Effects of gastrointestinal parasites on parasite burden, rectal temperature, and antibody titer responses to vaccination and infectious bovine rhinotracheitis virus challenge.

Thirty-three colostrum-deprived Holstein bull calves (initial BW of 131 ± 4 kg) were used to determine the effect of timing of anthelmintic administration relative to vaccination on antibody titer response to vaccine component antigens. When calves were at least 3 mo of age, they were sorted randomly into individual pens and assigned to 1 of 3 treatment groups, treatments consisted of 1) dewormed 2 wk before vaccination (DPV), 2) dewormed at the time of vaccination (DV), or 3) control, vaccinated but not dewormed (CONT). All calves were inoculated with infective larvae of brown stomach worms (Ostertagia ostertagi) and intestinal worms (Cooperia spp.) on d 1, 7, 10, 14, and 18 for a total dose of 235,710 infective larvae per calf. Calves (DPV and DV) were dewormed on d 21 or 35 with a 10% fenbendazole suspension at 5 mg/kg of BW. On d 35, all calves were vaccinated with a modified-live virus respiratory vaccine containing IBRV (infectious bovine rhinotracheitis virus), BVDV-1 (bovine viral diarrhea virus genotype 1), BVDV-2 (BVDV genotype 2), PI-3 (parainfluenza-3), and BRSV (bovine respiratory syncytial virus). During the 103-d experiment, weekly fecal egg counts, blood, and rectal temperatures were collected and health status was recorded daily. Blood samples were obtained weekly to determine serum neutralizing (SN) antibody titers to IBRV, BVDV-1, BVDV-2, and PI-3 and cytokine levels for IL-4, IL-6, TNF-α (tumor necrosis factor-α), and IFN-γ (interferon-gamma). There was a tendency (P < 0.09) for CONT calves to have greater IL-4 concentrations. By design, control calves had greater (P < 0.01) fecal egg counts during the experiment. All calves developed antibody titers to IBRV, BVDV-1, BVDV-2, and PI-3 by d 15 postvaccination. On d 88, all calves were challenged with IBRV and blood samples were obtained on d 88, 89, 90, 93, 95, 98, 99, and 103. All calves had increased rectal temperatures during the final 7 d of the IBRV challenge. However, the CONT group had greater (P < 0.01) rectal temperatures on each sampling day except d 90 compared with the DPV and DV treatments. Therefore, deworming before or at vaccination reduced parasite burden and decreased rectal temperature increase after an IBRV challenge. Deworming strategy had no effect on antibody response to vaccination or IBRV challenge.

Transgenic over-expression of plasminogen activator inhibitor-1 results in age-dependent and gender-specific increases in bone strength and mineralization.

The plasminogen activation system (PAS) and its principal inhibitor, plasminogen activator inhibitor-1 (PAI-1), are recognized modulators of matrix. In addition, the PAS has previously been implicated in the regulation of bone homeostasis. Our objective was to study the influence of active PAI-1 on geometric, biomechanical, and mineral characteristics of bone using transgenic mice that over-express a variant of human PAI-1 that exhibits enhanced functional stability. Femora were isolated from male and female, wildtype (WT) and transgenic (PAI-1.stab) mice at 16 and 32 weeks of age (n=10). Femora were imaged via DEXA for BMD and muCT for cortical mid-slice geometry. Torsional testing was employed for biomechanical properties. Mineral composition was analyzed via instrumental neutron activation analysis. Female femora were further analyzed for trabecular bone histomorphometry (n=11). Whole animal DEXA scans were performed on PAI-1.stab females and additional transgenic lines in which the functional domains of the PAI-1 protein were specifically disrupted. Thirty-two week female PAI-1.stab femora exhibited decreased mid-slice diameters and reduced polar moment of area compared to WT, while maintaining similar cortical bone width. Greater biomechanical strength and stiffness were demonstrated by 32 week PAI-1.stab female femora in addition to a 52% increase in BMD. PAI-1.stab trabecular bone architecture was comparable to WT. Osteoid area was decreased in PAI-1.stab mice while mineral apposition rate increased by 78% over WT. Transgenic mice expressing a reactive-site mutant form of PAI-1 showed an increase in BMD similar to PAI-1.stab, whereas transgenic mice expressing a PAI-1 with reduced affinity for vitronectin were comparable to WT. Over-expression of PAI-1 resulted in increased mineralization and biomechanical properties of mouse femora in an age-dependent and gender-specific manner. Changes in mineral preceded increases in strength/stiffness and deterred normal cross-sectional expansion of cortical bone in females. Trabecular bone was not altered in PAI-1.stab mice whereas MAR increased significantly, further supporting mineral changes as the underlying factor in strength differences. The primary influence of PAI-1 occurred during a period of basal bone remodeling, attributing a role for this system in remodeling as opposed to development. Comparison of transgenic lines indicates that PAI-1's influence on bone is dependent on its ability to bind vitronectin, and not on its proteolytic activity. The impact of PAI-1 on mouse femora supports a regulatory role of the plasminogen activation system in bone homeostasis, potentially elucidating novel targets for the treatment of bone disease.

alpha-Adrenergic activity and cardiovascular effects of besipirdine HCl (HP 749) and metabolite P7480 in vitro and in the conscious rat and dog.

Besipirdine displays potent adrenergic activity in a variety of pharmacological and behavioral tests. Based on this property, we evaluated the effects of besipirdine and its N-despropyl metabolite N-despropyl-besipirdine (P7480) on cardiovascular function in rats and dogs. Besipirdine and P7480 bind alpha-2 adrenoceptors (K(I): 380 and 10 nM, respectively) and facilitate the stimulated release of [3H]norepinephrine from rat cortical slices due to presynaptic autoreceptor blockade. In rat aorta rings and the pithed rat, P7480, but not besipirdine, also behaved as a postsynaptic alpha-1 adrenoceptor agonist. In conscious rats, besipirdine (2-10 mg/kg, p.o.) and P7480 (3-10 mg/kg, p.o.) produced dose-related increases in mean arterial pressure. Inhibition of hepatic cytochrome P-450 enzyme activity blocked the pressor effect of besipirdine, but not of P7480; therefore, P7480 mediated besipirdine's pressor effect. The bradycardia after either agent was unaffected. In conscious dogs, besipirdine (0.1-2 mg/kg, p.o.) also produced dose-related hypertension and bradycardia. The hypertension, but not the bradycardia, were sensitive to prazosin (3 mg/kg, p.o.), but not hexamethonium (10 mg/kg, p.o.). Muscarinic and beta-adrenergic receptor blockade studies in anesthetized dogs demonstrated the bradycardia to be due to withdrawal of cardiac sympathetic tone. These findings suggest that besipirdine's peripheral hypertensive effect is primarily mediated by the pressor metabolite P7480, although facilitated norepinephrine release may contribute. Besipirdine's bradycardic action appears to be centrally mediated, because both compounds lacked direct negative chronotropic activity on spontaneously beating guinea pig atria in vitro.

A multicase family with spondylarthropathies.

Thirty six members of a family with symptoms and signs from the skin and/or the joints were examined clinically and radiologically and HLA typed. Fourteen were classified as having inflammatory joint disease, eight of them with more than one disease within the spondylarthropathy group (SpA). Four had psoriasis of the skin, two of whom had psoriatic arthritis. Ten (five males, five females) had radiological signs of sacroiliitis, eight of them fulfilled the criteria for SpA. Five (four males, one female) with sacroiliitis had radiological signs of spine involvement. One female member was classified as having rheumatoid arthritis. Seven with sacroiliitis were HLA-B27 positive, related to the same haplotype. Two with psoriasis were B27 positive and the other two had another haplotype in common. No single HLA antigen or haplotype was associated with the inflammatory joint manifestations or skin lesions. This suggests involvement of other gene loci or coincidence of multicases.

Efficient modulation of glucolipid enzyme activities in membranes of Acholeplasma laidlawii by the type of lipids in the bilayer matrix.

It is generally anticipated, but so far not fully shown, that the physical properties of membrane lipid bilayers are governed by the concerted actions of the lipid-synthesizing enzymes. In the membrane of Acholeplasma laidlawii a constant surface charge density, similar phase equilibria, and a nearly constant spontaneous curvature are maintained for the polar lipids. Important for these properties are monoglucosyldiacylglycerol (MGlcDAG) and diglucosyldiacylglycerol (DGlcDAG), forming mainly reversed nonlamellar and lamellar phases, respectively. The syntheses of these lipids (from 1,2-DAG and MGlcDAG) by two consecutively acting, membrane-bound glucosyltransferases have been analyzed in synthetic lipid bilayers of selected physical properties. Both enzymes demanded the presence of activator lipids; for MGlcDAG synthesis a critical fraction of anionic lipids was important, whereas for the DGlcDAG synthesis substantial amounts of a liquid-crystalline phosphatidylglycerol (PG) with a certain chain length were essential. The rates of the syntheses for the two glucolipids increased with decreasing chain length of the DAG and MGlcDAG substrates. The enzymatic formation of DGlcDAG (bilayer-forming) was influenced in a dose-dependent manner by the nonbilayer (curvature) propensities of several amphiphilic and hydrophobic lipids in two different bilayer matrixes. However, the preceding synthesis of the nonlamellar MGlcDAG was only affected to a minor extent by such additives. The mechanism for modulation involved an enhancement of the activating potencies of PG in a cooperative fashion at physiological concentrations for PG.(ABSTRACT TRUNCATED AT 250 WORDS)

Membrane lipid composition and cell size of Acholeplasma laidlawii strain A are strongly influenced by lipid acyl chain length.

The small, cell-wall-less prokaryote Acholeplasma laidlawii strain A-EF22 could grow with membrane lipids having an average acyl chain length Cn varying over 14.5- almost 20 carbons by exogenous supplementation with selected fatty acids. For 16 < Cn < 18, the cells grew with lipids containing 100% (mol/100 mol) monounsaturated acyl chains, whereas for Cn < 16 and Cn > 18, cell growth only occurred with gradually lower fractions of unsaturated chains. Cn was actively increased and decreased by chain elongation or de novo fatty acid synthesis upon incorporation of short-chain and long-chain fatty acids, respectively. The membrane lipid composition was strongly affected by the acyl chain length and unsaturation, and the metabolic responses are readily explained as a regulation mechanism based on the established phase equilibria of the individual lipids in the A. laidlawii membrane. Monoglucosyldiacylglycerol (Glc-acyl2-Gro) was the dominating lipid with short chains but the fraction of this lipid decreased with increasing Cn, correlating with the decreasing lamellar to nonlamellar phase transition temperatures for this lipid. The fractions of diglucosyldiacylglycerol (Glc2-acyl2Gro) and phosphatidylglycerol (PtdGro), forming lamellar phases only, increased with increasing Cn over the entire chain-length interval. A weaker correlation was usually observed between the relative amount of a lipid and the extent of chain unsaturation; however, the fractions of Glc2-acyl2Gro and PtdGro increased clearly with an increasing degree of unsaturation. Moreover, the synthesis of the nonbilayer-forming lipids acyl2Gro and monoacyl-Glc-acyl2Gro was strongly stimulated by a high degree of chain saturation. Concomitantly, the phase equilibria of Glc-acyl2Gro are shifted towards lamellar phases at the growth temperature. The fraction of the three potentially nonbilayer-forming lipids varied over 10-80% (mol/100 mol) total lipids as a function of the acyl chain composition. The combined molar fractions of the three phospholipids increased strongly with chain unsaturation. However, the fraction of phosphate moieties in the different lipids was constant over the entire chain-length interval. It is concluded that the regulation of the membrane lipid composition aims at maintaining similar phase equilibria and surface charge densities of the lipid bilayer. The size of A. laidlawii cells was changed in a systematic manner and correlated qualitatively with the packing properties of the lipids. Cell diameters were increased by an increase in acyl chain length and saturation, and was affected by additives such an n-dodecane and acyl2Gro.

Fine mapping of Best's macular dystrophy localizes the gene in close proximity to but distinct from the D11S480/ROM1 loci.

The Best's macular dystrophy (BMD) gene has previously been mapped to the 11q13 region. In this study, recombination data localizes the BMD gene to the 6-cM genetic interval between the markers Fc epsilon RI and D11S480/ROM1 in a large Swedish 12-generation BMD family. Mutation analyses of the candidate gene ROM1 did not reveal any mutations that could explain the disease phenotype. However, one recombination event between intragenic ROM1 polymorphisms and the BMD phenotype was detected. Therefore, it is highly unlikely that mutations in the ROM1 gene cause BMD. Identification of the disease gene will elucidate the pathophysiological mechanism in BMD, which may also be of importance in other retinopathies such as age-related macular degeneration.

Variable expression of tapetoretinal degeneration in northern Sweden.

In the county of Västerbotten in northern Sweden, 20 families with 50 diagnosed cases and 53 sporadic cases of tapetoretinal degenerations (TRD), including retinitis pigmentosa (RP), were ascertained. The familial and sporadic cases were traced genealogically as far back as was possible. Ancestors born before 1890 (n = 12,033) were registered on a PC. The analysis of data showed that 7 families (20 cases) and 21 sporadic cases could be traced to ancestors in a parish in the northern part of the county. The results suggest, in that parish, a gene source of an autosomal recessive gene causing TRD, with varying phenotypic expression, including variants of RP.

The gene for Best's macular dystrophy is located at 11q13 in a Swedish family.

A large Swedish family with more than 250 cases of Best's macular dystrophy has been clinically and genetically studied. The gene was traced to a couple born in central Sweden in the 17th century. Highly significant evidence for genetic linkage to DNA markers on chromosome 11q13 was detected. A lod score of 15.12 was obtained at recombination fraction 0.01 with DNA marker INT2 (also called FGF3). The retinally expressed gene ROM1, which maps to the same chromosomal region is a candidate for this genetic disease.

Cardiotonic and coronary vasodilator responses to milrinone, forskolin, and analog P87-7692 in the anesthetized dog.

Forskolin and milrinone both increase cyclic AMP concentrations to enhance cardiac contractility and cause vascular dilation in vitro and in vivo. However, forskolin acts via direct stimulation of adenylate cyclase while milrinone inhibits phosphodiesterase (PDE-III) activity. The forskolin analog, 7-desacetyl-7-(O-propionyl)-hydroxyl-aminocarbonyl-forskolin (P87-7692) has also been shown to directly stimulate adenylate cylase and increase cyclic AMP production in isolated cardiac tissue; however, the in vivo activity of this compound has not been described. Thus, the purpose of this study was to compare the cardiovascular effects of equivalent doses of these compounds and to further characterize the cardiotonic activity of P87-7692 in the anesthetized dog. It was found that both i.v. (3-30 micrograms/kg) and intracoronary (0.1-30 micrograms) administration of milrinone, forskolin, and P87-7692 caused dose-related positive inotropic, coronary, and peripheral vasodilator effects in anesthetized dogs; however, P87-7692 produced significantly greater and more sustained cardiotonic activity following a single 30-micrograms/kg, i.v., bolus injection when compared to the same dose of milrinone and forskolin. Analysis of the dose-response relationship between the changes in contractile force and heart rate for these compounds revealed that a 50% augmentation in contractile force was associated with increases in heart rate of 2.1% for milrinone, 6.4% for P87-7692, and 13.7% for forskolin. These data indicate an improved separation between the chronotropic and inotropic effects for P87-7692 as compared to forskolin. All three compounds also produced coronary vasodilation in vivo and in vitro; however, P87-7692 consistently showed greater activity relative to the same doses of milrinone and forskolin. Moreover, P87-7692 was significantly (p less than 0.05) more potent at relaxing KC1-precontracted canine coronary rings, with an EC50 of 2.1 x 10(-7) M as compared to 1.1 x 10(-6) M for forskolin and 3.2 x 10(-6) M for milrinone. The results of these studies indicate that structural modification of the forskolin molecule can increase the separation between positive inotropic and chronotropic effects, improve the overall hemodynamic profile, and prolong the duration of cardiotonic activity for this class of compounds.

Cognitive test profile analysis for the identification of dementia of the Alzheimer type.

Two measures of profile similarity have been derived that offer complementary information about the classification of patients with diagnoses of probable dementia of the Alzheimer type (DAT). These measures were obtained for 31 probable DAT patients and 31 age- and education-matched controls using a set of six newly constructed cognitive scales designed to provide reliable measurement in both patient and control groups. A measure assessing similarity to the average performance of the controls provided perfect separation of the patient and control groups. A measure assessing similarity to the average performance of the probable DAT patients identified up to four atypical cases of probable DAT. One of these four cases has come to autopsy and was found to have Pick disease. The cognitive profiles of this Pick patient and an autopsy-confirmed DAT patient are compared to illustrate the potential advantages of using DAT patients as the reference group for profile analysis.

Genetic genealogical studies of 20 north Swedish families with the rare blood group p.

In the county of Västerbotten in northern Sweden, a large number of individuals with the rare blood group p have been found. The ancestors of all known 31 cases were studied genealogically, and the data showed that about one half of all cases (15 out of 31 in 9 out of 20 families) could be traced to one gene source in the north-eastern part of the county in the middle of the 17th century. In two of the families the parents were first cousins and in three they were second cousins. In the 18th and 17th centuries genealogical connections between the parents were found in another 10 of the families.

Thoracolumbar epidural anaesthesia blocks the circulatory response to laryngoscopy and intubation.

Laryngoscopy and endotracheal intubation cause a stress reaction resulting in an increase in heart rate and systemic blood pressure. This haemodynamic response is considered to be due to a sympathetic discharge caused by stimulation of the upper respiratory tract. This stress reaction during laryngoscopy and endotracheal intubation was studied in patients with total thoracolumbar epidural anaesthesia (EDA). Nine patients with thoracolumbar EDA including at least the segments T1 to L2 were compared to seven patients without EDA during induction of general anaesthesia. The epidural anaesthesia was achieved with 2% mepivacaine with adrenaline. General anaesthesia was induced with thiopentone 4-5 mg/kg followed by 100 mg suxamethonium. The highest blood pressure value during the first 2 min after intubation was compared to the value immediately before intubation. The epidural anaesthesia caused a reduction of the mean arterial blood pressure (MAP) by 25%, and a reduction of the heart rate (HR) by 7%, but neither the induction with thiopentone nor the laryngoscopy and intubation caused any changes in mean arterial blood pressure or heart rate. However, in the control group MAP increased 29% and HR 16% following intubation. Thus, the T1-L2 epidural anaesthesia with 2% mepivacaine with adrenaline blocked the blood pressure reaction to laryngoscopy and intubation, and consequently the efferent sympathetic nervous system was completely blocked.

Secondary aortoenteric fistulas--an analysis of 42 cases.

Secondary aortoenteric fistulas are seen with an increasing frequency which parallels the expansion of reconstructive vascular surgery. During a 12-year period 42 cases have been collected from the hospitals, which perform most of the vascular surgery in Sweden (0.7% of vascular operations). Twenty-five were seen after operation for aortic aneurysm, 15 for aortoiliac occlusive disease, one after renal artery ligation (as a part of reconstruction for renovascular hypertension) and one after operation for an iliac pseudoaneurysm. The frequency of complications during and after the primary operation was high. The interval between operation and onset of fistula symptoms was significantly shorter if there had been infectious complications, the median interval was 32 months, the longest being 10 years. The most important symptom was gastrointestinal haemorrhage, consisting of several small bleeds often combined with septic complications. A large number of negative investigations usually preceded the final diagnosis which was made at exploratory laparotomy. After surgery for the fistula the frequency of complications and mortality, were very high. Mortality was 58%, the most common cause of death being a blow out of the aortic stump. Of those leaving hospital, several further operations were performed with a high mortality. Recurrence of the fistula occurred in 16 out of 34 patients who survived surgery. At follow-up (12-74 months after fistula closure) seven patients were still alive.

Clastogenic effects in human lymphocytes of power frequency electric fields: in vivo and in vitro studies.

In vivo and in vitro studies of the clastogenic effects of power frequency electric fields and transient electric currents have been performed. For the in vivo investigation peripheral lymphocytes from twenty switchyard workers were screened for chromosome anomalies. The rates of chromatid and chromosome breaks were found to be significantly increased compared to the rates in 17 controls. Exposure of human peripheral lymphocytes, in vitro, to a 50-Hz current with 1 mA/cm2 current density did not induce any chromosome damage. Exposure to ten 3 mus-long spark discharge pulses with a peak field strength in the samples of 3.5 kV/cm, however, resulted in chromosome breaks at a frequency similar to that induced in lymphocytes in vitro by ionizing radiation at 0.75 Gy. The biological significance of chromosomal damage induced in somatic cells is discussed.

Vascular complications in the Ehlers-Danlos syndrome.

The Ehlers-Danlos syndrome is a rare condition, which usually is easily recognized. In one type of this disease, type IV, arterial fragility dominates, and the syndrome may remain undiscovered until the patient has a traumatic or spontaneous arterial rupture. Two cases with a fatal outcome are presented in order to emphasize some important aspects in the management of these patients.

Reproductive hazards among workers at high voltage substations.

A retrospective study on reproductive hazards was performed among 542 employees at Swedish power plants. Questionnaires were answered by 89% of the employees. Data on pregnancies were checked by studying hospital case records. There was a statistically significant, decreased frequency of "normal" pregnancy outcome, almost exclusively due to an increased frequency of congenital malformations, when the father was a high-voltage switchyard worker. The differences in pregnancy outcome could not be explained by any of the confounding factors analyzed. The total number of children with malformations (26) and the total number of pregnancies in this study, however, were very small.