Analysis of linkage between beta-lactoglobulin and J blood group system loci in cattle

Linkage between loci controlling variants of beta-lactoglobulin and blood groups of the J system in cattle was studied by means of stochastic genetic methods reported earlier. The studies were conducted on a herd of Black Pied cattle improved with Holstein sires; population genetic data were analyzed. A plot for lod score was constructed, and point (r - 0.28) and interval estimations of the coefficient of recombination were obtained. The results are in good agreement with earlier reported data on other subjects.     

A P-loop-like motif in a widespread ATP pyrophosphatase domain: implications for the evolution of sequence motifs and enzyme activity

A conserved amino acid sequence motif was identified in four distinct groups of enzymes that catalyze the hydrolysis of the alpha-beta phosphate bond of ATP, namely GMP synthetases, argininosuccinate synthetases, asparagine synthetases, and ATP sulfurylases. The motif is also present in Rhodobacter capsulata AdgA, Escherichia coli NtrL, and Bacillus subtilis OutB, for which no enzymatic activities are currently known. The observed pattern of amino acid residue conservation and predicted secondary structures suggest that this motif may be a modified version of the P-loop of nucleotide binding domains, and that it is likely to be involved in phosphate binding. We call it PP-motif, since it appears to be a part of a previously uncharacterized ATP pyrophophatase domain. ATP sulfurylases, NtrL, and OutB consist of this domain alone. In other proteins, the pyrophosphatase domain is associated with amidotransferase domains (type I or type II), a putative citrulline-aspartate ligase domain or a nitrilase/amidase domain. Unexpectedly, statistically significant overall sequence similarity was found between ATP sulfurylase and 3'-phosphoadenosine 5'-phosphosulfate (PAPS) reductase, another protein of the sulfate activation pathway. The PP-motif is strongly modified in PAPS reductases, but they share with ATP sulfurylases another conserved motif which might be involved in sulfate binding. We propose that PAPS reductases may have evolved from ATP sulfurylases; the evolution of the new enzymatic function appears to be accompanied by a switch of the strongest functional constraint from the PP-motif to the putative sulfate-binding motif.     

The correlation of the vasopressin- and oxytocin-producing activities of different nuclei in the hypothalamo-hypophyseal neurosecretory system]

Radioiodine long has proven to be a safe and effective treatment for thyroid disease. Nonetheless, persisting concerns regarding radiogenic stochastic risks (e.g., carcinogenesis) to patients, their families, and the general public have led regulators to establish criteria for release of 131I-containing patients from medical confinement, with limits ranging from as low as 2 mCi in some parts of Europe to as high as 30 mCi in the United States. To optimize clinical efficacy and cost-effectiveness of 131I therapy, such regulations should be based on logical dosimetric considerations. The thyroidal absorbed dose, proportional to maximum uptake and effective half-life and inversely proportional to mass, is typically approximately 1,500 rad/mCi of 131I administered to a euthyroid adult (based on a thyroid maximum uptake of 25%, effective half-life equivalent to the physical half-life of 131I (8.04 days), and mass of 20 g). As thyroid uptake increases from 0% to 100%, extrathyroidal absorbed doses range from a minimum of 0.15 to 0.5 rad/mCi for breast and gonads to a maximum of 1.5 to 2 rad/mCi for stomach and salivary glands; the absorbed doses of the urinary bladder wall, in contrast, decrease with increasing thyroid uptake, from 2 to 0.6 rad/mCi. In hyperthyroid patients (approximately 15%) with a small iodine pool (so-called small patients), the short effective half-life of radioiodine in the thyroid and high serum concentrations of long-lived protein-bound 131I result in a standard 7,000-rad absorbed dose for treatment of Graves' disease requiring an administered activity of 28 mCi of 131I and yielding a prohibitively high blood absorbed dose of 150 rad. Importantly, once the fetal thyroid begins to function and accumulate radioiodine at a gestational age of 10-12 weeks, fetal thyroid absorbed doses as large as 5,000 rad/mCi of 131I administered to the mother can result. Thus, pregnancy is an absolute contraindication to administration of 131I because of the risk of radiogenic cretinism. Based on actual measurements of thyroid activity and of external absorbed dose, the total thyroid and mean extrathyroidal absorbed doses to adult family members from immediately released 131I-treated patients are approximately 0.01 and approximately 0.02 rad/mCi administered, respectively, yielding an effective dose of approximately 0.02 rem/mCi. A maximum permissible effective dose of 0.5 rem for adults therefore is consistent with a release criterion of 30 mCi of retained 131I. Lower-activity release criteria therefore may be unnecessarily restrictive.     

The possibility of preserving the causative agent of plague in soil in resting (nonculturable) form

The purpose of this study was to find criteria characteristic for patients in need of care and social services. The criteria should serve as a guideline for patients and staff to facilitate care planning before discharge. The sample consisted of 49 patients, born before 1925, in need of emergency inpatient treatment, admitted to medical- or orthopaedic wards. Data of the patient's self care needs were collected by interviews, assessment of self care status and need of treatment. The patients could be divided into three groups depending on type of discharge. Group A (n = 27) discharged home, group B (n = 7) discharged to geriatric clinic and group C (n = 15) discharged and in need of further care and social services. Criteria indicating the patients further assistance from the community were in group C (medical- and orthopaedic wards) deficit in daily living activities and locomotion. Group B had an increased need of support from the physiotherapist and the occupational therapist, in locomotion as well as daily living activities The physician's assessment showed that the criteria behind the decision "no further medical treatment appropriate" and "ready for discharge" were not related to medical impairment but to lack of self care, need of care, rehabilitation and social services.     

Temperature denaturation of erythrocyte spectrin: rheology, deformability and resistance to detergents

The vigilance reaction is characterized by a large bradycardia, a pressor response, and inspiratory apnea in anesthetized rabbits and the inhibition of movement in conscious rabbits. This affective response pattern can be elicited by electrical stimulation of the dorsolateral hypothalamus (the hypothalamic vigilance area) or the ventrolateral periaqueductal gray (the periaqueductal gray vigilance area). The present study sought to advance our understanding of the functional relationship between the hypothalamic vigilance area (HVA) and the periaqueductal gray vigilance area (PVA) by measuring the effects of transverse transections of the caudal portion of the ventrolateral PAG (vlPAG) upon the cardiovascular responses elicited from the dorsolateral hypothalamus and the rostral vlPAG. Selective transverse transections of the caudal vlPAG significantly reduced the magnitudes of the bradycardia and pressor response elicited by stimulation of the PVA rostral to the transection site, but had minimal impact on the cardiovascular responses evoked by stimulation of the HVA. These findings suggest that the cardiovascular responses elicited by stimulation of the vlPAG are mediated by a neural pathway that is parallel, at least in part, to the one that subserves the response elicited from the HVA. The results also provide support for the view that the PAG is not an essential structure in the mediation of the autonomic components of affective behaviors involving behavioral inhibition.     

Benign intracranial hypertension in children

Ceftriaxone has a very high plasma protein binding (up to 98%) that is saturable and decreases with higher concentrations. This high protein binding results in high concentrations in plasma that are frequently related to the anti-infective activity. However, because only the free fraction of the drug is pharmacologically active and most of the infections are located in the tissues, it is more relevant to evaluate unbound concentrations in the interstitial space. Plasma and tissue pharmacokinetics of ceftriaxone in rats after single intravenous administration were investigated at two different concentrations (50 and 100 mg/kg). Both plasma and tissue samples were taken simultaneously from the same animal and analyzed by reversed-phase high-performance liquid chromatography. Free tissue levels in the thigh muscle were measured by microdialysis. The concentration in plasma is much higher than the free concentration in tissue. After determination of nonlinear protein binding by microdialysis and including these parameters in the pharmacokinetic model, it is possible to predict free concentrations in the interstitial space from plasma levels for any given dose.     

Dynamic course of neurological syndromes in very young children with the history of intrauterine growth retardation

90 infants with intrauterine growth retardation (IGR) and 100 normal infants (control group) were followed up from 5 days till 3 years of life. In IGR infants there was a more frequent combination of several neurologic syndromes, an early manifestation of motor disorders (from the very moment of birth), a delay of neuro-psychic development (during the first year of life), a tendency to development of moderate hydrocephalus by the age of 6 months. Autonomic-visceral disorders in them were mostly characterized by the symptoms of abaissement, but not of irritation.     

Toxicity of the styrene metabolite, phenylglyoxylic acid, in rats after three months' oral dosing

Male Wistar rats were dosed with 0, 1250, 3750 or 5000 mg/l of phenylglyoxylic acid (PGA) (CAS no. 611-73-4) in the drinking water ad libitum for 3 months. During the entire treatment period, there were no gross signs of toxicity related to PGA. No changes in neurobehavior were found after using a functional observational battery or radial arm maze. An increased relative kidney weight was seen in the highest dose-group (Controls: 0.504 +/- 0.031 g/100 g b.wt.; 5000 mg PGA/l: 0.579 +/- 0.033 g/100 g b.wt.; p<0.01). No other organ weights were affected. Histopathology revealed no change in kidney structure. No changes in clinical biochemistry. In the highest dose-group three animals out of ten showed reduction in peripheral nerve myelin sheath thickness. No such changes were seen in the control group. The study revealed no changes in auditory brain stem response but minor changes in electroretinography. The noradrenaline (NA) concentration decreased in pons and thalamus whereas it increased in medulla oblongata and whole brain. The dopamine (DA) concentration increased in cerebellum, hippocampus, pons, and whole brain. The most marked DA increase was seen in hippocampus (Controls: 0.56 +/- 0.10 nmol/g tissue; 5000 mg/l: 1.04 +/- 0.11 nmol/g tissue; p<0.001). The 5-hydroxytryptamine (5-HT) concentration decreased in cerebellum, cerebral cortex, hippocampus, and medulla oblongata, whereas it increased in thalamus. The yield of synaptosomal protein, synaptosomal NA, DA, and 5-HT concentrations, and DA uptake rate were not affected. When dosed males were mated with naive females, there were no differences between groups in the pregnancy rate, number of corpora luteae, implantations, live or dead fetuses, resorptions, preimplantation loss, or postimplantation loss. It is concluded that a part of the effects on kidney, peripheral nerves, and vision, which have previously been reported after exposure to styrene, might be induced by the styrene metabolite, PGA. If PGA has ototoxic effects in rats, the dosing in the present study is not sufficient to induce the necessary ototoxic concentration in blood. Alternatively, the ototoxicity of styrene, like toluene, may be caused the parent compound itself and not by a metabolite like PGA.     

Development of orally active oxytocin antagonists: studies on 1-(1-[4-[1-(2-methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy]-2- methoxybenzoyl]piperidin-4-yl)-1,4-dihydrobenz[d][1,3]oxazin-2-one (L-372,662) and related pyridines

The previously reported oxytocin antagonist L-371,257 (2) has been modified at its acetylpiperidine terminus to incorporate various pyridine N-oxide groups. This modification has led to the identification of compounds with improved pharmacokinetics and excellent oral bioavailability. The pyridine N-oxide series is exemplified by L-372,662 (30), which possessed good potency in vitro (Ki = 4.1 nM, cloned human oxytocin receptor) and in vivo (intravenous AD50 = 0.71 mg/kg in the rat), excellent oral bioavailability (90% in the rat, 96% in the dog), good aqueous solubility (>8.5 mg/mL at pH 5.2) which should facilitate formulation for iv administration, and excellent selectivity against the human arginine vasopressin receptors. Incorporation of a 5-fluoro substituent on the central benzoyl ring of this class of oxytocin antagonists enhanced in vitro and in vivo potency but was detrimental to the pharmacokinetic profiles of these compounds. Although lipophilic substitution around the pyridine ring of compound 30 gave higher affinity in vitro, such substituents were a metabolic liability and caused shortfalls in vivo. Two approaches to prevent this metabolism, addition of a cyclic constraint and incorporation of trifluoromethyl groups, were examined. The former approach was ineffective because of metabolic hydroxylation on the constrained ring system, whereas the latter showed improvement in plasma pharmacokinetics in some cases.