Hydroxychloroquine reverses thrombogenic properties of antiphospholipid antibodies in mice

BACKGROUND: Previous studies have demonstrated that human monoclonal and polyclonal anticardiolipin antibodies have thrombogenic properties in vivo. Using such a model in which these antibodies have been shown to increase both the size of an induced thrombus and the duration of time in which such a clot lasts, we investigated whether hydroxychloroquine alters the dynamics of such thrombus formation. METHODS AND RESULTS: Three groups of nine mice were injected with purified immunoglobulin G (IgG) from a patient with the antiphospholipid syndrome (IgG-APS) and then fed with hydroxychloroquine at various doses (100, 6, and 3 mg/kg body wt). Three control groups of mice were also studied, including mice injected with IgG-APS and then fed with placebo, as well as two other groups injected with IgG from normal human serum and fed either hydroxychloroquine or placebo. A standardized thrombogenic injury was subsequently induced in the femoral vein of each mouse and the area (size) of thrombus measured as well as the total period of time that thrombus was present. Mice treated with hydroxychloroquine and IgG-APS showed significantly smaller thrombi that persisted for a shorter period of time compared with animals treated with IgG-APS and placebo. CONCLUSIONS: Hydroxychloroquine significantly diminished both thrombus size and total time of thrombus formation in mice previously injected with IgG-APS.     

Delayed onset of malignant hyperthermia induced by isoflurane and desflurane compared with halothane in susceptible swine

BACKGROUND: Desflurane (difluoromethyl 1-fluoro 2,2,2-trifluoroethyl ether) is a new inhalational anesthetic currently under investigation for use in humans. Recently, the authors showed that desflurane is a trigger of malignant hyperthermia (MH) in susceptible swine. To date, there has been no in vivo comparison of the relative ability of inhalational anesthetics to trigger MH. The effects of desflurane, isoflurane, and halothane on six MH-susceptible purebred and six MH-susceptible mixed-bred Pietrain swine were examined. METHODS: The animals were exposed to 1 MAC and 2 MAC (if MH was not triggered after 1 MAC hour) doses of each of the three volatile anesthetics in random sequence at 7-10-day intervals and changes in end-tidal CO2, arterial blood gases, serum lactate, core and muscle temperature, blood pressure, and heart rate were measured. RESULTS: There was a statistical difference between anesthetics in the time required to trigger MH; halothane exposure resulted in the fastest onset of an MH episode (20 +/- 5 min), compared with isoflurane (48 +/- 24 min) and desflurane (65 +/- 28 min), both of which required significantly longer exposures. There was no statistical difference between the MH purebred and mixed-bred swine in the time required to trigger MH (defined as a PaCO2 of 70 mmHg) with a given agent, and time to triggering was also independent of the order of exposure to the three anesthetics. Malignant hyperthermia susceptibility was confirmed in ten surviving animals, by both in vivo succinylcholine challenge and in vitro contracture testing. CONCLUSIONS: Although all three volatile anesthetics triggered MH, exposure to halothane resulted in significantly shorter times to MH triggering when compared with desflurane and isoflurane.     

The prognostic value of NCAM, p53 and cyclin D1 in resected non-small cell lung cancer

Expression of the neural cell adhesion molecule, NCAM, in frozen sections has been associated with decreased postoperative survival in non-small cell lung carcinoma. Of the various isoforms of NCAM described, the highly sialylated isoform plays a role in the migration of embryonal cells from the neural crest and is expressed by highly malignant tumours such as small cell lung carcinomas. We investigated the clinical significance of expression of this NCAM isoform as a prognostic factor in a series of 96 non-small cell lung carcinomas resected with curative intent. We also evaluated the effect of microwave pre-treatment of formalin-fixed, paraffin-embedded sections on the NCAM immunostaining and related the outcome to the postoperative clinical course of disease. In addition, in an attempt to extend our search for possible molecular markers of unfavourable prognosis in lung cancer, we evaluated increased immunostaining for p53 and cyclin D1 in the same series. We did not find a significant relation between expression of NCAM or its highly sialylated isoform and the length of postoperative survival. The numbers of positive cases (9 and 14, respectively) were relatively low. Increased p53 and cyclin D1 immunostaining (50 and 55 of the 96 tumours) failed to show a significant relation with postoperative survival. In our material, tumour stage was the only significant prognostic factor.     

Lipid and lipoprotein distributions in children by ethnic group, gender, and geographic location--preliminary findings of the Child and Adolescent Trial for Cardiovascular Health (CATCH)

Male and female isometric strength curves for elbow fixation, shoulder flexion, and wrist supination-pronation are obtained during systematic variation in arm configuration. The shape of a given moment-angle curve is found to be a function of the orientations of joints kinematically coupled to the primary joint. It is also found that female elbow strength curves are shifted toward flexion with respect to male elbow-strength curves, suggesting that the in situ rest length of upper-limb muscles relative to joint angle may be longer for males than for females. Experimental results were contrasted with simulation results obtained using a three-dimensional musculoskeletal model which estimates the relationships between initial joint orientations, muscle tension-length behavior, and joint moments. In most of the cases, simulation results complimented experimental data and provided insights into likely in situ muscle rest lengths and moments arms, especially for the multiarticular biceps brachii muscle. Where inconsistencies exist between simulated and experimental data, subtle biomechanical complexities within the forearm and the shoulder girdle complex are identified that require future investigation.     

Strains of Synechocystis sp. PCC 6803 with altered PsaC. II. EPR and optical spectroscopic properties of FA and FB in aspartate, serine, and alanine replacements of cysteines 14 and 51

A psaC deletion mutant of the unicellular cyanobacterium Synechocystis sp. PCC 6803 was utilized to incorporate site-specific amino acid substitutions in the cysteine residues that ligate the FA and FB iron-sulfur clusters in Photosystem I (PS I). Cysteines 14 and 51 of PsaC were changed to aspartic acid (C14DPsaC, C51DPsaC, C14D/C51DPsaC), serine (C14SPsaC, C51SPsaC), and alanine (C14APsaC, C51APsaC), and the properties of FA and FB were characterized by electron paramagnetic resonance spectroscopy and time-resolved optical spectroscopy. The C14DPsaC-PS I and C14SPsaC-PS I complexes showed high levels of photoreduction of FA with g values of 2.045, 1. 944, and 1.852 after illumination at 15 K, but there was no evidence of reduced FB in the g = 2 region. The C51DPsaC-PS I and C51SPsaC-PS I complexes showed low levels of photoreduction of FB with g values of 2.067, 1.931, and 1.881 after illumination at 15 K, but there was no evidence of reduced FA in the g = 2 region. The presence of FB was inferred in C14DPsaC-PS I and C14SPsaC-PS I, and the presence of FA was inferred in C51DPsaC-PS I and C51SPsaC-PS I by magnetic interaction in the photoaccumulated spectra and by the equal spin concentration of the irreversible P700(+) cation generated by illumination at 77 K. Flash-induced optical absorbance changes at 298 K in the presence of a fast electron donor indicate that two electron acceptors function after FX in the four mutant PS I complexes at room temperature. These data suggest that a mixed-ligand [4Fe-4S] cluster is present in the mutant sites of C14X-PS I and C51X-PS I (where X = D or S), but that the proposed spin state of S = 3/2 renders the resonances undetectable in the g = 2 region. The C14APsaC-PS I, C51APsaC-PS I and C14D/C51DPsaC-PS I complexes show only the photoreduction of FX, consistent with the absence of PsaC. These results show that only those PsaC proteins that contain two [4Fe-4S] clusters are capable of assembling onto PS I cores in vivo.     

Acid-base and electrolyte effects of shortening steeplechase in a three-day-event

This study was designed to characterise the acid-base and electrolyte effects of shortening the distance required during steeplechase (Phase B) in the face of hot and humid weather conditions during a treadmill-simulated Speed and Endurance test. Eight conditioned Thoroughbred horses underwent 3 randomised permutations of a standardised exercise test on a high speed treadmill. Each test consisted of trotting at 3.7 m/s for 10 min (Phase A); galloping at 11 m/s (Phase B) for 4 (cool laboratory conditions), 3 (hot and humid), or 2 (hot and humid) min; trotting at 3.7 m/s for 30 min (Phase C); and walking at 1.8 m/s for 10 min (Phase X). The treadmill slope was 4% for trotting and galloping and 0% for walking. Cool versus hot and humid conditions were 20 degrees C and 50-60% relative humidity vs. 26-28 degrees C and 80-85% relative humidity, respectively. Pulmonary artery blood samples were obtained at rest prior to exercise (Rest); at the end of Phases A (A10) and B (B2-4); at 10 (C10), 20 (C20) and 30 (C30) min through Phase C; and at 5 min into Phase X (X5). Additional samples for lactate (LA) and glucose (GLC) analysis were obtained 5 min into Phase C (C5) and at the end of Phase X (X10). Samples were analysed for packed cell volume (PCV), haemoglobin (HB), total plasma protein (TP), sodium (Na), potassium (K), chloride (Cl), anion gap (AG), plasma glucose (GLC) and lactate (LA), pH, PCO2, bicarbonate (HCO3) and base excess (BE). Shortening steeplechase distance by 50% under hot and humid conditions (2 min B) resulted in a consistent return to control measurements (4 min B) only for plasma LA. Changes in PCV, HB, TP, K and Cl were related more to the longer galloping distance in the 4 min B trials than to hot vs. cold laboratory conditions. Alternatively, changes in LA, GLC, pH, PCO2 and AG were more related to hot and humid laboratory conditions than they were to galloping distance. These latter variables, when combined with physical measures such as core temperature, bodyweight loss, point of fatigue on Phase C and recovery heart rates may serve as the best monitors of positive responses in future studies of proposed modifications to Phase C, rather than those variables which were more distance than weather-related.     

Slipped capital femoral epiphysis associated with radiation therapy

We reviewed 32 children with 41 radiation-therapy associated slipped capital femoral epiphyses (RTASCFE). Ten were from the authors' institutions and 22 from the literature. Gender distribution was equal. The age at diagnosis of the malignancy was 4.3 +/- 3.1 years; the amount of radiation was 4,240 +/- 1,445 rads. Children with RTASCFE presented younger (10.4 +/- 3.2 years) than a routine SCFE. The average symptom duration was 5 +/- 6 months. Children with RTASCFE are usually thin (median weight, 10th percentile) in contrast to children with typical SCFE, who are usually obese (<95th percentile). The majority (82%) of the slips were mild, compared to routine SCFEs (approximately 50%); 28% were bilateral. There was a positive linear relationship between the age at presentation of the SCFE and the age at diagnosis of the malignancy; there was a negative linear relationship between the age at presentation of the SCFE and the amount of radiation therapy.     

Efficacy of monensin for the prevention of subclinical ketosis in lactating dairy cows

A total of 1010 dry cows and pregnant heifers was randomly selected from 25 dairy farms near Guelph, Ontario, Canada to receive either a controlled-release capsule of monensin or a placebo at 3 wk prior to expected calving. Serum samples were obtained at the time of treatment administration, and both serum and milk samples were collected at wk 1, 2, 3, 6, and 9 postcalving. The threshold used to define subclinical ketosis was selected a priori at a concentration of > or = 1200 mumol/L of beta-hydroxybutyrate. Using this threshold, the prevalence and incidence of subclinical ketosis were significantly reduced (50%) by monensin treatment. The duration of subclinical ketosis for cows that had been treated with monensin was also shorter than that for cows treated with the placebo. Monensin treatment significantly reduced the incidence of subclinical ketosis when the threshold was defined using higher concentrations of serum beta-hydroxybutyrate (1400 and 2000 mumol/L). In addition, monensin significantly reduced the prevalence of positive milk ketone tests.