for depression, or nursing home placement. There was a tendency for heart disease to be more prevalent and the duration of illness to be shorter in the patients with pure HS. CONCLUSIONS: Pure hippocampal sclerosis (HS) occurred in only 0.4% of our dementia patients. Clinically, the seven patients with pure HS were similar to our AD control group. Further research is needed to determine the causes of HS and why HS appears to mimic AD.

Aged↗